Preterm birth

Preterm birth
– challenges and opportunities
in prediction and prevention
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Contents
What is preterm birth?...........................................................................................3
Definition..........................................................................................................3
Preterm birth rate.............................................................................................5
Why the concern?.............................................................................................6
Cost of the disorder..........................................................................................7
Public knowledge about preterm birth............................................................8
Symptoms..........................................................................................................9
Risk factors........................................................................................................9
Etiology................................................................................................................. 10
Infection and inflammation........................................................................... 10
Genetic risk factors......................................................................................... 14
Biological pathways leading to preterm birth............................................... 16
Screening..............................................................................................................20
The traditional method of screening............................................................. 21
Screening of symptomatic women................................................................. 21
Screening of asymptomatic women...............................................................23
Predictive markers...............................................................................................24
Cervical assessment........................................................................................24
Biochemical markers......................................................................................24
Combination of markers................................................................................. 27
Potential future biomarkers...........................................................................29
Prevention............................................................................................................36
Traditional recommendations........................................................................36
Home uterine monitoring...............................................................................36
Cerclage...........................................................................................................36
Antibiotics.......................................................................................................38
Progesterone.................................................................................................... 39
Nutritional supplementation..........................................................................42
Diagnosis and management.................................................................................43
Diagnosis.........................................................................................................43
Management....................................................................................................44
Challenges that clinicians are facing.................................................................48
Concluding remarks............................................................................................. 49
Global efforts in preventing preterm birth.........................................................50
Glossary and abbreviations.................................................................................53
References............................................................................................................. 59
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What is preterm birth?
Definition
A full-term human pregnancy lasts 40 weeks. Delivery that occurs before 37
completed weeks of pregnancy is considered to be preterm birth, regardless of
birth weight (World Health Organization). Although all births before 37 weeks
of gestation are defined as preterm, most damage and death occurs in infants
delivered before 34 weeks [1, 2]. It is therefore often convenient to consider preterm birth as being divided into subgroups such as extremely preterm, very
preterm, moderately preterm and, sometimes, late preterm.
• Preterm, birth occurring from 23 to 37 weeks
• Late preterm, birth at 34-36 weeks
• Moderately preterm, birth at 32-34 weeks
• Very preterm, before 32 weeks
• Extremely preterm, before 28 weeks
Preterm birth can be either spontaneous or iatrogenic (induced by the physician).
About 20 % of all preterm deliveries are iatrogenic. In these the physician has
decided that the baby needs to be delivered preterm, due to serious maternal or
fetal complications such as severe pre-eclampsia (PE) or intra uterine growth
retardation (IUGR). In these cases labor is medically induced or a cesarean
section is performed.
Spontaneous preterm birth
Classically categorized, spontaneous
Iatrogenic
preterm birth is associated with either
preterm labor (PTL) or preterm pre­
PTL
mature rupture of fetal membranes
(PPROM) [3,4] (Figure 1). Preterm labor
PPROM
is defined as labor (regular contractions
and cervical ripening) starting before
37 complete weeks of gestation, with
or without intact fetal membranes.
PPROM is defined as rupture of fetal
Figure 1. Distribution of different forms of
preterm birth.
membranes prior to 37 weeks gestation
and it very often leads to preterm birth.
Spontaneous preterm birth is a common and serious public health problem.
In the remainder of this booklet, unless distinction is made, preterm birth or
PTB should be understood to mean spontaneous preterm birth.
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Low birth weight
A low birth weight (LBW) baby is one that weighs less than 2,500 grams at deli­
very, regardless of the gestational age at birth. This means that low birth weight
babies are not necessarily born prematurely, although there is an obvious association between birth weight and prematurity (Figure 2). In developed countries,
most low-birth weight infants are preterm. In under-developed countries, the
proportion of term low-birth weight infants is higher due to the greater prevalence of malnutrition. The low birth weights may also be divided into the additional categories, very low birth weight (VLBW), and extremely low birth weight
(ELBW).
• Low birth weight, less than 2500 g
• Very low birth weight, less than 1500 g
• Extremely low birth weight, less than 1000 g
Low birth weight babies include both those born preterm and those whose
growth has been impaired in utero. A baby whose weight is significantly lower
than the population norm is termed small for gestational age, SGA. The cut-off
level is usually weight below the 10th percentile for gestational age. An SGA
baby is thus smaller than 90 percent of all other babies of the same gestational
age. SGA has been defined in some publications on the basis of length rather
than weight. Alternative cut-off levels such as the 5th, or 3rd percentile for
gestational age have also been applied.
The cause of SGA can be either pathological or non-pathological. Intrauterine
growth restriction, IUGR is a failure of normal fetal growth. It is caused by
multiple adverse effects on the fetus that prevent normal growth potential from
being realized. IUGR and SGA are related terms but are not synonymous. Not
all IUGR infants are small enough to meet the criteria for SGA and not all SGA
infants are small as a result of a growth restrictive process for which the term
IUGR would be appropriate.
PTB
�������
PTB/LBW
LBW
Figure 2. An overlap
between preterm birth
and low birth weight.
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Preterm birth rate
Premature birth occurs in one in ten pregnancies. There are about 13 million
PTBs annually worldwide. The incidence is about 11% in North America, about
5.6% in Oceania and about 5.8% in Europe (Table 1) [5]. In the US, on average,
one preterm baby is born every minute. Since 1990, for reasons that are not
fully understood, worldwide the preterm birth rate has risen by approximately
14%. The increase over the past decade may in part be explained by increasing
iatrogenic preterm births, increasingly aggressive resuscitation of very preterm
babies, higher maternal age, higher rates of assisted reproductive technologies
(ART) and multiple gestations related to these technologies. Singleton pregnancies after in-vitro fertilization are also at increased risk of preterm birth
[190]. This increase is quite alarming, considering that preterm birth is associated with a significant risk of disease and death in the newborn baby. Rates of
preterm delivery are not distributed evenly among fertile women. It has been
observed that the prevalence of PTB is twice as high in African-American
women compared with Caucasians or Hispanic women in the US. Preterm birth
rates are in the range of 16-18 % among black women compared with 5-9 % for
white women in the US and UK. Black women are also three to four times more
likely to have a very early preterm birth than women from other racial or ethnic
groups [193]. Also the causes of preterm births differ by ethnic group. Preterm
birth is most commonly caused by preterm labor in white women, while PPROM
is the more frequent cause in black women [189].
Table 1. Assessments of preterm birth rates in various countries
Country
US
Canada
Preterm birth rate
Ref
12.7 % [6]
7.6 %
[7]
UK
7.6 %
[8]
Germany
7.6 %
[9]
France
6.2 %
[9]
Finland
5.2 %
[10]
Sweden
5.6 %
[11]
Norway
8.5 %
[12]
Denmark
6.1 %
[207]
Australia
7.9 %
[206]
15.4 %
[13]
Mozambique
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Why the concern?
Preterm birth is a serious health problem. It is associated with a significant risk
of disease and death of the newborn baby. Preterm birth surpassed birth defects
as the leading cause of neonatal death in 2001 [14]. Improvements in neonatal
care have led to higher survival of very premature infants but premature babies
are still at great risk for adverse health and developmental problems compared
with term infants. The risks are highest at the lowest gestational ages. (Figure 3).
According to a recent study infant survival was significantly lower when the onset of preterm birth was PPROM as compared with preterm labor and iatrogenic
delivery [187].
100
90
80
70
%
60
Alive
Healthy
50
40
30
20
10
0
24
25 26
27 28 29 30 31 32 33 34 35
Gestation at birth
Figure 3. Numbers of live and healthy babies by gestational age. Data points from [19, 20].
The emotional impact on a family encountering this problem is enormous.
In many cases the baby is admitted to a hospital far from the family home, and
parents and siblings suffer considerable anxiety, with doubts about the baby’s
survival and full recovery.
Premature babies are at increased risk for both newborn health complications
and for lasting disabilities, such as mental retardation, cerebral palsy (CP), lung
and gastrointestinal problems and vision and hearing loss (Table 2). Babies born
just a few weeks early are also six times more likely to die in their first week
of life than full-term babies and three times more likely to die before their first
birthday [15]. In the long term, children born prematurely have an increased
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risk of cardiovascular disease, hypertension and diabetes as adults and a possible increase in cancer risk [16, 17]. Prematurity-associated medical complications also portend future educational and occupational impairment that extend
into late childhood and beyond. In a Swedish study preterm birth was found to
be associated with a lower chance of completing a university education and a
lower net salary [18].
Table 2. Complications and disabilities related to prematurity [18].
Neonatal
Short term
Long term
Respiratory distress syndrome (RDS)
Feeding and growth difficulties
Cerebral palsy
Intraventricular hemorrhage (IVH)
Infection
Sensory deficits
Periventricular Apnea
leukomalacia (PVL)
Special health care
needs
Necrotizing Neurodevelopmental difficulties
enterocolitis (NEC)
Incomplete catch-up
growth
Patent ductus arteriosus (PDA)
Retinopathy
Difficulties at school
Infection
Transient dystonia
Behavioral problems
Metabolic abnormalities
Chronic lung disease
Nutritional deficiencies
Cost of the disorder
Preterm birth is associated with substantial use of healthcare resources. The
economic cost of preterm birth is not well established but the emerging data are
alarming. The costs of a preterm birth are not just those incurred while in the
hospital’s neonatal intensive care unit. Some health problems that develop at
this time can persist for years. It was recently estimated that preterm/low birth
weight infants in the United States account for half of infant hospitalization
costs and one quarter of pediatric costs, suggesting that major infant and pedi­
atric cost savings could be realized by preventing preterm birth [22].
Studies in the United Kingdom and Ireland show that the cumulative costs of
hospital admissions incurred during the first 10 years of life are more than
twice as high in preterm infants compared to children born at term [208].
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It has been predicted that even higher cost differences will occur at a later age,
especially in the extremely preterm group. The increasingly complex educational and job demands in society are exacerbating the lifelong problems associated
with preterm birth [209]. A study in Norway has shown that very early preterm
birth is associated with a significantly increased risk in mortality during childhood especially in males, decreased reproductive performance in later life for
both sexes, and increased risk of having preterm offspring in preterm women [210].
Compared with term births premature births are associated with significant
incremental expenditures.
• Maternal delivery costs
• Early intervention costs
• Special education costs
• Rehabilitation for physical handicaps
• Lifelong care
• Family support
• Lost household productivity costs related to cerebral palsy,
mental retardation and hearing impairment.
Predictably, the costs associated with preterm infants are gestational age dependent. The highest costs per case generally occur in the very preterm and extremely preterm groups but the incremental aggregate annual medical care cost
for the large number of infants born between 28 and 32 weeks is approximately
80 % of the aggregate cost for infants born at less than 28 weeks. The loss of
human potential cannot be calculated.
Public knowledge about preterm birth
A study conducted in 2002 in the US revealed that there is considerable misunderstanding of preterm birth among adults. Although nearly one in eight babies
is born prematurely, most U.S. adults do not consider prematurity to be a serious
public health problem. While the etiology can be identified in only half of spontaneous preterm births, the public largely blames the mother’s prenatal behavior.
Misperceptions are prevalent and may impede future research and prevention
efforts if not corrected. [23] The general public, and health professionals, need to
be aware that it is still not known what initiates the spontaneous onset of labor
in women and this makes the prevention and management of preterm labor
difficult. There is a need for more clinical and laboratory research into preterm
labor and public pressure can be instrumental in persuading governments and
research foundations to put more resources into this area. [211]
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Symptoms
The symptoms of preterm labor include:
• Uterine contractions every 10 minutes or more often
• Change in vaginal discharge (leaking fluid or bleeding from vagina)
• Pelvic pressure
• Low, dull backache
• Cramps that feel like period pains
Risk factors
Preterm labor and delivery can occur in any pregnancy, but some women are
more prone than others. Several demographic characteristics associated with an
increase risk of preterm birth have been identified.
• Previous preterm birth.
This is the strongest risk factor for spontaneous preterm labor. Women with
a history of preterm birth have a significantly increased risk of subsequent
preterm birth.
• Multifetal pregnancy (twins, triplets or more)
• Low socioeconomic status
• African-American ancestry
(although it may be difficult to separate ethnicity from socioeconomic factors)
• Extremes of weight (underweight or obesity)
• Extremes of age <16 or >35
• Tobacco use
• Stress
• Genital tract infection
• Preterm premature rupture of the membranes (PPROM)
• Antepartum hemorrhage
• Cervical incompetence
• Congenital uterine abnormalities
The mechanisms by which the maternal demographic characteristics are related
to preterm birth are unknown. Risk factors for PPROM are generally similar to
those for preterm labor with intact membranes although infections and tobacco
exposure play important roles [191]. The most common reasons for iatrogenic
preterm deliveries are pre-eclampsia and other medical disorders in pregnancy,
intrauterine fetal growth restriction, congenital abnormalities and trauma [212].
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Etiology
The etiology of preterm birth, like the mechanism of term labor, is unclear. It is
though to be a multifactorial, complex disorder with both physiopathological,
genetic and environmental factors. The “preterm labor syndrome” proposes that
preterm labor is the result of multiple causes including infection/inflammation,
uterine stretch and vascular disorders [213]. However, it is not known whether
preterm labor results from a physiological process similar to term labor, but
occurring too early in pregnancy, or whether it is a pathological process
resulting from an abnormal set of signals.
Infection and inflammation
Infections seem to be associated with some preterm births. It has been suggested
that bacterial infection that spreads to the uterus and amniotic fluid may trigger
inflammation and consequently preterm labor or preterm rupture of membranes.
Goldenberg et al. reported that up to 80% of women who deliver before 30 weeks
of gestation have evidence of bacterial infection of the amniotic fluid and/or
membranes, compared with only 30 % of those who deliver after 37 weeks of
gestation.[24]
Maternal urogenital infections
Vaginal infections such as bacterial vaginosis (BV) are thought to be related to
preterm birth. As the most common lower genital tract infection in women of
reproductive age, BV is a mainly asymptomatic syndrome in which the normal
vaginal lactobacilli are replaced by a mixed flora with high concentrations of
anaerobic bacteria Gardrenella vaginalis and Mycoplasma homnis. BV may result in a vaginal discharge, which can be grey in color and with characteristic
“fishy” odor. Its presence in pregnancy is associated with a two-fold increase in
the risk of preterm birth. Other forms of infection connected to preterm birth include urinary tract infections that progress to pyelonephritis (kidney infection)
[25], asymptomatic bacteriuria (presence of bacteria in urine) [26,27] and some
sexually transmitted diseases such as chlamydia [28]. Andrews et al. 2000 found
that women with chlamydia had up to three times the risk of PTB [28]. Presence
of the bacteria Ureaplasma urealyticum, Fusobacterium spp. [29], Trichomonas
vaginalis, Klebsiella preumoniae, Escherichia coli and Hemophilus vaginalis
have also been associated with PTB. The role of group
B. streptococcus is unclear [30].
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Viral infections may be associated with PTB. Spontaneous second trimester loss
was demonstrated to be strongly associated with any viral infection in placental
tissue [231]. According to a recent study, human papillomavirus (HPV) infection
of extravillous trophoblast induces cell death and may reduce placental invasion
into the uterine wall. Thus, HPV infection may cause placental dysfunction and
is associated with adverse pregnancy outcomes, including spontaneous preterm
delivery [233]. Also exposure to Cytomegalovirus (CMV) may be associated with
PTB [232].
Chorioamnionitis (infection of fetal membranes and amniotic fluid) is strongly
associated with preterm birth. The earlier the preterm birth the stronger the
association [24, 31, 32]. Inflammatory infiltration of the fetal membranes and
decidua in early preterm labor provokes a large increase in prostaglandin output
by these tissues, which may trigger delivery [214]. An underlying mechanism
is apparently an ascending bacterial infection from the lower genital tract to
the chorio-decidual space and subsequently to the amniotic cavity and fetus
(Figure 4). Some investigators believe that normal delivery is associated with
a local inflammatory process leading to the liberation of uterotonic agents. In
the course of an ascending infection, the inflammatory cascade may be prematurely activated [33]. Since the membranes generally form a barrier to ascending
infection, a common complication of PPROM is development of intrauterine
infection and preterm labor [192]. Microorganisms produce enzymes such as
proteases and mucinases, which allow penetration of the cervical mucous plug
favoring the ascent of bacteria [34]. Bacteria also release phospholipases, which
initiate the formation of arachidonic acid, from which prostaglandins are produced. Prostaglandins are important mediators of uterine activity. They have a
pivotal role in contraction of the smooth muscle of the uterus and the biophysical changes associated with cervical ripening. Bacteria also release endotoxins,
which cause release of proinflammatory cytokines such as interleukin-1 (IL-1),
interleukin-1 (IL-6) and tumor necrosis factor (TNF). The proinflammatory
cytokines in turn stimulate the expression of enzymes in the prostaglandin biosynthetic pathway [35]. Microorganisms also enhance the production of matrix
metalloproteinases, leading to the breakdown of the fetal membranes, ripening
of the cervix and uterine contractions [36].
The remaining question is why do some women with colonized genitourinary
tract bacteria deliver preterm while others do not? The possible explanation is
that individual variations in inflammatory response may contribute to the occurrence of preterm birth. According to studies, inflammatory activation occurs
only moderately with term labor, but much more robustly in preterm delivery,
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particularly in the presence of intrauterine infection. [33] The importance of the
cervix as a barrier to ascending infection is also suggested by the increased frequency of chorionamnionitis in premature cervical dilation with or without cerclage. The cervical mucus plug, which thickens following conception, may have
an important role as a local immunological gatekeeper. This is supported by the
fact that most pregnancies continue to term despite the presence of potentially
pathogenic microbes in the vagina. The cervical mucus is also a rich source of
antimicrobial proteins and peptides, including lysozyme, lactoferrin, defensin
and immunoglobulins so the mucus plug is not only a mechanical but also a
chemical barrier to infection that ascends from the vagina [152].
Amniotic fluid
Amnion
Amniotic fluid
infection
Chorion
Decidua
Myometrium
Chorioamnionitis
PG
TNF
IL-1
Ascending infection
Figure 4. Ascending bacterial infection. Modified from [24, 29].
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Infections at other sites
Infection, even remote from the uterus, may activate an inflammatory process
that triggers a uteroplacental response leading to preterm delivery. Systemic infections associated with preterm delivery include appendicitis (inflammation of
the appendix usually due to a blockage inside it), pneumonia (inflammation of
the lungs), and periodontal disease (gum inflammation). In a systemic infection
microorganisms invade the bloodstream and spread via circulating blood
to several organs.
In recent years there has been a mounting body of evidence that indicates an
association between periodontal disease and preterm birth. Periodontal disease or
periodontitis, is a Gram-negative, anaerobic infection of the oral cavity which results in degradation of the bones and connective tissue which support the teeth.
The destruction of these supporting structures involves both direct tissue damage caused by bacterial products and indirect damage caused by the cytokines
that appear in the gingival fluid as part of the host immune response [37]. While
periodontal disease affects up to 50% of the population, there is a relatively high
incidence of periodontal disease among pregnant women [38, 39]. Periodontal
disease has also been shown to be associated with delivery of SGA infants [40]
Maternal-fetal conflict and infection
To establish and maintain a pregnancy, the immune response, which normally
destroys foreign material, must make an exception for the fetus. 50% of the fetal
genes are inherited from the father and as a result the fetus produces paternal
antigens that should be targeted for destruction by the maternal immune system
[41]. In the presence of infection maternal immune pressure may favor fetal expulsion if overall maternal reproductive interests outweigh fetal interests. Both
mothers and babies exposed to amniotic fluid infection are at risk of sepsis (an
infection of the blood) and, eventually, death. Intrauterine infection may also
elicit a fetal inflammatory response [42, 43, 44]. The fetal inflammatory res­
ponse syndrome (FIRS) is a condition characterized by systemic inflammation
of the fetus and an elevation of fetal plasma IL-6. FIRS is associated with the
impending onset of preterm birth. Babies who survive the inflammatory-mediated insult of preterm delivery are at higher risk of critical illness
including cerebral palsy. There is thus evidence to support the idea that the
preterm onset of labor may be the fetus’ mechanism to exit a hostile intrauterine
environment. [45, 46]
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Inflammation without infection
Inflammatory response can occur also in the absence of microbial infection, and
is thus also called sterile inflammatory response. Inflammatory response in the
membranes appears to be associated with normal parturition. A sterile inflammatory response has also been shown to be sufficient to cause PPROM and preterm labor [167]. Both infection driven and sterile inflammation induce many of
the same cytokine receptors but they probably have distinct pathways. There are
many different stimuli capable of causing sterile inflammation. Relaxin expression is one of them. Relaxin is a collagenolytic hormone that causes increased
production of the matrix metalloproteinases. Relaxin causes increased secretion
of cytokines IL-6 and IL-8 from the membranes, with a similar but less robust
effect than infection [168].
