Key Abbreviations

Adrenocorticotropic hormone ACTH
Assisted reproductive technology ART
Bacterial vaginosis BV
Biophysical profile BPP
Bronchopulmonary dysplasia BPD
Confidence interval CI
Corticotropin-releasing hormone CRH
Cyclic adenosine monophosphate cAMP
Cyclooxygenase COX
Estrogen receptor ER
Extremely low birthweight ELBW
Ex utero intrapartum treatment EXIT
Fetal inflammatory response syndrome FIRS
Glycosaminoglycan GAG
Granulocyte-colony stimulating factor G-CSF
Group B Streptococcus GBS
Interleukin-6 IL-6
Intravenous IV
Intraventricular hemorrhage IVH
In vitro fertilization IVF
Low birthweight LBW
Matrix metalloproteinase MMP
Messenger RNA mRNA
Myosin light-chain kinase MLCK
National Institute of Child Health and Human Development NICHD
Necrotizing enterocolitis NEC
Nitric oxide NO
Nonsteroidal antiinflammatory drugs NSAIDs
Odds ratio OR
Omega-3 polyunsaturated fatty acid PUFA
Patent ductus arteriosus PDA
Pathogen-associated molecular pattern PAMP
Polymerase chain reaction PCR
Preterm premature rupture of membranes PPROM
Progesterone receptor PR
Relative risk RR
Respiratory distress syndrome RDS
Retinopathy of prematurity ROP
Thyrotropin-releasing hormone TRH
Tissue inhibitor of metalloproteinases TIMP
Tissue-type plasminogen activator tPA
Tumor necrosis factor α TNF-α
Urokinase-type plasminogen activator uPA
US Food and Drug Administration FDA
Very low birthweight VLBW
White blood cell WBC

The average duration of a normal human pregnancy is 267 days, counted after conception, or 280 days (40 weeks) from the first day of the last normal menstrual period. Infants born at 39 and 40 weeks of gestation have the lowest rates of adverse outcomes. Complications related to preterm birth (PTB) account for more newborn and infant deaths than any other cause. Although advances in neonatal care have led to increased survival and reduced short- and long-term morbidity for infants born preterm, surviving infants have increased risks of visual and hearing impairment, chronic lung disease, cerebral palsy, and delayed development in childhood. The causes of PTB are diverse but can be usefully considered according to whether the parturitional process—which includes cervical remodeling, decidual membrane activation, and myometrial contractions—had begun before birth occurred. PTBs that do not follow spontaneous initiation of parturition most often are iatrogenic, when the health of the mother or fetus is at risk (e.g., with major hemorrhage, hypertension, or poor fetal growth).

Definitions

A preterm birth is commonly defined as one that occurs after 20 weeks’ gestation and before the completion of 37 menstrual weeks of gestation regardless of birthweight. Low birthweight (LBW) is defined as birthweight below 2500 g regardless of gestational age; very low birthweight (VLBW) is birthweight below 1500 g, and extremely low birthweight (ELBW) is birthweight below 1000 g. Gestational age and birthweight (BW) are related by the terms small for gestational age (SGA; a BW less than the 10th percentile for gestational age) , average for gestational age (BW between the 10th and 90th percentiles) , and large for gestational age (BW above the 90th percentile). A preterm or premature infant is one born before 37 weeks of gestation—that is, 259 days from the first day of the mother's last normal menstrual period or 245 days after conception. The gestational boundaries of 20 and 37 weeks are historic, not scientific. Infants born at 36, 37, and even 38 weeks of gestation may experience neonatal and even lifetime morbidity related to immaturity of one or more organs. The risk factors, etiologies, and recurrence risk for spontaneous births at 16 to 19 weeks do not differ from those of births at 20 to 25 weeks. The American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) have adopted the nomenclature later preterm (34 0/7 to 36 6/7 weeks of gestation) and early term (37 0/7 to 38 6/7 weeks of gestation) to acknowledge the contribution of gestational age in these ranges to neonatal risks. Recognition that some infants born after 37 weeks are not fully mature and that many births before 20 weeks arise from the same causes that lead to PTBs has led to reevaluation of these definitions and boundaries.

Frequency of Preterm and Low-Birthweight Delivery

The World Health Organization has estimated nearly 1 in 10 of all births in 2010 were preterm—almost 15 million worldwide. Africa and Asia accounted for almost 11 million.

Births before 37 weeks in the United States increased annually from 9.4% in 1980 to a peak of 12.8% in 2006 ( Fig. 36.1 ). The rate has since fallen each year to just under 11.99% in 2015. The rise resulted from improved pregnancy dating by ultrasound, which shifted the gestational age distribution to the left; increased use of assisted reproduction technology (ART); and, most importantly, from increased willingness to choose delivery when medical or obstetric complications occur after 34 weeks’ gestation. The decline has been attributed to improved fertility practices that reduce the risk of higher-order multiple gestation; quality improvement programs that limit scheduled late-preterm and near-term births to only those with valid indications; and increased use of strategies to prevent recurrent PTB.

Fig. 36.1, Preterm and Low-Birthweight Rates: United States, Final 1981 Through 2009, Preliminary 2009.

The rates of PTB vary substantially across the United States ( Fig. 36.2 ). Reasons for the geographic variation are complex but are heavily influenced by the percentage of the population that is black. Black women have rates of PTB that are almost twofold higher than those of other racial/ethnic groups ( Fig. 36.3 ).

Fig. 36.2, Percentage of Live Preterm Births in the United States by State, 2013.

Fig. 36.3, Percentage of Live Preterm Births by Racial Group.

Outcomes for Infants Born Preterm

Gestational age at birth is strongly correlated with adverse pregnancy outcomes that include stillbirth (fetal death after 20 weeks’ gestation), deaths of neonates (<28 days) and infants (<12 months), and long-term physical and intellectual morbidities.

Perinatal Mortality

Perinatal mortality is defined as the sum of stillbirths after 20 weeks’ gestation plus neonatal deaths through 28 days of life per 1000 total births (liveborn plus stillborn). Perinatal mortality increases markedly as gestational age and birthweight decline. Because this measure encompasses prenatal, intrapartum, and neonatal events, it reflects obstetric and neonatal care. Stillbirth and PTB have a similar epidemiologic profile, especially before 32 weeks. Fetal deaths account for more than half of perinatal deaths and are almost as frequent as infant deaths. In 2013, there were 23,595 fetal deaths (50.3% between 20 and 27 weeks, and 49.7% after 28 weeks), and 15,983 neonatal deaths (80.7% before 7 days, and 19.3% between 7 and 28 days after birth).

Infant Mortality

The infant mortality rate is the number of deaths among liveborn infants before 1 year of age per 1000 live births. Although congenital malformations are often listed as the leading cause of infant mortality, this ranking is achieved by separating conditions related to PTB into several categories. The proportion of all infant deaths in the United States in 2008 by gestational age at birth is shown in Fig. 36.4 .

Fig. 36.4, Proportion of All Infant Deaths in the United States in 2008 by Gestational Age at Birth.

Infant and childhood mortality and morbidity in surviving preterm infants rise as gestational age at birth declines, and they vary with the level of neonatal care received. In 2008, the overall infant mortality rate was 6.6 infant deaths per 1000 live births; however, infant mortality rates varied widely by gestational age. For infants born at less than 32 weeks’ gestation, the infant mortality rate was 175.5 infant deaths per 1000 live births, compared with a rate of 2.1 for infants born at 39 to 41 weeks’ gestation, the age group with the lowest risk. Infant mortality rates generally decreased with increasing gestational age, and even infants born at 37 to 38 weeks had a mortality rate that was 50% higher than that for infants born at 39 to 41 weeks.

Regionalized care for high-risk mothers and preterm LBW infants, antenatal administration of corticosteroids, neonatal administration of exogenous pulmonary surfactant, and improved ventilator technology have improved outcomes for very preterm infants. Survival rates rise with gestational age at birth, from 6% for infants born at 22 weeks’ gestation to more than 90% at 28 weeks’ gestation for infants cared for in tertiary intensive care units. Outcomes can be more accurately predicted by considering fetal number (singleton or multiple), gender, exposure or nonexposure to antenatal corticosteroids, and birthweight in addition to gestational age. Probabilities of infant outcomes based upon antenatal factors can be estimated utilizing an online calculator available from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network. Long-term survival rates by gestational age at birth in 903,402 infants born in Norway are shown in Fig. 36.5 .

Fig. 36.5, Cumulative Long-Term Survival by Gestational Age at Birth in 903,402 Infants Born in Norway.

Perinatal Morbidity

Preterm infants are at risk for specific diseases related to immaturity of various organ systems as well as to the causes and circumstances of PTB. Common complications in premature infants include respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), sepsis, apnea, and retinopathy of prematurity (ROP). Rates of morbidity vary primarily by gestational age but are also affected by birthweight, fetal number (singleton vs. multiple gestations), geographic location, proximity to a neonatal intensive care unit (NICU), and any maternal or fetal conditions that may have led to PTB. The frequency of major morbidity rises as gestational age decreases, especially before 30 weeks’ gestation. Wide geographic variation is apparent in the frequency of neonatal morbidities, especially for VLBW infants. Reports of survival and morbidity also vary according to the denominator used. Obstetric datasets include all living fetuses at entry to the obstetric suite, whereas neonatal datasets exclude intrapartum and delivery room deaths and thus report rates based on newborns admitted to the nursery. Rates of survival and morbidity at the same gestational age and birthweight are thus somewhat higher in neonatal datasets.

