Prevention and Management of Preterm Parturition

41 Prevention and Management of Preterm Parturition

HYAGRIV N. SIMHAN, MD, MS | VINCENZO BERGHELLA, MD | JAY D. IAMS, MD

Preterm birth is the principal unsolved problem in perinatal to this approach and alternative classification systems that medicine. Nearly 15 million infants were born prematurely in reflect a modern understanding of clinical presentation and 20101—more than 1 in 10 of all births. Over 1 million babies biology. The physiology and pathophysiology of preterm par- die of the consequences of being born too soon: one every 30 turition are discussed in Chapters 6 and 7. This chapter addresses seconds. The majority of premature births—60%—occur in the overall problem of preterm birth, including the epidemiol- south Asia and sub-Saharan Africa. In 2010, the United States ogy and burden of disease for all preterm neonates and specific ranked sixth in the world for the number of babies (517,443) care for the clinical syndrome of preterm labor. pPROM and born preterm. The rate of preterm birth in the United States stillbirth are discussed in Chapters 42 and 45, respectively. rose by more than one-third between 1980 and 2006, even as Newborn and childhood complications of preterm birth are the perinatal and infant mortality rates decreased. In the past discussed in Chapter 73. 10 years, the rate of preterm birth plateaued and, for the first time since 1980, decreased slightly. Advances in care have improved outcomes for preterm infants, but prematurity is still The Problem of Preterm Birth 2 the most common underlying cause of perinatal and infant DEFINITIONS morbidity and mortality3 in developed nations. Consequences of preterm birth for surviving infants extend across the life A birth at less than 245 days after conception (with good ges- course and include neurodevelopmental, respiratory, gastro- tational dating criteria), or at or after 20 and before 37 weeks’ intestinal, and other morbidities. (259 days) gestation from the first day of the last normal men- Preterm birth is a unique condition, defined by time rather strual period, is commonly defined as preterm or premature. than a distinct phenotype or pathology. The duration of preg- Births at or after 37 0/7 weeks are considered to be term, nancy at birth reflects two major correlates of maternal and fetal nomenclature that has been recently revisited to reflect fetal health: (1) whether the birth was occasioned by a normal or an maturity (e.g., 37 weeks: term, near-term, or early term; 39 aberrant pathway, and (2) whether the infant has reached matu- weeks: full term). Infants who weigh less than 2500 g at birth, rity at birth. Infants born at full term after the spontaneous regardless of gestational age, are designated as low birth weight onset of normally progressive labor are most likely to be healthy (LBW). Infants who weigh less than 1500 g are called very low and mature. A process that leads to birth before the fetus has birth weight (VLBW), and those below 1000 g are extremely fully matured suggests that continued pregnancy may carry low birth weight. Preterm and LBW infants have in the past some health risk for the mother or the fetus, or both. Thus, been considered together, but advances in the accuracy of preg- premature parturition may provide a health advantage over nancy dating increasingly allow outcomes related to gestational continued pregnancy for the mother and infant and yet also age to be distinguished from outcomes related to birth weight. may compromise an immature infant’s health. This is important, because perinatal and infant morbidities vary Classifications of preterm birth may advance biologic under- substantially according to age and maturity as well as weight.4 standing, define clinical phenotypes, and aid in designing trials Obstetric data are reported by gestational age. Traditionally and interpreting their data. The most commonly used catego- reported by birth weight, newborn and infant data are increas- ries are based on clinical presentation as either a spontaneous ingly described by gestational age as well.5 or an indicated preterm birth. Spontaneous preterm births are Both lower and upper boundaries of “preterm” are currently preceded by activation of one or more steps of the parturition under scrutiny. The lower boundary between preterm birth and process: cervical ripening, membrane and decidual activation, spontaneous abortion (SAB) was historically based on maternal and coordinated uterine contractility (see Chapter 6). Clinical perception of fetal movement, and it is commonly defined as presentations of spontaneous preterm delivery include preterm 20 weeks’ gestation in the United States, but it varies among labor with intact membranes, preterm premature rupture of states2 and countries. The 20-week boundary is challenged by membranes (pPROM), preterm cervical effacement or insuffi- data showing that pregnancies ending between 16 and 20 weeks ciency, and some instances of uterine bleeding of uncertain have pathophysiology similar to that of births at 20 to 26 weeks, origin. Indicated preterm births are medically caused or initiated and that that pathophysiology confers a similarly increased and are actively undertaken in response to maternal or fetal risk for preterm birth between 16 and 36 weeks in future compromise. This categorization scheme has fallen under scru- pregnancies,6 regardless of whether the fetus was liveborn or tiny in recent years. In this chapter, we address some limitations stillborn.7,8 679

TABLE Gestational Age Terminology 41.1 Description Gestational Age (wk) < 28 Preterm <37 28−31 Late preterm 34 0/7 to 36 6/7 32−33 Term 37 0/7 to 41 6/7 34−36 Early term 37 0/7 to 38 6/7 Full term 39 0/7 to 41 6/7 37−38 Postterm ≥42 39 From Fleischman AR, Oinuma M, Clark SL. Rethinking the definition 40−41 of “term pregnancy.” Obstet Gynecol. 2010;116:136–139. ≥42

14 Figure 41.2 Chart showing relative frequency of births by gesta- Preterm Low birth weight tional age intervals in weeks. (Data from Martin JA, Hamilton BE, 13 Ventura SJ, et al. Births: final data for 2010. Natl Vital Stat Rep. 2012;61:1–72.) 12 11 10