Genetic risk factors
It has long been proposed that there is a maternal or fetal genetic predisposition
toward PTB. There is a body of evidence to support this argument.
• Women who deliver prematurely are at a greater risk of preterm delivery
during their subsequent pregnancies [47, 48].
• There is a tendency for repeat preterm birth to occur at the same
gestational age as the previous pregnancies.
• A woman who herself was delivered preterm is more likely to suffer
spontaneous preterm labor and preterm birth [49].
• Mothers with an older sister who has given birth to a preterm infant had
an 80% higher risk of giving birth to a preterm infant [48].
• It has long been recognized that there is a racial predisposition to
preterm birth with African-American mothers being more prone than
Hispanic mothers, who are, in turn, more prone than Caucasian mothers.
Genetic differences between individuals i.e. gene polymorphisms, can result
in variations in production and activity of proteins. Researchers have begun
to investigate the effects of candidate gene polymorphisms on PTB, focusing
on polymorphisms related to inflammatory and immune response because of
the evidence of involvement of inflammation in pregnancy and parturition.
Discovery of a specific gene that predisposes women to PTB would signify an
enormous scientific breakthrough that could possibly suggest novel therapeutic
and preventive targets.
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Maternal genome
One significant candidate gene associated with PTB is the gene coding for
tumor necrosis factor alpha (TNF-α), a proinflammatory cytokine present in
amniotic fluid of women with intrauterine infection who deliver preterm [50].
Homozygosity of the less common allele, TNF-2 that correlates with enhanced
TNF-α production has been associated with PTB in several studies [51, 52, 53].
It has also been documented that black women who were carriers of the IL-6
allele and had bacterial vaginosis had a two fold greater risk of preterm birth
than white women [198]. The effect on birth weight of an interaction between
maternal smoking and gene polymorphism has also been described [199].
Fetal genome
The fetus also has potential to influence pregnancy outcome. A recent study
found an association between multifetal pregnancies and PPROM in cases where
the first-born fetus had a TNF-2 genotype. The researchers speculated that the
possession of the TNF-2 allele by the fetus nearest the uterine cervix will result
in a higher concentration of TNF-α at the membrane surface adjacent to the
cervix and promote the rupture of membranes [54].
Paternal genome
The genetic effects of the paternal genome are not clear. There is evidence that
changing partner between the first two births increases the risk of infant mortality, preterm birth, and low birth weight for the second birth compared with
having the same partner. Increased risk of preterm birth was considered more
likely to reflect changes in lifestyle rather than genetic changes or different
paternal antigens [56]. Findings from another study suggest that the effect of
changing paternity depends on the pregnancy outcome with the previous partner and support the hypothesis that parental human leukocyte antigen (HLA)
sharing may be related to preterm delivery [55]. This finding is consistent with
our knowledge that inbred mating is associated with deleterious reproductive
outcomes. It is now generally recognized that to sustain a pregnancy without
rejecting the fetus that carries alloantigens, a mother needs to establish immuno­
logic tolerance. Although still not well understood, the tolerance is probably
initiated by fetal (via paternal) immunologic stimulation. Parental HLA sharing
results in a lack of adequate antigenic stimulation and failure to establish the
maternal immune tolerance, which could lead to a series of adverse pregnancy
outcomes [235].
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Gene environment interaction
Studies suggest that multiple genetic and environmental factors may affect the
risk of PTB independently or interactively. The contribution of genes is still
controversial. Although certain gene mutations increase the risk of PTB, there
are many women who have these mutations but experience normal delivery.
This fact has led some to hypothesize that these mutations require the presence
of certain environmental stimuli to have clinical significance. For example,
pregnant women or their fetuses who are genetically programmed to produce
high levels of pro-inflammatory mediators would be more likely than those
producing low levels to exceed the threshold necessary to initiate preterm labor
in response to environmental factors. [57] Further research into genetic risk
factors in preterm birth is much needed because most of the studies reported
so far have been underpowered and are inconclusive.
Biological pathways leading to preterm birth
Studies of the epidemiology and pathophysiology of preterm labor have suggest­
ed four pathways that may lead to preterm birth.
• Infection and inflammation
• Activation of maternal-fetal hypothalamic-pituitary-adrenal (HPA) axis
• Decidual hemorrhage (bleeding)
• Uterine stretching
Risk factors for preterm birth frequently initiate the pathogenic pathways leading to preterm birth. Each of the four different pathways will lead to a common
final pathway resulting in uterine contractions, cervical dilation, ruptured
membranes and ultimately premature delivery. Several pathways may occur
simultaneously in one pregnant woman. The four pathogenic pathways leading
to preterm birth each have a unique set of biochemical mediators (Figure 5).
A potential fifth pathway is susceptibility to environmental toxins [58].
Infection and inflammation
Inflammation, caused by maternal urogenital infection or systemic infection
at another site accounts for about 40 percent of preterm births. The mechanism
leading to PTB may involve activation of cytokines including interleukin-1β (IL-1β)
and TNF-α. Cytokines stimulate synthesis of prostaglandins and also enhance
the production of matrix metalloproteinases and IL-8, leading to the breakdown
of the fetal membranes and ripening of the cervix.
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Social -environmental risk factors
Genetic risk factors
1.
2.
3.
4.
Inflammation
Activation of
maternal -fetal
hypothalamic
-pituitary-adrenal
(HPA) Axis
Decidual
hemorrhage
Uterine distension
Infection – 40 %
Stretching – 10 %
Abruption – 20 %
Stress – 30 %
Risk factors:
Risk factors:
Risk factors:
Risk factors:
• Sexually transmitted
infections
• Maternal psycho­‑
­ logical or physical
stress
• Smoking
• Multifetal pregnancy
• Cocain use
• Polyhydramanios
Domestic violence
• Hypertension
Lack of support
• Maternal trauma
• Structural uterine
anomalies
• Bacterial vaginosis
• Periodontal disease
• Genitourinary infections
Trauma
• Fetal physiological
stress
• Pneumonia
Compromised
utero­placental
blood flow
• IUGR
• Hereditary
coagulopathies
Placental pathology
IL-1 TNF
Thrombin
CRH Estradiol
Myometrial
stretch
COMMON FINAL PATHWAY TO PRETERM BIRTH
Uterotonins, Proteases
Contractions
Cervical change
Rupture of membranes
PTB
Figure 5. Potential pathways and mediators of preterm birth.
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Activation of maternal-fetal hypothalamic-pituitary-adrenal axis
Premature activation of the maternal or fetal hypothalamic-pituitary-adrenal
(HPA) axis in response to maternal or fetal stress is estimated to account for
about 30% of preterm births. Maternal stress can be both physical and psychological. There is an increased prevalence of preterm births among unmarried
mothers, mothers with low income and among mothers experiencing major
stressful events such as racism or personal violence. Fetal stress may be due to
problems in the placental function.
Stress raises the risk of preterm delivery apparently by increasing levels of
corticotropin-releasing hormone (CRH). CRH mediates pituitary adrenocorticotropin (ACTH) secretion in both the maternal and fetal pathways, which in
turn increases maternal and fetal adrenal cortisol secretion. Increased cortisol
levels rapidly increase the amount of circulating CRH. The elevated CRH levels
cause prostaglandin production. Prostaglandins cause contractions (act as direct
uterotonins), cervical ripening and sensitize the myometrium e.g. to oxytocin´s
effects. CRH also enhances placental estrogen production by stimulating the
secretion of its precursor from the fetal adrenal gland. Estrogens interact with
the myometrium leading to contractions and cervical changes.
Decidual hemorrhage
Decidual hemorrhage, means bleeding in the decidua (the tissue of endometrial
origin lining of the uterus, which is in contact with the fetal membranes and
the placental plate). It is manifested as vaginal bleeding in only a small number
of cases. The profile of women at risk of decidual hemorrhage is quite different from that for both infection- and stress-associated preterm delivery. Those
susceptible may well be older, married, and well educated women. The pathway
is involved in about 20 percent of preterm births, especially those related to
PPROM. The possible reason behind the bleeding is placental abruption (separation of the placenta from the wall of the uterus). The risk factors include maternal cigarette smoking and cocaine use, chronic hypertension and pre-eclampsia,
maternal trauma, IUGR, and hereditary coagulopathies (defect in the body’s
mechanism for blood clotting). Each of these conditions is associated with
damage to the uterine spiral arteries.
The biochemical pathway from decidual bleeding to preterm delivery is closely
related to thrombin generation. Thrombin acts to stimulate coagulation and
clot formation; however, it also stimulates the production of proteases capable
of ripening the cervix and damaging fetal membranes, leading to preterm
18
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premature rupture of the membranes. Thrombin may also exert an indirect
uterotonic effect on the myometrium and stimulate contractions.
Uterine stretching
Premature delivery may be triggered by mechanical stretching of the myometrium caused by an increase in uterine size that exceeds the ability of the uterus to
compensate. The risk factors are multifetal pregnancy (twins, triplets or more) or
polyhydramnios (too much amniotic fluid). The mechanism involves the transduction of a signal initiated by the mechanical stretch on the uterus through the
cellular structures that in turn activates the production of cytokines and prostaglandins.
19
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Screening
Preterm birth fulfills some of the WHO criteria for screening [59]. It is an important health problem for the individual and community, the screening would
probably be economically balanced in relation to possible expenditure on medical care as a whole, and there is evidence that treatment started at an early stage
would be of more benefit than treatment started later. As for the criteria still
lacking, the natural history of the disease is not yet adequately understood,
there is no universally accepted treatment or useful intervention for patients
with the disease, and a suitable and acceptable screening test or examination is
not yet established.
Model
Risk factors
Ref.
62
Risk factor scoring system
Points assigned
1 • 1 spontaneous abortion
2 • 2 spontaneous abortions
2 • vaginal bleeding>10 wk
2 • urinary tract infection in pregnancy
2 • smoking
2 • maternal age >40 y
3 • >2 spontaneous abortions
3 • >3 induced abortions
4 • maternal age <18y
10 • previous preterm delivery
10 • cervical suture
10 • multiple gestation
10 • uterine anomaly
Papiernik-Berkhauer- Creasy
risk scoring system
Social factors
Current pregnancy problems
60, 61
Past medical history
CLEOPATRA I score
Cervical length (≤ 2,5 cm) Previous preterm delivery
CLEOPATRA II score
Fetal fibronectin
Cervical length (≤ 2,5 cm)
Previous preterm delivery
Delivery Probability Profile (DPP curves)
Combinations of:
Cervical length (≤ 2,5 cm)
Prior preterm birth
fFN
65
65
64
Table 3. Risk scoring systems
20
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The traditional method of screening
The traditional method of screening for PTB is based on obstetric history, symptoms or epidemiological risk factors such as previous preterm birth, maternal
age, race and smoking status. Several risk scoring systems (Table 3.) focusing on
these risk factors have been developed. The most commonly used scoring system
is Creasy´s score [60], which is a modified Papiernik-Berkhauer system [61]. The
score systems are developed by either ascribing a numerical value to individual
risk factors and by weighting risk factors differently depending on their importance or by statistical methods (regression analysis). These predicting methods
are neither sensitive nor specific. Thus most women who deliver preterm are not
identified by the risk-scoring system and most women identified as high risk do
not deliver preterm. About half of the women who experience preterm birth have
no obvious risk factors. Furthermore, because a traditional risk factor score is
based largely on previous obstetric history its accuracy is particularly low among
women expecting their first child; such women constitute approximately 50 % of
those affected by PTB. [62] New markers for the prediction of preterm birth have
therefore been explored. The new delivery probability profile system [63, 64] that
takes into account sonographic and biochemical markers besides traditional risk
factors may have more potential than traditional risk factor scoring.
Screening of symptomatic women
It is important to be able to distinguish between inconsequential abdominal pain
or uterine activity, and true premature labor. This enables physicians to prevent
unnecessary hospitalization of patients who are not at risk of premature delivery and many unwanted side effects and complications of potentially hazardous
tocolytic therapy can be prevented. The central problem is that by the time a
woman in spontaneous preterm labor is admitted, there may already be irreversible changes in the uterus, which renders futile any attempts to reverse or inhibit
the process. There are both invasive and noninvasive commercial tests available
to predict preterm birth. Noninvasive tests use samples that are easily obtained,
such as cervicovaginal secretions, serum, plasma, urine or saliva. Such tests
present little or no risk to the woman and fetus. Commercially available noninvasive tests measure biochemical markers such as cervicovaginal fetal fibronectin
(fFN), phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1)
or salivary estriol. These tests can be useful in identifying women who will not
deliver within the next few days but they are not optimal because of limitations in
their positive predictive value (Table 4). Invasive tests, such as the MMP-8 bedside
test, require amniotic fluid sampling by inserting a syringe to withdraw the fluid.
A syringe is usually inserted through the mother’s abdominal wall and the procedure involves a slight increase in the risk of miscarriage.
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Table 4. Ability of selected noninvasive markers to predict PTB in symptomatic women
(preferably before 37 weeks, if these data not available, other endpoints have been accepted).
Marker
Combination
of IL-6, -8, CL
Se
LR+
LR-
FP
PPV
NPV
Ref
30
10
0.7
3
-
-
CRP
38
6.3
0.7
6
-
-
[171]
CRH
39
3.9
0.7
10
-
-
[172]
phIGFBP-1
60
-
-
-
55
90
[173]
fFN
-
1.83
0.62
-
-
-
[174]
Estriol
71
3.1
-
23
-
-
[182]
IL-6
100
3
-
33
-
-
[175]
Combination
of fFN, CL
55
3.1
0.5
18
52.4
-
[176]
Relaxin
58
2.6
0,5
22
-
-
[177]
CL
79
2.3
0.3
33
-
-
[178]
Bacterial
vaginosis
-
1.3
0.9
-
-
-
[179]
[170]
Se = sensitivity, LR+/- = likelihood ratio, FP = false-positive rate, PPV = positive predictive
value, NPV= negative predictive value, CL = cervical length, fFN = fetal fibronectin, IL-6 =
interleukin-6, CRP = C-reactive protein, CRH = corticotrophin releasing hormone.
Table 5. Ability of selected noninvasive biomarkers to predict PTB in asymptomatic women.
(preferably before 37 weeks, if these data not available, other endpoints have been accepted).
Marker
Se
LR+
FP
Ref
Combination, 2 out of 5*
59
24
2
[164]
Relaxin
27
6.8
4
[180]
Bishop score ≥ (4)
23.4 -
-
[181]
fFN
23.4 -
-
[181]
CL
31.9 -
-
[181]
Bishop score + CL
14.1 -
-
[181]
fFN + CL
15.5 -
-
[181]
CRH
39
3
13
[183]
G-CSF
49
3.3
15
[184]
IL-6
20
3.3
6
[185]
AFP
35
2.6
13
[164]
CRP
26
1.8
15
[186]
Estriol
92
-
26
[182]
Bacterial vaginosis
-
1.6
-
[179]
* tested markers: fFN, CL, defensin, α-fetoprotein (AFP), granulocyte colony stimulating factor
Se = sensitivity, LR+/- = likelihood ratio, FP = false-positive rate, CL = cervical length, fFN =
fetal fibronectin, G-CSF = granulocyte colony stimulating factor, IL-6 = interleukin-6, AFP =
alpha fetoprotein, CRH = corticotrophin releasing hormone, CRP = C-reactive protein.
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Screening of asymptomatic women
In the absence of major historical or prenatal risk factors, identification of women
who will deliver prematurely is difficult. Most women who deliver preterm
have no major risk factors, yet more than half of all preterm births occur in
apparently low-risk pregnancies. There is a need for a reliable screening test that
could identify women at high risk of PTB before symptoms appear. This would
allow initiation of early and targeted interventions when they become available.
At the moment there is no commercial test available that would fulfill the need.
Attempts to screen low-risk women with traditional scoring systems or digital
examination have had low sensitivities and low predictive values. Transvaginal
ultrasound measurement of cervical length can be used to identify a proportion of asymptomatic women who have an increased risk of preterm birth [66].
Biochemical markers have shown some potential but their performance has been
clinically limited (Table 5). An ideal predictive biochemical test for preterm
birth would identify women who present with various subtypes of the same
condition (i.e. preterm birth attributable to several different etiologies).
23
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Predictive markers
Cervical assessment
Traditionally, the assessment of symptomatic patients for preterm delivery has
involved digital (v. lat. digitus, “finger”) examination of the cervix and monitoring of contractions. The classic digital examination assesses the position, effacement, softness, and dilatation of the cervix. All of these parameters are subjective and have high intra- and interobserver variability. Bishop score is a digital
scoring system. The total score is achieved by assessing the five components on
vaginal examination, cervical dilatation, cervical effacement, cervical consistency, cervical position and fetal station. It is traditionally used to determine
how successful an induction of labor might be but in some countries it is also
used to predict preterm birth.
Cervical sonography
The most accurate and reproducible method of cervical evaluation is trans­vaginal
ultrasonography (TVU) (Figure 6). Sonographic measurement of cervical length
is an established predictor for preterm birth. The shorter the sonographic cervical length, the higher the risk of spontaneous preterm labor/delivery (Figure 7).
However there is no agreement on what a sonographic short cervix is. Some
investigations have proposed a cut-off of 25 mm while others prefer a cut-off of
15 mm. When using a cut-off of 15 mm at 22 weeks of gestation a subgroup comprising about 1.5 % of the female population at particularly high risk for early
preterm delivery was identified [66]. Cervical length measurement is a useful
tool but it requires a change in current ultrasound practices. Measurement of
cervical length takes about 5 min and it could be carried out at the time of the
second scan [67]. Sonographic cervical length is not a comprehensive screening
test for spontaneous preterm delivery due to the limitations in the sensitivity of
the method. The sensitivity is greater than 50 %, usually 60-80 % [68] meaning
that not all women who will have a spontaneous preterm birth have a short
cervix at mid-trimester.
Biochemical markers
The term biochemical marker is not well defined. The following definition has
been suggested: “a parameter which can be measured in a biological sample and
which provides information on an exposure, or on the actual or potential effects
of that exposure in an individual or in a group.”
The clinical utility of biochemical markers is that they can give objective results
when measured with an accurate test.
24
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Uterus
Cervix
Vagina
Ultrasound transducer
Figure 6. Transvaginal ultrasonographic measurement of cervical length.
���������������������������������������
������������������������������������
70
60
50
40
�����
��� 30
20
10
0
0
10
20
30
40
50
��������������������
60
Figure 7. Association between ultrasonographic cervical length measured at 23 weeks
and preterm birth (>32 weeks). [69]
25
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Fetal fibronectin
Fetal fibronectin (fFN) is an extracellular glycoprotein that is thought to act as
an adhesive substance, a “tissue glue” between the membranes and the uterine
wall. Although it can normally be found in cervico-vaginal fluids it is not commonly found between weeks 26-34. Fetal fibronectin leaks into the vagina if a
preterm delivery is likely to occur. It can be measured with a diagnostic immunochromatographic test (Full Term, Hologic, Inc.). The specimen is collected
during speculum examination using a swab. The fetal fibronectin test cannot
confirm that a woman is in labor, but it can tell if she is not. A negative result
with the fFN test means it is highly unlikely that the woman will give birth
within the next week or two. A positive result, on the other hand, is not as useful. It means the woman is at a higher risk of giving birth early, but it does not
provide an assurance that she is about to give birth, so it will not help the practitioner to decide how to manage the situation. The poor positive predictive value
(PPV) of the test is the reason why the fetal fibronectin test is not recommended
by the American College of Obstetricians and Gynecologists (ACOG) for routine
screening, but only for screening of symptomatic women [70]. The fFN test result
may be affected by urine, seminal plasma or blood, and is not indicated if the
membranes have ruptured.