Long-Term Outcomes

Major neonatal morbidities related to PTB that carry lifetime consequences include chronic lung disease, grades 3 and 4 IVH (associated with cerebral palsy), NEC, and vision and hearing impairment. Follow-up studies of infants born preterm and of LBW infants reveal increased rates of cerebral palsy, neurosensory impairment, reduced cognition and motor performance, academic difficulties, and attention-deficit disorders.

The incidence of long-term morbidity in survivors is especially increased for those born before 26 weeks’ gestation. In a study from the United Kingdom, 78% of 308 survivors born before 25 weeks’ gestation were followed and compared with classmates of normal birthweight. Almost all had some disability at age 6 years: 22% had severe neurocognitive disabilities (cerebral palsy, IQ more than 3 standard deviations below the mean, blindness, or deafness), 24% had moderate disability, 34% had mild disability, and 20% had no neurocognitive disability.

Epidemiology of Preterm Birth

The numerous maternal and fetal diagnoses that precede PTB may be considered according to whether parturition began spontaneously or not. Spontaneous preterm parturition may first manifest as cervical softening and ripening, decidual activation, and/or uterine contractions. Cervical softening is the most common initial evidence that parturition has begun. In women who later delivered spontaneously between 28 and 36 weeks’ gestation, cervical length (CL) measurements at 22 to 24 weeks’ gestation were significantly shorter than in women who delivered at term, indicating that cervical softening had begun before 24 weeks. This same study found that more than half of women with evidence of very preterm cervical effacement delivered after 35 weeks’ gestation, indicating that spontaneous preterm parturition does not always progress to PTB. Women with signs and symptoms of spontaneous preterm parturition often have one or more of the demographic characteristics shown in Box 36.1 , but it is important to note that approximately half of women who deliver preterm have no obvious risk factors. Among 2521 women who received prenatal care at 10 collaborating university clinics, 323 (12.8%) delivered before 37 weeks’ gestation. Of these, 234 (9.3% of the total and 72% of those delivered preterm) were born after spontaneous initiation of parturition, and 89 (3.5% of the total and 27% of those delivered preterm) were born preterm because of medical or obstetric indications.

Box 36.1
Demographic Profile of Women With Spontaneous Preterm Birth

  • History of genital tract colonization, infection, or instrumentation

    • Urinary tract infection and bacteriuria

    • Sexually transmitted infections such as Chlamydia, gonorrhea, human papillomavirus, or Trichomonas

    • Bacterial vaginosis

    • Cervical dysplasia and treatment for this diagnosis

    • Spontaneous or induced abortion

  • Black race

  • Bleeding of uncertain origin in pregnancy

  • History of a previous spontaneous preterm birth

  • Uterine anomaly

  • Use of assisted reproductive technology

  • Multifetal gestation

  • Cigarette smoking, substance abuse

  • Prepregnancy underweight (body mass index <19.6) and prepregnancy obesity (body mass index >30)

  • Periodontal disease

  • Limited education, low income, and low social status

  • Late registration for prenatal care

  • High levels of personal stress in one or more domains of life

As noted previously, women whose PTB is not preceded by spontaneous parturition have medical and/or obstetric conditions that lead to the onset of parturition or to iatrogenic intervention to benefit the mother or fetus. Their demography reflects this ( Box 36.2 ), and efforts to prolong pregnancy are primarily aimed at optimal management of their medical condition. This strategy is more successful in some—for example, those with diabetes mellitus, in whom maintenance of eugly­cemia often leads to birth at term—than in others, such as those with chronic hypertension, in whom effective blood pressure control does not prevent preeclampsia.

Box 36.2
Demographic and Medical Profile of Women With Indicated Preterm Birth

  • Diabetes mellitus diagnosed before or during pregnancy

  • Chronic or acute (preeclamptic) hypertension

  • Obstetric disorders or risk conditions in the current or previous pregnancy

    • Preeclampsia

    • Previous uterine surgery (e.g., prior cesarean delivery via a vertical or T -shaped uterine incision)

    • Cholestasis

    • Placental disorders

      • Placenta previa

      • Premature separation (abruption) of the placenta

  • Medical disorders

    • Seizures

    • Thromboembolism

    • Connective tissue disorders

    • Asthma and chronic bronchitis

    • Maternal human immunodeficiency virus or herpes simplex virus

    • Obesity

    • Smoking

  • Advanced maternal age

  • Fetal disorders

    • Fetal compromise

      • Chronic (poor fetal growth)

      • Acute (fetal distress; for example, abnormal fetal testing on a nonstress test or biophysical profile)

      • Excessive (polyhydramnios) or inadequate (oligohydramnios) amniotic fluid

      • Fetal hydrops, ascites, blood group alloimmunization

      • Birth defects

      • Fetal complications of multifetal gestation (e.g., growth deficiency, twin-to-twin transfusion syndrome)

Clinical Risk Factors for Spontaneous Preterm Birth

Risk factors for spontaneous preterm birth (sPTB) arise from maternal factors, prior pregnancy history, and current pregnancy risks.

Maternal Factors

Many maternal factors impact PTB. These may be medical or dental, such as infection or disease; behavioral, related to maternal demographics or stress; or related to genetics and anatomy, including abnormalities of the genitourinary tract. Each of these factors will be discussed.

Medical

Infections

Systemic and genital tract infections are associated with PTB. In women in spontaneous preterm labor with intact membranes, lower genital tract flora are commonly found in the amniotic fluid, placenta, and membranes. The flora include Ureaplasma urealyticum, Mycoplasma hominis, Fusobacterium species, Gardnerella vaginalis, peptostreptococci, and Bacteroides species. Clinical and histologic evidence of intraamniotic inflammation and infection is more common as the gestational age at delivery decreases, especially before 30 to 32 weeks. Bacteria in the amniotic fluid, whether detected by cultivation or by molecular methods, have been reported in 20% to 60% of women with preterm labor before 34 weeks’ gestation. The frequency of positive cultures increases as gestational age decreases, from 20% to 30% after 30 weeks to 60% at 23 to 24 weeks’ gestation. Evidence of infection is less common after 34 weeks.

Bacterial vaginosis (BV) is a condition in which the ecosystem of the vagina is altered so that gram-negative anaerobic bacteria (e.g., Gardnerella vaginalis, Bacteroides, Prevotella, Mobiluncus, and Mycoplasma species) largely replace the normally predominant lactobacilli. BV is associated with a twofold increased risk of sPTB. The association between BV and PTB is stronger when BV is detected early in pregnancy. Despite the association, antibiotic eradication of BV does not consistently reduce the risk of PTB. Infections outside the genital tract have also been related to PTB, most commonly urinary tract and intraabdominal infections (e.g., pyelonephritis and appendicitis). The presumed mechanism of disease is inflammation of the nearby reproductive organs, but infections at remote sites—especially if they are chronic—have also been associated with increased risk of sPTB.

Periodontal Disease

Women with periodontal disease have an increased risk of PTB that is not reduced by periodontal care, suggesting shared susceptibility rather than a cause-effect relation. The genitourinary and alimentary tracts are both major sites of microbial colonization where host immune factors defend the interior of the body, so shared risk factors are not surprising.

Genitourinary Tract Factors

Cervical Length

CL as measured by transvaginal ultrasound (TVU) is inversely related to the risk of PTB in both singletons and twins. Women whose CL at 22 to 24 weeks’ gestation was at or below the 10th percentile (25 mm by endovaginal ultrasound) had a 6.5-fold increased risk (95% confidence interval [CI], 4.5 to 9.3) of PTB before 35 weeks’ gestation and a 7.7-fold increased risk (95% CI, 4.5 to 13.4) of PTB before 32 weeks’ gestation when compared with women whose CL measurement was greater than the 75th percentile. The explanation for the linkage between CL and PTB risk was once thought to reflect a “continuum of cervical competence” in which variable cervical resistance to uterine contractions explained the relationship. However, there is now substantial evidence that contractions do not herald the onset of PTB and that progesterone supplementation slows the progression of cervical shortening and reduces the risk of PTB when initiated before 24 weeks in women with and without a prior PTB. These studies support the conclusion that preterm cervical shortening (softening and ripening) is not the passive result of tissue weakness but instead is an active process indicating that pathologic preterm parturition has begun, regardless of its underlying cause.

Cervical Procedures

A history of cervical surgery, including conization and the loop electrosurgical excision procedure (LEEP), has been suggested to be a risk factor for PTB. A recent meta-analysis supports the concept that when women with a history of LEEP are compared with women with prior dysplasia but no cervical excision, the risk of PTB is similar. This finding suggests that common factors for both PTB and dysplasia confound the association between LEEP and PTB.

Congenital Abnormalities of the Uterus

Congenital structural abnormalities of the uterus, known as müllerian fusion defects, may affect the cervix, the uterine corpus, or both. The risk of PTB in women with uterine malformations is 25% to 50% depending on the specific malformation and the obstetric history. Implantation of the placenta on a uterine septum may lead to PTB by means of placental separation and hemorrhage. A T-shaped uterus in women exposed in utero to diethylstilbestrol has also been associated with an increased risk of preterm labor and birth.