Percent 9 8 < 28 7 28−31 0 32−33 1990 1995 2000 2006 2011 34−36

SOURCE: CDC/NCHS, National Vital Statistics System. Figure 41.1 Rates of liveborn infants who were preterm (<37 weeks) and low birth weight (<2.5 kg), United States, 1990–2011. (From Martin JA, Hamilton BE, Ventura SJ, et al. Births: final data for 2010. Natl Vital Stat Rep. 2012;61:1–72.) Figure 41.3 Gestational age distribution of all preterm births (PTBs). Of all PTBs, 16% occur before 32 weeks’ gestation, 13% occur at 32 to 33 weeks, and 71% occur at 34 to 36 weeks. (Data from Martin Similarly, the disadvantages of an upper boundary based on JA, Hamilton BE, Ventura SJ, et al. Births: final data for 2010. Natl Vital age rather than maturity have become increasingly apparent. Stat Rep. 2012;61:1–72.) Fetal and neonatal maturation are not complete at 37 weeks’ gestation. Infants born at 37 and even 38 weeks display clinical features of immaturity more commonly than those born at 39 More than 70% of preterm births occur between 34 and 36 weeks, and they often suffer related short- and long-term weeks’ gestation (Fig. 41.3). Although these late preterm infants morbidity.9-11 Current practice acknowledges the less-than- experience significant morbidity, most16 perinatal mortality and complete maturity of 37- to 38-week infants by adoption of the serious morbidity occur among the 16% of preterm infants categories shown in Table 41.1. (<3.5% of all births) who are born before 32 weeks’ gestation, commonly called very preterm births (see Fig. 41.3). More than INCIDENCE OF PRETERM BIRTH half (52%) of all infant mortality occurs among infants born before 32 weeks’ gestation.16 Births before 37 weeks in the United States increased annually from 9.4% in 1980 to a peak of 12.8% in 2006. The rate Ascertainment of Preterm Birth and has since fallen each year from 11.99% in 201012 (Figs. 41.1 Low Birth Weight and 41.2) to just under 9.6% in 2015.13 This recent decrease Reported rates of preterm birth vary according to the gesta- is due to many factors. One is certainly a previously inflated tional age boundaries chosen and whether and when prenatal rate due to the use of incorrect gestational age based on LMP. ultrasound was employed. Definitions of preterm birth vary Gestational age is now calculated by the Centers for Disease internationally and within the United States.2 The lower bound- Control and Prevention birth data analysts based on ultra- ary of gestational age is 20 weeks in most of the United States, sound dating. Other reasons include reduced teenage birth rate but it varies from 20 to 24 weeks in other countries.17,18 The and fewer higher-order multiple births. Additionally, a public definition of LBW is universally accepted as a birth weight of policy shift to prevent non–medically indicated births at less less than 2500 g, but the lower boundary ranges from 350 to than 39 weeks’ gestation and smoking bans in several states 500 g, is variably applied, and is often affected by cultural and have been associated with the reduced rate of preterm births. religious beliefs and whether the infant shows signs of life. Low Last, interventions such as 17α-hydroxyprogesterone caproate birth weight is no longer considered an appropriate surrogate (17-OHPC), vaginal progesterone, and the use of cerclage in for preterm birth in developed countries. selected populations may contribute to the reduction in preterm Determination of gestational age by ultrasound measure- deliveries.14,15 ment of fetal structures has greater accuracy than other methods

300 BOX 41.1 AMERICAN SOCIETY OF 250 REPRODUCTIVE MEDICINE RECOMMENDATIONS TO LIMIT 200 HIGHER-ORDER MULTIFETAL 150 GESTATIONS • Use of single-embryo transfer in in vitro fertilization (IVF) 100 cycles to reduce twinning

Per 100,000 births • Use of low-dosage gonadotropins in ovulation induction 50 insemination cycles 0 • Moving from low-dosage ovulation induction drugs directly to IVF cycles rather than to higher-dosage induction cycles 1990 1995 1998 2000 2005 2009 • Extensive education and counseling on the risks of multifetal pregnancies and prematurity for families, professionals, and Non-Hispanic white Non-Hispanic black the public All births Hispanic

NOTE: Triplet/+ births are births in triplet and higher-order multiple deliveries. SOURCE: CDC/NCHS, National Vital Statistics System. Figure 41.4 Triplet and higher-order birth rates by race and His- prior preterm birth, preeclampsia, abruptio placentae, placenta panic origin of mother, United States, 1990–2009. (From Martin JA, previa, fetal growth restriction, maternal diabetes, hyperten- Hamilton BE, Ventura SJ, et al. Births: final data for 2009. Natl Vital Stat sion, pyelonephritis). Designation of clinical presentations (e.g., Rep. 2011;60(1):1–72.) preterm labor and pPROM) as separate pathogenic entities has impaired understanding of the pathways leading to preterm birth. It is more useful to consider preterm birth as preterm when used in the first 12 to 20 weeks of pregnancy. As access to pathologic initiation of one or more steps in the parturition and quality of prenatal ultrasound services have increased, the process, or as a means to resolve maternal or fetal risk (or both) distribution of gestational age has shifted earlier, reducing the related to continuing the pregnancy. number of postterm births and producing a corresponding The concept of spontaneous versus indicated preterm birth increase in births before 37 weeks’ gestation. offered by Meis and colleagues is consistent with this distinction.22 Indicated preterm deliveries account for about 25% of Changes in the Incidence of Preterm Birth preterm births in the United States, and they follow medical or Regardless of the definitions chosen and methods used to deter- obstetric conditions that could create undue risk for the mother mine gestational age, the incidence of preterm birth increased (e.g., maternal sepsis, hypoxia), the fetus (e.g., poorly controlled in developed countries between 1990 and 2006. The rise was maternal diabetes, intrauterine growth restriction), or both caused by the rising number of multifetal pregnancies resulting (e.g., maternal hypertension, placenta previa or abruption) if from assisted reproductive technology (ART), and by practice the pregnancy were to continue. The most common diagnoses changes favoring delivery over expectant management in the leading to indicated preterm birth are preeclampsia (40%), care of complicated late preterm singleton births. The US abnormal fetal status (25%), fetal growth restriction (10%), preterm birth rate rose in singleton pregnancies from 7.3% in placental abruption (7%), and stillbirth (7%).22,23 Other 1990 to a peak of 9.2% in 2006,12 but it has since declined annu- common causes and contributors include pregestational and ally as perinatal and infant morbidities associated with late gestational diabetes, renal disease, Rh sensitization, and con- preterm birth were recognized and reported.19 The frequency of genital malformations.24,25 higher-order multifetal gestations related to fertility therapies Spontaneous preterm births may appear as preterm labor, has also declined significantly since 1998, but only in non- pPROM, or related diagnoses when parturition begins in the Hispanic white women (Fig. 41.4).12,20 The rate of twin preg- apparent absence of maternal or fetal illness. Risk factors associ- nancies has continued to increase. ated with spontaneous preterm birth include genital tract colo- In response to the increased number of preterm infants born nization and infection, nonwhite race, multiple gestation, from multifetal pregnancies after fertility treatments, the Amer- bleeding in the second trimester, low prepregnancy weight, and ican Society for Reproductive Medicine issued guidelines that a history of previous spontaneous preterm birth.26 Approxi- curbed the rise. In 2017, the Society issued recommendations mately 75% of preterm births in developed countries are to achieve successful pregnancies while reducing the risk for spontaneous.22,27,28 preterm birth (Box 41.1).21 The rise in preterm births related to The distinction between indicated and spontaneous preterm fertility therapies is also discussed in Chapter 7. births is not always clear, but the terms are useful as a framework for evaluation of trends and causes of preterm delivery. Clinical Presentations of Preterm Birth Consequences of Preterm Birth Preterm birth has been called multifactorial because of the (See also Chapter 73.) numerous obstetric and medical conditions that accompany it. Traditional obstetric taxonomy has not distinguished the clini- PERINATAL AND INFANT MORTALITY cal presentations of preterm parturition (e.g., preterm labor, pPROM, cervical insufficiency) from causative mechanisms Preterm birth is the leading cause of perinatal and infant mor- such as infection, hemorrhage, uterine distention, trauma, or tality for infants born to women of all races and ethnic back- fetal compromise, or from risk factors (e.g., multiple gestation, grounds, and particularly for non-Hispanic black women.3,29