Ph-IGFBP-1
Phosphorylated insulin-like growth factor binding protein (phIGFBP-1) is a protein
secreted by decidual cells. When the delivery is approaching, fetal membranes begin to detach from the decidua and phIGFBP-1 leaks into cervical secretions.
Detection of phIGFBP-1 in cervical secretions of symptomatic patients is a marker
for prediction of preterm delivery. phIGFBP-1 can be measured with a commercial
rapid immunochromatographic test (Actim Partus, Medix Bio­chemica). The test
result is not affected by urine or seminal plasma but maternal blood may interfere
with the assay. The strength of the test is the high negative predictive value (NPV).
A negative phIGFBP-1 indicates a very low risk of PTD and thus that there is no
need for additional care beyond the antenatal care program.
Estriol
Estriol (E3) is a naturally occurring derivative of the hormone estrogen. There
is a surge in salivary estriol several weeks prior to the onset of spontaneous
preterm labor. Therefore, measurement of salivary estriol has been explored
as a risk predictor for preterm labor. SalEST™ is a laboratory technique for
measuring salivary estriol levels. The method is not satisfactory. For example,
ACOG does not recommend the salivary estriol test as a screening test for
26
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premature labor because it produces a high percentage of false positive results
and could potentially add significant costs and unnecessary interventions
to prenatal care [71]. The positive predictive value of a salivary estriol test is
only about 20%, (the negative predictive value is about 98%) [72]. Furthermore,
salivary estriol predicts late preterm birth quite well, but it is not especially
useful for the prediction of earlier preterm births [197].
Combination of markers
Many markers have been reported to be associated with preterm birth. However,
few have demonstrated sufficiently good predictive value when used alone.
Today´s data strongly suggests that a single predictive marker effectively accounting for a large proportion of premature delivery is unlikely to be found
simply because of the multifactorial etiology of PTB. Combination of non-overlapping biochemical markers may considerably improve the success of any individual marker to predict PTB.
Combination of biochemical markers, cervical length and previous obstetric
history may provide a useful screening tool [163, 164] (Figure 8). Several studies
have tested the effect of a combination of potential markers for predicting PTB
and some of them have shown improved performance (Table 6.).
Multiparas
All negative
Nulliparas
fFN+
70
60
70
60
CL < 25 mm
All negative
50
History of PTB
40
30
fFN+ and CL <
25 mm
20
fFN+ and
History of PTB
10
0
31 32 33 34 35 36 37 38
weeks
CL< 25 mm
and History of
PTB
All three
Risk %
Risk %
50
fFN +
40
CL < 25 mm
30
fFN + and CL <
25 mm
20
10
0
31 32 33 34 35 36 37 38
weeks
Figure 8. Risk of spontaneous PTB at various gestational ages with various combinations
of risk factors in nulliparas and multiparas. [164]
27
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Table 6. Examples of combinations of markers for predicting PTB.
Women
(n)
Primary
outcome
102
Test
Se
Sp
PPV
NPV
67.0 %
83.0 %
27.0 %
96.0 %
PTB
<35 w
phIGFBP-1
CL ≤ 30 mm
100.0 %
45.0 %
15.0 % 100.0 %
phIGFBP-1 +
CL 20-30 mm
75.0 %
74.0 %
23.0 %
97.0 %
phIGFBP-1 +
CL <20 mm
60.0 %
77.0 %
50.0 %
83.0 %
51
phIGFBP-1
83.3 %
84.4 %
41.7 %
97.4 %
fFN
83.3 %
80.0 %
35.7 %
97.3 %
PTB
Within 7 d
CL < 20 mm
66.7 %
95.6 %
66.7 %
95.6 %
CL < 25 mm
66.7 %
88.9 %
44.4 %
95.2 %
phIGFBP-1 +
CL < 20mm
80.0 %
97.3 %
80.0 %
97.3 %
fFN +
CL <20mm
80.0 %
97.2 %
80.0 %
97.2 %
phIGFBP-1 +
CL <25mm
80.0 %
97.1 %
80.0 %
97.1 %
fFN +
CL <25 mm
80.0 %
97.0 %
80.0 %
97.0 %
45
PTB < 32 w
1 out of 5
92.7 % 65.9 %
-
markers* +ve
2 out of 5
marker +ve
3 out of 5
marker +ve
Serum only**
37
97.6 %
-
-
19.5 %
100 %
-
-
80.5 %
78.1 %
-
-
CRH
24 %
-
-
-
AFP
25 %
-
-
-
AFP + CRH +
risk factor score
37 %
-
-
CL ≤ 26 mm
-
-
50
fFN
-
-
45.2
86.6
CL + fFN
-
-
52.4
94.4
IL-6
73 %
61 %
-
-
IL-8
64 %
55 %
-
-
phIGFBP-1
48 %
68 %
-
-
CL <29.3 mm
82 %
48 %
-
-
77
PTB<37 w
58.5 %
76
Ref
PTB<37 w
PTB<37 w
[165]
[166]
[164]
[169]
89.1
IL-6 + IL-8 + cervical index 0.36
30 %
97 %
-
-
IL-6 + IL-8 + cervical index 0.36
+ phIGFBP-1
10 %
98 %
-
-
[176]
[170]
*tested markers: fFN, CL, defensin, α-fetoprotein (AFP), granulocyte colony stimulating factor
28
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** Serum only = result considered as positive if any serum marker, defensin,
α-fetoprotein or granulocyte colony stimulating factor, was positive.
12.1.2009 15:04:45
Potential future biomarkers
Cytokines
Cytokines have been investigated as protein biomarkers of impending premature delivery. Cytokines are low-molecular weight glycoproteins that mediate
the activation of immune cells and coordinate the production and secretion of
antibodies and other cytokines. They also stimulate uterine contractions via the
production of prostaglandins and perhaps cause preterm cervical ripening and
PPROM via stimulation of metalloproteinases [73]. Elevation of pro-inflammatory cytokines in maternal serum and cervicovaginal fluids during infection
and before parturition has been extensively described. Pro-inflammatory cytokines such as IL-1β, IL-6, IL-8 and TNF-α protect the host against invading micro­
organisms [74]. In addition to protective effects this response can also be harmful to the host. For this reason the pro-inflammatory immune cascade is tightly
regulated. Resolution of the inflammatory process and healing occurs through
the activity of anti-inflammatory cytokines such as interleukin-re­ceptor
antagonist. An imbalance between pro- and anti-inflammatory response has
been implicated in the pathogenesis of infection related premature birth [75].
Preterm birth has been associated with elevated levels of IL-1, IL-6 and IL-8
cytokines even in the absence of signs of intrauterine infection [51].
Matrix metalloproteinases
Matrix metalloproteinases (MMPs) are responsible for the turnover and degradation of connective tissue proteins. MMPs affect the activity of various cytokines,
indicating dual role for MMPs in the activation and inactivation of the inflammatory system. MMPs are involved as proteolytic enzymes in preterm labor and
PPROM as well as in pre-eclampsia, intrauterine growth restriction, chronic
lung disease, necrotizing enterocolitis, intraventricular hemorrhage, cystic
periventricular leucomalacia and retinopathy of prematurity [188]. MMP-9 is
involved in the degradation of the basement membrane and other extra­cellular
matrix components and increase in humans at the time of parturition [76].
Maternal serum MMP-9 concentration raises 24 h before the initiation of labor.
Such late prediction is of little value in allowing initiation of preventive steps,
but can aid in understanding the mechanisms of PTB [77]. Recent studies suggest that increased fetal levels of MMP-9 are involved with PPROM and differentiate fetuses with PPROM from those undergoing premature labor with intact
membranes [46]. Thus, it has been questioned whether PPROM is simply an accident or whether a sick fetus may initiate preterm parturition by activating the
mechanisms responsible for rupture of membranes. The teleologic advantage of
the latter would be a more rapid exit from a hostile environment. Alterations in
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the concentrations of other MMPs (MMP-1, -2, -3, -7, -8, -12, -13 and -14) have also
been associated with preterm birth. Since MMPs are involved in the perinatal
complications of prematurity they are thus potential targets for therapeutic intervention [188].
Relaxin
Relaxin is a collagenolytic hormone that causes increased production of the matrix metalloproteinases. Decidual expression of relaxin is increased in patients
with PPROM. Relaxin causes increase in expression MMP-1, MMP-3 and MMP9. Local relaxin could therefore cause activation of specific enzyme cascade resulting in degradation of membranes [168].
Stress related biomarkers
Empirical evidence, based on prospective population-based studies provide substantial support for the premise that infants of mothers experiencing high levels
of psychological or social stress during pregnancy are at significantly increased
risk for preterm birth and low birth weight. Stress is known to evoke a variety
of adaptational responses, including stimulation of the hypothalamic-pituitaryadrenal (HPA) axis. Several studies have shown elevated levels of placental
corticotrophin releasing hormone, CRH to be implicated in spontaneous preterm
birth. Stress-related physiological responses may thereby contribute to adverse
birth outcomes. Evidence suggests that chronic stress is associated with immunosuppression. Maternal stress and infection are risk factors in premature birth.
However, the nature of the stress-immune system relationship has been little
studied in human pregnancy. Women at risk for spontaneous preterm delivery
may possibly be identified solely by stress related biomarkers e.g., CRH, cortisol
and urocortin, obtained from maternal blood in early pregnancy. Urocortin is a
member of the CRH family and according to recent studies its measurement in
maternal plasma suggests it may have potential as a new biochemical marker of
PTD [78].
Endocannabinoids
Endocannabinoids are substances produced within the body, which activate
cannabinoid receptors. Anandamide (N-arachidonoylethanolamine) was the
first endocannabinoid discovered. In recent years it has been demonstrated
that high circulating levels of this endogenous cannabinoid, as a result of low
expression of its metabolizing enzyme, fatty acid amide hydrolase (FAAH),
may contribute to spontaneous miscarriage [79]. Endocannabinoids and fatty
30
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acid amide hydrolase have been found to have a potential role in signaling for
implantation and maintenance of pregnancy. Abnormal secretory endometrial
changes may adversely affect early pregnancy outcome [80]. The roles of endo­
cannabinoids and agents modulating their receptors are potentially very ex­
citing areas to be explored further.
PAPP-A
Pregnancy associated plasma protein A (PAPP-A) is a glycoprotein which is secreted from the trophoblastic tissues of the placenta. Decreased levels of PAPP-A
can be seen in pregnancies affected with Down syndrome in the first trimester
of the pregnancy. Low levels of maternal serum PAPP-A have been shown to be
associated, in the absence of an abnormal karyotype, with an increased risk
of preterm or early preterm delivery [200]. Low maternal serum PAPP-A levels
during the first trimester may reflect a trophoblast invasion defect in the
maternal-fetal interface, resulting in subsequent preterm delivery, particularly
in the case of PPROM [201].
sFlt1, sEng and PlGF
Pre-eclampsia is accompanied by elevated maternal serum concentrations of
angiogenic factors such as soluble fms-like tyrosine kinase (sFlt1), soluble endoglin (sEng) and reduced levels of free placental growth factor (PlGF). A modest
increase in maternal sFlt1 and sEng and decreases in free PlGF have been found
to be associated with preterm birth [204].
Fetal cells and fetal cell-free DNA
There is a certain degree of fetal-maternal transfusion in every pregnancy.
Feto-maternal cell trafficking has long been associated with pre-eclampsia.
Subsequent studies have shown that changes in fetal cells, and more recently
cell free fetal nucleic acids may also occur in other pregnancy related disorders
including preterm labor, intra-uterine growth retardation, hyperemesis gravidarum or even pregnancies at high altitude. Theoretically all new and paternal
inherited disorders with a known gene defect can be detected in maternal plasma. Small scale studies have described elevated concentrations of free fetal DNA
in maternal plasma in (threatening) preterm labor, pre-eclampsia and aneuploidy. Large-scale studies are necessary to demonstrate the value of these findings
[202]. According to the studies, preterm labor seems to be associated with an
elevated release of cell free fetal nucleic acids only but not with an increment in
feto-maternal cell trafficking [203].
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Genetic polymorphism
Well-established observations support a genetic influence on the risk of premature birth. Many studies have found associations between single nucleotide
polymorphisms (SNP) in cytokine genes responsible for inflammation in women
who experienced premature birth (Table 7). However most studies lack sufficient
power to make strong associations. Polymorphisms in the TNF-α, IL-6 and IL-4
genes as well as other inflammatory mediators have been reported. Fetal polymorphisms have also been evaluated. Candidate gene studies can be used in
premature birth to understand the contribution of DNA polymorphism/genetic
predisposition to disease risk. SNP analysis may reveal opportunities even for
pre-pregnancy testing for premature birth. Besides developing assays for these
SNP genotypes one of the major challenges is to investigate further the mole­cular
mechanisms behind already established SNPs associated with premature birth.
Table 7. Studies about genetic polymorphisms associated with PTB
Candidate gene PTB
Interleukin 1 α
Symbol
IL1A
Publications
(Ref)
Annells 2004
[81]
Interleukin 1 b
IL1B
Goepfert 2005
Moore 2004
Annells 2004
Genc 2002
[82]
[83]
[81]
[84]
Interleukin 1 receptor antagonist
IL-1RN
Murtha 2006
Kalish 2006
Genc-2004
Perni 2004
Hao 2004
Witkin 2003
Kalish 2003
Batron 2003
Genc 2002
[85]
[86]
[87]
[88]
[89]
[90]
[91]
[92]
[84]
Interleukin 4
IL4
Kalish 2004
Annells 2004
[93]
[81]
Interleukin 6
IL6
Menon 2006
Goepfert 2005
Simhan 2003
[110]
[82]
[112]
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Candidate gene PTB
Symbol
Publications
(Ref)
Interleukin 10
IL10
Annells 2005
Annells 2004
Kalish 2004
Tumor necrosis factor alpha
TNFA
Menon 2006
[110]
Genc 2006
[111]
Goepfert 2005
[82]
Macones 2004
Kalish 2004
[93]
Moore 2004
[83]
Valdez 2004
[106]
Annells 2004
[81]
Amory 2004
[113]
Chen 2003
[114]
Aidoo 2001
[115]
Roberts 1999
[116]
Dizon-Townson 1997[117]
Wilson 1993
[118]
Tumor necrosis factor receptor I
& II
Menon 2006
[110]
Toll-like receptor-4
TLR4
Goepgert 2005
Genc 2004
Härtel 2004
Nguyen 2004
Ferrand 2002
Lorenz 2002
Arbour 2000
[82]
[87]
[119]
[120]
[96]
[121]
[122]
Mannose binding lectin
MBL2
Annells2005
Annells 2004
[101]
[81]
Heat shock protein 70
Hsp 70
Kalish 2006
Kalish 2004
[86]
[93]
Heat shock protein 47
Hsp 47
Wang 2006
[94]
Matrix metalloproteinase-1
MMP1
Fujimoto 2002
[95]
Matrix metalloproteinase-9
MMP9
Ferrand 2002
[96]
Sziller 2006
Fuks 2005
[97]
[98]
TNFRI
TNRFII
Fas/Fas ligand
Fas
(CD95, Fas/APO-1)
[101]
[81]
[93]
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Candidate gene PTB
Symbol
Publications
(Ref)
Kalish 2005
Sziller 2005
Annells 2005
[99]
[100]
[101]
CD14
CD14
Kalish 2006
[86]
Beta-2-adrenergic receptor
B2AR
ADRB2
Landau 2002
[102]
Corticotropin releasing hormone
CRH
Baerwald 1996
[103]
Corticotropin releasing hormone
binding protein
CRHBP
Hao 2004
[89]
Methylenetetrahydrofolate reductase.
MTHFR
Engel 2006
Nurk 2004
Valdez 2004
Lauszus 2001
[104]
[105]
[106]
[107]
Methionine synthase
MTR
Engel 2006
[104]
Methionine synthase reductase
MTRR
Engel 2006
[104]
Cytosolic serine hydroxymethyl
transferase
SHMT1
Engel 2006
[104]
Vascular endothelial growth factor
VEGF
Papazoglou 2004
[108]
Factor V
FV
Hao 2004
[89]
Inducible nitric oxide synthase
NOS2A
Hao 2004
[89]
Mu-opioid receptor
OPRM1
Hao 2004
[89]
Angiotensin converting enzyme ACE
Valdez 2004
[106]
Cytochrome P450IA1
CYP1A1
Wang 2001
[109]
Cytochrome P450IID6
CYP2D6
Wang 2001
[109]
Cytochrome P450IID6
CYP2E1
Wang 2001
[109]
Aldehyde dehydrogenase 2
ALDH2
Wang 2001
[109]
NAD(P)H quinine oxidoreductase 1
NQO1
Wang 2001
[109]
Glutathione S-transferase theta 1
GSTT1
Wang 2001
[109]
Glutathione S-transferase mu 1
GSTM1
Wang 2001
[109]
Epoxide hydrolase
EPHX
Wang 2001
[109]
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Cervicovaginal markers
A case-control proteomic study identified several proteins with greater differential expression than fFN when comparing an asymptomatic group and a symptomatic group. Among these proteins were calgranulins, annexins, S100 calcium
binding protein A7, α-1 acid glycoprotein, and α-1 antitrypsin precursor. Further
characterization of these markers in a large cohort of subjects may provide the
basis for a new test for early, noninvasive prediction of PTB. [205]
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Prevention
For many years the interventions for the prevention of preterm birth have been
reactive rather than proactive and have been associated with poor results.
A delay of a few days in the delivery is often associated with a significant increase in survival. Delaying delivery may reduce the rate of long-term morbidity by facilitating the maturation of developing organs and systems. There is
conflicting evidence as to how to manage such patients effectively and further
research is needed in this field.
Traditional recommendations
Bed rest, hydration and pelvic rest have been standard recommendations for
women at risk or receiving tocolysis for PTL. None of these has been shown to be
effective. [123]
Home uterine monitoring
Home uterine monitoring (HUAM) has been studied as a method of closely
observing uterine activity and thus enabling intervention in a timely manner.
A lightweight, portable patient unit includes a sensor (i.e., tocodynamometer)
and a device for recording, storing and transmitting data picked up by the sensor. The practitioner analyzes the data along with the patient’s reported symptoms and advises the patient on her status and recommended course of action
[234]. Research has not shown a clear advantage of home monitoring. [124]
Cerclage
The traditional intervention for women with recurrent preterm deliveries or
second trimester losses is cervical cerclage. Cervical cerclage is a surgical procedure, in which the cervix is sewn closed during pregnancy. It was introduced
in 1955 by Shirodkar [144], yet remains one of the more controversial surgical
interventions in obstetrics [145]. A closed cervix helps a developing baby stay
inside the uterus until the mother reaches 37-38 weeks of pregnancy.
The cervix is the lowest part of the uterus and extends into the vagina. During
normal pregnancy it remains closed until the third trimester. The stitch is removed when it is time for the baby to be delivered. Cervical cerclage has been
widely used to prevent early preterm birth when a woman’s cervix is weak
(sometimes called cervical insufficiency/incompetence). If a woman has a cervical insufficiency she is more likely to have a baby born prematurely because
the cervix shortens or opens too early. When the cervix is healthy, it thins out
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and opens at the end of pregnancy when labor begins. With cervical insuffici­
ency, the cervix opens without labor. The woman may deliver the baby without
feeling contractions. The diagnosis of cervical insufficiency is notoriously
difficult. There is no objective diagnostic test and the diagnosis is usually a
retrospective one.
There are five different techniques for performing the cerclage. These are either
vaginal or abdominal. The two most common are the McDonald procedure and
Shirodkar operation.
1.
McDonald procedure
2.
Shirodkar operation
3.
Wurm procedure (Hefner cerclage)
4.