Behavioral

In general, studies of behavioral influences on PTB have not found a consistent relationship between maternal activities and PTB, except with tobacco smoking.

Smoking and Substance Abuse

Smoking is associated with an increased risk of PTB, and unlike most other risks, it is amenable to intervention during pregnancy.

Physical Activity

Controversy exists as to whether excessive physical activity is associated with early delivery.

Nutritional Factors

Low maternal prepregnancy weight (body mass index 19.8 kg/m 2 ) has been consistently found to be associated with an increased risk of PTB. Prepregnancy overweight and obesity are also linked to an increased risk of PTB, especially extremely PTB . Women who consume one or more servings of fish per month have lower rates of PTB than women who rarely or never eat fish. Numerous studies of various nutritional deficiencies have been reported to be related to the risk of PTB, but there are few if any for which supplementation has been found to reduce the incidence of prematurity.

Demography, Stress, and Social Determinants of Health

Social disadvantage is persistently associated with increased risk of PTB: poverty; educational attainment; geographic residence in disadvantaged neighborhoods, states, and regions; and lack of access to prenatal care are all linked to significantly higher rates of PTB. These associations were once deemed to be social, not medical, and thus beyond the reach of medical care. Stress and depression are consistently reported to have a moderate association with PTB, although the mechanisms again remain uncertain.

The effect of the social environment on reproduction has since been examined in greater detail and reveals evidence of a causative relationship. The magnitude of the increased risk of PTB according to educational level and race/ethnicity is shown in Table 36.1 and Fig. 36.6 .

TABLE 36.1
Magnitude of Increased Risk Based on Education and Race/Ethnicity
From Behrman RE, Stith Butler A. Committee on Understanding Premature Birth and Assuring Healthy Outcomes: Causes, Consequences, and Prevention. Washington, DC: National Academies Press; 2007.
Years of Education Non-Hispanic Black Non-Hispanic White Asian/Pacific Islander Native American Hispanic
<8 19.6 11.0 11.5 14.8 10.7
8–12 16.8 9.9 10.5 11.8 10.4
13–15 14.5 8.3 9.1 9.9 9.3
≥16 12.8 7.0 7.5 9.4 8.4

Fig. 36.6, Risk of Preterm Birth According to Educational Level (Years) by Race/Ethnicity (See Table 36.1 ).

A nearly twofold difference is seen in the rate of PTB for women of all racial and ethnic groups between those with the highest and lowest levels of education. Equally striking is the persistence of the disparity in rates of PTB in black women regardless of their educational level, and in Table 36.2 and as shown in Fig. 36.7 , their access to early prenatal care.

TABLE 36.2
Preterm Birth Rate Percentages by Maternal Race/Ethnicity and Prenatal Care Access by Trimester of Initiation of Prenatal Care, 1998–2000
Data from National Committee on Health Statistics for U.S. birth cohorts from 1998 to 2000 and from Berhman RE, Butler AS. Sociodemographic and Community Factors Contributing to Preterm Birth: Causes, Consequences, and Prevention. Institute of Medicine (US) Committee on Understanding Premature Birth and Assuring Healthy Outcomes. Washington, DC: National Academies Press; 2007.
Trimester Non-Hispanic Black Non-Hispanic White Asian/Pacific Islander Native American Hispanic
First 14.7 8.3 8.6 10.4 9.7
Second 17.5 10.2 10.8 12.7 11.0
Third 16.0 10.0 9.5 12.3 10.0
No prenatal care 33.4 21.7 19.4 24.0 19.8

Fig. 36.7, Risk of Preterm Birth According to Access to Early Prenatal Care by Race/Ethnicity and Trimester (See Table 36.2 ).

Black Race

Black women have a uniquely increased risk for PTB when compared with women from any other racial or ethnic background. In 2005 through 2007, the rate of PTB averaged 18.4% among black women, compared with 10.8% in Asian American, 11.6% in white, 12.6% in Hispanic, and 14.2% in Native American women. The disparity in the PTB rate persists after social and medical risk factors are accounted for and is evident in black Americans but not in African women. The origins of the disparity are not well understood. Regardless of the etiology, all African American women may be considered to have an increased risk of PTB even in the absence of other risk factors.

Genetic Contributors to Preterm Birth

The notion of some genetic contribution to PTB is based on several observations. First, a woman's family history of PTB influences her own risk. Porter and colleagues found that a mother who was herself born preterm had an increased risk for delivering a child preterm; the magnitude of that increased risk was inversely related to the gestational age of her own birth. The odds ratio (OR) for PTB ranged from 1.18 (95% CI, 1.02 to 1.37) for women who were born at 36 weeks’ gestation to 2.38 (95% CI, 1.37 to 4.16) for women who were born at 30 weeks’ gestation. A second set of observations from twin studies supports a genetic contribution to PTB. Treloar and colleagues studied 905 Australian female twin pairs to determine whether delivery had occurred more than 2 weeks before term. In this study, all-cause PTB was the outcome. Twin-pair correlations were higher from monozygotic twin pairs than from dizygotic twin pairs ( r = 0.3 ± 0.08 vs. 0.03 ± 0.11 standard error, respectively). Heritability was calculated at 17% for preterm delivery in the first pregnancy and 27% for preterm delivery in any pregnancy. A population-based twin study in Scandinavia investigated 868 monozygotic and 1141 dizygotic female twin pairs who delivered singletons between 1973 and 1993. Correlation for gestational length was higher for monozygotic compared with dizygotic twins, and heritability estimates from model fitting were approximately 30% for gestational age and 36% for PTB. This heritability appears to be the result of maternal, rather than paternal, lineage. The pattern of PTBs that occur in family pedigrees suggests that the most likely form of inheritance is nonmendelian; rather, the observed pedigrees are more consistent with the influence of many genes. Numerous studies have aimed at discovering variation in genes that contribute to PTB, and many associations have failed to replicate across populations. However, four genes are significantly associated with PTB in genome-wide studies: follicle-stimulating hormone receptor ( FSHR ), insulin-like growth factor 1 receptor ( IGF1R ), protein col-52, and serpin peptidase inhibitor, clade B, member 2 ( SERPINB2 ). GWAS studies may be useful in elucidation of possible contributors to PTB that may have otherwise remained underappreciated. Zhang et al. found that EEFSEC (eukaryotic elongation factor, selenocysteine tRNA-specific) demonstrated genomewide significance for both gestational length and PTB risk. EEFSEC participates in the incorporation of selenocysteine into selenoproteins. Selenoproteins, such as the glutathione peroxidases and thioredoxin reductases, serve critical cellular homeostatic functions in maintaining redox status and antioxidant defenses, as well as modulating inflammatory responses. These physiologic functions have previously been linked to the parturition process and PTB . Intriguingly, the identification of the selenocysteine pathway suggests the potential benefit for further evaluating the role of maternal selenium micronutrient status on prematurity risk.

Insights into the complex genetics of PTB hold promise for giving insight into pathophysiology and, potentially, to risk identification; at present, neither of these potential benefits influences clinical care.

Pregnancy History

The strongest historic risk factor is a previous birth between 16 and 36 weeks’ gestation. This history is often reported to confer a 1.5-fold to twofold increased risk but varies widely according to the number, sequence, and gestational age of prior PTBs ( Fig. 36.8 ).

Fig. 36.8, Risk of Recurrent Preterm Birth in 19,025 Women With Two Prior Births According to the Order and Gestational Age of the Previous Birth.

When the prior PTB occurs in a twin pregnancy, the risk of PTB in a subsequent singleton gestation rises as the gestational age at delivery of the twins falls below 34 weeks’ gestation. There is minimal if any increased risk for women whose prior twin birth occurred after 34 weeks’ gestation, but the risk of singleton PTB may be as much as 40% when the prior twin birth occurred before 30 weeks’ gestation.

Prior stillbirth and pregnancies ending between 16 and 20 weeks’ gestation are also associated with increased risk of PTB in subsequent pregnancies.

Pregnancy termination in the first and second trimesters is linked to an increased risk of subsequent PTB, especially when performed with mechanical dilation or curettage or when performed repeatedly. Increased risk of PTB has been found after spontaneous, as well as induced, abortion.

Current Pregnancy Risks

Mode of conception also affects the risk of PTB. The increased rate of PTB after assisted reproduction is due not only to the increased occurrence of multiple gestations but also to an increased rate of PTBs in singleton pregnancies as well. A nearly twofold increased risk of PTB is observed in singleton pregnancies conceived with all methods of fertility care, including ovulation promotion. A meta-analysis of 15 studies that compared 12,283 pregnancies resulting from in vitro fertilization (IVF) with 1.9 million spontaneously conceived singleton births found approximately twofold increased rates of perinatal mortality, PTB, LBW and VLBW, and SGA infants born after IVF. Rates of PTB among multiple gestations do not appear to be increased after assisted conception relative to spontaneously conceived twins and triplets, so the explanation for the increased rates in singletons is unclear. Microbial colonization of the upper genital tract, increased stress among infertile couples, side effects of superovulation, and increased rates of birth defects have been proposed as possible causes.