10 Infant mortality 9 Fetal mortality 8% 30% 8 Fetal death: 20 to 27 weeks 32% Fetal death: 28 weeks + Infant death: Within 7 days Infant death: 7 to 28 days 7

Rate per 1000 30% 6

0 Figure 41.6 Relative magnitudes of fetal and postnatal deaths 1990 1995 2000 2005 contributing to perinatal deaths: United States, 2013. (Data from 2006 MacDorman M, Kirmeyer S. The challenge of fetal mortality. NCHS Data Brief. 2009;(16):1–8.) NOTE: Infant mortality rates are the number of infant deaths per 1000 live births. Fetal mortality rates are the number of fetal deaths at 20 weeks of gestation or more per 1000 live births and fetal deaths. SOURCE: CDC/NCHS, National Vital Statistics System. Figure 41.5 Fetal and infant mortality rates in the United States, age-specific mortality decreased for each gestational age category 1990–2006. (From MacDorman MF, Kirmeyer SE, Wilson EC. Fetal between 2007 and 2013 except 33 weeks and greater than 42 and perinatal mortality, United States, 2006. Natl Vital Stat Rep. weeks. About 31% of the decrease in the US infant mortality rate 2012;60:1–11.) from 2007 through 2013 was due to changes in the gestational age distribution, and 69% was due to improvements in gestational age–specific survival. Improvements in the gestational age distri- The perinatal mortality ratio is defined in two ways accord- bution from 2007 through 2013 benefited infants of non- ing to the boundaries of the fetal and neonatal data reported.2 Hispanic white women (48%) the most, followed by infants of Perinatal definition I begins with fetal deaths at 28 weeks’ gesta- non-Hispanic black (31%) and Hispanic (14%) women. Infant tion and extends to infant deaths at less than age 7 days. Peri- mortality improved between 2007 and 2013 as a result of both natal definition II is more inclusive, comprising all fetal deaths improvements in the distribution of gestational age at birth and at 20 weeks’ gestation or more, and all infant deaths less than improvements in survival after birth. The differential contribu- age 28 days. The denominators for both perinatal rate computa- tion of improvements in the gestational age distribution at birth tions are per 1000 live births and fetal deaths for their respective by race and ethnicity suggests that preconception and antenatal time periods. health, and health care aimed at preventing or delaying preterm Perinatal definition I is most useful when data are compared birth, are not reaching all populations equally. between states, whereas definition II more accurately represents the combined effects of prenatal, intrapartum, and neonatal Factors Affecting Perinatal, Infant, and Childhood care. The infant mortality rate is the number of deaths of live- Mortality and Morbidity born infants before 1 year of age per 1000 live births; stillbirths (See also Chapter 73.) are not included in the denominator. Rates of fetal, perinatal, and infant mortalities have declined since 19902 (Fig. 41.5). Data Collection. Reports of survival and morbidity vary Fetal deaths account for more than half of perinatal deaths according to the denominator employed. Obstetric data and are almost as frequent as infant deaths. In 2013, there were sets include all living fetuses at entry to the obstetric suite,32 23,595 fetal deaths (50.3% between 20 and 27 weeks’ gestation, whereas neonatal data sets exclude intrapartum and delivery and 49.7% after 28 weeks), and 15,983 neonatal deaths (80.7% room deaths and thus report rates based on newborns admit- before 7 days after birth, and 19.3% between 7 and 28 days after ted to the nursery.33 Rates of survival and morbidity at the birth) (Fig. 41.6).30 same gestational age or birth weight are therefore somewhat Preterm birth is the most frequent cause of infant mortality, higher in neonatal data sets and in data from tertiary care accounting for at least a third of infant deaths (Fig. 41.7). Despite centers. A related phenomenon is the influence of inclusion or a rising rate of preterm birth, fetal and infant mortality rates exclusion of pregnancy terminations. Terminations may occur declined between 1990 and 2004. The decline in perinatal mor- without medical or obstetric indication, but they may also be tality was related primarily to a decrease in fetal deaths after 28 predicated on severe growth restriction, absence of amniotic weeks’ gestation, driven by a substantial decline in births and fluid, pPROM, advanced cervical dilation, or a major anomaly stillbirths after 40 weeks and because of an increase in indicated detected at a previable gestational age above the lower thresh- preterm births during this time. The infant mortality rates were old for defining preterm birth. Some of these fetuses either 5.72 and 4.92 per 1000 live births for 2007 and 2013, respectively, are liveborn or die before birth. From a pathophysiologic per- with an absolute difference of −0.80 (14% decrease).31 Infant spective, and in terms of the ultimate consequence of fetal/ mortality rates declined by 11% for non-Hispanic whites, by 19% neonatal death, stillbirths before 24 weeks,34 spontaneous losses for non-Hispanic blacks, and by 14% for Hispanics during the after 16 weeks,35 and terminations have significant common- period. Compared with 2007, the proportion of births in each ality with other preterm births.8 Inclusion of stillbirths and gestational age category was lower in 2013 with the exception of pregnancy terminations will have a major influence on preterm 39 weeks, during which there was an increase in the proportion birth frequency estimates and preterm birth–attributable of births from 30.1% in 2007 to 37.5% in 2013.30 Gestational mortality.

2500 Deaths resulting from conditions caused by preterm birth Deaths resulting from conditions not caused by preterm birth

2000

1500

1000 No. of infant deaths

500

0 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 Gestational age, wk Not stated Figure 41.7 Relative contribution of prematurity-related conditions to overall infant mortality in 2004. Infant mortality increases markedly as gestational age declines. (From Callaghan WM, MacDorman MF, Rasmussen SA, et al. The contribution of preterm birth to infant mortality rates in the United States. Pediatrics. 2006;118:1566–1573.)