Transabdominal cerclage
5.
Lash procedure.
Currently, three categories of patients with cervical insufficiency can be defined.
Prophylactic or elective cerclage is performed on those women with classic historical features of cervical insufficiency, i.e. those with two or more second trimester
losses lacking bleeding or clear signs of labor preceding the loss. The second
category is urgent cerclages that are performed on asymptomatic women where
digital or ultrasonographic examination reveals a short cervix or funneling.
The third category includes women with clear signs of cervical dilation and
significant effacement but no uterine contractions. These women are candidates
for nonelective emergency cerclage.[146]
Cervical cerclage is not without risk. Reported adverse effects shortly after suture insertion include abdominal pain, vaginal bleeding, PPROM and bladder
injury. Late complications can include infections such as chorioamnionitis.
Obstetrically, cervical cerclage is contraindicated in the presence of uterine
contractions, PPROM, fetal demise and congenital lethal malformations.
Despite cervical cerclage being a relatively common operative procedure, there
is still little evidence as to its efficacy. The probability of it being of benefit is
highest in women with a very high risk of PTB. Since there are relatively few
complications, it is likely that cerclage will continue to be offered to women
with clear cervical insufficiency. Some clinicians base the decision to insert
cervical cerclage on an ultrasonographic short cervical length. Serial cervical
ultrasound examinations with cerclage insertion only if indicated, has been
suggested to be a reasonable practice, as most women treated with cerclage do
not need it [145, 147, ].
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In low risk women (based on obstetric history) with a short cervix (< 15 mm),
cerclage does not appear to reduce the risk of PTB probably due to the association with visible fetal membranes [148]. The evidence is conflicting as to whether cerclage is beneficial once the pathological process has begun and cervical
shortening is seen and at what cervical length to intervene. The efficacy of cerclage can vary according to the cause of the short cervix. Sakai et al. found that
women with an elevated concentration of IL-8 in cervical secretions and short
cervix may not benefit from cerclage. These patients may have an inflammatory
or infection related process ongoing and cerclage does not help or it may even be
harmful [149, 150]. These results suggest that cerclage will only be beneficial if
the shortening happened in the absence of inflammation. Therefore identification of patients who can benefit from cerclage cannot be made based on obstetric
history or cervical ultrasound alone. Combination of IL-8 concentration measurement from cervical secretions, sonographic measurement of cervical length
and obstetric history is more likely to identify patients who would most benefit
from cerclage to prevent PTB [151]. Until such a diagnosis can be made, cerclage
should be reserved for patients with anatomic insufficiency [162].
Antibiotics
Infection may be an important cause of PTB. Antibiotic use for prenatal prophylaxis of preterm labor and membrane rupture and for prevention of preterm
birth in women in preterm labor has been widely debated for more than 30
years. Different antibiotics (e.g. clindamycin, metronidazole and erythromycin)
with varying doses and by different routes have been administered to women at
a range of gestational ages with differing risks of PTB. This has, not surprisingly,
resulted in different results. In these studies, about a third have suggested that
antibiotic regimens are beneficial in reducing preterm birth, while the rest have
not. In contrast, other studies have shown that in some populations, the use of
antibiotics has been associated with an increase in preterm births [126, 127].
Romero et al. have proposed that preterm labor is a complex syndrome and
that many factors other than infection may be involved. Therefore antibiotic administration as a preventive strategy is destined to fail, or even cause harm,
if we assume that infection is the only cause of preterm labor [128]
Early PTB is strongly associated with infection. Early detection of abnormal
flora (even if this returns to normal) is associated with a greater risk of adverse
events rather than late detection. Therefore, the conception of today is that,
if they are to be effective antibiotics, they should be used early in pregnancy
before inflammatory feto-maternal tissue damage occurs. Prophylactic use of
antibiotics is more likely to be successful if only used in women at risk of PTB
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due to infection or abnormal flora, or in women with a predisposition to mount
a damaging inflammatory response to infection. [129]
Can antibiotic treatment of bacterial vaginosis prevent or delay
preterm birth
Bacterial vaginosis, both symptomatic and asymptomatic has in numerous studies been associated with poor perinatal outcome; in particular an increased risk
of preterm birth. The treatment of bacterial vaginosis in women at low risk for
preterm birth is not recommended today and whether it is effective in high-risk
patients is subject to debate.
Progesterone
The female hormone progesterone has been used to prevent preterm birth.
The first trial of progestational agents (of which progesterone is one) for the
prevention of preterm birth in women at increased risk was published in 1970
by Papiernik. The exact mechanism of progesterone in the prevention of preterm
birth is still not fully understood, though, for example, progesterone has been
shown to be responsible for myometrial quiescence in vitro by inhibiting myometrial contractions, blocking effects of oxytocin by inhibiting formation of gap
junctions [130]. The evidence accumulated until the 1990s was fraught by mixed
results, and was based on mostly underpowered studies with variable eligi­
bility criteria. When the available randomized, placebo controlled trials were
analyzed in a meta analysis in 1989 no reduction in the risk of PTB could be
confirmed [131]. Another analysis using the same studies but different criteria
found a 50 % reduction in PTB but no significant reduction in death or disease
was observed [132]
Two recent studies from the United States [133] and Brazil [134] have re-awoken
the interest in progesterone supplementation. Both of these studies showed a statistically significant reduction in the incidence of PTB by about 50-60 % among
women with a history of preterm birth. The studies used different progestational
agents and different administration routes. The NICHD trial (National Institute
of Child Health and Human Development), conducted in the United States, used
weekly intramuscular administration of synthetic progesterone, 17 alpha hydroxyprogesterone caproate (17P), initiated before 21 weeks gestation whereas in
the Brazilian study women were treated prophylactically with vaginal natural
progesterone suppositories. Neither study showed a reduction in the incidence
of spontaneous preterm birth suggesting that progesterone may sensitize the
uterus to tocolytics, which subsequently prevent PTB rather than prevent preterm labor by itself.
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Today, progesterone therapy is thought to be a promising, cost efficient intervention for women at high risk of recurrent preterm birth. Bailit and Votruba (2007)
concluded that treating expectant mothers with a prior spontaneous preterm
birth with 17P would generate future medical cost savings that substantially
exceed the cost of treatment. According to their calculation, if the eligible population were universally treated, discounted lifetime medical costs of their offspring could be reduced by more than $2.0 billion annually [136].
Several studies have recently been conducted to find an optimal progesterone
formulation, administration route, timing and indication (Table 8).
Table 8. Summary* of recent progesterone studies.
Author [Ref]
Treatment Primary Outcome
Women (n)
outcome in treated
Criteria
group
Outcome Statistical
in control significance
group
Facchinetti (2007) [141]
• 55 women
Singletons undelivered after
episode of preterm labour
IM 17P
PTB
5/23
< 37 wks (55 %)
12/22
(22 %)
P < 0.05
Rouse (2007) [135]
• 661 women
Twin pregnancy IM 17P
(250 mg)
PTB
< 35 wks
135/325
(42 %)
123/330
(37 %)
ns
Vaginal
natural
progest.
(100 mg)
PTB
< 34 wks
2/72
(2.8 %)
13/70
(18.6 %)
P = 0.02
IM 17P
(250 mg)
PTB
< 37 wks
90/306
(29.4 %)
69/153
(45 %)
P < 0.05
PTB
< 34 wks
24/125
(19.2 %)
43/125
(34.4 %)
P = 0.007
Fonseca (2003) [134]
• 142 women Singleton pregnancies with history of PTB
Meis (2003) [133]
• 463 women
Singleton pregnancies
with history of PTB
Fonseca (2007) [66]
• 250 women
Vaginal
Singleton/twin pregnancies natural
+
low risk progest.
No history of cerclage (200 mg)
& PPROM or short cervix
O’Brien (2007)
• 309 women
Vaginal
CL
Singleton, history of PTB
(90 mg)
changes
or mid trimester natural
CL shortening
progest.
+
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CL short-
ening significantly less
than in placebo group
P = 0.038
IM= intra muscular, ns= not significant
Randomisation to progesterone only if CL < 15 mm at > 20 weeks’ gestation.
*Acknowledgements to Dr Manju Chandiramani and Dr Rachel Tribe,
King’s College London, UK.
12.1.2009 15:04:48
The effect of supplemental progesterone compounds is not universal in women
with previous PTB, indicating that some pathways to PTB are not influenced by
this therapy. For example, in a study of women with a short cervix, treatment
with natural progesterone was successful in reducing the rate of spontaneous early preterm delivery [66] whereas synthetic 17P had no effect on women
with twin pregnancies [135]. This suggests that the effect of progesterone might
be related to modulation of inflammation or cervical ripening rather than to
uterine contractility [162]. There is still uncertainty whether treatment with
progestational agents can also reduce the risk of perinatal and neonatal mortality. This evidence is essential before recommending the treatment, as there is
always the potential risk of unanticipated adverse effects from fetal exposure to
hormonal or other medical therapies. The American College of Obstetricians and
Gynecologists (ACOG ) recommends that the use of progesterone supplementation in pregnancy to prevent PTB should be restricted to women with a documented history of prior spontaneous PTB [140].
Safety of synthetic 17P and natural progesterone
During the 1950s and 1960s synthetic progestins were frequently administered
to pregnant women, e.g for treatment or prevention of miscarriage. With the thalidomide tragedy in the 1960s, all pharmaceuticals became suspect as to their
potential for unanticipated adverse effects on fetal development. Some progestins had been thought to be associated with masculinization and malformation
of the fetus [155, 156] and considerable concern was raised regarding their use.
In response to these concerns the US FDA required a warning label on all progestational agents stating that there was an increased risk of birth defects if taken during the first 4 months of pregnancy. The warning was removed in 1999.
A recent extensive literature search has again raised concerns about the safe use
of synthetic 17P in the prevention of preterm birth. It revealed that there was
a signal for embryo-fetal toxicity associated with 17P in the two largest clinical trials conducted to date, the NICHD-study being one of them [137, 133, 154].
Despite their positive interest, the NICHD-study results also included a warning
that the synthetic progesterone17P may be associated with an increase of miscarriage and stillbirths. The study was followed by an FDA requested, four year
follow up study of children exposed to 17P in utero, but this time the researchers did not notice any difference between the 17P exposed children and the
placebo children [153]. Recently, a retrospective analysis by Rebarber et al. 2007
emphasized the importance of continuation of treatment with 17P because early
cessation of 17P was found to be associated with an increased risk of preterm
delivery [138]. Rebarber has also found an association between the use of 17P
for the prevention of recurrent preterm delivery with an increased risk of
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developing gestational diabetes mellitus [139]. Another problem with 17P is its
preparation using castor oil (a vegetable oil obtained from the castor bean). The
FDA withdrew approval for manufacturing castor oil by pharmaceutical companies but compounding pharmacies are still permitted to prepare 17P using castor oil. Some have speculated that the castor oil in the formulation may not be
beneficial to pregnancy [155].
Natural progesterone seems to be a safe option according to a large study made
by the Fetal Medicine Foundation Second Trimester Screening Group in 2007.
No serious adverse events associated with the use of vaginally administered
natural progesterone were found [66].
Unresolved issues regarding progesterone therapy:
• What is the optimal progesterone formulation (synthetic or natural)?
• What is the optimal route of administration (injections, vaginal administration)?
• Has the long-term safety of these drugs been established?
• There is no FDA approved drug available for PTB indication.
Nutritional supplementation
The mother´s nutritional status has an impact on pregnancy outcome. For example low serum folate, iron or zinc levels during pregnancy are thought to be
associated with an increased risk of preterm birth [142, 194, 195]. Malone et al
(2007) reported that preconceptional folate supplementation is associated with a
50-70 % reduction in the incidence of early preterm birth [158]. Also low
consumption of seafood has been reported to be associated with premature
birth [143]. According to a French study, different categories of seafood may be
differently associated with birth outcomes. Fish consumption was found to be
associated with increased length of gestation and shellfish consumption with
decreased fetal growth [159]. Although the evidence for the use of fish oils to
prevent PTB is strong, particularly in women with poor fish oil intake who are
at risk of PTB, recommendations on the dosage of omega-3 and the timing, and
on the profiling of subjects require further research. Nutritional supplementation has a role in helping the mother to receive those substances that her diet
may lack. The role of nutrient supplementation in women with a well-balanced
diet that already provides all necessary nutrients, vitamins and minerals is less
clear. There are many potential mechanisms by which maternal nutritional status might affect preterm birth. Thin women may have decreased blood volume
and reduced uterine blood flow. Obese women are more likely to have congenital anomalies and their infants are more likely to be delivered preterm [196].
Also obese women are more likely to develop pre-eclampsia and diabetes, with
iatrogenic preterm birth indicated by these conditions.
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Diagnosis and Management
The mechanism of human parturition is not known and currently there are no
methods for predicting when women will go into labor at term, let alone preterm
labor. Once the threat of preterm labor is established clinicians may attempt to
stop or attenuate uterine contractions using tocolytic drugs. However about half
of women receiving placebo therapy do not deliver within a week from the start
of therapy. In other words, either the diagnosis of preterm labor is wrong or
the threat of preterm labor neutralizes naturally and the uterus returns to a
quiescent state. These questions may not be resolved until the physiological
mechanism of parturition is fully understood.
There is no evidence that tocolytics can prolong pregnancy for sufficient time to
improve perinatal outcome, however many clinicians use tocolytics to achieve
short-term gains such as enabling the transfer of the mother to a tertiary referral
centre with good obstetric and neonatal facilites, or gaining time to administer
glucocorticoids to improve fetal lung maturation. Nevertheless, it must be emphasized that many episodes of threatened preterm labor are false alarms and
some women are treated unnecessarily.
Diagnosis
The diagnosis or preterm labor is made when a woman between 22 and 37 weeks
gestation presents with persistent uterine activity (contractions, at least one
every 10 minutes or more often) and progressive cervical changes (> 2 cm dilatation; > 80% shortening), with or without premature rupture of the membranes or
some vaginal bleeding. Initial investigations include an assessment of fetal heart
rate (cardiotocography); speculum examination or digital examination (depending on the state of the membranes) for cervical assessment and high vaginal
swabs for microbiology. An evaluation should be made of possible predisposing
factors, e.g. fetal abnormalities, placental abruption, intrauterine infection.
The presence of uterine contractions alone cannot be used to diagnose preterm
labor because often it is difficult to distinguish true uterine activation that is
going to lead to preterm delivery from Braxton Hicks contractions that occur in
numerous pregnancies that deliver at term. The diagnosis must be supported by
evidence of progressive changes in the uterine cervix. Some patients may present without contractions, but with a dilated cervix (silent cervical dilatation).
If the cervical length is ≥ 30 mm the woman is unlikely to be in preterm labor,
especially if the fetal fibronectin test is negative. On the other hand the presence of progressive and advanced cervical changes is a strong indicator of true
preterm labor and the risk of delivery increases with decreasing cervical length
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(< 25 mm), especially if there is “funneling” of the cervix as the fetal membranes
penetrate the cervical canal.[215] [216]
The correct diagnosis of PPROM is important, because it influences the management of preterm labor, even though it is not always associated with it. Persistent
loss of clear fluid per vagina is diagnostic in a high percentage of cases, however
loss of urine or excessive production of vaginal fluid may be mistaken for amniotic fluid. Sometimes there can be loss of clear fluid as a consequence of cervical incompetence without true rupture of the membranes. Changes in vaginal
pH can help in the diagnosis of ruptured membranes; during pregnancy vaginal
pH is acidic (4.5 or lower) but it turns alkaline in the presence of amniotic fluid.
However the presence of seminal fluid or some vaginal infections that increase
the pH can give false positives. Persistent loss of amniotic fluid, can lead to oligohydramnios (too little fluid in the uterine cavity). Some clinicians advocate
amnioinfusion in early PPROM to try to prevent fetal pulmonary hypoplasis
secondary to oligohydramnios. All cases of PPROM require careful monitoring,
independent of uterine activity, because of the risk of ascending vaginal infection. Signs of infection (clinical chorioamnionitis) include elevated temperature
(≥ 38.5 °C), maternal tachycardia, high white blood cell count, uterine tenderness and foul smelling vaginal discharge. However sub-clinical infection may
be difficult to detect. [217]
Management
The diagnosis of preterm labor is very difficult before advanced cervical dilatation and repeat vaginal examinations may be required to ascertain progressive
cervical changes. This is important in order to minimize the unnecessary treatment of women who are not in preterm labor. Once the diagnosis of preterm
labor is firmly established, the benefits of trying to prolong the pregnancy must
be weighed against the risks of fetal or maternal side-effects. The most important factor in the management of preterm labor is gestational age. After 34 weeks
there is no measurable benefit for the baby and most clinicians will not attempt
to stop labor. From 28 to 34 weeks prolonging pregnancy will decrease significantly perinatal morbidity. At less than 28 gestation gaining a few weeks or even
a few days is associated with a significant improvement in perinatal morbidity and mortality. The management of threatened preterm labor at less than 24
weeks gestation is extremely difficult requiring careful consideration of the risk
of serious long term disability in the surviving infants.
If the presence of active preterm labor is confirmed with persistent uterine contractions, cervical effacement of more than 80% and progressive cervical dilatation reaching 3-5 cm, the management involves bed rest and psychological reas44
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surance of the patient. The relatives must be informed. Of the risks tocolytics to
inhibit uterine contractions and corticosteroids to induce lung maturation may
be given (see below). At this stage it is important to contact the pediatrician to
prepare neonatal support or, if this is not available locally, a decision has to be
made about transporting the patient to a tertiary referral centre with good neonatal facilities. If there is no PPROM the prophylactic use of antibiotics is not
recommended [218]. If the episode of preterm labor is associated with PPROM
and/or if there are any signs of bacterial colonization, e.g. by group B streptococcus the use of antibiotics is recommended. The choice of antibiotic is not clear
and some studies have warned against the use of co-amoxiclav in women at risk
of preterm delivery because of a possible link with neonatal complications such
as necrotizing enterocolitis [219].
If after 48 hours of tocolytic treatment uterine activity remains inhibited and
there are no further cervical changes, the treatment may be stopped and the patient will either continue with the pregnancy and deliver at term or return with
another episode of preterm labor, which will need to be treated again.
If contractions persist despite treatment (3 or more every 10 minutes) and the
cervix is fully effaced with ≥ 5 cm dilatation the possibilities to stop labor
are minimal and efforts should concentrate on making the delivery as safe
as possible, bearing in mind that in advanced preterm labor delivery can occur
very rapidly. Although referral to a tertiary hospital is desirable, transfer is not
indicated if there is imminent risk of delivery [220].
The preterm fetus is less able to cope with asphyxia or birth trauma than a fetus
at term so extra care is necessary to minimize these risks, especially in breech
presentations, which are more common in preterm labor than in labor at term.
If the presentation is cephalic, vaginal delivery is the preferred route. In breech
presentations there is controversy as to whether vaginal or caesarean delivery
should be the method of choice [221].
Fetal monitoring during the dilatation stage will include electronic recording of
the fetal heart rate, and when indicated, fetal blood sampling for gases and pH
to diagnose hypoxia. Epidural analgesia is the ideal form of pain relief during
labor and delivery because it avoids the risk of systemic drug depression in the
preterm newborn. The general guidelines for term vaginal deliveries apply to
preterm deliveries, but it is important to minimize trauma. Ventouse deliveries
should be avoided, especially in very preterm infants, to avoid the risk of intracranial hemorrhage.
There are no differences in the indications for caesarean section between term
and preterm deliveries, however the lower uterine segment is narrower in the
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preterm uterus and the surgical technique is more demanding. It is important
to deliver the preterm fetus with minimal trauma and sometimes a longitudinal
rather than a transverse incision has to be performed to create enough space for
a safe delivery. Surgical complications (bladder damage, broad ligament tears)
are more common in preterm caesarean sections than at term.