Bleeding and Vanishing Twins

Women who experience unexplained vaginal bleeding after the first trimester have an increased risk of subsequent PTB that increases with the number of bleeding episodes. Perhaps reflecting similar causes, the risk of PTB is also increased in women whose pregnancies are complicated by a vanishing twin (see Chapter 39 ) or by an unexplained elevation in maternal serum α-fetoprotein.

Multifetal Gestation and Uterine Distension

Multifetal gestation is one of the strongest risk factors for PTB. Rates of preterm, very preterm, LBW, and VLBW births according to fetal number are described in Chapter 39 . Slightly more than 50% of women with twins deliver before 37 weeks’ gestation. The risk of early birth rises with the number of fetuses, which suggests uterine overdistension and fetal signaling as potential pathways to the early initiation of labor. In addition to spontaneous preterm labor, multiple gestations are more commonly complicated by medical and obstetric disorders that lead to indicated preterm delivery. Poor fetal growth, fetal anomalies, hypertension, abruptio placentae, and fetal compromise are more common in multiple gestations and increase with the number of fetuses. The chronicity of twin gestations is also an important factor in the risk for adverse pregnancy outcomes. Monochorionic twin pregnancies are more likely than dichorionic twin gestations to be complicated by stillbirth and fetal growth restriction (FGR). Newborn monochorionic twins are more likely than dichorionic twins to experience NEC and neurologic morbidity. It is unclear how much of the excess rate of PTB among monochorionic twins is due to indicated versus spontaneous PTB.

Risk-Scoring Systems

Attempts to develop scoring systems based on historic and epidemiologic data plus current pregnancy risk factors have had low sensitivity to identify women who will give birth preterm, but they have not included some of the historic risks listed here.

Pathophysiology of Spontaneous Preterm Birth

Term and preterm parturition share anatomic, physiologic, and biochemical features that are considered part of the common pathway of parturition. This pathway includes (1) cervical changes ( softening , and ripening ), (2) membrane/decidual activation, and (3) increased uterine contractility. However, although spontaneous labor at term results from physiologic activation of the common pathway of parturition, preterm labor is the result of a pathologic activation of this pathway. The insult responsible for activation may lead to asynchronous recruitment of each pathway. Asynchrony is recognized clinically as (1) cervical insufficiency when the process affects predominantly the cervix; (2) preterm uterine contractions when the process affects the myometrium; or (3) preterm premature rupture of membranes (PPROM) if the insult acts on the chorioamniotic membranes. Synchronous activation in the preterm gestation would be labeled as preterm labor with intact membranes. Whether at or before term, parturition culminates in a common pathway composed of cervical changes, persistent uterine contractions, and activation of the decidua and membranes. The fundamental difference is that labor at term is a normal physiologic activation of the common pathway, whereas preterm parturition is the result, entirely or in part, of pathologic processes that activate one or more of the components of the common pathway.

Although labor is of short duration (hours or days at the most), parturition is a longer process that includes a preparatory phase of the key tissues involved in the common pathway. Thus cervical changes occur over weeks, myometrial contractility is increased before the onset of labor, and the appearance of fetal fibronectin (FFN) in the cervicovaginal mucus can be considered to reflect extracellular matrix (ECM) degradation, which indicates activation of the decidua and membranes.

A fetal maturity–based signal for labor originates in the fetal hypothalamus and leads to increased secretion of corticotropin-releasing hormone (CRH), which in turn stimulates adrenocorticotropic hormone (ACTH) and cortisol production by the fetal adrenals, which ultimately leads to activation of the common pathway of parturition. The fetus may contribute to the onset of preterm labor in the context of the fetal inflammatory response syndrome (FIRS; discussed later).

Spontaneous PTB may best be understood as a syndrome in which the clinical presentations of preterm labor, preterm ruptured membranes, and preterm cervical effacement and dilation without labor occur as the result of multiple etiologies that can occur alone or in combination. Some act to initiate preterm parturition acutely—for example, with acute posttraumatic placental abruption—but most follow a more subacute or indolent path over several weeks. It is helpful to remember that the normal process of parturition proceeds for several weeks before clinically evident labor begins. Thus pathologic stimuli of parturition may act in concert with the normal physiologic preparation for labor, especially after 32 weeks’ gestation. Before 30 to 32 weeks, a greater proportion of preterm labor has a pathologic stimulus.

Cervical Changes: Softening and Ripening

The cervix is a critical structure in pregnancy and parturition; it must maintain structural integrity and act as a physical barrier during pregnancy and subsequently transition to allow passage of the fetus during delivery. This change is not acute; physiologic parturition occurs over the course of gestation and requires evolving biochemical and biomechanical changes in the cervix that manifest as cervical ripening. Molecular processes that underlie cervical ripening are different between physiologic and pathologic parturition, and may differ among etiologies of pathologic parturition.

Although collagen is the main contributor to the tensile strength of the cervix, glycosaminoglycans (GAGs) are critical to determining the viscoelastic properties of the tissue. GAGs are long, unbranched polysaccharides—vital components of the ECM—that serve many roles: they help determine tissue hydration, which contributes to viscous tissue properties, and they stabilize the overall architecture of the ECM. In addition, small leucine-rich proteoglycans (GAGs linked to core proteins) such as decorin have been shown to interact with soluble growth factors and mediators of inflammation. Tight junctions in the cervical epithelial cells provide structural support and regulate fluid fluxes.

Cervical epithelia have numerous functions that include proliferation, differentiation, maintenance of fluid balance, protection from environmental hazards, and paracellular transport of solutes via tight junctions. Epithelial functions must be carefully regulated during pregnancy and parturition, and molecules important in epithelial integrity and function are key components of cervical changes in animal models and in women at term. ECM turnover in the cervix is high, and thus the mechanical properties of the cervix can change rapidly. Changes in ECM during cervical ripening include an influx of inflammatory cells—macrophages, neutrophils, mast cells, eosinophils, and so on—into the cervical stroma in a process similar to an inflammatory response. These cells produce cytokines and prostaglandins that affect ECM metabolism. Prostaglandins effect cervical ripening physiologically and have been widely used as pharmacologic agents to ripen the cervix for induction of labor. Cervical ripening is influenced by estrogen, which induces ripening by stimulating collagen degradation, and by progesterone, which blocks these estrogenic effects. Furthermore, administration of a progesterone receptor (PR) antagonist can induce cervical ripening, and administration of progesterone has been reported to delay or even reverse ripening. Another mediator implicated in the mechanisms of cervical ripening is nitric oxide (NO), which can act as an inflammatory mediator.

Cervical changes normally precede the onset of labor, are gradual, and develop over several weeks. PTB is often preceded by cervical ripening over a period of weeks in the second and third trimesters, evidenced on clinical examination by softening and thinning of the cervix, and on ultrasound examination of the cervix by cervical “funneling” and shortening of the length of the endocervical canal.

Increased Uterine Contractility

Labor is characterized by a change in uterine contractility from episodic uncoordinated myometrial contractures that last several minutes and produce little increase in intrauterine pressure to more coordinated contractions of short duration that produce marked increases in intrauterine pressure that ultimately effect delivery. The change from the contracture to the contraction pattern typically begins at night, which suggests neural control. The transition from contractures to contractions may progress to normal labor or may occur dyssynchronously as the result of inflammation (e.g., with maternal infection or abdominal surgery). Fasting may also induce the switch in humans. Oxytocin is produced by the decidua and the paraventricular nuclei of the hypothalamus, indicating both an endocrine and a paracrine role. Plasma concentrations of oxytocin mirror uterine contractility, which suggests oxytocin may mediate the circadian rhythm in uterine contractility.

Cellular communication is another feature of labor, promulgated by formation of gap junctions that develop in the myometrium before labor and disappear after delivery. Gap-junction formation and the expression of the gap-junction protein connexin 43 in the human myometrium is similar in term and preterm labor. These findings suggest that the appearance of gap junctions and increased expression of connexin 43 may be part of the underlying molecular and cellular events responsible for the switch from contractures to contractions before the onset of parturition. Estrogen, progesterone, and prostaglandins have been implicated in the regulation of gap-junction formation and in influencing the expression of connexin 43. Lye and colleagues have proposed that changes in a set of distinct proteins called contraction-associated proteins are characteristic of this stage of parturition.

Decidual Membrane Activation

The maternal decidua and adjacent fetal membranes undergo anatomic and biochemical changes during the final weeks of gestation that ultimately result in a spontaneous rupture of the membranes. Premature activation of this mechanism leads to PPROM, the clinical antecedent for up to 40% of all preterm deliveries. Although rupture of the membranes normally occurs during the first stage of labor, histologic studies of prematurely ruptured membranes show decreased amounts of collagen types I, III, and V; increased expression of tenascin, expressed during tissue remodeling and wound healing; and disruption of the normal wavy collagen pattern, which suggests that preterm rupture is a process that precedes the onset of labor.