Gestational Age. Gestational age is the strongest predelivery Development (NICHD) website (https://www1.nichd.nih.gov/ predictor of survival and morbidity for the infant. The perinatal epbo-calculator/Pages/epbo_case.aspx).38 mortality rate is strongly related to gestational age at birth, Very-Low-Birth-Weight Infants. Regionalized care for especially between 22 and 32 weeks.36 Although mortality high-risk mothers and infants, antenatal fetal treatment with declines sharply after 32 weeks, infants born between 32 and 37 glucocorticoids, neonatal administration of exogenous pulmo- weeks still have increased rates of adverse outcomes. A French nary surfactant, and improved ventilator technology have pro- study of outcomes at 5 years of age for infants born between 30 duced survival rates that now exceed 90%, and survival without and 34 weeks found a progressive decline in rates of perinatal major morbidity in more than 80% of infants born at 28 weeks’ mortality and neonatal morbidity with advancing gestational gestation or weighing 1000 g at birth. age at birth. Rates of cerebral palsy and cognitive impairment Extremely-Low-Birth-Weight Infants. Increasing attention at 5 years of age also declined with advancing gestational age has been paid to infants born at the periviable thresholds of at birth.36 age (22 to 25 weeks’ gestation) and weight (400 to 600 g). In a Neonatal mortality rates at 34, 35, and 36 weeks’ gesta- study of singleton births between 1991 and 1996, 56.1% of 406 tion were 1.1, 1.5, and 0.5 per 1000 live births, respectively, infants born at 24 weeks and 68% of 454 infants born at 25 compared with 0.2 per 1000 live births at 39 weeks, in a weeks survived to hospital discharge.36 Data from the Vermont single US center.19 Five percent of infants born at 34 weeks Oxford Network and the NICHD Neonatal Research Network required neonatal intensive care, compared with 2% of those indicate that rates of survival and morbidity for infants born born at 35 weeks, 1.1% at 36 weeks, 0.6% at 37 weeks, and between 23 and 25 weeks’ gestation are unlikely to improve any 0.5% at 39 weeks. More than three-quarters of late preterm further. Survival rates for extremely-low-birth-weight babies births followed preterm labor or ruptured membranes, with born at 23 to 25 weeks into the tertiary nurseries of the NICHD the remainder caused by obstetric complications. Of 15,136 Neonatal Research Network did not improve between 2003 and late preterm births reported by the Safe Labor Consortium, 2007 from previous reports.39 In 2016, the Society for Maternal- 30% followed preterm labor, 32% followed preterm rupture of Fetal Medicine and the American College of Obstetricians and membranes, 32% were iatrogenic, and 6% had no associated Gynecologists (ACOG) produced an obstetric care consen- diagnosis.37 sus statement on perinatal care at the limits of viability (see Chapter 73).40 Birth Weight. After delivery, birth weight and neonatal sex Survival of infants born weighing less than 500 g is uncom- can be combined with gestational age to predict mortal- mon. A Vermont Oxford Network study reported that 48% of ity. Estimates of neonatal outcomes for infants with birth 4172 infants with birth weights between 401 and 500 g and a weights of 400 to 1000 g that are based on gestational age, mean gestational age of 23.3 weeks died in the delivery room.41 birth weight, sex, treatment with antenatal steroids, and mul- Among 17% who survived to hospital discharge, the mean ges- tiple versus singleton gestation are available from the Eunice tational age was more than 25 weeks, and significant morbidity Kennedy Shriver National Institute of Child Health and Human was universal. Notably, the risk for neonatal mortality does not

Downloaded for Rodrigo Terra ([email protected]) at Clinica Alemana de Santiago - JCon from ClinicalKey.com by Elsevier on October 19, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 684 PART 4 Disorders at the Maternal-Fetal Interface exceed 50% for babies of any ethnicity or race until the gesta- neurocognitive disability.50 More recent data support that the tional age at birth is less than 24 weeks and birth weight is less rate of survival without neurodevelopmental impairment than 500 g. increased between 2000 and 2011 in this large cohort of periviable infants.52 Maternal Race. Perinatal deaths vary significantly by maternal Health care workers regularly overestimate the likelihood race and ethnicity. The perinatal mortality rate in 2004 for and severity of neurologic morbidity in infants born before infants born to non-Hispanic black women in the United States term.53 This is important, because these expectations may was 20.17 (per 1000 live births plus fetal deaths), compared with adversely influence outcomes.54 10.73 for all other racial and ethnic groups.42 Self-esteem among prematurely born infants followed to The relationship of maternal race to risk for neonatal mor- adolescence does not differ from that among persons born at tality is complex. African-American infants have a greater term. Although 24% of 132 adolescents who weighed less than overall perinatal mortality rate than do white or Hispanic 1 kg at birth had significant sensory deficits, they did not differ infants. This higher risk is related to an increased risk for still- from controls of normal birth weight in their self-perception of birth at all gestational ages, especially before 23 weeks’ gestation, global self-worth, scholastic or job competence, or social and an increased risk for neonatal mortality for infants born acceptance.55 at term and after term. However, neonatal mortality rates for black preterm and LBW infants are lower than rates for other Epidemiology and Risk Factors for 43 ethnic groups. Preterm Birth Other Factors. Mortality rates for preterm and VLBW infants Spontaneous preterm birth is similar to other multifactorial are lower if the child is female (odds ratio [OR] = 0.42; 95% disorders, such as cancer or heart disease, wherein multiple confidence interval [CI], 0.29 to 0.61), is growth restricted (OR endogenous and exogenous risk factors interact to cause disease. = 0.58; 95% CI, 0.38 to 0.88), or was treated with antenatal In the case of spontaneous preterm birth, such interaction gen- corticosteroids (OR = 0.52; 95% CI, 0.36 to 0.76), compared erates the premature and often asynchronous initiation of one with infants at the same gestational age who are male, grew or more steps in parturition. As noted earlier, the clinical pre- normally, or did not receive steroids.44,45 Intrauterine infection sentations of preterm labor, pPROM, and cervical insufficiency adversely influences survival and morbidity.45 Mortality rates are indistinct and overlapping. Thus it is not surprising that the also vary among neonatal intensive care units, despite similar risk factors for preterm labor are similar to those for pPROM care practices and patient demographics.46 Therefore local sta- and cervical insufficiency. tistics should be combined with data from the NICHD website38 when counseling patients. MATERNAL CHARACTERISTICS Familial Risk PERINATAL MORBIDITY Studies showing familial risk patterns suggest that there is a Preterm infants are at risk for specific diseases related to the heritable predisposition for preterm birth. Women whose sisters immaturity of various organ systems and the cause and circum- have had a preterm birth have a 1.8-fold higher risk for preterm stances of preterm birth. Common complications in premature delivery,56 and grandparents of women who deliver preterm are infants include respiratory distress syndrome (RDS), intra more likely to have been preterm themselves than the grand- ventricular hemorrhage (IVH), bronchopulmonary dysplasia, parents of women who deliver at term.57 Genetic association patent ductus arteriosus, necrotizing enterocolitis (NEC), studies discovered polymorphisms in several genes in the sepsis, apnea, and retinopathy of prematurity. The frequency of mother and fetus associated with spontaneous preterm birth58-60 major morbidity rises as gestational age decreases, especially and LBW.61 Gene-environment interaction was identified in a before 32 weeks. There is wide geographic variation in the fre- study wherein neither maternal bacterial vaginosis (BV) nor quency of neonatal morbidities, especially for VLBW infants.46 maternal carriage of an allele of the tumor necrosis factor Morbidity rates among survivors also vary according to the (TNF)-α gene was associated with spontaneous preterm birth occurrence of adverse neonatal events47 (see also Chapter 73). if present alone, but the combination significantly increased risk for preterm birth.62 Another study demonstrated that a Long-Term Outcomes polymorphism in the interleukin (IL)-6 gene was related to an Major neonatal morbidities related to preterm birth that carry increased risk for spontaneous preterm birth in African- lifetime consequences include chronic lung disease, grades 3 American women with BV but was not linked to preterm birth and 4 IVH, NEC, and vision and hearing impairment. Increased risk in African-American women who did not have BV or in rates of cerebral palsy, neurosensory impairment, reduced cog- white women regardless of BV status.59 An interaction between nition and motor performance, academic difficulties, and atten- maternal smoking and a genetic polymorphism that increases tion deficit disorders are reported for preterm infants and rise the likelihood of LBW has also been identified.61 These studies in frequency as the gestational age at birth declines.32,48-50 support a role for gene-environment interactions in the patho- Approximately one-third of cases of cerebral palsy have been genesis of spontaneous preterm birth. Studies to date have attributed to early preterm birth (<32 weeks’ gestation).51 A employed both candidate gene and whole genome approaches study of 308 surviving infants born before 25 weeks found that to study DNA variants of biologically suspected genes, with almost all had some disability at age 6 years: 22% had severe limited insight into prematurity causation.63 Alterations in the neurocognitive disabilities (cerebral palsy, IQ > 3 standard devi- regulation of type I collagen expression26 and genetic disorders ations below the mean, blindness, or deafness), 24% had mod- affecting collagen (e.g., Ehlers-Danlos syndrome) have been erate disability, 34% had mild disability, and 20% had no associated with increased risk for preterm birth.27 Familial