Ideally, before delivery a neonatologist should be alerted and the parents should
be counselled and involved in any plans for resuscitation of the baby. Whether
delivery is vaginal or by caesarean section, the presence of an experienced neonatologist to provide immediate care under the best possible conditions are essential to improve the outcome of the newborn.[222]
Emergency cerclage
The decision to perform an emergency cerclage as part of the management of
preterm labor in women with advanced cervical effacement and dilatation but
no contractions (cervical incompetence) requires careful consideration on an
individual basis. The operation may prove to be technically difficult and may
provoke membrane rupture [223, 224].
Corticosteroids
A baby that is born very early is at risk of breathing difficulties (respiratory
distress syndrome). A single course of corticosteroids, given to a woman who
may give birth early, helps develop her baby’s lungs. However, this benefit does
not last beyond seven days. It is not clear whether there is benefit in repeating
the dose of prenatal corticosteroids for women who remain at risk of preterm
birth after an initial course. According to Crowther and Harding repeat doses of
prenatal corticosteroids reduce the occurrence and severity of neonatal lung disease and the risk of serious health problems in the first few weeks of life [160].
However, these benefits are associated with a reduction in some measures of
weight, and head circumference at birth, and there is still insufficient evidence
on the longer-term benefits and risks [160, 161].
Tocolytics
Tocolytics are medications used to suppress premature labor. They are given
to gain time for administration of corticosteroids, which greatly accelerate
fetal lung maturity, but take one to two days to work. Another goal of tocolytic
therapy is to allow transportation of the mother to a tertiary care center.
Delaying delivery may reduce the rate of long-term morbidity by facilitating the
maturation of developing organs and systems. Tocolytics are not without risk
to the mother and fetus. Typical side effects are nausea and headache.
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Beta agonists and calcium channel blockers may cause problems with heart
rhythm.
For these reasons tocolytics must be reserved for women with real risk of PTB
and not given prophylactically to asymptomatic women or to women whose
contractions are not true labor contractions. Various types of agents are used,
with varying success rates and side effects. The choice of tocolytic agent for
treating PTL is based on local experience and availability. All of the medications prolong pregnancy beyond 48 hours. The use of tocolytic therapy in an
attempt to reduce preterm delivery has not reduced the overall preterm birth
rate [125]. Although tocolytic treatment is the standard of care, there is no FDA
approved drug for therapy, and there is no unanimity of drug regimens among
physicians.
• Beta agonists- ritodrine, terbutaline, salbutamol, isoxuprine
• Calcium channel blockers – nifedipine
• Prostaglandin synthetase inhibitors - indomethacin
• Nitric oxide donors-glyceryltrinitrate
• Oxytocin receptor antagonists – atosiban, barusiban
• Magnesium sulfate
Ethyl alcohol was frequently prescribed as a tocolytic in the mid-20th century,
but later double-blind studies showed that it was not effective.
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Challenges that clinicians are facing
Preterm birth remains a major cause of neotatal mortality and long term disability
and the biggest challenge for clinicians is to identify women at risk so that unnecessary treatment is not given to women who do not require it. Moreover being able
to identify women at high risk of preterm labor will allow the design of clinical
studies to target women who are the most likely to benefit from any intervention.
The major stumbling block for progress in the management of preterm labor is
the lack of knowledge of the mechanism of parturition. We need to identify the
endocrine and biochemical processes that explain why women go into labor. Only
then will it possible to know whether preterm labor is an acceleration of the same
mechanism that operates at term or whether it is precipitated by other physiopathological shortcuts. This knowledge will also help in the management of dysfunctional labor and improve the success rate of induction of labor. For neonatologists
very early and extremely early preterm birth will continue to pose very difficult
challenges. Further work is required to assess the long term impact of the sensorineural deficits and behavioral alterations associated with preterm birth.
The consensus views of experts in preterm birth can be summarized as follows [225]:
• The elucidation of the physiological pathways of normal labor at term is
essential, as a prerequisite for understanding preterm labor.
This should include further studies on the physiology of the human
myometrium and of cervical ripening.
• To this end more interdisciplinary research is needed including high quality
clinical studies of adequate power to address neonatal and infant outcome.
• More clinical studies are needed to:
– determine the risk and benefits of repeated administration of corticosteroids
– determine the optimal timing for induction of labor in women with PPROM
• The benefits/risks of tocolysis, progesterone or any other treatments
should be investigated in randomized placebo-controlled trials.
• Pharmacological targets that are selective to the uterus should be
identified to increase effectiveness and minimize side effects.
• The significance of abnormal intrauterine bacterial colonization in
spontaneous preterm labor requires further investigation.
• The role of intrauterine immune cells and inflammatory mediators in
spontaneous labor needs to be defined.
• The management of PPROM will benefit from improved understanding
of the repair process in the fetal membranes.
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Concluding remarks
The last trimester of pregnancy is necessary for the maturation of the fetal lungs
and other organs in preparation for extrauterine life. If this process is interrupted by an early delivery the chances of survival of the newborn are severely
decreased [226]. Preterm birth affects both rich and poor countries but the
former often have the advantage of better neonatal care. Despite considerable
improvements in obstetrics and neonatology the perinatal mortality rates in
many countries have remained relatively constant for decades. Even in hospitals
where survival rates have improved, there is a wide range of both short-term and
long-term morbidity and handicap in the surviving infants, particularly in the
very preterm and extremely preterm groups. The high rate of neurosensory disabilities in these infants poses a severe and lasting challenge to society [227] .
The quality of research into human parturition and preterm labor is high; however it reflects fragmented efforts from groups that work in relative isolation.
There is a need for concerted research efforts from different laboratories to
make substantial contributions towards solving the problem of preterm labor.
This will require traditional physiological and biochemical studies as well as
modern genomic and proteomic approaches and new imaging techniques, electromyography, bioengineering and nanotechnology. Moreover the development
of any new biomarkers, diagnostic methods and uterine selective drugs must be
validated with appropriately designed clinical trials of sufficient power to reach
robust conclusions.[228, 229, 230]
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Global efforts in preventing
preterm birth
Examples of efforts made to address the growing problem of PTB
The March of Dimes
(www.marchofdimes.com) USA (Founded 1938)
March of Dimes is an organization with a mission to improve the health of babies by preventing birth
defects, premature birth, and infant mortality. The March of Dimes carries out this mission through
programs of research, community services, education and advocacy to save babies’ lives.
The March of Dimes Prematurity Campaign is a multimillion-dollar research, awareness and education
effort that helps families to have healthier babies (launched on January 30, 2003).
Campaign Goals:
• Raising awareness of prematurity
• Reducing the rate of premature births
March of Dimes has published an evidence-based Preterm Labor Assessment Toolkit. The objective of the
toolkit is to standardize the assessment and diagnosis of preterm labor among health care professionals.
EAPM, European Association of Perinatal Medicine
(www.europerinatal.com/new_site) Europe (Founded in 1968)
The purpose of the Association is to bring together groups and individuals in a European organization in
order to promote the science of perinatal medicine for the benefit of a high level of physical and mental
health for women, mothers and their children in Europe.
Current study group:
European Association of Perinatal Medicine-Study Group on “Preterm Birth”
SMFM, Society for Materna-Fetal Medicine
(www.smfm.org) USA (Founded in 1977)
The Society for Maternal-Fetal Medicine is the membership organization for obstetricians/gynecologists
who have additional formal education and training in Maternal-Fetal medicine. The Society hosts an
annual scientific meeting. The Society is also an advocate for improving public policy and expanding
research funding and opportunities in the area maternal-fetal medicine.
Specially educated Maternal-Fetal Medicine sub-specialists provide care or consultation for both mother
and fetus in a complicated pregnancy. Examples of types of patients seen by Maternal-Fetal Medicine
sub-specialists:
• Twins, triplets or more
• Recurrent pre-term labor and delivery
• Premature rupture of membranes
• Recurrent pregnancy loss
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ACOG, American College of Obstetrics and Gynecology
(www.acog.org) USA (Founded in 1951)
The American College of Obstetricians and Gynecologists is a professional association of medical doctors
specializing in obstetrics and gynecology in the United States.
ACOG pursues its PTB mission through:
• Education
• Research
• Practice
• Guidelines and recommendation
NANEA, North Atlantic Neuro-Epidemiology Alliances
(www.nanea.dk) Denmark and USA
NANEA is a scientific collaboration between two organizations: University of Aarhus, Denmark (AU),
and Centers for Disease Control and Prevention, Atlanta, USA (CDC).
NANEA’s main areas of research presently include:
• cerebral palsy
• preterm delivery
• lifestyle during pregnancy
• autism
PREBIC Preterm Birth International Collaborative
(www.prebic.net) International (Founded in 2004)
The International PREterm BIrth Collaborative (PREBIC) was initiated on June 7th 2004 during a
workshop on Biomarkers and Preterm Birth in Denmark.
The purpose of the collaborative is to support and enhance international networking among researchers
in preterm birth and the establishment of multinational research projects on preterm birth.
PGP, Preterm birth Genome Project
International (Founded in 2007)
PGP consortium includes investigators from 4 continents. This community of researchers collaborates to
identify PTB susceptibility genes.The PGP Management Committee consists of members chosen from the
PGP and PREBIC. A WHO representative serves as Chair of the Management Committee.
The goal of the collaboration is to identify genes that affect susceptibility to preterm birth (PTB) and
other adverse pregnancy outcomes associated with preterm birth. This objective will be expedited by
combining the resources of multiple research groups from around the world.
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SAFE, The Special Non-Invasive Advances in Fetal and Neonatal Evaluation
Network
(www.safenoe.org) Europe (Founded in 2004)
The Special Non-Invasive Advances in Fetal and Neonatal Evaluation Network is a European consortium
aiming at developing of noninvasive diagnosing methods. The SAFE Network is set to run for a period of
5 years. It is sponsored under the EU Framework 6 program and has 49 partners from 19 countries.
European Preterm Labour Group, was created following scientific meetings sponsored by SAFE, to
cement collaboration and publicize the need to invest research funds into a better understanding
of human parturition and preterm labor.
Action Medical Research
(www.action.org.uk) UK (Founded 2003)
An independent national charity relying on voluntary support. Action Medical Research currently fund
68 top-quality research projects, representing a funding commitment of £7million.
Touching Tiny Lives is Action Medical Research’s campaign highlighting the urgent need for more
research to help sick and vulnerable babies. The aim is to raise £3 million for vital new research to help
prevent premature birth and life-threatening pregnancy complications.
Tommy´s the Baby Charity
(www.tommys.org) UK (Founded 1992)
UK’s leading baby charity committed to funding medical research and providing pregnancy information.
Tommy’s exists to save babies’ lives through funding research into and providing information on the
causes and prevention of miscarriage, premature birth and stillbirth. The goal is to halve the number of
babies who die during pregnancy or birth by 2030.
CPN, BILBO, Canadian Neonatal Network, Birth before 29 weeks project
(www.cpn-rpc.org) Canada (Founded 2003)
CPN is made up of Canadian researchers who will collaborate on research issues relating to perinatal care.
BILBO will be building a standardized national database of pregnancies at high risk of very preterm birth
at 22 to 28+ weeks’ gestation. These networks provide an opportunity for researchers to participate in
collaborative projects on a national scale.
GAPPS, The Global Alliance for the Prevention of Prematurity and Stillbirth
(gappsseattle.org) USA
Based at Seattle Children’s Hospital. Director Craig Rubens, MD, PhD.
GAPPS brings together an international team of maternal and child health researchers to address the
worldwide problems of preterm births and stillbirth.
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Glossary and abbreviations
A
Adrenocorticotropic hormone (ACTH
or corticotropin)
Polypeptide hormone produced and secreted by
the pituitary gland. It is an important player in
the hypothalamic-pituitary-adrenal axis.
Alloantigen
An antigen existing in alternative (allelic) forms
in a species, thus inducing an immune response
when one form is transferred to members of the
species who lack it.
American College of Obstetricians
and Gynecologist (ACOG)
A professional association of medical doctors
specializing in obstetrics and gynecology in the
United States.
Amnioinfusion
the instillation of fluid into the pregnant uterine
cavity before delivery.
Amniotic fluid
A clear, slightly yellowish liquid that surrounds
the unborn baby (fetus) during pregnancy. It is
contained in the amniotic sac.
Antepartum hemorrhage
Assisted reproductive technologies
(ART)
All fertility treatments in which both eggs and
sperm are handled.
B
Bacteremia
Presence of bacteria in blood
Bacterial vaginosis (BV)
A mainly asymptomatic syndrome in which the
normal vaginal lactobacilli are replaced by a
mixed flora with high concentrations of anaerobic
bacteria.
Bacteriuria
Presence of bacteria in urine.
Bishop score
is a pre-labor scoring system to assist in predicting whether induction of labor will be required.
Also used to estimate the risk of preterm birth.
Braxton Hicks contractions
Sporadic uterine contractions, also known as
false labor or practice contractions.
Bleeding from the vagina during pregnancy..
C
Antigen
Cerebral palsy (CP)
is any substance that causes the immune system
to produce antibodies against it. An antigen may
be a foreign substance from the environment such
as chemicals, bacteria, viruses, or pollen. An antigen may also be formed within the body, as with
bacterial toxins or tissue cells.
Any one of a number of neurological disorders
that appear in infancy or early childhood and
permanently affect body movement and muscle
coordination but do not become worse with time.
Cervical cerclage
A technical term for suspension of external
breathing. During apnea there is no movement of
the muscles of respiration and the volume of the
lungs initially remains unchanged.
A surgical procedure, in which the cervix is sewn
closed during pregnancy. It is used for the treatment of cervical incompetence, a condition where
the cervix has become slightly open and there is
a risk of miscarriage or preterm birth because it
may not remain closed throughout pregnancy.
Appendicitis
Cervical insufficiency/incompetence
A condition characterized by inflammation of the
appendix. While mild cases may resolve without
treatment, most require removal of the inflamed
appendix.
Weakened cervix that predisposes a woman
to mid-term miscarriage or early (premature)
delivery because it opens too early.
Apnea
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Cervical length (CL)
Cortisol
Length of the cervix is a measure inversely
related to the risk of preterm labor. It is assessed
manually or, more reliably with transvaginal
ultrasonography.
A corticosteroid hormone produced by the
adrenal cortex (in the adrenal gland). It is a vital
hormone that is often referred to as the “stress
hormone” as it is involved in the response to
stress.
Cervix
The lower, narrow end of the uterus where it
joins with the top end of the vagina.
Cervical ripening
A complex process that results in physical
softening and distensibility of the cervix, ultimately leading to partial cervical effacement and
dilatation.
Cesarean section= (C-section
A surgery to deliver a baby. The baby is taken
out through the mother’s abdomen. Most Csections are done when unexpected problems
occur during delivery.
Chorioamnionitis
An infection of the membranes (placental tissues)
and amniotic fluid.
Chorion
The outermost of the two fetal membranes
– the amnion is the innermost – which together
surround the embryo.
Chlamydia
A common sexually transmitted disease (STD)
caused by the bacterium, Chlamydia trachomatis.
Coagulopathy
A medical term for a defect in the body’s mechanism for blood clotting.
Corticosteroid
Hormones given to mature fetal lungs, for arthritis, or other medical conditions.
Complex disorder
Disorder caused by the interaction of multiple
genes, or by a combination of genetic and environ­
mental risk factors.
Corticotropin-releasing hormone (CRH)
A polypeptide hormone and neurotransmitter
involved in the stress response.
Cytokines
A group of proteins and peptides that are used in
organisms as signaling compounds. These chemical signals are similar to hormones and neuro­
transmitters and are used to allow one cell to
communicate with another. Cytokines have been
variously called lymphokines, interleukins and
chemokines, based on their presumed function,
cell of secretion or target of action.
D
Decidua
The term for the uterine lining (endometrium)
during a pregnancy, which forms the maternal
part of the placenta.
Demographic
Demographics refers to selected population.
Commonly-used demographics include race, age,
income, disabilities, mobility, educational attainment, and employment status.
Digital examination
A n examination with fingers (v. lat. digitus,
“finger”).
E
Endotoxins
Toxic, natural compounds found inside pathogens
such as bacteria. Endotoxin is not secreted by
live bacteria, but is a structural component in the
bacteria, which is released mainly when bacteria
are lysed.
Endocannabinoids
Substances produced within the body which activate cannabinoid receptors.
Estriol (E3)
One of the three main estrogens produced by the
human body. It is only produced in significant
amounts during pregnancy as it is made by the
placenta.
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Etiology
The study of the causes of a disease.
Extremely low birth weight (ELBW)
An infant that weighs less than 1000 g at delivery,
regardless of the gestational age at birth.
F
Fetus
A baby growing in the woman’s uterus.
Fetal fibronectin (fFN)
An extracellular glycoprotein that is thought to
act as the adhesive substance, or “tissue glue”
between the membranes and the uterine wall.
Fetal membranes
Thin layers of tissue which surround the embryo
or fetus and provide for its nutrition, respiration,
excretion and protection; they are the yolk sac,
allantois, amnion, and chorion.
Fetal inflammatory response
syndrome (FIRS)
A condition characterized by systemic inflammation of the fetus and an elevation of fetal
plasma interleukin-6. FIRS is associated with the
impending onset of preterm birth.
Folate
Granulocyte colony-stimulating factor
(G-CSF)
A blood growth factor that stimulates the bone
marrow to produce more infection-fighting white
blood cells called neutrophils.
H
Home uterine monitoring (HUAM)
An at-home device used to monitor a pregnant
woman’s uterine contractions to detect premature
labor.
Hypermesis gravidarum
A rare disorder characterized by severe and
persistent nausea and vomiting during pregnancy
that may necessitate hospitalization.
Hypothalamic-Pituitary-Adrenal (HPA)
axis
The body’s neuroendocrine system that involves
the hypothalamus, pituitary, and adrenal glands.
This complex communication system is responsible for effectively handling stress and regulates
various body processes including digestion, the
immune system, mood and sexuality, and energy
usage by regulating the production of cortisol,
neurotransmitters and key hormones.
I
A form of a water-soluble B vitamin. Folate
occurs naturally in food (e.g. leafy vegetables
such as spinach, dried beans and peas). Folate is
necessary for the production and maintenance
of new cells. This is especially important during
periods of rapid cell division and growth such as
infancy and pregnancy. Folate is needed to make
DNA and RNA. It also helps prevent changes to
DNA that may lead to cancer.
Iatrogenic = “intentional”
G
Intrauterine growth restriction (IUGR)
Gap junction
Intercellular channels that permit the free passage
between the cells of ions and small molecules. As
the time of birth approaches, gap junctions between
the smooth muscle cells of the uterus enable coordinated, powerful contractions to begin.
Genetic polymorphism
A difference in DNA sequence among individuals,
groups, or populations.
In a preterm birth context it means that the physician decides that the baby needs to be delivered
preterm, due to serious maternal or fetal complications.
Interleukins (IL)
The cytokines that act specifically as mediators
between leucocytes.
A failure of normal fetal growth. It is caused by
multiple adverse effects on the fetus that inhibit
normal growth potential.
Intraventricular hemorrhage (IVH)
Bleeding inside or around the ventricles, the
spaces in the brain containing the cerebral
spinal fluid.
Intraventricular hemorrhage is most common
in premature babies, especially very low birth
weight babies. Bleeding in the brain can put
pressure on the nerve cells and damage them.
Severe damage to cells can lead to brain injury.
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L
P
Low-birth weight (LBW)
Patent ductus arteriosus (PDA)
An infant that weighs less than 2,500 grams at
delivery, regardless of the gestational age at birth.
A congenital heart defect wherein a child’s
ductus arteriosus fails to close after birth.
M
Matrix metalloproteinases (MMPs)
A member of a group of enzymes that can break
down proteins, such as collagen, that are
normally found in the spaces between cells
in tissues (i.e., extracellular matrix proteins).
Because these enzymes need zinc or calcium
atoms to work properly, they are called metalloproteinases. Matrix metalloproteinases are
involved in wound healing, angiogenesis, and
tumor cell metastasis.
Mucinase
An enzyme that acts upon mucin (glycoproteins
found in the secretions of mucous membranes).
Myometrium
The middle layer of the uterine wall consisting of
smooth muscle cells and supporting stromal and
vascular tissue.
N
Necrotizing enterocolitis (NEC)
A medical condition primarily seen in premature
infants, where portions of the bowel undergo
necrosis (tissue death).