Structural ECM proteins such as collagens have been implicated in the tensile strength of the membranes, whereas the viscoelastic properties have been attributed to elastin. Dissolution of extracellular cements (e.g., fibronectins) is thought to be responsible for the process that allows the membranes to separate from the decidua after the birth of the infant. Degradation of the ECM, assessed by the detection of FFN, is part of the common pathway of parturition. The presence of FFN or pathogen-associated molecular patterns (PAMPs) in cervicovaginal secretions between 22 and 37 weeks’ gestation is evidence of disruption of the decidual-chorionic interface and is associated with an increased risk of PTB.

The precise mechanism of membrane/decidua activation is uncertain, but matrix-degrading enzymes and apoptosis—programmed cell death—have been proposed. Increased levels of matrix metalloproteinases (MMPs) and their regulators (tissue inhibitors of metalloproteinases [TIMPs]) have been documented in the amniotic fluid of women with PPROM.

Apoptosis may also play a role in the mechanism of membrane rupture through increased expression of proapoptotic genes and decreased expression of antiapoptotic genes. MMP-9 may induce apoptosis in the amnion.

Fetal Participation in the Onset of Labor

A fetal signal contributes to the onset of labor in animals and humans. Destruction of the paraventricular nucleus of the fetal hypothalamus results in prolongation of pregnancy in sheep. The human counterpart to this animal experiment is anencephaly, which is also characterized by prolonged pregnancy when women with polyhydramnios are excluded. The current paradigm is that once maturity has been reached, the fetal brain—specifically the hypothalamus—increases CRH secretion that, in turn, stimulates ACTH and cortisol production by the fetal adrenals. This increase of cortisol in sheep and of dehydroepiandrosterone sulfate in primates eventually leads to activation of the common pathway of parturition.

Preterm Parturition Syndrome

Obstetric taxonomy is largely based on clinical presentation, not the mechanism of disease. Preterm labor may occur as the common clinical presentation of infection, vascular insult, uterine overdistension, abnormal allogeneic recognition, stress, or other pathologic processes. Often more than one of these factors is operative in the same patient. Thus preterm labor is a syndrome for which no single diagnostic test or treatment exists. Obstetric syndromes share the following features:

  • Multiple etiologies

  • Chronicity

  • Fetal involvement

  • Clinical manifestations that are adaptive

  • Variable susceptibility due to gene-environment interactions

Each of these features is true of PTB. As listed earlier, preterm labor clearly has multiple etiologies . Pathways to preterm labor are demonstrated to be chronic , as seen in the time interval between observation of a short cervix or increased concentrations of FFN in vaginal fluid in the midtrimester of pregnancy and subsequent preterm labor or delivery. Fetal involvement has been demonstrated in women with microbial invasion of the amniotic cavity, in which fetal bacteremia and cytokine production have been detected in 30% of women with PPROM and an amniotic fluid culture positive for microorganisms. Similarly, neonates born after spontaneous preterm labor or PPROM are more likely to be SGA, which suggests chronically compromised fetal supply. Preterm labor may be seen as an adaptive mechanism of host defense against infection that allows the mother to eliminate infected tissue and allows the fetus to exit a hostile environment. If the clinical manifestations are adaptive, it is not surprising that treatments aimed at the common terminal pathway of parturition, such as tocolysis or cerclage, and not at the fundamental mechanism of disease-inducing activation of the pathway—myometrial contractility, cervical dilation, and effacement—would not be effective. Increasing evidence suggests gene-environment interaction in the steps leading to preterm labor complicated by the presence, and even perhaps the conflicting interests, of two genomes: maternal and fetal. This is most evident in studies of the relationship between maternal genital tract colonization and PTB. Finally, additional mechanisms may be at play that have not yet been identified.

Pathologic processes implicated in the preterm parturition syndrome include intrauterine inflammation/infection, vascular disorders, uterine overdistension, breakdown of maternal-fetal tolerance, allergy-induced causes, cervical insufficiency, and endocrine disorders.

Intrauterine Infection

Systemic maternal infections such as pyelonephritis and pneumonia are frequently associated with the onset of premature labor in humans. Intrauterine infection is a frequent and important mechanism of disease leading to preterm delivery. Intrauterine infection or systemic administration of microbial products to pregnant animals can result in preterm labor and delivery, and substantial evidence shows that subclinical intrauterine infections are associated with preterm labor and delivery. Moreover, fetal infection and inflammation have been implicated in the genesis of fetal or neonatal injury leading to cerebral palsy and chronic lung disease. Microbiologic and histopathologic studies suggest that infection-related inflammation may account for 25% to 40% of cases of preterm delivery .

Frequency of Intrauterine Infection in Spontaneous Preterm Birth

The prevalence of amniotic fluid cultures positive for microorganisms in women with preterm labor and intact membranes is approximately 13%, with additional instances of infection that are identifiable using polymerase chain reaction (PCR) techniques rather than culture. The earlier the gestational age at PTB, the more likely that microbial invasion of the amniotic cavity is present. In PPROM, the prevalence of positive amniotic fluid cultures for microorganisms is approximately 32%. Among women with a dilated cervix in the midtrimester, the prevalence of positive amniotic fluid cultures is 51%. Microbial invasion of the amniotic cavity occurs in 12% of twin gestations with preterm labor and when delivering a preterm neonate. The most common microorganisms found in the amniotic cavity are Mycoplasma and U. urealyticum.

Intrauterine Infection as a Chronic Process

Evidence in support of chronicity of intrauterine inflammation/infection is derived from studies of the microbiologic state of the amniotic fluid, as well as the concentration of inflammatory mediators, at the time of genetic amniocentesis. Genital mycoplasmas that include M. hominis and also U. urealyticum have been recovered from amniotic fluid samples obtained at second-trimester genetic amniocentesis, with subsequent preterm delivery and histologic chorioamnionitis, especially in those with U. urealyticum. Increased levels of many inflammatory markers have been found in second-trimester amniotic fluid samples obtained from women who subsequently delivered preterm. These observations suggest that infection and inflammation in the amniotic cavity in the midtrimester of pregnancy can lead to preterm delivery weeks later. The most advanced stage of intrauterine infection is fetal infection. Fetal bacteremia has been detected in blood obtained by cordocentesis in 33% of fetuses with positive amniotic fluid culture and in 4% of those with negative amniotic fluid culture.

Molecular mediators that trigger parturition (cytokines and other inflammatory mediators) are similar to those that protect the host against infection. The onset of preterm labor in response to intrauterine infection is thus very likely a host defense mechanism with survival value for the mother and, after viability, for the fetus.

Infection, Preterm Labor, and Neonatal Outcomes

The scenario postulated from the preceding evidence is that microorganisms that reside in or ascend to reach the decidua may, depending on host defense and environmental influences, stimulate a local inflammatory reaction and the production of proinflammatory cytokines, chemokines, and inflammatory mediators. This inflammatory process, which is initially extraamniotic, may produce cervical effacement, further inflammation of the choriodecidual interface, and uterine contractions, and it may progress to the amniotic fluid and ultimately to the fetus. Microorganisms are known to cross intact membranes into the amniotic cavity, where inflammatory mediators are produced by resident macrophages and other host cells within the amniotic cavity. Finally, microorganisms that gain access to the fetus may elicit a systemic inflammatory response, the FIRS, characterized by increased concentrations of interleukin-6 (IL-6) and other cytokines, as well as cellular evidence of neutrophil and monocyte activation.

FIRS is a subclinical condition originally described in fetuses of mothers with preterm labor and intact membranes and PPROM. Fetuses with FIRS have a higher rate of neonatal complications and are frequently born to mothers with subclinical microbial invasion of the amniotic cavity. Evidence of multisystemic involvement in cases of FIRS includes increased concentrations of fetal plasma MMP-9, neutrophilia, a higher number of circulating nucleated red blood cells, and higher plasma concentrations of granulocyte-colony stimulating factor (G-CSF). The histologic hallmark of FIRS is inflammation in the umbilical cord (funisitis) or chorionic vasculitis. The systemic fetal inflammatory response may result in multiple organ dysfunction, septic shock, and death in the absence of timely delivery. Newborns with funisitis are at increased risk for neonatal sepsis and long-term handicaps that include BPD and cerebral palsy.

When the inflammatory process does not involve the chorioamniotic membranes and decidua, systemic fetal inflammation and injury may occur in the absence of labor with eventual delivery at term. An example of this is fetal alloimmunization (see Chapter 40 ), in which fetal plasma concentrations of IL-6 are elevated, but preterm labor does not occur.

Gene-Environment Interactions

Gene-environment interactions underlie many complex disorders such as atherosclerosis and cancer. A gene-environment interaction is said to be present when the risk of a disease (occurrence or severity) among individuals exposed to both genotype and an environmental factor is greater or less than that predicted from the presence of either the genotype or the environmental exposure alone. The inflammatory response to the presence of microorganisms is modulated by interactions between the host genotype and environment that determine the likelihood and course of some infectious diseases. An example of such an interaction has been reported for BV, an allele for tumor necrosis factor α (TNF-α) and preterm delivery. Maternal BV is a consistently reported risk factor for spontaneous preterm delivery, yet treatment of BV does not reliably prevent PTB in women with BV. One potential explanation has come from a study of PTB rates in women according to their carriage of BV and whether or not they had allele 2 of TNF-α, known to be associated with sPTB. Both BV (OR, 3.3; 95% CI, 1.8 to 5.9) and TNF-α allele 2 (OR, 2.7; 95% CI, 1.7 to 4.5) were associated with increased risk for preterm delivery, but the risk of sPTB was substantially increased (OR, 6; 95% CI, 1.9 to 21.0) in women with both BV and the TNF-α allele 2. It is reasonable to assume that other gene-environment interactions may contribute to PTB.