TABLE Risk of Preterm Birth (%) by Maternal Race and Education 41.2 Native American Asian or (American Indian Years of Education Non-Hispanic Black Non-Hispanic White Pacific Islander and Eskimo) 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 Data from Behrman RE, Stith Butler A, eds; Institute of Medicine Committee on Understanding Preterm Birth and Assuring Healthy Outcomes. Preterm Birth: Causes, Consequences, and Prevention. Washington, DC: National Academies Press; 2007. collagen disorders may explain familial aggregation of cervical 20 insufficiency.28 As an example, a study of women with and without cervical insufficiency observed that 27% of those with 18 cervical insufficiency had a first-degree relative with the same 16 diagnosis and had polymorphisms in the collagen type I α1 and transforming growth factor-β genes, which appear to be associ- 14 29 ated with this condition. 12 A major limitation in the quest to identify gene sequence Percent variants that increase the risk for preterm birth is the aforemen- 10 tioned heterogeneity of the phenotype of preterm birth. The 8 more pathophysiologically and epidemiologically varied the phenotype, the more difficulty there is in identifying a mean- 0 ingful, parsimonious underlying genetic risk model. 1990 1992 1994 199819962000 200420022006 2008 2010 Year Education and Economic Status, Age, and Marital Status Total Non-Hispanic black Non-Hispanic white Hispanic Low socioeconomic and educational status, low or high mater- Figure 41.8 Preterm birth rates, by race and Hispanic origin: nal age, and single marital status are correlated with an increased United States, 1990–2010. (From CDC/NCHS, National Vital Statistics 64,65 risk for preterm birth. The rate of preterm birth declines System.) with advancing education for all ethnic groups but remains higher among non-Hispanic blacks at all educational levels (Table 41.2). prevalence (20% to 25% of pregnant women smoke) and the Race and Ethnic Background potential for successful intervention.72 The mechanisms by Rates of preterm birth are almost twofold higher among black which smoking is related to preterm birth are unclear, but nico- (African-American and Afro-Caribbean) women (16% to 18%) tine and carbon monoxide are vasoconstrictors that decrease than among Asian, Hispanic, and white women in the United uteroplacental blood flow. Smoking also affects the immune States and Great Britain. Preterm births before 32 weeks are also system. Neutrophil degranulation and superoxide production increased in black women compared with women from other are increased in smokers.73 Cytokine production after in vivo or racial or ethnic groups (Fig. 41.8).12 in vitro stimulation is greater in smokers than in nonsmokers.74 Rates of preterm and LBW infants remain higher for black Smoking might promote preterm birth by altering the immu- women than for white, Asian, or Hispanic women, after control- nology of the reproductive tract. Cigarette smoking in preg- ling for social disadvantage66 and education. Remarkably, nancy is associated with an increase of cervical antiinflammatory preterm birth rates are higher for well-educated, non-Hispanic cytokines without a commensurate increase of proinflamma- black women than for poorly educated, non-Hispanic white, tory cytokines. This may have adverse effects on the host Asian, or Hispanic women (see Table 41.2). response to infection.75 The biologic effects of smoking may Rates of preterm birth among Arab-American women are differ by race. Blacks manifest a higher nicotine intake per ciga- the same as or lower than those among non-Hispanic white rette and also a slower clearance of cotinine (the major nicotine women, despite increased socioeconomic risk.67 Rates of metabolite) in response to cigarette smoking.76 preterm delivery among black women born outside the United Substance abuse may be linked to preterm birth risk directly, States are generally lower than among African-American as well as through concurrent exposure to lifestyle-related risk women or among Afro-Caribbean women living in the United factors such as limited prenatal care, nutritional deficiencies, Kingdom,68 suggesting a risk that is somehow induced or genital tract infections, and cigarette smoking. Marijuana use enhanced by residence in the United States or Britain. has not been independently related to preterm birth. Initial reports associating cocaine with preterm birth resulting from Maternal Behaviors and Environment abruption may have been influenced by ascertainment bias; the Maternal smoking is related to poor pregnancy outcomes such magnitude of the risk for preterm birth among cocaine users is as growth restriction, placental abruption, infant mortality, and now considered uncertain5 (see Chapter 68). Maternal alcohol preterm birth.69-71 Smoking is important because of its high consumption has a complex association with preterm birth,