Negative predictive value (NPV)
The probability that a person does not have the
target disorder when a negative test result is
observed.
O
Oligohydramnios
Periventricular leukomalacia (PVL)
A condition characterized by the death of the
white matter near the cerebral ventricles due to
softening of the brain tissue. It can affect fetuses
or newborns; premature babies are at the greatest
risk of the disorder.
Periodontal disease (PD)
= “gum disease”
A chronic bacterial infection that affects the gums
and bone supporting the teeth. It has been found
to be associated with preterm birth.
Phospholipase
An enzyme that catalyzes the hydrolysis of a
phospholipid.
Phosphorylated insulin like growth
factor binding protein-1 (phIGFBP-1)
A carrier protein for insulin-like growth factor 1.
During pregnancy, IGFs and their binding proteins (IGFBPs) are important for the growth of
fetal and maternal tissues. The highly phosphorylated isoform (phIGFBP-1) is produced by the
decidua. It is an indicator of tissue damage at
the choriodecidual interface in pregnant women
and a marker of increased risk of infectious
complications such as bacterial vaginosis.
Placental abruption
Separation of the placenta from the wall of the
uterus.
Pneumonia
Inflammation of the lungs.
Polyhydramnios
The medical condition of too much amniotic
fluid in the amniotic sac.
Too little fluid in the uterine cavity.
Positive predictive value (PPV)
Oxytocin
The probability that a person has the target disorder when a positive test result is observed.
A hormone that also acts as a neurotransmitter
in the brain. In females, it is released in large
amounts after distension of the cervix and vagina
during labor, and after stimulation of the nipples,
facilitating birth and breastfeeding, respectively.
Pre-eclampsia (PE)
A disorder that occurs during pregnancy.
Characterized by increased blood pressure and
protein in urine.
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Preterm premature rupture of
membranes (PPROM)
S
Rupture of fetal membranes prior to 37 weeks
gestation. Very often leads to preterm birth.
Sepsis
Preterm birth (PTB)
Delivery that occurs before 37 completed weeks of
pregnancy.
Preterm labor (PTL)
Labor (regular contractions and cervical ripening)
starting before 37 complete weeks of gestation,
with intact fetal membranes.
Progesterone
A female hormone that is produced in the ovaries
and makes the lining of the uterus grow. When
the level of progesterone decreases, menstruation
occurs.
Progestin
A natural or synthetic substance that mimics
some or all of the actions of progesterone.
Proinflammatory cytokines
Cytokines that are involved in the amplification
of inflammatory reactions. These include IL-1,
IL-6, TNF-a, and TGF-b.
Prostaglandin
One of a number of hormone-like substances that
participate in a wide range of body functions
such as the contraction and relaxation of smooth
muscle, the dilation and constriction of blood
vessels, control of blood pressure, and modulation of inflammation. Prostaglandins are derived
from a chemical called arachidonic acid.
Protease
An enzyme that digests proteins.
Pyelonephritis
An infection of the blood
Single nucleotide polymorphism
(SNP) (pronounced snip)
A DNA sequence variation occurring when a
single nucleotide - A, T, C, or G - in the genome
differs between members of a species or between
paired chromosomes in an individual.
Small for gestational age, SGA
An infant whose weight is lower than the population norms. It is defined as weight below the 10th
percentile for gestational age.
Spiral artery
The corkscrew-like arteries in premenstrual or
progestational endometrium.
Systemic infections
Invasion of the bloodstream by virulent microorganisms (such as bacteria, viruses, or fungi) from
a focus of infection that is accompanied by acute
systemic illness.
T
Thrombin
Is an enzyme that presides over the conversion of
fibrinogen to fibrin. Thrombin is thus a key clot
promoter.
Tocolytic
Medications used to suppress or slow preterm
premature labor.
Transient dystonia
An ascending urinary tract infection that has
reached the pyelum (pelvis) of the kidney.
An abnormality of muscle tone often demonstrated in infants under one year of age who were
born preterm. It may mimic the condition of cerebral palsy.
R
Transvaginal ultrasonography (TVU)
Respiratory distress syndrome (RDS)
Ultrasonography in which a probe is inserted into
the vagina.
A syndrome caused in premature infants by
developmental insufficiency of surfactant pro­
duction and structural immaturity in the lungs.
U
Retinopathy
Urocortin
A general term that refers to some form of noninflammatory damage to the retina of the eye. Pre­
maturity is one of the main causes of retinopathy.
With urocortin II a member of the corticotropinreleasing hormone (CRH) family of neuropeptides
that function to regulate stress responses.
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Uterotonin
Cause uterine contractions (e.g. oxytocin and
prostaglandins).
Ultrasonography= (or sonography)
A test in which sound waves are used to examine
internal structures. During pregnancy, it can be
used to examine the fetus. Transvaginal ultrasonography is used to measure cervical length.
V
Ventouse
A vacuum device used to assist the delivery of a
baby when labor has not progressed adequately.
Very low birth weight (VLBW)
An infant that weighs less than 1500 g at delivery,
regardless of the gestational age at birth.
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References
1. Marlow N, Wolke D, Bracewell M, Samara M. Neurologic and developmental disability at six years of
age after extremely preterm birth. N Engl J Med 2005;352:9-19.
2. Veen S, Ens-Dokkum M, Schreuder A, Verloove-Vanhoric S, Brand R, Ruys J. Impairments, disabilities
and handicaps of very preterm and very low birth weight infants at five years of age: the collaborative
project on preterm and small for gestational age infants (POPS) in the Netherlands Lancet 1991;338:336.
3. Di RenzoG, Roura L and the European association of perinatal medicine study on preterm birth.
Guidelines for the management of spontaneous preterm labor. J. Perinat Med. 2006, 34;359-366.
4. Hollier LM. Preventing preterm birth: what works, what doesn’t. Obstet Gynecol Surv. 2005
Feb;60(2):124-31.
5. Villar J, Ezcurra EJ, Gurtner De La Fuenta V, Campodonica I: Preterm delivery syndrome: the unmet
need. In New perspective for the effective treatment of preterm labour-an international Consensus.
Keirse MJ (Ed.), Research and Clinical forums, Wells Medical Turnbridge Wellsm UK, 1994; 16:9-38
6. Martin JA. United States vital statistics and the measurement of gestational age. Paediatr Perinat
Epidemiol. 2007 Sep;21 Suppl 2:13-21.
7. Joseph K. S., MD, PhD, Ling Huang, MD, MSc, Shiliang Liu, MB, PhD, Cande V. Ananth, PhD, MPH,
Alexander C. Allen, MD, Reg Sauve, MD, MPH, Michael S. Kramer: Reconciling the High Rates of
Preterm and Postterm Birth in the United States. Obstetrics & Gynecology 2007;109:813-822
8. The Information Centre. NHS Maternity Statistics, 2005-06.
9. EURO-PERISTAT 1998-2001
10. Stakes http://www.stakes.fi/tilastot/tilastotiedotteet/2007/ennakkotilastot/taulukko_synnyttajat2006ennakko.pdf
11. Morken, Nils-Halvdan; Källen, Karin; Hagberg, Henrik; Jacobsson, Bo. Preterm birth in Sweden
1973–2001: Rate, subgroups, and effect of changing patterns in multiple births, maternal age, and smoking. Acta Obstetricia et Gynecologica Scandinavica, Volume 84, Number 6, June 2005 , pp. 558-565(8)
12. Medical Birth Registry of Norway. Preterm births: Norway 1995-2002.
13. Osman Nafissa Bique, Kenneth Challis, Manuel Cotiro, Gunnar Nordahl, Staffan Bergstrom:
Maternal and Fetal Characteristics in an Obstetric Cohort in Mozambique. African Journal of
Reproductive Health / La Revue Africaine de la Santé Reproductive, Vol. 4, No. 1 (Apr., 2000), pp.
110-119
14. Anderson RN, Smith BL. Deaths: leading causes for 2001. Natl Vital Stat Rep 2003;52-1-85
15. Tomashek KM, Shapiro-Mendoza CK, Davidoff MJ, Petrini JR.. Differences in mortality between latepreterm and term singleton infants in the United States, 1995-2002. J Pediatr. 2007 Nov;151(5):450-6,
456.e1. Epub 2007 Jul 24
59
1244-9856-02.indd 61
12.1.2009 15:04:53
16. Rich-Edwards JW, Stampfer MJ, Manson JE, Rosner B, Hankinson SE, Colditz GA, Willett WC,
Hennekens CH. Birth weight and risk of cardiovascular disease in a cohort of women followed up since
1976. BMJ. 1997 Aug 16;315(7105):396-400.
17. Spong CY. Prediction and prevention of recurrent spontaneous preterm birth.Obstet Gynecol. 2007
Aug;110(2 Pt 1):405-15. Review.
18. Lindström K, Winbladh B, Haglund B, Hjern A. Preterm infants as young adults: a Swedish national
cohort study. Pediatrics. 2007 Jul;120(1):70-7.
19. Michael G Ross, http://www.emedicine.com/med/topic3245.htm, updated May 31, 2007
20. Mercer BM. Preterm premature rupture of the membranes. Obstet Gynecol 2003;101:178-93
21. Iams JD, Creasy RK. Preterm labor and delivery, Chapter 34. In: Maternal-Fetal Medicine: Principles
and Practice, 5th ed., 2004.
22. Russell RB, et al , March of dimes, Pediatrics. 2007 Jul;120(1):e1-9)
23. Massett HA, Greenup M, Ryan CE, et al. Public perceptions about prematurity: a national survey.
Am J Prev Med 2003;24:120-7
24. Goldenberg RL, Hauth JC, Andrwes WW, Intrauterine infections and preterm delivery. N Engl J Med
2000;342:1500-7.
25. Lang JM, Leiberman E, Cohen A. A comparison of risk factors for preterm labor and small for gestational age birth. Epidemiology 1966;7:569-76.
26. Thomsen AC, Morup L, Hansen KB, Antibiotic elimination of group-B streptococci in urine in prevention of preterm labor. Lancet 1987;1:591-3
27. Romero R, Oyazum E, Mazor M, Sitori M, Hobbins JC, Bracken M. Meta analysis of the relationship
between asymptomatic bacteriuria and preterm delivery/low birth weight. Obstet Gynecol 1989;75:57682
28. Andrews WW, Goldenberg RL, Mercer B, Iams J, Meis P, Moawad A et. Al. The preterm Prediction
Study: Association odf second-trimester genitourinary Chlamydia infection with subsequent spontaneous preterm birth: Am J Obstet Gynecol 2000;183:662-8.
29. Romero R, Mazor M: Infection and preterm labor. Clin Obstet Gynecol. 1988;31:553.
30. Reedy N. Born too soon: The Continuing Challenge of preterm labor and birth in the united states.
J Midwifery & Women´s health. 2007;52:281-290.
31. Andrews WW, Goldenberg RL,Hauth JC. Preterm labor:emerging role of genital trackt infection.
Infect Agents Dis 1995;4:196-211.
32. Gibbs RS, Romero MD, Hillier SL, Eschenbach DA, Sweet RL. A review of premature birth and subclinical infection. Am J Obstet Gynecol 1992:166:1515-28.
33. Keelan JA, Blumenstein M, Helliwell RJ, Sato TA, Marvin KW, Mitchell MD. Cytokines, prostaglandins and parturition – a review. Placenta. 2003 Apr;24 Suppl A:S33-46.
60
1244-9856-02.indd 62
12.1.2009 15:04:54
34. McGregor JA, French JJ, Jones W, et al. Bacterial vaginosis is associated with prematurity and vaginal fluid mucinase and sialidase: results of controlled trial of topical clindamycin cream. Am J Obst
Gynecol 1994;170:1048-1060.
35. Vidaeff A, Ramin S: From Concept to practice: The recent History of Preterm delivery Prevention,
Part II: Subclinical infection and hormonal effects. Am J Perinatology 2006: Vol 23 Number 2.
36. Oliver R, Lamont R: The role of cytokines in spontaneous preterm labour and preterm birth.
Proggress in obstetrics and Gynecology; 2004 16;83-106
37. Genco RJ: Host responses in periodontal diseases: current concepts. J periodontal 63 (1992) 1515.
38. Boggess KA: Patophysiology of preterm birth: emerging concepts of maternal infection: Clin
Perinatol 32 (2005) 561.
39. Moore S, Ide M, Wilson RF. Coward PY, Borkowska E, Baylis R, et al. Periodontal health of London
women during early pregnancy. Br Dent J 191 (2001) 570.
40. Boggess KA, Moss K, Madianos P, Murtha AP, Beck J, Offenbacher S. Fetal immune response to oral
pathogens and risk of preterm birth. Am J Obstet Gynecol. 193 (2005) 1121.
41. Mellor A, Dunn H. Immunology at the maternal-fetal interface:lesson for T cell tolerance and
suppression. Annual Reviews in Immunology, 2000;18: 367-391
42. Baud O, Emilie D, Pelletier E, Lacaze-Masmonteil T, Zupan V, Fernandez H, Dehan M, Frydman R,
Ville Y. 1999. Amniotic fluid concentrations of interleukin-1b, interleukin-6 and TNF-α in chorioamnionitis before 32 weeks of gestation: histological associations and neonatal outcome. British Journal
of Obstetrics and Gynaecology 106:72–77.
43. Wu Y W, Colford J M. 2000. Chorioamnionitis as a risk factor for cerebral palsy: a meta-analysis.
Journal of American Medical Association 284:1417–1424.
44. Toti P, De Felice C. 2001. Chorioamnionitis and fetal/neonatal brain injury. Biology of the Neonate
79:201–204.
45. Gotsch F, Romero R, Kusanovic JP, Mazaki-Tovi S, Pineles BL, Erez O, Espinoza J, Hassan SS.
The fetal inflammatory response syndrome.Clin Obstet Gynecol. 2007 Sep;50(3):652-83.
46. Romero R, Chaiworapongsa T, Espinoza J, Gomez R, Yoon BH, Edwin S, Mazor M, Maymon E, Berry
S.Fetal plasma MMP-9 concentrations are elevated in preterm premature rupture of the membranes.
Am J Obstet Gynecol. 2002 Nov;187(5):1125-30
47. Bakketeig LS, Hoffman HJ, Harley EE. The tendency to repeat gestational age and birth weight in
successive births. Am J Obstet Gynecol 1979: 135;1086-1103
48. Winkvist A, Morgen I, Hogberg U. Familial patterns in birth characteristics: Impact on indicidual
and population risks. Int J Epidemiol 1998;27:248-254.
49. Porter TF, Fraser A, Hunter CY et al. The risk of preterm birth across generations. Obstet Gynecol
1997;90:63-67.
50. Adams KM, Eschenbach DA. The genetic contribution towards preterm delivery. Semin Fetal
Neonatal Med. 2004 Dec;9(6):445-52.
61
1244-9856-02.indd 63
12.1.2009 15:04:54
51. Arntzen KJ, Kjollesdal AM, Halgunset J et al. TNF IL-1, IL-6 and IL-8 and soluble TNF receptors in
relation to chorioamnionitis and premature labour. J. Perinat Med. 1998; 26:17-26
52. Wilson AG, de Vries N, Pociot F et al. An allelic polymorphism within the human tumor gecrosis
factor alpha promoter region is strongly associated with HLA A1, B8 and DR alleles. J Exp Med 1993;
177;557-560
53. Aidoo M, McElroy PD, Kolczak MS et al. Tumor necrosis factor alpha promoter variant 2 (TNF2) is
associated with preterm delivery, infant mortality and malaria morbidity in western Kenya: Asembo bay
cohort project IX. Genet Epidemiol 2001;21:202-211.
54. Kalish R, Vardhana S, Gupta M, Perni S, Chasen S, Witkin S. Polymorphism in the tumor necrosis
factor-alpha gene at position -308 and inducible 70kd heat shock protein gene at position +1267 in
multifetal pregnancies and preterm rupture of membranes. Am J Obstet Gynecol 2004;191:1368-74.
55. Li, D.K., Changing paternity and the risk of preterm delivery in the subsequent pregnancy.
Epidemiology, 1999. 10(2): p. 148-152.
56. Vatten Lars J, Rolv Skjærven: Effects on pregnancy outcome of changing partner between first two
births: prospective population study. BMJ 2003;327:1138 (15 November).
57. Genc M. The role of gene-environmental interaction in predicting adverse pregnancy outcome.
2007;21:491-501.
58. Wang X, Zuckerman B, Kaufman G, Wise P, Hill M, Niu T, Ryan L, Wu D, Xu X. Molecular epidemiology of preterm delivery:methodology and challenges. Peadiatr. Perinat. Epidemiol .2001;15 (2):63-77.
59. Wilson and Jungner 1968 cited in Mak et al 1998:646
60. Creasy RK, Gummer BA, Liggins GC. System for predicting spontaneous preterm birth. Obstet
Gynecol. 1980 Jun;55(6):692-5.
61. Papiernik-Berkhauer E. Coefficient of premature delivery risk (C.P.D.R) Presse Med. 1969 Apr
26;77(21):793-4
62. Davari Tanha F , Sadari F, Eftekhar Z, Kaveh M, Mood N. Predicting the risk of preterm labor by second trimester measurement of maternal alpha-fetoprotein levels and risk factor scoring system. Medical
Journal of the Islamic republic of Iran 2005;Vol 19 No 2, 127-130.
63. Goldenberg RL, Iams JD, Mercer BM, Meis PJ, Moawad AH, Copper RL, Das A, Thom E, Johnson F,
McNellis D, Miodovnik M, Van Dorsten JP, Caritis SN, Thurnau GR, Bottoms SF. Am J Public Health.
1998 Feb;88(2):233-8. The preterm prediction study: the value of new vs standard risk factors in predicting early and all spontaneous preterm births. NICHD MFMU Network Am J Public Health. 1998
Feb;88(2):183-4.
64. Kurtzman JT . Oral presentation at 8th WCPM, Florence Italy 2007.
65. Tekesin I. Evaluation and validation of a new risk score CLEOPATRA score) to predict the propability of premature delivery for patients with threatened preterm labor. Ultrasound Obstet Gynecol
2005;26:699-706.
66. Fonseca Eduardo B., M.D., Ebru Celik, M.D., Mauro Parra, M.D., Mandeep Singh, M.D., Kypros H.
Nicolaides, Progesterone and the risk of preterm birth among women with a short cervix. New England
journal of medicine, Volume 357:462-469 August 2, 2007 Number 5.
62
1244-9856-02.indd 64
12.1.2009 15:04:54
67. Nicolaides K. Comment on Progesterone and Preterm birth. N Engl J Med. 2007;29:2307.
68. Berghella V, Tolosa J, Kuhlman K. Cervical ultrasonography compared to manual examination as a
predictor of preterm delivery. Am J Obstet Gynecol 1997; 177:723-730.
69. To MS, Alfirevic Z, Heath VC, Cicero S, Cacho AM, Williamson PR, Nicolaides KH; Fetal Medicine
Foundation Second Trimester Screening Group. Cervical cerclage for prevention of preterm delivery in
women with short cervix: randomised controlled trial. Lancet. 2004 Jun 5;363(9424):1849-53.
70. American College of Obstetricians and Gynecologists (ACOG). Assessment of risk factors for preterm
birth. Washington (DC): American College of Obstetricians and Gynecologists (ACOG); 2001 Oct. 8 p.
71. American College of Obstetricians and Gynecologists (ACOG) press release. SalEst™ not recommended as a screening tool for predicting premature labor. Washington, D.C.; January 31, 2001
72. Heine RP, McGregor JA, Dullien VK. Accuracy of salivary estriol testing compared to traditional risk
factor assessment in predicting preterm birth. Am J Obstet Gynecol 1999;180(1Pt3):S214-18
73. Vogel I, Thorsen p, Curry A, Sandager P, Uldbjerg N. Biomarkers for the prediction of preterm
delivery, review. Acta Obstet Gynecol Scand 2005;84:516-525.
74. Keelan JA, Marvin K, Sato T,Coleman M, L, McCowan L, Mitchell M: Cytokine abundance in placental tissues:evidence of inflammatory activation in gestational membranes with term and preterm parturition. Am J Obstet Gynecol 1999;181: 1530-1536.