Uteroplacental Ischemia and Decidual Hemorrhage

After inflammation, the most common abnormalities seen in placental pathology specimens from sPTBs are vascular lesions of the maternal and fetal circulations. Maternal lesions include failure of physiologic transformation of the spiral arteries, atherosis, and thrombosis. Fetal abnormalities include a decreased number of villous arterioles and fetal arterial thrombosis.

One proposed mechanism linking vascular lesions and preterm labor/delivery is uteroplacental ischemia , evidenced in primate models and in studies that found failure of physiologic transformation in the myometrial segment of the spiral arteries—a phenomenon typical of preeclampsia and intrauterine growth restriction—in women with preterm labor and intact membranes and PPROM. Abnormal uterine artery Doppler velocimetry indicative of increased impedance to flow in the uterine circulation has been reported in women with apparently idiopathic preterm labor.

The mechanisms responsible for preterm parturition in cases of ischemia have not been determined, but uterine ischemia has been postulated to lead to increased production of uterine renin from the fetal membranes. Angiotensin II can induce myometrial contractility directly or through the release of prostaglandins.

Decidual necrosis and hemorrhage can activate parturition through production of thrombin, which stimulates myometrial contractility in a dose-dependent manner. Thrombin also stimulates production of MMP-1, urokinase-type plasminogen activator (uPA), and tissue-type plasminogen activator (tPA) by endometrial stromal cells in culture. Directly or indirectly, these factors can digest important components of the ECM in the chorioamniotic membranes. Thrombin/antithrombin complexes, a marker of in vivo generation of thrombin, are increased in plasma and amniotic fluid of women with preterm labor and PPROM. The decidua is a rich source of tissue factor, the primary initiator of coagulation and of thrombin activation. These observations are consistent with clinical associations among vaginal bleeding, retroplacental hematomas, and preterm delivery.

Uterine ischemia should not be equated with fetal hypoxemia. Studies of fetal cord blood do not support fetal hypoxemia as a cause or consequence of preterm parturition.

Uterine Overdistension

The mechanisms responsible for the increased frequency of PTB in multiple gestations and other disorders associated with uterine overdistension are unknown. Central questions are how the uterus senses stretch, and how these mechanical forces induce biochemical changes that lead to parturition. Increased expression of oxytocin receptor, connexin 43, and the c-fos messenger RNA (mRNA) have been consistently demonstrated in the rat myometrium near term. Progesterone blocks stretch-induced gene expression in the myometrium. Mitogen-activated protein kinases have been proposed to mediate stretch-induced c-fos mRNA expression in myometrial cells. Stretch can have effects on the membranes; for example, in vitro studies have demonstrated an increase in the production of collagenase, interleukin 8 (IL-8), and prostaglandin E 2 , as well as the cytokine pre–B-cell colony-enhancing factor. These observations provide a possible link between the mechanical forces that operate in an overdistended uterus and in the rupture of membranes.

Breakdown of Fetal-Maternal Tolerance

The fetoplacental unit is the most successful transplant. This is made possible by the development of a tolerogenic state, a state of immune tolerance during normal pregnancy that requires participation of the maternal and fetal immune systems, as well as active suppression at the maternal-fetal interface. Recent evidence suggests that maternal antifetal rejection is a common mechanism of disease in premature labor. Chronic chorioamnionitis, a lesion in which maternal lymphocytes infiltrate the chorioamniotic membranes, is the most common pathologic finding in sPTB. Maternal lymphocytes can induce destruction of the trophoblast in the chorion and can thus induce preterm labor. This lesion, as well as chronic villitis, is considered to represent evidence of maternal antifetal rejection.

Allergy-Induced Preterm Labor

Case reports indicate that preterm labor has occurred after exposure to an allergen that generates an allergic-like mechanism (type I hypersensitivity reaction) and that some women with preterm labor have eosinophils as the predominant cells in amniotic fluid, suggesting a form of uterine allergy. Mast cells in the uterus produce histamine and prostaglandins, both of which can induce myometrial contractility. Premature birth can be induced by exposure to an allergen in sensitized animals, and it can be prevented by treatment with a histamine H 1 receptor antagonist.

Cervical Insufficiency

Prompted by knowledge of the relationship between a sonographic short cervix with and a subsequent PTB, the understanding of cervical function evolved from a categorical concept of cervical incompetence versus competence to one of “competence as a continuum.” However, subsequent analyses of these same data were conducted in response to clinical trials that demonstrated that preterm cervical shortening (softening and ripening) is not the passive result of tissue weakness but instead is an active process that can be slowed or prevented by progesterone supplementation in some women. These studies have led to the conclusion that a short cervix in the second trimester of pregnancy is evidence that parturition has begun, presumably triggered by decidual membrane activation in response to microbial colonization and/or decidual hemorrhage, perhaps aided by cervical factors and/or subclinical myometrial activity. Fig. 36.9 shows the length of the cervix at 22 to 24 weeks’ gestation and the subsequent rate of cervical shortening in women who later presented after 28 weeks’ gestation with preterm labor or PPROM compared with women who delivered at term or preterm because of a medical indication. Significant differences in CL were already evident at 22 to 24 weeks, more than a month before clinical presentation, and accelerated for several weeks before clinical presentation.

Fig. 36.9, Length of the cervix at 22 to 24 weeks’ gestation and the subsequent rate of cervical shortening in women who present after 28 weeks with preterm labor (PTL) or preterm premature rupture of membranes (PPROM) compared with women who delivered at term or preterm for medical indications.

Endocrine Disorders

Estrogen and progesterone play a central role in the endocrinology of pregnancy . Progesterone is thought to maintain myometrial quiescence and inhibit cervical ripening. Estrogens have been implicated in increasing myometrial contractility and excitability, as well as in the induction of cervical ripening before the onset of labor. In many species, a fall in maternal serum progesterone concentration occurs before spontaneous parturition, but the mechanism for this progesterone withdrawal depends primarily on whether the placenta or the corpus luteum is the major source of progesterone.

A decrease in serum progesterone levels has not been demonstrated before parturition in humans. Nevertheless, inhibition of progesterone action could result in parturition. Alternative mechanisms posited to explain a suspension of progesterone action without a serum progesterone withdrawal include binding of progesterone to a high-affinity protein and thus a reduction in the functional active form; increased cortisol concentration that competes with progesterone for binding to the glucocorticoid receptors, resulting in functional progesterone withdrawal; and conversion of progesterone to an inactive form within the target cell before interaction with its receptor. None of these hypotheses are proven. Recent research has focused on alterations in the number and function of estrogen-progesterone receptors and progesterone binding.

The human PR exists as two major subtypes, PR-A and PR-B. Another isoform, PR-C, has recently been described, but its function is not well understood. The human estrogen receptor (ER) also exists as two major subtypes, ERa and ERb. A functional progesterone withdrawal has been proposed in which expression of PR-A in the myometrium suppresses progesterone responsiveness and that functional progesterone withdrawal occurs by increased expression of PR-A relative to PR-B. An alternative mechanism of functional progesterone withdrawal has been proposed wherein activation of nuclear factor κB (NFκB) in the amnion represses progesterone function. Regardless of the mechanism, consensus is building for the idea that a localized functional progesterone withdrawal occurs in the myometrium during human parturition.

Summary of the Preterm Parturition Syndrome

Preterm parturition is a syndrome caused by multiple etiologies with several clinical presentations, including uterine contractility (preterm labor), preterm cervical ripening without significant clinical contractility (cervical insufficiency or advanced cervical dilation and effacement), or rupture of the amniotic sac (PPROM). The clinical presentation varies with the type and timing of the insult or stimulus to the components of the common pathway of parturition, the presence or absence of environmental cofactors, and individual variations of the host response by both mother and fetus. This conceptual framework has implications for the understanding of the mechanisms responsible for the initiation of preterm parturition, as well as the diagnosis, treatment, and prevention of PTB.

Clinical Care for Women in Preterm Labor

Clinical evaluation of preterm parturition begins with assessment of potential causes of labor, looking first for conditions that threaten the health of the mother and fetus. Acute maternal conditions—for example, pyelonephritis, pneumonia, asthma, peritonitis, trauma, and hypertension—or obstetric conditions that include preeclampsia, placental abruption, placenta previa, and chorioamnionitis may mandate delivery. Fetal compromise may be acute, manifested by an abnormal fetal heart rate tracing, or it may be chronic, indicated by FGR or oligohydramnios; it may require delivery depending on the severity and potential for in utero versus ex utero treatment. FGR is more common in infants delivered after preterm labor or PPROM, even in apparently otherwise uncomplicated pregnancies. Conditions such as preterm ruptured membranes or cervical insufficiency, which suggest specific therapy, should then be treated accordingly.

The next concerns are the accuracy of preterm labor diagnosis and the balance of risks and benefits that accompany active attempts to inhibit labor versus allowing delivery ( Box 36.3 ).