Downloaded for Rodrigo Terra ([email protected]) at Clinica Alemana de Santiago - JCon from ClinicalKey.com by Elsevier on October 19, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 686 PART 4 Disorders at the Maternal-Fetal Interface with some studies showing no relationship or even a modest Coitus during pregnancy commonly leads to a transient reduction in the rate of preterm birth among light drinkers,23,77 increase in uterine activity91 and is an opportunity to acquire and others confirming an increased risk related to regular and genital tract infections, but self-reported sexual activity was not heavy alcohol intake.77,78 related to the risk for preterm birth in a study of women with Environmental exposures may also predispose to preterm a prior preterm birth.92 The practice of douching before or birth. For example, in a geospatial population-based cohort during pregnancy has been suggested to increase the risk for study using live birth records from Ohio (2007–2010) linked to preterm birth, but the association is confounded by the higher average daily measures of fine (upper limit of 2.5 µm) particu- prevalence of BV in African-American women, who are more 93,94 late matter (PM2.5) air pollution, recorded by 57 Environmental likely to practice douching. Protection Agency network monitoring stations across the state, Nutritional Status exposure to high levels of PM2.5 air pollution during pregnancy is associated with a 19% increased risk of preterm birth, with The risk for preterm birth has been related to maternal nutri- the greatest risk with high third-trimester exposure. Although tional status during pregnancy, as measured by body mass index the risk increase associated with high PM2.5 levels is modest, the (BMI), nutritional intake, and serum markers of nutritional potential impact on overall preterm birth rates is robust because status.95-98 Low maternal prepregnancy weight and BMI have all pregnant women are potentially at risk.79 consistently been associated with spontaneous preterm birth. After adjusting for confounders, Moutquin noted that women Stress and Depression with a BMI of less than 20 were nearly four times as likely as Studies relating preterm birth risk to stress during pregnancy heavier women to have a spontaneous preterm birth.99 Indeed, generally report a modest relationship, with relative risks (RRs) the relationship between low prepregnancy BMI and sponta- of 1.3 to 1.4 for stressful life events such as death of a family neous preterm birth is consistent (OR = 1.7 to 3.9) among member, loss of employment, or divorce.80 Stress is often North American whites,99 African-Americans,100 and urban accompanied by other known risk factors, such as socioeco- Latinas.101,102 Low BMI also modifies the contribution of low nomic disadvantage, smoking, or African-American ethnicity. pregnancy weight gain to the risk for preterm birth.103 Com- Lu and Chen found that adding stress to a statistical model of pared with normal-weight women with adequate weight gain, risk factors for preterm birth in 33,542 women had little effect the risk for spontaneous preterm birth at less than 37 weeks’ on the observed relationship between race and preterm birth; gestation is sixfold greater for underweight women with poor they concluded that stressful life events, even events immedi- gain and threefold greater for normal-weight women with ately preceding or during pregnancy, do not significantly con- poor gain. tribute to racial and ethnic disparities in preterm birth.81 Women with low serum iron, folate, or zinc levels have more Chronic stress may influence preterm birth risk by altering preterm births than those with measurements in the normal immunologic function.82,83 Chronic stress related to long-term range.97 A relationship between folate deficiency and preterm exposure to cultural prejudices and racism is a potential expla- birth was suggested originally in 1944 by Callender, who nation for the disparity in preterm birth rates between African- reported an increased incidence of preterm birth in women American or Afro-Caribbean women and women of other with megaloblastic anemia.104 Since that time, a number of ethnic backgrounds.84 studies have explored whether maternal folate status is linked Depression before and during pregnancy is a risk factor for with preterm birth. Investigations of dietary, supplemental, or adverse pregnancy outcomes, including preterm birth. Clinical biomarker folate in relationship to preterm birth have produced depression occurs in as many as 15% to 35% of women. The conflicting results, probably because of varying ranges and reported relationship between depression and risk for preterm timing of folate assessment, ascertainment of gestational age, birth is modest (less than twofold).85,86 Risk factors for depres- and population characteristics. Interestingly, among low- sion are similar to those related to preterm birth and include income women, low dietary folate has been shown to increase non-Hispanic black race, young age, limited education, and the risk for preterm birth threefold. The mechanisms by which exposure to stressful life events87 (see also Chapter 67). maternal nutritional status might influence preterm birth risk are unclear but may involve effects on uterine blood flow or Maternal Physical Activity resistance to infection.105,106 Work and physical activity have been studied in relationship to risk for preterm birth, with conflicting results. Although rates Infections of preterm birth are lower in women who are employed than (See also Chapter 51.) in those who are unemployed, the risk among employed women may be increased by work that is physically demanding or Genital Tract Infection and Colonization. The risk for stressful. In a European study, the risk for preterm birth was not preterm birth related to infection is sometimes considered to related to employment per se but was increased among women be a risk that is acquired during pregnancy—an accurate who worked more than 42 hours per week (OR = 1.33; 95% CI, concept for extragenital infections such as pyelonephritis or 1.1 to 1.6) or who were required to stand for more than 6 hours pneumonia, but one that does not fully apply to genital tract per day (OR = 1.26; 95% CI, 1.1 to 1.5).88 Work while standing colonization and infection. Prepregnancy colonization of the was associated with preterm birth (OR = 1.56; 95% CI, 1.04 to upper and lower genital tract and the maternal immune 2.60) in a study from Guatemala,89 but this finding was not response to that colonization are increasingly recognized as observed by researchers from North Carolina, where the risk for important aspects of infection-related risk for preterm birth. preterm birth was higher in women who worked nights than in The correlation between genital tract infection and preterm those who worked days.90 There are no data to relate specific birth has long been recognized,107 but the pathways by which work tasks to preterm birth risk. infection leads to preterm birth have not, until recently, been