75. Genc MR, Witkin SS, Delaney ML, Paraskevas LR, Tuomala RE, Norwitz ER, Onderdonk AB.A disproportionate increase in IL-1beta over IL-1ra in the cervicovaginal secretions of pregnant women with
altered vaginal microflora correlates with preterm birth.Am J Obstet Gynecol. 2004 May;190(5):1191-7.
76. McLaren J, Taylor DJ, Bell SC. Prostaglandin E(2)-dependent production of latent matrix metalloproteinase-9 in cultures of human fetal membranes. Mol Hum Reprod. 2000 Nov;6(11):1033-40.
77. Tu FF, Goldenberg RL, Tamura T, Drews M, Zucker SJ, Voss HF. Prenatal plasma matrix metalloproteinase-9 levels to predict spontaneous preterm birth.Obstet Gynecol. 1998 Sep;92(3):446-9
78. Florio P, Linton EA, Torricelli M, Faldini E, Reis FM, Imperatore A, Calonaci G, Picciolini E,
Petraglia F. Prediction of preterm delivery based on maternal plasma urocortin.J Clin Endocrinol Metab.
2007 Dec;92(12):4734-7. Epub 2007 Nov 6.
79. Helliwell RJ, Chamley LW, Blake-Palmer K, Mitchell MD, Wu J, Kearn CS, Glass M. Characterization
of the endocannabinoid system in early human pregnancy. J Clin Endocrinol Metab. 2004
Oct;89(10):5168-74.
80. Potdar N, Konje JC. The endocrinological basis of recurrent miscarriages. Curr Opin Obstet Gynecol.
2005 Aug;17(4):424-8.
81. Annells, M. F., Hart, P. H., Mullighan, C. G., Heatley, S. L., Robinson, J. S., Bardy, P., and McDonald,
H. M. Interleukins-1, -4, -6, -10, tumor necrosis factor, transforming growth factor-beta, FAS, and mannose-binding protein C gene polymorphisms in Australian women: Risk of preterm birth.Am.J.Obstet.
Gynecol. 2004;191(6):2056-2067.
82. Goepfert AR, Varner M, Ward K, Macpherson C, Klebanoff M, Goldenberg RL, Mercer B, Meis P,
Iams J, Moawad A, Carey JC, Leveno K, Wapner R, Caritis SN, Miodovnik M, Sorokin Y, O’Sullivan MJ,
Van Dorsten JP, Langer O; NICHD Maternal-Fetal Medicine Units Network. Differences in inflammatory
cytokine and Toll-like receptor genes and bacterial vaginosis in pregnancy. Am J Obstet Gynecol. 2005
Oct;193(4):1478-85.
63
1244-9856-02.indd 65
12.1.2009 15:04:54
83. Moore S, Ide M, Randhawa M, Walker JJ, Reid JG, Simpson NA. An investigation into the association among preterm birth, cytokine gene polymorphisms and periodontal disease. BJOG. 2004
Feb;111(2):125-32.
84. Genç MR, Gerber S, Nesin M, Witkin SS. Polymorphism in the interleukin-1 gene complex and
spontaneous preterm delivery. Am J Obstet Gynecol. 2002 Jul;187(1):157-63.
85. Murtha AP, Nieves A, Hauser ER, Swamy GK, Yonish BA, Sinclair TR, Heine RP. Association of
maternal IL-1 receptor antagonist intron 2 gene polymorphism and preterm birth. Am J Obstet Gynecol.
2006 Nov;195(5):1249-53.
86. Kalish, R. B., Vardhana, S., Normand, N. J., Gupta, M., and Witkin, S. S. Association of a maternal
CD14 -159 gene polymorphism with preterm premature rupture of membranes and spontaneous preterm
birth in multi-fetal pregnancies. J.Reprod.Immunol. 2006;70(1-2):109-117.
87. Genc MR, Onderdonk AB, Vadraha S et al. Polymorphism in the intron 2 of the interleukin-I reseptor antagonist gene, local midtrimester cytokine response to vaginal flora, and subsequent preterm birth.
Am J Obstet Gynecol 2004; 191: 1324-1330.
88. Perni SC, Vardhana S, Tuttle SL, Kalish RB, Chasen ST, Witkin SS. Fetal interleukin-1 receptor antagonist gene polymorphism, intra-amniotic interleukin-1beta levels, and history of spontaneous abortion. Am J Obstet Gynecol. 2004 Oct;191(4):1318-23
89. Hao, K., Wang, X., Niu, T., Xu, X., Li, A., Chang, W., Wang, L., Li, G., Laird, N., and Xu, X. A candidate gene association study on preterm delivery: application of high-throughput genotyping technology
and advanced statistical methods.Hum.Mol.Genet. 1-4-2004;13(7):683-691.
90. Witkin SS, Vardhana S, Yih M, Doh K, Bongiovanni AM, Gerber S. Polymorphism in intron 2 of
the fetal interleukin-1 receptor antagonist genotype influences midtrimester amniotic fluid concentrations of interleukin-1beta and interleukin-1 receptor antagonist and pregnancy outcome. Am J Obstet
Gynecol. 2003 Nov;189(5):1413-7.
91. Kalish RB, Vardhana S, Gupta M, Chasen ST, Perni SC, Witkin SS. Interleukin-1 receptor antagonist
gene polymorphism and multifetal pregnancy outcome. Am J Obstet Gynecol. 2003 Oct;189(4):911-4.
92. Barton PT, Gerber S, Skupski DW, Witkin SS. Interleukin-1 receptor antagonist gene polymorphism,
vaginal interleukin-1 receptor antagonist concentrations, and vaginal ureaplasma urealyticum colonization in pregnant women. Infect Immun. 2003 Jan;71(1):271-4.
93. Kalish RB, Vardhana S, Gupta M, Perni SC, Witkin SS. Interleukin-4 and -10 gene polymorphisms
and spontaneous preterm birth in multifetal gestations. Am J Obstet Gynecol. 2004 Mar;190(3):702-6.
94. Wang H, Parry S, Macones G, Sammel MD, Kuivaniemi H, Tromp G, Argyropoulos G, Halder I,
Shriver MD, Romero R, Strauss JF 3rd. A functional SNP in the promoter of the SERPINH1 gene increases risk of preterm premature rupture of membranes in African Americans. Proc Natl Acad Sci U S
A. 2006 Sep 5;103(36):13463-7.
95. Fujimoto T, Parry S, Urbanek M, Sammel M, Macones G, Kuivaniemi H, Romero R, Strauss JF. A
single nucleotide polymorphism in the matrix metalloproteinase-1 (MMP-1) promoter influences amnion cell MMP-1 expression and risk for preterm premature rupture of the fetal membranes. J Biol Chem.
2002 Feb 22;277(8):6296-302.
64
1244-9856-02.indd 66
12.1.2009 15:04:55
96. Ferrand PE, Fujimoto T, Chennathukuzhi V, Parry S, Macones GA, Sammel M, Kuivaniemi H,
Romero R, Strauss JF. The CARD15 2936insC mutation and TLR4 896 A>G polymorphism in African
Americans and risk of preterm premature rupture of membranes (PPROM). Mol Hum Reprod. 2002
Nov;8(11):1031-4.
97. Sziller, I., Hupuczi, P., Normand, N., Halmos, A., Papp, Z., and Witkin, S. S. Fas (TNFRSF6) Gene
Polymorphism in Pregnant Women With Hemolysis, Elevated Liver Enzymes, and Low Platelets and in
Their Neonates.Obstet.Gynecol. 2006;107(3):582-587.
98. Fuks, A., Parton, L. A., Polavarapu, S., Netta, D., Strassberg, S., Godi, I., and Hsu, C. D.
Polymorphism of Fas and Fas ligand in preterm premature rupture of membranes in singleton pregnancies.Am.J.Obstet.Gynecol. 2005;193(3 Pt 2):1132-1136.
99. Kalish, R. B., Nguyen, D. P., Vardhana, S., Gupta, M., Perni, S. C., and Witkin, S. S. A single nucleotide A>G polymorphism at position -670 in the Fas gene promoter: relationship to preterm premature
rupture of fetal membranes in multifetal pregnancies.Am.J.Obstet.Gynecol. 2005;192(1):208-212.
100. Sziller, I., Nguyen, D., Halmos, A., Hupuczi, P., Papp, Z., and Witkin, S. S. An A > G polymorphism
at position -670 in the Fas (TNFRSF6) gene in pregnant women with pre-eclampsia and intrauterine
growth restriction. Mol.Hum.Reprod. 2005;11(3):207-210.
101. Annells MF, Hart PH, Mullighan CG, Heatley SL, Robinson JS, McDonald HM. Polymorphisms in
immunoregulatory genes and the risk of histologic chorioamnionitis in Caucasoid women: a case
control study. BMC Pregnancy Childbirth. 2005 Feb 21;5(1):4.
102. Landau R, Xie HG, Dishy V, Stein CM, Wood AJ, Emala CW, Smiley RM.Am J Obstet Gynecol. 2002
Nov;187(5):1294-8. beta2-Adrenergic receptor genotype and preterm delivery.
103. Baerwald C, Panayi G, Lanchbury J. A new XmnI polymorphism in the regulatory region of the
corticotrophin releasinh hormone gene. Human Genetics 1996;97:697-698.
104. Engel SM, Olshan AF, Siega-Riz AM, Savitz DA, Chanock SJ. Polymorphisms in folate metabolizing
genes and risk for spontaneous preterm and small-for-gestational age birth. Am J Obstet Gynecol. 2006
Nov;195(5):1231.e1-11.
105. Nurk E, Tell GS, Refsum H, Ueland PM, Vollset SE. Associations between maternal methylenetetrahydrofolate reductase polymorphisms and adverse outcomes of pregnancy: the Hordaland
Homocysteine Study. Am J Med. 2004 Jul 1;117(1):26-31.
106. Valdez LL, Quintero A, Garcia E, Olivares N, Celis A, Rivas F, Rivas F. Thrombophilic polymorphisms in preterm delivery. Blood Cells Mol Dis. 2004 Jul-Aug;33(1):51-6.
107. Lauszus FF, Grøn PL, Klebe JG. Association of polymorphism of methylene-tetrahydro-folate-reductase with urinary albumin excretion rate in type 1 diabetes mellitus but not with pre-eclampsia,
retinopathy, and preterm delivery. Acta Obstet Gynecol Scand. 2001 Sep;80(9):803-6.
108. Papazoglou D, Galazios G, Koukourakis MI, Kontomanolis EN, Maltezos E. Association of -634G/C
and 936C/T polymorphisms of the vascular endothelial growth factor with spontaneous preterm delivery. Acta Obstet Gynecol Scand. 2004 May;83(5):461-5.
109. Wang, X., Zuckerman, B., Kaufman, G., Wise, P., Hill, M., Niu, T., Ryan, L., Wu, D., and Xu, X.
Molecular epidemiology of preterm delivery: methodology and challenges.Paediatr.Perinat.Epidemiol.
2001;15 Suppl 2:63-77.
65
1244-9856-02.indd 67
12.1.2009 15:04:55
110. Menon R, Velez DR, Thorsen P, Vogel I, Jacobsson B, Williams SM, Fortunato SJHum Hered.
2006;62(2):107-18. Epub 2006 Oct 17. Ethnic differences in key candidate genes for spontaneous preterm birth: TNF-alpha and its receptors.
111. Genc MR, Vardhana S, Delaney ML, Witkin SS, Onderdonk AB. TNFA-308G>A polymorphism influences the TNF-alpha response to altered vaginal flora. Eur J Obstet Gynecol Reprod Biol 2006 Nov 21
112. Simhan, H. N., Krohn, M. A., Roberts, J. M., Zeevi, A., and Caritis, S. N. Interleukin-6 promoter
-174 polymorphism and spontaneous preterm birth.Am.J.Obstet.Gynecol. 2003;189(4):915-918.
113. Amory JH, Adams KM, Lin MT, Hansen JA, Eschenbach DA, Hitti J. Adverse outcomes after preterm labor are associated with tumor necrosis factor-alpha polymorphism -863, but not -308, in motherinfant pairs. Am J Obstet Gynecol. 2004 Oct;191(4):1362-7.
114. Chen D, Hu Y, Wu B, Chen L, Fang Z, Yang F, Wang L Tumor necrosis factor-alpha gene G308A
polymorphism is associated with the risk of preterm delivery. Beijing Da Xue Xue Bao. 2003
Aug;35(4):377-81.
115. Aidoo M, McElroy PD, Kolczak MS, Terlouw DJ, ter Kuile FO, Nahlen B, Lal AA, Udhayakumar V.
Tumor necrosis factor-alpha promoter variant 2 (TNF2) is associated with pre-term delivery, infant mortality, and malaria morbidity in western Kenya: Asembo Bay Cohort Project IX. Genet Epidemiol. 2001
Nov;21(3):201-11.
116. Roberts AK, Monzon-Bordonaba F, Van Deerlin PG, Holder J, Macones GA, Morgan MA, Strauss JF,
Parry S. Am J Obstet Gynecol. 1999 May;180(5):1297-302.LinksAssociation of polymorphism within the
promoter of the tumor necrosis factor alpha gene with increased risk of preterm premature rupture of
the fetal membranes.
117. Dizon-Townson DS, Major H, Varner M, Ward K. A promoter mutation that increases transcription
of the tumor necrosis factor-alpha gene is not associated with preterm delivery. Am J Obstet Gynecol.
1997 Oct;177(4):810-3.
118. Wilson AG, de Vries N, Pociot F, di Giovine FS, van der Putte LB, Duff GW.An allelic polymorphism within the human tumor necrosis factor alpha promoter region is strongly associated with HLA
A1, B8, and DR3 alleles.J Exp Med. 1993 Feb 1;177(2):557-60.
119. Härtel Hartel Ch, Finas D, Ahrens P, Kattner E, Schaible T, Muller D, Segerer H, Albrecht K, Moller
J, Diedrich K, Gopel W; Genetic Factors in Neonatology Study Group. Polymorphisms of genes involved
in innate immunity: association with preterm delivery.Mol Hum Reprod. 2004 Dec;10(12):911-5.
120. Nguyen DP, Genc M, Vardhana S, Babula O, Onderdonk A, Witkin SS. Ethnic differences of polymorphisms in cytokine and innate immune system genes in pregnant women. Obstet Gynecol. 2004
Aug;104(2):293-300.
121. Lorenz E, Hallman M, Marttila R, Haataja R, Schwartz DA. Association between the Asp299Gly
polymorphisms in the Toll-like receptor 4 and premature births in the Finnish population. Pediatr Res.
2002 Sep;52(3):373-6.
122. Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, Frees K, Watt JL, Schwartz
DA.TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet. 2000
Jun;25(2):187-91.
123. Crowther C, Moore V. Magnesium maintenance therapy for preventing preterm birth after threatened preterm labour. Cochrane Dataabase Syst Rev. 1998;1:CD000940.
66
1244-9856-02.indd 68
12.1.2009 15:04:55
124. Goldenberg R, Mercer B, Meis P, Das A, McNellis D, Management of preterm labor. Evidence
Report/Technology assessment No 18. AHRQ Publication No.01-E021. Rockville MD Agency for
Healthcare Research and Quality. December 2000.
125. How HY, Zafaranchi L, Stella CL, Recht K, Maxwell RA, Sibai BM, Spinnato JA. Tocolysis in
women with preterm labor between 32 0/7 and 34 6/7 weeks of gestation: a randomized controlled pilot
study. Am J Obstet Gynecol. 2006 Apr;194(4):976-81.
126. Andrews WW, Sibai BM, Thom EA, Dudley D, Ernest JM, McNellis D, Leveno KJ, Wapner R,
Moawad A, O’Sullivan MJ, Caritis SN, Iams JD, Langer O, Miodovnik M, Dombrowski M. Randomized
clinical trial of metronidazole plus erythromycin to prevent spontaneous preterm delivery in fetal fibronectin-positive women.Obstet Gynecol. 2003 May;101(5 Pt 1):847-55.
127. Klebanoff MA, Carey JC, Hauth JC, Hillier SL, Nugent RP, Thom EA, Ernest JM, Heine RP, Wapner
RJ, Trout W, Moawad A, Leveno KJ, Miodovnik M, Sibai BM, Van Dorsten JP, Dombrowski MP,
O’Sullivan MJ, Varner M, Langer O, McNellis D, Roberts JM; Failure of metronidazole to prevent preterm delivery among pregnant women with asymptomatic Trichomonas vaginalis infection. N Engl
J Med. 2001 Aug 16;345(7):487-93.
128. Romero R, Mazor M, Munoz H, Gomez R, Galasso M, Sherer D, The preterm labor syndrome.
Ann NY Acad Sci 1994; 734;414-29.
129. Lamont RF. Can antibiotics prevent preterm birth--the pro and con debate BJOG. 2005 Mar;112
Suppl 1:67-73.
130. Sexton DJ, O’Reilly MW, Friel AM, Morrison JJ. Functional effects of 17alpha-hydroxyprogesterone
caproate (17P) on human myometrial contractility in vitro. Reprod Biol Endocrinol. 2004 Dec 7;2(1):80.
131. Goldstein P, Berrien J, Rosen S. A meta analysis of randomized control trials of progestational
agents in pregnancy. Br J Obstet Gynaecol 1989;96:265-274.
132. Keirse Mj. Progesterone administration in pregnancy may prevent preterm delivery. Br J Obstet
Gynaecol 1990;97:149-154.
133. Meis P, Klebanoff M, Thom E. Prevention of recurrent preterm delivery by 17 alpha-hydroxy progesterone caproate. N Engl J. Med 2003, 348:2379-2385.
134. Da Fonseca EB, Bittar R, Carvalho M, Zugaib M. Prophylactic administration of progesterone by
vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk:
a randomized placebo controlled double blind study. Am J Obstet Gynecol 2003, 188:419-424.
135. Rouse DJ et al. A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins.
N Engl J Med. 2007 Aug 2;357(5):454-61
136. Bailit J, Votruba M. Medical cost savings associated with 17 alpha-hydroxyprogesterone caproate.
Am J Ostet Gynecol 2007: 196;219e1-219e7.
137. Christian MS, Brent RL, Calda P. Embryo-fetal toxicity signals for 17alpha-hydroxyprogesterone
caproate in high-risk pregnancies: a review of the non-clinical literature for embryo-fetal toxicity with
progestins. J Matern Fetal Neonatal Med. 2007 Feb;20(2):89-112.
138. Rebarber A, Ferrara LA, Hanley ML, Istwan NB, Rhea DJ, Stanziano GJ, Saltzman DH. Increased
recurrence of preterm delivery with early cessation of 17-alpha-hydroxyprogesterone caproate. Am J
Obstet Gynecol. 2007 Mar;196(3):224.e1-4.
67
1244-9856-02.indd 69
12.1.2009 15:04:55
139. Rebarber A, Istwan NB, Russo-Stieglitz K, Cleary-Goldman J, Rhea DJ, Stanziano GJ, Saltzman DH.
Increased incidence of gestational diabetes in women receiving prophylactic 17alpha-hydroxyprogesterone caproate for prevention of recurrent preterm delivery. Diabetes Care. 2007 Sep;30(9):2277-80.
140. American College of Obstetricians and Gynecologists. Use of progesterone to reduce preterm birth.
Committee opinion No 291. Washington DC: American College of Obstetrics and Gynecologists 2003.
141. Facchinetti F, Paganelli S, Comitini G, Dante G, Volpe A. Cervical length changes during preterm cervical ripening: effects of 17-alpha-hydroxyprogesterone caproate. Am J Obstet Gynecol. 2007
May;196(5):453.e1-4; discussion 421.
142. Siega-Riz AM, Savitz DA, Zeisel SH, Thorp JM, Herring A. Second trimester folate status and preterm birth. Am J Obstet Gynecol. 2004 Dec;191(6):1851-7. ‘
143. Secher N. Does fish oil prevent preterm birth? J. Perinat Med 2007; S25-S27.
144. Shirodkar JN. A new method for operative treatment of habitual abortions in the seconf trimester
of pregnancy. Anticeptic 1995, 52:299-300.