Box 36.3
Diagnosis of Preterm Labor and Initial Assessment

  • What is the gestational age, and what is the level of confidence about the accuracy of the gestational age?

  • In the absence of advanced labor (cervical effacement >80% with dilation >2 cm) and a clear cause of preterm labor, what is the accuracy of the diagnosis of preterm labor?

  • Are confirmatory diagnostic tests such as cervical sonography, fetal fibronectin, or amniocentesis for infection necessary?

  • What is the anticipated neonatal morbidity and mortality at this gestational age in this clinical setting?

  • Should labor be stopped?

  • Is transfer to a more appropriate hospital required?

  • Should fetal lung maturity be tested?

  • What interventions can be applied that will reduce the risks of perinatal morbidity and mortality?

  • Should drugs to arrest labor (tocolytics), glucocorticoids, or antibiotics be given?

Diagnosis of Preterm Labor

Given the pathways for preterm parturition described earlier, clinical recognition of preterm labor requires attention to the biochemical as well as the biophysical features of the onset of labor. Pathologic uterine contractility rarely occurs in isolation; cervical ripening and decidual membrane activation are almost always in progress as well, most often before uterine contractions are clinically evident. Therefore preterm labor must be considered whenever a pregnant woman reports recurrent abdominal or pelvic symptoms that persist for several hours in the second half of pregnancy. Symptoms of preterm labor such as pelvic pressure, increased vaginal discharge, backache, and menstrual-like cramps occur frequently in normal pregnancy and suggest preterm labor more by persistence than by severity. Contractions may be painful or painless, depending on the resistance offered by the cervix. Contractions against a closed, uneffaced cervix are likely to be painful, but persistence of recurrent pressure or tightening may be the only symptoms when cervical effacement precedes the onset of contractions.

For decades, the clinical diagnosis of preterm labor has been based on the presence of regular, painful uterine contractions accompanied by cervical dilation and/or effacement. These criteria assume a crisp demarcation between preterm parturition and preterm labor that is increasingly understood as being more gradual than previously thought. If considered a screening criterion for the outcome “preterm birth,” clinical signs and symptoms demonstrate poor sensitivity and specificity. Identifying women with preterm contractions who will actually deliver preterm is an inexact process. In like fashion, identifying those women who are at increased risk of not just PTB, but imminent PTB, remains elusive. A systematic review noted that approximately 30% of preterm labor cases resolved spontaneously. In subsequent studies, 50% of patients hospitalized for preterm labor actually delivered at term.

The inability to accurately distinguish women with an episode of preterm labor who will deliver preterm from those who deliver at term has greatly hampered the assessment of therapeutic interventions because as many as 50% of untreated (or placebo-treated) subjects do not actually deliver preterm. Optimal criteria for initiation of treatment are unclear. A contraction frequency of six or more per hour, cervical dilation of 3 cm, effacement of 80%, ruptured membranes, and bleeding are symptoms of preterm labor most often associated with preterm delivery. When lower thresholds for contraction frequency and cervical change are used, a false-positive diagnosis—defined in randomized controlled trials as delivery at term after treatment with placebo only—occurs in nearly 40% of women, but sensitivity does not rise. Difficulty in accurate diagnosis is the product of the high prevalence of the symptoms and signs of early preterm labor in normal pregnancy, the gradual onset of preterm labor discussed earlier, and the imprecision of digital examination of the cervix below 3 cm dilation and 80% effacement. The practice of initiating tocolytic drugs for contraction frequency without additional diagnostic criteria results in unnecessary treatment of women who are not at increased risk of imminent sPTB.

Diagnostic Tests for Preterm Labor

Symptomatic women whose cervical dilation is less than 2 cm and whose effacement is less than 80% present a diagnostic challenge. Diagnostic accuracy may be improved in these patients by testing other features of parturition such as cervical ripening; measurement of CL by TVU; and decidual activation, tested by an assay for FFN in cervicovaginal fluid. Both tests aid diagnosis primarily by reducing false-positive results. Transabdominal ultrasound has poor reproducibility for cervical measurement and should not be used clinically without confirmation by a TVU. If the examination is properly performed, a CL of 30 mm or more by endovaginal sonography indicates that preterm labor is unlikely in symptomatic women.

Similarly, a negative FFN test in women with symptoms before 34 weeks’ gestation with cervical dilation less than 3 cm can also reduce the rate of false-positive diagnosis if the result is returned promptly and the clinician is willing to act on a negative test result by not initiating treatment. When both tests were performed in a study of 206 women with possible preterm labor, the FFN test improved the performance of sonographic CL only when the sonographic CL was less than 30 mm ( Box 36.4 ).

Box 36.4
Clinical Evaluation of Patients With Possible Preterm Labor

  • 1

    Patient presents with signs/symptoms of preterm labor

    • Persistent contractions, painful or painless

    • Intermittent abdominal cramping, pelvic pressure, or backache

    • Increase or change in vaginal discharge

    • Vaginal spotting or bleeding

  • 2

    General physical examination

    • Sitting pulse and blood pressure

    • Temperature

    • External fetal heart rate and contraction monitor

  • 3

    Sterile speculum examination

    • pH

    • Fern

    • Pooled fluid

    • Fibronectin swab (posterior fornix or external cervical os, avoiding areas with bleeding)

    • Cultures for Chlamydia (cervix), Neisseria gonorrhoeae (cervix), and group B Streptococcus (outer third of vagina and perineum)

  • 4

    Transabdominal ultrasound examination

    • Placental location

    • Amniotic fluid volume

    • Estimated fetal weight and presentation

    • Fetal well-being

  • 5

    Cervical examination (after ruptured membranes are excluded)

      • a

        Cervix >3 cm dilation, ≥80% effaced

      • Preterm labor diagnosis confirmed. Evaluate for tocolysis.

      • b

        Cervix 2 to 3 cm dilation, <80% effaced

      • Preterm labor likely but not established. Monitor contraction frequency and repeat digital examination in 30 to 60 min. Diagnose preterm labor if cervix changes. If not, send fibronectin or obtain transvaginal cervical ultrasound. Evaluate for tocolysis if any cervical change occurs, cervical length is <20 mm, or fibronectin is positive.

      • c

        Cervix <2 cm dilation and <80% effaced

      • Preterm labor diagnosis uncertain. Monitor contraction frequency, send fibronectin and/or obtain cervical sonography, and repeat digital examination in 1 to 2 h. Evaluate for tocolysis if change in cervical dilation is 1 cm, effacement is >80%, cervical length is <20 mm, or fibronectin is positive.

  • 6

    Use of cervical ultrasound

    • Cervical length <20 mm and contraction criteria met: preterm labor

    • Cervical length 20 to 30 mm and contraction criteria met: probable preterm labor

    • Cervical length >30 mm: preterm labor very unlikely regardless of contraction frequency

Amniocentesis for Women With Preterm Labor

The goal of care for women with preterm labor is to reduce perinatal morbidity and mortality, most of which is caused by immaturity of the respiratory, gastrointestinal, coagulation, and central nervous systems of the preterm infant. Fetal pulmonary immaturity is the most frequent cause of serious newborn illness, and the fetal pulmonary system is the only organ system whose function is directly testable before delivery. If the quality of obstetric dating is good and intrauterine fetal well-being is not compromised, the likelihood of neonatal RDS may be estimated from the gestational age.

Amniotic fluid studies may be useful in women with possible preterm labor in the following circumstances:

  • 1

    Fetal pulmonary maturity testing. Gestational age at birth is the best predictor of the frequency and severity of the consequences of prematurity to the newborn. Labor inhibition and antenatal glucocorticoid therapy are used when birth is anticipated to occur between 24 and 34 weeks’ gestation. When dates are uncertain—such as with late prenatal care or fetal size larger than expected for dates, suggestive of a more advanced gestation—it may be reasonable in some circumstances to use amniotic fluid lung maturity studies to help guide management decisions.

  • 2

    Testing for infection. Among women with preterm labor and intact membranes, early gestational age, a short cervix, and progressive labor despite a tocolytic are all risk factors for occult amniotic fluid infection. In this setting, amniotic fluid studies for infection may guide the counseling of women and can influence management decisions in regard to antibiotics, inhibition of labor, and delivery. Amniotic fluid glucose (levels <20 mg/dL suggest intraamniotic infection) and Gram stain for bacteria, cell count, and culture may be used.

  • 3

    Determining fetal karyotype. The presence of polyhydramnios or a fetal anomaly suggests that preterm labor may have occurred because of uterine distension or placental insufficiency associated with fetal aneuploidy. Fluorescence in situ hybridization studies for the most common aneuploid conditions can be available within 48 hours and do not require culture; chromosomal microarrays likewise do not require cell culture (see Chapter 10 ). In the absence of other fetal features suggestive of aneuploidy, the presence of preterm labor alone is an insufficient indication for the determination of a fetal karyotype.

Treatment for Women in Preterm Labor

Successful treatment with tocolytic drugs to inhibit labor after contractions have begun and cervical change has been documented is well established. However, treatment after membranes have ruptured does not prolong pregnancy sufficiently to allow further intrauterine growth and maturation, but therapy can often delay PTB long enough to permit four interventions that have been shown to reduce neonatal morbidity and mortality:

  • 1

    Antenatal transfer of the mother and fetus to the most appropriate hospital.