Downloaded for Rodrigo Terra ([email protected]) at Clinica Alemana de Santiago - JCon from ClinicalKey.com by Elsevier on October 19, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 41 Prevention and Management of Preterm Parturition 687 understood to involve activation of the innate immune system. women (13%) than in other groups.120 It has been associated Microorganisms are recognized by pattern recognition recep- with a modest increase in the risk for preterm birth (RR = 1.3) tors such as Toll-like receptors, which, in turn, elicit the release in some121 but not all122 studies. of inflammatory chemokines and cytokines such as IL-8, IL-1β, Sexually transmitted infections, including Chlamydia tracho- and TNF-α. During intrauterine infection, microbial products matis, syphilis, and gonorrhea, confer an increased risk for and proinflammatory cytokines stimulate the production of preterm birth approaching twofold,123 but eradication of these prostaglandins and other inflammatory mediators as well as organisms does not reduce that risk, suggesting involvement of matrix-degrading enzymes. Prostaglandins stimulate uterine host factors. contractility, and degradation of extracellular matrix in the fetal Clinical markers of genital tract infection that correlate with membranes leads to pPROM.108 The contribution of infection an increased risk for preterm birth include the detection of BV to preterm birth has been estimated to be 25% to 40% on the and an increased level of fetal fibronectin in cervicovaginal fluid basis of microbiologic studies, but this may be an underesti- after 22 weeks’ gestation.124 mate, because intrauterine infection is difficult to detect with Extragenital infections, including pyelonephritis, asymp- conventional culture techniques. For example, molecular tomatic bacteriuria, pneumonia, and appendicitis, are also asso- microbiological studies based on the polymerase chain reaction ciated with preterm birth through mechanisms that are not well show Ureaplasma urealyticum in amniotic fluid samples with understood.125,126 negative cultures.109,110 Intrauterine colonization and infection can occur in the Periodontal Disease. Maternal periodontal disease has been decidua, the chorioamniotic space, or the amniotic cavity. linked to an increased risk for preterm birth,127 but the basis Because microbial colonization is more common in the chorio- for the association is uncertain.128 It most likely results from amnion than in the amniotic cavity, amniotic fluid cultures shared variations in the inflammatory response to microorgan- underestimate the contribution of infection to preterm birth. isms in the oral and genital tracts.129-132 Goepfert and colleagues However, bacteria are known to be present in the chorioamnion demonstrated that, after adjusting for other factors, periodon- in women who deliver healthy infants at term,111 indicating that tal disease was not related to increased intrauterine bacte- bacteria in the chorioamnion do not always generate an inflam- rial colonization, histologic chorioamnionitis, or cord blood matory response that leads to preterm labor and birth. The cytokine levels.133 most common pathway by which microorganisms gain access The biologic pathway explaining the relationship between to the choriodecidua and amniotic cavity is probably ascent periodontal disease and preterm birth is unknown. Variations from the vagina and the cervix, but the timing of this spread is in host response to microbial colonization related to genetic uncertain. It may occur before or during pregnancy.112 Regard- polymorphisms or concurrent environmental exposures, or less of when colonization occurs, intrauterine inflammation is both, have been proposed as contributors to the disparate rates postulated to cause clinical symptoms, such as vaginal dis- of preterm birth among ethnic groups, particularly in relation- charge, cervical effacement, ruptured membranes, or labor, only ship to infection-driven preterm birth,61,134 and may apply to when microbial counts increase as the membranes try to adhere other inflammation at extragenital sites, such as periodontal to the decidua in the second trimester.108 This phenomenon is inflammation. A recent meta-analysis of 11 randomized trials consistent with the strong association between increased con- with a total of 5671 participants showed no clear difference in centrations of fetal fibronectin, the choriodecidual “glue,” in preterm birth less than 37 weeks’ gestation (RR = 0.87; 95% CI, vaginal fluid between 13 and 22 weeks’ gestation, with sponta- 0.70 to 1.10; low-quality evidence) between periodontal treat- neous preterm birth in the second trimester.113 The microor- ment and no treatment.135 ganisms most commonly recovered from the amniotic cavity and chorioamnion are genital mycoplasma species, especially U. Uterine Abnormalities urealyticum, and other organisms of low virulence, consistent Uterine Anomalies. Women with müllerian duct fusion with the chronicity of intrauterine infections and the frequent anomalies have an increased risk for pregnancy loss, with lack of overt clinical signs of infection.108 clinical presentations that vary according to uterine anatomy, Specific Infections. BV, an alteration in the microbial eco- cervical involvement, and placental implantation site.136,137 system of the vagina, is a clinical correlate of lower and upper Preterm births are reported in 25% to 50% of pregnancies genital tract infection. BV is diagnosed clinically by the presence among women with uterine malformations.138,139 Among 246 of clue cells, a vaginal pH greater than 4.5, a profuse white pregnancies in 130 women with uterine anomalies, 20.3% discharge, and a fishy odor when the vaginal discharge is were delivered preterm, 8.5% delivered in the second trimes- exposed to potassium hydroxide.114 BV in pregnancy has been ter, and 25% were first-trimester losses.139 The preterm birth consistently associated with an increased risk for preterm birth, rate was particularly increased (approximately 35%) in women but apparently only as a marker, because eradication of BV from with bicornuate, didelphys, or arcuate uteri, compared with the genital tract of pregnant women does not consistently those who had septate or subseptate uteri (approximately reduce the likelihood of preterm birth.115,116 BV is more com- 15%) in this report. Müllerian fusion anomalies may involve monly detected in African-American women, and it is more the cervix as well as the uterine cavity, so the clinical presen- strongly related to preterm birth in African-American women tation may include cervical insufficiency, bleeding related to than in women of other racial or ethnic backgrounds.117 This abnormal placental implantation, and preterm labor. Clini- association is unrelated to differences in sexual behaviors.118 cal presentations leading to preterm birth in a study of 61 Moreover, eradication of BV does not reduce the risk for women with uterine anomalies included preterm labor in 39%, preterm birth in either African-American or white women.116,119 pPROM in 13.7%, and abruption in 5.9%.140 Prenatal expo- Trichomonas vaginalis is present in 3.1% of women of repro- sure to diethylstilbestrol is associated with an increased risk for ductive age, and it is more common in African-American preterm labor and birth related to the typical T-shaped uterine

100

60 57 50 40 38 40 23 21 20 15 12

Preterm delivery risk (%) 5 0

Very/Very Term/Very Very/ Term Term/Term Moderate/VeryVery/Moderate Term/Moderate Moderate/Term Moderate/Moderate

Prior preterm delivery status by order and gestational age at delivery Figure 41.9 Preterm delivery risk for third births according to gestational age at birth in previous pregnancies. (From McManemy J, Cooke E, Amon E, Leet T. Recurrence risk for preterm delivery. Am J Obstet Gynecol. 2007;196:576.e1–576.e7.) anomaly.141 However, these studies should be interpreted with subsequent pregnancies, the recurrence risk for spontane- caution due to selection bias since uterine abnormalities are ous preterm birth is twofold or higher. This yields an actual usually only ascertained in women with obstetric complica- risk that ranges from 15% to 20% to more than 50% to 60% tions. Most women with uterine anomalies have normal when maternal race, ethnicity, and the number and gesta- pregnancies. tional age of prior preterm deliveries are considered.146-152 The recurrence risk rises in women of all races as the number of Cervical Surgery. Women treated for cervical dysplasia with a prior preterm births increases, with a nearly twofold rise for loop electrosurgical excision procedure (LEEP), or with cervical each prior preterm birth.26 The most recent birth is the most conization using either laser or cold knife, have an increased predictive (Fig. 41.9).153 risk for later preterm birth, but the basis of the association is The risk increases further as the gestational age of the index uncertain. The largest studies of this relationship have come preterm birth declines, especially with gestational age before from Scandinavian registries in which long-term follow-up is 32 weeks.154 A prior preterm birth as early as 16 to 18 weeks possible.142-144 Among 8210 women treated surgically for dyspla- has been found to confer an increased risk in subsequent sia between 1986 and 2003, the risk for preterm birth before 37 pregnancies.35,155 weeks’ gestation was increased after cervical conization (RR = The risk for recurrence is almost twofold higher for non- 1.99; 95% CI, 1.81 to 2.20), as were the risks for birth between Hispanic black women than for any other group. Adams 28 and 31 weeks (RR = 2.86; 95% CI, 2.22 to 3.70) and before and colleagues related maternal race and gestational age 28 weeks (RR = 2.10; 95% CI, 1.47 to 2.99). Risks of LBW and of the initial preterm birth to recurrence risk.152 If the first perinatal death were also increased after conization (RR = 2.06; preterm birth occurred before 32 weeks, the risk for recurrent 95% CI, 1.83 to 2.31, and RR = 1.74; 95% CI, 1.30 to 2.32, preterm birth was 28% for white women and 36% for African- respectively). A Danish cohort of 11,088 women was monitored American women. from 1991 through 2004; of 14,982 deliveries in the cohort, 542 When multiple risk factors occur in African-American occurred between 21 and 37 weeks. The rate of preterm birth women, recurrence rates exceeding 50% have been reported.156,157 was 3.5% in women with no previous LEEP and 6.6% in women In a placebo-controlled trial of 17-OHPC to reduce the risk for previously treated with LEEP (OR = 1.8; 95% CI, 1.1 to 2.9). recurrent preterm birth, 54% of women in the placebo arm A recent meta-analysis suggested that women with a history of delivered before 37 weeks’ gestation, and 30.7% delivered before LEEP have a similar risk of preterm birth when compared to 35 weeks. The mean gestational age at delivery in the qualifying women with prior dysplasia but no cervical excision. Common pregnancy was 31.3 ± 4.2 weeks; 46% of subjects had more than risk factors for both preterm birth and dysplasia likely explain one prior preterm birth, and 59% were African-American.156 In findings of association between LEEP and preterm birth, but another study of 611 women with one (75%) or more (25%) LEEP itself may not be an independent risk factor for preterm prior preterm births, 40% delivered before 37 weeks, and 25% birth.145 This suggests that host factors may be more impor- delivered before 35 weeks’ gestation. One-quarter of the sub- tant than treatment in explaining the associations observed jects in this trial were African Americans.157 These rates are by others. consistent with prior studies showing a 1.5-fold to twofold increased risk for each risk factor (African-American race, REPRODUCTIVE HISTORY more than one prior preterm birth, and gestational age <32 weeks)5,35,146,150 and with prior observational studies.158 Prior Preterm Birth The mechanisms of recurrence are not clear but have been Prior Spontaneous Preterm Birth. Although most women related to short cervix,150 infection,159 and short interpregnancy who experience a preterm birth will deliver at term in interval. After adjusting for confounding variables, a short