145. Simcox R, Shennan A. Cervical cerclage: A review. International Journal of Surgery. 2007,
5:205-209.
146. Harger J. Cerclage and cervical insufficiency: An evidence based analysis. Obstetrics and
Gynecology. 2002, Vol 100, No 6 1313-1327.
147. MRC/RCOG Working Party on Cervical Cerclage. Final report of the Medical Research Council/
Royal College Of Obstetricians and Gyneacologists multicenter randomiced trial of cervical cerclage.
BJOG 1993, 100:516-523.
148. Groom K, Shennan A, Bennett P, Ultrasound-indicated cervical cerclage: outcome depends on preoperative cervical length and presence of visible membranes at time of cerclage. Am J Obstet Gynecol
2002, 187:445-449.
149. Sakai M, Shiozaki A, Tabata M, Sasaki Y, Yoneda S, Arai T, et al. Evaluation of effectiveness of prophylactic cerclage of a short cervix according to interleukin-8 in cervical mucus. Am J Obstet Gynecol
2006, 194:14-9.
150. Sakai M, Sasaki Y, Yoneda S, Kasahara T, Arai T, Okada M et al. Elevated interleukin-8 in cervical
mucus as an indicator for treatment to prevent premature birth and preterm, pre-labor rupture of membranes: a prospective study. Am J Reprod Immunol 2004, 51:220-225.
151. Romero R, Espinoza J, Erez O, Hassan S. The role of cervical cerclage in obstetric practice: Can the
patient who could benefit from this procedure be identified? Am J Obstet Gynecol 2006, 194:1-19.
152. Hein M, Petersen A, Helming R, Uldbejrg N, Reinholt J. Immunoglobulin levels and phagocytes in
the cervical mucus plug at term of pregnancy. Acta Obstet Gynecol Scand. 2005, 84:734-42.
153. Northern A. www.obgyn.net (Recorded Feb 8, 2007 at the Society for Maternal Fetal Medicine
Annual Meeting by OBGYN.net).
154. Yemini M, Borenstein E, Dreazen S, Apelman Z, Mogliner B, Kessler I, Lancet M. Prevention of
premature labor by 17α-hydroxyprogesterone caproate. Am J Obstet Gynecol.
155. Schardein J. Congenital abnormalities and hormones during pregnancy: A clinical review.
Teratology 1980, 22:251-270.
68
1244-9856-02.indd 70
12.1.2009 15:04:56
156. Wilkins L. Masculinization of female fetus due to use of orally given progestins. JAMA 1960,
172:1028-1032.
157. O´Brien J, Defranco E, Adair D, Lewis F, Bsharat M, How H, Creasy G, the Provaggel study group.
Progesterone reduces the rate of cervical shortening in women at risk for preterm birth: a secondary analysis from randomized double blind, placebo control trial. Am J Obstet Gynecol 2007, Dec,
Supplement.
158. Malone F, Porter F, Nyberg D, Comstock c, Hankins G, Eddleman K, Gross S, Dugoff L, Craigo S,
Timor-Tritsch I, Carr S, Wolfe H, D´Alton M.Preconceptional folate prevents preterm delivery.
Am J Obstet Gynecol 2007, Dec, Supplement.
159. Guldner L, Monfort C, Rouget F, Garlantezec R, Cordier S. Maternal fish and shellfish intake and
pregnancy outcomes: a prospective cohort study in Brittany, France. Environ Health. 2007 Oct 24;6:33
160. Crowther CA, Harding JE. Repeat doses of prenatal corticosteroids for women at risk of preterm birth for preventing neonatal respiratory disease. Cochrane Database Syst Rev. 2007 Jul 18;(3):
CD003935.
161. Murphy K, for the MACS Collaborative Group. Multiple courses of antenatal corticosteroids for
preterm birth study. Am J Obstet Gynecol 2007, Dec, Supplement.
162. Iams J, Romero R, Culhane J, Goldenberg R. Primary, secondary and tertiary interventions to reduce
the morbidity and mortality of preterm birth. Lancet 2008, 371:164-75.
163. Goldenberg R, Iams J, Mercer B, Meis P, Moawad A, Das A, et al. What have we learned about the
predictors of preterm birth. Semin Perinatol 2003, 27:185-93.
164. Goldenberg R, Iams J, Mercer B, Meis P, Moawad A, Das A, et al. The preterm prediction study:
toward a multiple marker test for spontaneous preterm birth. Am J Obstet Gynecol 2001:185:643-51.
165. Danti L, Gabanelli S, Barbeiri C, Testori A, Corini S, Perfumo F, Lojacono A. The combination of
short cervical length and phIGFBP-1 in the prediction of preterm delivery. Ultrasound in Obstetrics and
Gynecology 2007, 30:367-455.
166. Eroglu D, Yanik F, Otem M, Zeyneloglu H, Kuscu E. Prediction of Preterm delivery among women
with threatened preterm labor. Gynecol Obstet Invest 2007, 64:109-116.
167. Shim SS, Romero R, Hong JS, Park CW, Jun JK, Kim BI, Yoon BH. Clinical significance of intraamniotic inflammation in patients with preterm premature rupture of membranes. Am J Obstet Gynecol.
2004 Oct;191(4):1339-45.
168. Bryant-Greenwood G, Kern A, Yamamoto S, Sadowsky D, Novy M. Relaxin and the human fetal
membranes. Reproductive sciences 2007 Dec, Vol 14, No 8S 42-45.
169. McLean M, Bisits A, Davies J, Walters W, Hackshaw A, De Voss K, Smith R, Predicting preterm
delivery by second trimester measurement of maternal plasma corticotrophin-releasing hormone and
α-fetoprotein concentrations. Am J Obstet Gynecol 1999, 1881: 207-215.
170. Kurkinen-Räty M, Ruokonen A, Vuopala S, Koskela M, Rutanen E, Karkkainen T et al. Combination
of cervical interleikin-6 and -8, phosphorylated insulin-like growth factor binding protein-1 and transvaginal cervical ultrasonography in assessment of the risk of preterm birth. BJOG 2001, 108:975-81.
69
1244-9856-02.indd 71
12.1.2009 15:04:56
171. Foulon W, Van Liedekerke D, Demanet C, Decatte L, Dewaele M, Naessens A. Markers of infection
and their relationship to preterm delivery. Am J Perinatol. 1995, 12:208-211.
172. Coleman M, France J, Schellenberg J, Ananiev V, Townend K, Keelan J, et al. Corticotropin releasing hormone, corticotrophin releasing hormone-binding protein, and activin A in maternal serum:prediction of preterm delivery and response to glucocorticoids in women with symptoms of preterm labor.
Am J Obstet Gynecol 2000, 183:643-8.
173. Danti C, Barbieri A, Testori S, Corini S, Perfumo F, Lojacono A. A comparison of cervical length
measurement and phIGFBP-1 in the prediction of preterm delivery. ISUOG 2007, Florence, Italy
OP19.05.
174. Tanir HM, Sener T, Yildiz Z. Cervicovaginal fetal fibronectin (FFN) for prediction of preterm delivery in symptomatic cases: a prospective study. Clin Exp Obstet Gynecol. 2008, 35(1):61-4.
175. Lange M, Chen F, Wessel J, Burscher U, Dudenhausen J, Elevation of interleukin-6 levels in cervical
secretions as a predictor of preterm delivery. Acta Obstet Gynecol Scand 2003, 82:326-9.
176. Rozenberg P, Goffinet F, Malagrida L, Giudicelli Y, Perdu M, Houssin I, Sage-Femme, Nisand I.
Evaluating the risk of preterm delivery: a comparison of fetal fibronectin and transvaginal ultrasonographic measurement of cervical length. Am J Obstet Gynecol 1997, 176.
177. Vogel I, Glavind-Kristensen M, Thorsen P, Armbuster F, Uldbjerg N. S-relaxin as a predictor of preterm delivery in women with symptoms of preterm labour. Br J Obstet Gynaecol 2002, 109:977-82.
178. Goffinet F, Rozenberg P, Kauyem G, Perdu M, Philippe H, Nisand I. The value of intravaginal ultrasonography in the cervix uteri for evaluation of the risk of premature labor. J Gynecol Obstet Biol
Reprod. 1997, 26:623-9.
179. Honest H, Bachmann L, Knox E, Gupta J, Kleijnen J, Khan K. The accuracy of various tests for bacterial vaginosis in predicting preterm birth: a systemic review. BJOG 2004, 111:409-22.
180. Vogel I, Salvig J, Uldbjerg N, Association between raised S-relaxin dusing the eighteenth gestational week and very preterm delivery. Am J Obstet Gynecol 2001, 184:390-3.
181. Iams J, Goldenberg M, Mercer B, Moawad A, Meis P, Das A, Caritis S, Miodovnik M, Menard M,
Thurnau G, Dombrowski M, Roberts J, The preterm prediction study: can low-risk women destined for
spontaneous preterm birth be identified? Am J Obstet Gynecol 2001, 184:652-5.
182. McGregor JA, Jackson GM, Lachelin GC, Goodwin TM, Artal R, Hastings C, Dullien V.
Salivary estriol as risk assessment for preterm labor: a prospective trial. Am J Obstet Gynecol. 1995
Oct;173(4):1337-42.
183. McLean M, Bisits A, Davies J, Walters W, Hackshaw A, De Voss K, et al. Predicting risk of preterm
delivery by second trimester measurement of maternal plasma corticotrophin releasing hormone and
alpha-fetoprotein concentrations. Am J Obstet Gynecol. 1999, 181:207-15.
184. Goldenberg R, Andrews W, Mercer B, Moawad A, Meis P, Iams J, et al. The preterm prediction
study: granulocyte colony-stimulating factor and spontaneous preterm birth. A, J Obstet Gynecol 2000,
182:625-30.
70
1244-9856-02.indd 72
12.1.2009 15:04:56
185. Goepfert A, Goldenberg R, Andrews W, Hauth J, Mercer B, Iams J et al. The preterm prediction
study: association between cervical interleukin 6 concentration and spontaneous preterm birth. Am J
Obstet Gynecol 2001, 184:483-8.
186. Hvilsom G, Thorsen P, Jeune B, Bakketeig L, C-reactive protein: A serological marker for preterm
delivery? Acta Obstet Gynecol Scand 2002, 81:424-9.
187. Johanzon M, Ödesjö H, Jacobsson B, Sandberg K, Wennerholm U. Extreme preterm birth. Obstetrics
& Gynecology, 2008, 111:42-50.
188. Cockle, Gopichandran N, Walker J, Levene M, Orsi N. Matrix metalloproteinases and their inhibitors in preterm perinatal complications. Reproductive sciences 2007, 14: 629-645.
189. Ananth C, Vintzileos A. Epidemiology of preterm birth and its clinical subtypes. J Matern Fetal
Neonatal Med 2006, 19:773-82.
190. Jacson R, Gibson K, Wu Y, Croughan M. Perinatal outcomes in singeltons following in vitro fertilization: a meta analysis. Obstet Gynecol 2004, 103:551-63.
191. Mercer B, Goldenberg R, Meis P, et al. The preterm prediction study: prediction of preterm premature rupture of membranes through clinical findings and ancillary testing. Am J Obstet Gynecol 2000,
183:738-45.
192. Romero R, Quintero R, Oyarzun E et al. Intraamniotic infection and the onset of labor in preterm
premature rupture of membranes. Am J Obstet Gynecol 1988, 159:661-66.
193. Goldenberg R, Cliver S, Mulvihill F et al. Medical, psychosocial and behavioral risk factors do
not explain the increased risk for low birth weight among black women. Am J Obstet Gynecol 1996,
175:1317-24.
194. Tamura T, Goldenberg R, Freeberg L, Cliver S, Cutter G, Hoffman H. Maternal serum folate and zinc
concentrations and their relationship to pregnancy outcome. Am J Clin Nutr 1992, 56:365-70.
195. Scholl T. Iron status during pregnancy: setting the stage for mother and infant. Am J Clinic Nutr
2005, 81:1218S-22S.
196. Goldenberg R, Tamura T. Prepregnancy weight and pregnancy outcome. JAMA 1996, 257:1227-28.
197. Ramsey P, Andrews W. Biochemical predictors of preterm labor: fetal fibronectin and salivary estriol. Clin Perinatol 2003, 30:701-33.
198. Engel S, Erichsen H, Savitz D, Throp J, Chanock S, Olshan A. Risk of spontaneous preterm birth is
associated with common proinflammatory cytokine polymorphism. Epidemiology 2005, 16:469-77.
199. Wang X, Zuckerman B, Pearson C et al. Maternal cigarette smoking, metabolic gene polymorphism
and infant birth weight. JAMA 2002, 287:195-202.
200. Spencer K, Cowans NJ, Molina F, Kagan KO, Nicolaides KH. First-trimester ultrasound and biochemical markers of aneuploidy and the prediction of preterm or early preterm delivery. Ultrasound
Obstet Gynecol. 2008 Feb;31(2):147-52.
201. She BQ, Chen SC, Lee FK, Cheong ML, Tsai MS. Low maternal serum levels of pregnancy-associated plasma protein-A during the first trimester are associated with subsequent preterm delivery with
preterm premature rupture of membranes. Taiwan J Obstet Gynecol. 2007 Sep;46(3):242-7.
71
1244-9856-02.indd 73
12.1.2009 15:04:57
202. Rijnders RJ, Christiaens GC, de Haas M, van der Schoot CE. Ned Tijdschr Geneeskd. Fetal DNA in
maternal blood. 2004 Jan 24;148(4):170-4.
203. Hahn S, Huppertz B, Holzgreve W. Fetal cells and cell free fetal nucleic acids in maternal blood:
new tools to study abnormal placentation? Placenta. 2005 Aug;26(7):515-26. Epub 2004 Dec 23.
204. Tsai J, Klebanoff M, Qian C, Yu K, Levine R. Circulating angiogenetic factors in spontaneous preterm labor and delivery.Am J Obstet Gynecol. 2008 SMFM Feb 2 Dallas, TX.
205. Pereira L, Reddy A, Jacob T, Thomas A, Schneider K, Dasari S, Lapidus J, Roland M, Roberts C,
Gravett M, Nagalla S. Identification of novel protein-biomarkers of preterm birth in human cervicalvaginal fluid. Journal of Proteome Research 2007, 6:1269-1276.
206. Australian Government, Australian Institute of Health and Welfare. Australia´s babies: their health
and wellbeing. Bulletin, Issue 21, December 2004.
207. Sundhedsstyrelse, Fødsler og fødselskomplikationer, http://sbank.sst.dk
208. Petrou S. The economic consequences of preterm birth during the first 10 years of life. BJOG,
112 Suppl 1:10-5.
209. Petrou S. Preterm birth--what are the relevant economic issues? Early Hum Dev. 2006 Feb;
82(2):75-6.
210. Swamy GK, Ostbye T, Skjaerven R. Association of preterm birth with long-term survival, repro­
duction, and next-generation preterm birth. JAMA 2008 Mar 26;299(12):1429-36.
211. Consensus views 46th Study Group: Preterm Birth. http://www.rcog.org.uk/index.asp?PageID=2203
212. Haas DM. Preterm birth Clin Evid. 2006 Jun;(15):1966-85.
213. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth Lancet.
2008 Jan 5;371(9606):75-84.
214. López Bernal A, Hansell DJ, Cañete Soler R, Keeling JW, Turnbull AC. Prostaglandins, chorioamnionitis and preterm labour. Br J Obstet Gynaecol. 1987 Dec;94(12):1156-8.
215. Berghella V, Owen J, MacPherson C, Yost N, Swain M, Dildy GA 3rd, Miodovnik M,Langer O,
Sibai B. Natural history of cervical funneling in women at high risk for spontaneouspreterm birth.
Obstet Gynecol. 2007 Apr;109(4):863-9. National Institute of Child Health and Human Development
(NICHD) Maternal-Fetal Medicine Units Network (MFMU).
216. Grimes-Dennis J, Berghella V. Cervical length and prediction of preterm delivery. Curr Opin Obstet
Gynecol. 2007 Apr;19(2):191-5.
217. Mercer BM. Management of preterm premature rupture of the membranes. Clin Obstet Gynecol.
1998 Dec;41(4):870-82.
218. King J, Flenady V. Prophylactic antibiotics for inhibiting preterm labour with intact membranes.
Cochrane Database Syst Rev. 2002;(4):CD000246.
219. Kenyon S, Boulvain M, Neilson J.Antibiotics for preterm rupture of membranes. Cochrane Database
Syst Rev. 2003;(2):CD001058.
72
1244-9856-02.indd 74
12.1.2009 15:04:57
220. Zeitlin J, Gwanfogbe CD, Delmas D, Pilkington H, Jarreau PH, Chabernaud JL, Bréart G, Papiernik
E. Risk factors for not delivering in a level III unit before 32 weeks of gestation: results from a population-based study in Paris and surrounding districts in 2003. Paediatr Perinat Epidemiol. 2008 Mar;22(2):
126-35.
221. Kayem G, Baumann R, Goffinet F, El Abiad S, Ville Y, Cabrol D, Haddad B. Early preterm breech
delivery: is a policy of planned vaginal delivery associated with increased risk of neonatal death?
Am J Obstet Gynecol. 2008 Mar;198(3):289.e1-6. Epub 2008 Feb 1.
222. Allen MC. Neurodevelopmental outcomes of preterm infants. Curr Opin Neurol. 2008
Apr;21(2):123-8.
223. Kurup M, Goldkrand JW. Cervical incompetence: elective, emergent, or urgent cerclage. Am J
Obstet Gynecol. 1999 Aug;181(2):240-6.
224. Simcox R, Shennan A.Cervical cerclage: a review. Int J Surg. 2007 Jun;5(3):205-9. Epub 2006
Jun 16.
225.Consensus views 46th Study Group: Preterm Birth. http://www.rcog.org.uk/index.asp?PageID=2203
226. Morrison JJ, Rennie JM. Clinical, scientific and ethical aspects of fetal and neonatal care at extremely preterm periods of gestation. Br J Obstet Gynaecol 1997;104:1341.
227. Msall ME, Park JJ. The spectrum of behavioral outcomes after extreme prematurity: regulatory,
attention, social, and adaptive dimensions. Semin Perinatol 2008;32:42.
228. Keirse MJ. New perspectives for the effective treatment of preterm labor. Am J Obstet Gynecol
1995;173:618.
229. López Bernal A, TambyRaja RL. Preterm labour. Baillieres Best Pract Res Clin Obstet Gynaecol
2000;14:133.
230. Msall ME. The limits of viability and the uncertainty of neuroprotection: challenges in optimizing
outcomes in extreme prematurity. Pediatrics 2007;119:158.
231. Srinivas SK, Ma Y, Sammel MD, Chou D, McGrath C, Parry S, Elovitz MA. Placental inflammation and viral infection are implicated in second trimester pregnancy loss. Am J Obstet Gynecol. 2006
Sep;195(3):797-802.
232. Gibson CS, Goldwater PN, MacLennan AH, Haan EA, Priest K, Dekker GA. Fetal exposure to herpesviruses may be associated with pregnancy-induced hypertensive disorders and preterm birth in a
Caucasian population. BJOG. 2008 Mar;115(4):492-500.
233. Gomez LM, Ma Y, Ho C, McGrath CM, Nelson DB, Parry S. Placental infection with human papillomavirus is associated with spontaneous preterm delivery. Hum Reprod. 2008 Mar;23(3):709-15. Epub
2008 Jan 8.
234. Hayes Medical Technology Directory™. Home Uterine Activity Monitoring Systems. Lansdale, PA:
2002 Winifred S. Hayes, Inc. 2002 Jun. Update search, 2007 Jun 18.
235. Changing Paternity and the Risk of Preeclampsia/Eclampsia in the Subsequent Pregnancy. DeKun Li and Soora Wi. .American Journal of Epidemiology. Copyright © 2000 by The Johns Hopkins
University School of Hygiene and Public Health.
1244-9856-02.indd 75
12.1.2009 15:04:57
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