  • 2

    Antibiotics in labor to prevent neonatal infection with group B Streptococcus (GBS).

  • 3

    Antenatal administration of glucocorticoids to the mother to reduce neonatal morbidity and mortality due to RDS, IVH, and other causes.

  • 4

    Administration of maternal magnesium sulfate at the time of PTB before 32 weeks to reduce the incidence of cerebral palsy.

Maternal Transfer

Many states have adopted systems of regionalized perinatal care in recognition of the advantages of concentrating care for preterm infants, especially those born before 32 weeks. Hospitals and birth centers that care for normal mothers and infants are designated as level I. Larger hospitals that care for the majority of maternal and infant complications are designated as level II centers; these hospitals have NICUs staffed and equipped to care for most infants with birthweights greater than 1500 g. Level III centers typically provide care for the sickest and smallest infants and for maternal complications that require intensive care. This three-tiered approach has been associated with improved outcomes for preterm infants.

Antibiotics

Women with preterm labor should be treated with antibiotics to prevent neonatal GBS infection (see Chapters 57 and 58 ). Because preterm infants have a greater risk of neonatal GBS infection than those born at term, intrapartum prophylaxis with penicillin is recommended. This policy has successfully reduced the incidence of neonatal GBS infection to such a degree that most such infections now occur in full-term infants. Evidence also shows that infants born to women with PPROM have reduced perinatal morbidity when antepartum antibiotic prophylaxis has been administered for 3 to 7 days.

Antibiotic therapy in women with preterm labor and intact membranes is not effective in prolonging pregnancy or preventing preterm delivery. The failure of antibiotics to prolong pregnancy may be attributed to treatment of women whose preterm labor did not result from infection and to the timing of treatment relative to the infectious process. Rather than an acute infection due to the recent ascent of vaginal organisms into the uterus, the pathologic sequence in which infection-driven preterm labor occurs is often much more indolent. Antimicrobial therapy for women in preterm labor should be limited to GBS prophylaxis, women with PPROM, or treatment of a specific pathogen (e.g., urinary tract infection).

Antenatal Corticosteroids

Glucocorticoids act generally in the developing fetus to promote maturation over growth. In the lung, corticosteroids promote surfactant synthesis, increase lung compliance, reduce vascular permeability, and generate an enhanced response to postnatal surfactant treatment. Glucocorticoids have similar maturational effects on other organs, including the brain, kidneys, and gut.

Studies by Liggins of mechanisms of parturition in sheep led to the discovery of the beneficial effect of antenatal glucocorticoids on the maturation and performance of the lung in prematurely born infants. Subsequent studies have shown conclusively that antepartum administration of the glucocorticoids betamethasone or dexamethasone to the mother reduces the risk of death, RDS, IVH, NEC, and PDA in the preterm neonate. Guidelines for appropriate clinical use of antenatal glucocorticoids have evolved from initial skepticism and selective use, through a period of broad and repeated treatment following the first NICHD panel report in 1994, to the practice of a single course of treatment for all women between 24 and 34 weeks’ gestation who are at risk for preterm delivery within 7 days as recommended by the NICHD Consensus Panel in 2000. More recently, clinical trials support the notion that administration of a single rescue course of corticosteroids before 33 weeks’ gestation improves neonatal outcome (e.g., it decreases RDS, ventilator support, and surfactant use) without apparent increased short-term risk. A single rescue course of antenatal corticosteroids may be considered if the antecedent treatment was given more than 2 weeks prior, the gestational age is less than 32 6/7 weeks, and the woman is judged by the clinician to be likely to give birth within the coming week. However, regularly scheduled repeat courses or multiple courses (i.e., more than two) are not recommended. Betamethasone and dexamethasone, the only drugs found beneficial for this purpose, are potent glucocorticoids with limited if any mineralocorticoid effect. A course of treatment consists of two doses of 12 mg of betamethasone administered intramuscularly twice, 24 hours apart; or four doses of 6 mg of dexamethasone given intramuscularly every 12 hours. Other corticosteroids (prednisolone, prednisone) and routes of administration (oral) are not suitable alternatives because of reduced placental transfer, lack of demonstrated benefit, and, in the case of oral dexamethasone, increased risk of adverse effects when compared with the intramuscular route.

Recent data also suggest that betamethasone can be beneficial in pregnant women at high risk of late PTB , between 34 0/7 weeks and 36 6/7 weeks of gestation and who have not received a prior course of antenatal corticosteroids. The Maternal Fetal Medicine Units (MFMU) Network Antenatal Late Preterm Steroids trial was a double-blind, placebo-controlled, randomized clinical trial designed to evaluate the use of antenatal steroids for women at high risk for late preterm delivery. Women were considered high risk if they presented in preterm labor, had preterm PROM, or if they had a planned delivery in the late preterm period. Tocolysis was not given, and delivery was not delayed for obstetric indications. The administration of steroids led to a decrease in the need for neonatal respiratory support. A larger decrease was demonstrated for severe respiratory complications, from 12.1% in the placebo group to 8.1% in the betamethasone group (RR, 0.67; 95% CI, 0.53 to 0.84; P < .001). There were also improvements in transient tachypnea of the newborn; BPD; a composite of RDS, transient tachypnea of the newborn and RDS; and the need for postnatal surfactant. There was no increase in proven neonatal sepsis, chorioamnionitis, or endometritis with late preterm betamethasone. Hypoglycemia was more common in the infants exposed to betamethasone, 24.0% versus 14.9% (RR, 1.61; 95% CI, 1.38 to 1.88). The American Academy of Pediatrics recommends the monitoring of neonatal blood sugars for late preterm infants.

Groups not included in this trial are women with multiple gestations, women with pregestational diabetes, women who previously had received a course of corticosteroids, and women who gave birth by cesarean at term. Neither the effectiveness nor the safety of steroids in these populations is known.

Fetal Effects

Randomized placebo-controlled trials and meta-analyses confirm the beneficial effects of antenatal corticosteroids. Infants born to treated women were significantly less likely to experience RDS (OR, 0.53), IVH (OR, 0.38), or neonatal death (OR, 0.60). The beneficial effects on IVH are independent of the effects on respiratory function. Other morbidities of PTB are also reduced by antenatal glucocorticoids, including NEC, PDA, and BPD. Although both are considered effective, betamethasone may be superior to dexamethasone with respect to reduction of morbidity and mortality in the preterm newborn.

Other Fetal Effects of Glucocorticoids

Transient reduction in fetal breathing and body movements sufficient to affect the interpretation of the biophysical profile have been described with both drugs but are more common after administration of betamethasone, typically lasting 48 to 72 hours after the second dose. Transient suppression of neonatal cortisol levels has been reported, but neonatal response to ACTH stimulation was unimpaired.

Maternal Effects

Antenatal glucocorticoids produce a transient rise in maternal platelet and white blood cell (WBC) counts that lasts 72 hours; a WBC count in excess of 20,000 is rarely due to steroids. Maternal glucose tolerance is also challenged, and treatment often requires insulin therapy to maintain euglycemia in those with previously well-controlled gestational or pregestational diabetes. Maternal blood pressure is unaffected by antenatal steroid treatment; neither betamethasone nor dexamethasone has a significant mineralocorticoid effect. Women treated with multiple courses of steroids during pregnancy had a blunted response to ACTH stimulation later in pregnancy and in the puerperium.

Duration of Benefit

The duration of the beneficial fetal effects after a single course of glucocorticoids is unclear. The issue is difficult to study because the interval between treatment and delivery in clinical trials is variable and because some effects may be transient, whereas others are permanent. Neonatal benefit has been most easily observed when the interval between the first dose and delivery exceeds 48 hours, but some benefit is evident after an incomplete course . One large multicenter trial found evidence of benefit for as long as 18 days after the initial course of treatment.

Risks of Antenatal Corticosteroid Treatment

The recommendation of the 1994 NICHD Consensus Conference to increase the use of antenatal steroids, coupled with uncertainty about the duration of neonatal protection from a single course of treatment and difficulty in predicting imminent preterm delivery, resulted in increased treatment of mothers at risk. Although more women received treatment, many did not deliver within 7 days but remained at risk and were treated weekly until delivery or 34 weeks’ gestation. The safety and benefit of one course of steroids has never been questioned. Long-term follow-up studies of infants in the original cohorts of infants treated with a single course of antenatal steroids have displayed no differences in physical characteristics or mental function when compared with gestational age–matched controls. The increasing use of repeated courses prompted animal and human studies that have raised concerns about the effects of prolonged exposure to steroids on fetal growth and neurologic function. The animal studies may be summarized as showing reduced fetal growth and adverse brain and neurologic development in several species.

Human studies also observed reduced growth in fetuses exposed to multiple courses of antenatal steroids. An Australian study found a twofold increase in birthweights below the 10th percentile and significantly reduced head circumference in infants exposed to more than three antenatal courses of steroids. Others have also found reduced head circumference. Follow-up work from this Australian study noted that babies exposed to weekly doses of repeat antenatal corticosteroids demonstrate postnatal growth acceleration 3 to 5 weeks after birth.

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