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.

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 Figure 29-4 .

Proportion of all infant deaths in the United States in 2008 by gestational age at birth.

(Modified from Centers for Disease Control and Prevention. Mathews TJ, MacDorman MF. Infant mortality statistics from the 2008 period linked birth/death data set. Natl Vital Stat Rep. 2012; 60[5]:1-27. Available at www.cdc.gov/nchs/vitalstats.htm .)

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 (ICUs). 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 Figure 29-5 .

Cumulative long-term survival by gestational age at birth in 903,402 infants born in Norway.

(Modified from Moster D, Lie RT, Markestad T. Long-term medical and social consequences of preterm birth. N Engl J Med. 2008;359[3]:262-273.)

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 intraventricular hemorrhage (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 [SDs] below the mean, blindness, or deafness), 24% had moderate disability, 34% had mild disability, and 20% had no neurocognitive disability.

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.

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 29-1 and Figure 29-6 .

TABLE 29-1

MAGNITUDE OF INCREASED RISK BASED ON EDUCATION AND RACE/ETHNICITY

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

 

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.

Risk of preterm birth according to educational level (years) by race/ethnicity (see Table 29-1 ).

(Data 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.)

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 29-2 and as shown in Figure 29-7 , their access to early prenatal care.

TABLE 29-2

PRETERM BIRTH RATE PERCENTAGES BY MATERNAL RACE/ETHNICITY AND PRENATAL CARE Access BY TRIMESTER OF INITIATION OF PRENATAL CARE, 1998-2000

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

 

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.

Risk of preterm birth according to access to early prenatal care by race/ethnicity and trimester (see Table 29-2 ).

(Data from National Center for Health Statistics: U.S. Birth Cohorts From 1998 to 2000. 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.)

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.

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. 29-8 ).

Risk of recurrent preterm birth in 19,025 women with two prior births according to the order and gestational age of the previous birth. Very preterm, 21 to 31 weeks’ gestation; moderate preterm, 32 to 36 weeks’ gestation.

(Modified from McManemy J, Cooke E, Amon E, Leet T. Recurrence risk for preterm delivery. Am J Obstet Gynecol. 2007;196[6]:576.e1-e7.)

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.

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 to 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 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 (DHEAS) 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 small for gestational age, 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 .

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 (IUGR)—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 (PGE 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. Figure 29-9 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.

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 progesterone receptor (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 kappa B (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.

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 transvaginal ultrasound; and decidual activation, tested by an assay for FFN in cervicovaginal fluid. Both tests aid diagnosis primarily by reducing false-positive results. Transabdominal ultrasound (TAU) has poor reproducibility for cervical measurement and should not be used clinically without confirmation by a transvaginal ultrasound (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 29-4 ).

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 (FISH) 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.

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 53 and 54 ). 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; the combination of 6 mg each of betamethasone acetate and betamethasone phosphate, 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 (IM) route.

Sequelae of Antenatal Treatments to Reduce Fetal/Neonatal Morbidity

Tocolysis in Preterm Labor

Because the contracting uterus is the most often recognized antecedent of PTB, stopping contractions has been the focus of therapeutic approaches. This strategy is based on the naïve assumption that clinically apparent contractions are commensurate with the initiation of the process of parturition; by logical extension, successfully inhibiting contractions should prevent delivery. The inhibition of myometrial contractions is called tocolysis, and an agent administered to that end is referred to as a tocolytic . Although no medications have been approved for the indication of tocolysis by the U.S. Food and Drug Administration (FDA), a number of classes of drugs are used for this purpose.

Choosing a Tocolytic Agent

Pharmacology

Figure 29-10 depicts a myometrial cell and the sites of action of commonly used tocolytic agents. The key process in actin-myosin interaction, and thus contraction, is myosin light-chain phosphorylation. This reaction is controlled by myosin light-chain kinase (MLCK). The activity of tocolytic agents can be explained by their effect on the factors that regulate the activity of this enzyme, notably calcium and cyclic adenosine monophosphate (cAMP). For the myometrium to contract in a coordinated and effective manner (i.e., labor, whether term or preterm), individual smooth muscle cells must be functionally interconnected and able to communicate with adjacent cells. No agents used for tocolysis influence the function or expression of gap junctions.

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