Downloaded for Rodrigo Terra ([email protected]) at Clinica Alemana de Santiago - JCon from ClinicalKey.com by Elsevier on October 19, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 41 Prevention and Management of Preterm Parturition 689 interval between pregnancies is associated with a twofold significantly more likely to have a subsequent spontaneous increased risk for preterm birth.160-162 A short interpregnancy preterm delivery. A prior elective abortion did not affect the risk interval is more common among women whose first birth was for subsequent indicated preterm birth. The risk for preterm a preterm birth. birth increased with the number of abortions, and the strength of the association increased with decreasing gestational age at Prior Twin Preterm Birth. Prior preterm birth of twins birth.172 In another study of 12,432 women, rates of preterm confers an increased risk for preterm birth in a subsequent delivery were compared according to the occurrence and singleton pregnancy that is related to the gestational age at number of previous induced abortions; other risk factors were delivery of the index twin pregnancy,151,163,164 as most recently controlled for. Previous induced abortion was associated with found in a study of 1957 women in the Netherlands Perinatal an increased risk for preterm birth (OR = 1.4; 95% CI, 1.1 to Registry with a twin birth followed by a subsequent singleton 1.8), and the risk for preterm delivery increased with the pregnancy.165 The risk for singleton preterm birth was almost number of previous induced abortions (OR = 1.3; 95% CI, 1.0 sevenfold higher (OR = 6.9; 95% CI, 3.1 to 15.2) in women to 1.7 for one previous abortion, and OR = 1.9; 95% CI, 1.2 to whose twins were born before term, an increase similar to that 2.8 for two or more).174 Saccone and associates recently con- reported by Facco and colleagues.164 Menard and coworkers163 ducted a meta-analysis of 36 studies (1,047,683 women).175 found a 40% risk for preterm birth in a subsequent singleton Thirty-one studies reported data about prior uterine evacua- gestation if the prior twin birth occurred before 30 weeks’ gestation for termination, whereas five studies reported data for SAB. tion, a modestly increased risk when the twin birth was at 30 to In the overall population, women with a history of uterine 33 weeks, and no increased risk if the twin birth occurred evacuation for either termination or SAB had a significantly between 34 and 37 weeks. higher risk of preterm birth (5.7% versus 5.0%; OR = 1.44; 95% CI, 1.09 to 1.90), an LBW infant (7.3% versus 5.9%; OR = 1.41; Prior Indicated Preterm Birth. Women with indicated 95% CI, 1.22 to 1.62), and a small-for-gestational-age (SGA) preterm births also have an increased risk for another indicated infant (10.2% versus 9.0%; OR = 1.19; 95% CI, 1.01 to 1.42) preterm birth, because the underlying condition (e.g., maternal compared with controls. Of the 31 studies on termination, 28 diabetes, hypertension) often persists.146,166 Unexplained fetal included 913,297 women with a history of surgical termination, growth restriction can also be recurrent.167,168 In a recent large whereas 3 included 10,253 women with a prior medical termi- cohort study, there were 3836 women who delivered preterm in nation. Women with a prior surgical termination had a signifi- the first observed pregnancy (7.6%), of whom 1160 repeated in cantly higher risk of preterm birth (5.4% versus 4.4%; OR = the second (30.7%).169 The rate of recurrent preterm delivery 1.52; 95% CI, 1.08 to 2.16), an LBW infant (7.3% versus 5.9%; was 31.6% for prior spontaneous, 23.0% for prior indicated, OR = 1.41; 95% CI, 1.22 to 1.62), and an SGA infant (10.2% and 27.4% for prior elective preterm delivery. Prior spontane- versus 9.0%; OR = 1.19; 95% CI, 1.01 to 1.42) compared with ous preterm delivery was associated with an RR of 5.64 (95% controls. Women with a prior medical termination had a similar CI, 5.27 to 6.05) of subsequent spontaneous preterm delivery risk of preterm birth compared with those who did not have a and an RR of 1.61 (95% CI, 0.98 to 2.67) of subsequent indi- history of induced termination of pregnancy (28.2% versus cated preterm delivery. Prior indicated preterm delivery was 29.5%; OR = 1.50; 95% CI, 1.00 to 2.25). Five studies, including associated with an RR of 9.10 (95% CI, 4.68 to 17.71) of sub- 124,133 women, reported data about a subsequent pregnancy sequent indicated preterm delivery and an RR of 2.70 (95% CI, in women with a prior SAB. In all of the included studies, the 2.00 to 3.65) of subsequent spontaneous preterm delivery. Thus SAB was surgically managed. Women with a prior surgical SAB prior indicated preterm delivery was strongly associated with had a higher risk of preterm birth compared with those who subsequent indicated preterm delivery and with increased risk did not have a history of SAB (9.4% versus 8.6%; OR = 1.19; for subsequent spontaneous preterm delivery.169 95% CI, 1.03 to 1.37).175 However, a very large, population-based registry study from Prior Stillbirth. The risk for preterm birth is increased as the Scotland noted a change in this association over time. Overall, gestational age at birth of a prior preterm pregnancy falls. Data previous abortion was associated with an increased risk of from the Stillbirth Collaborative Research Network demon- preterm birth (OR = 1.12; 95% CI, 1.09 to 1.16). When analyzed strated that this observation extends to include spontaneous by year of delivery, the association was strongest in 1980–1983 births that occur before the threshold of viability, so that a (OR = 1.32; 95% CI, 1.21 to 1.43), progressively declined history of stillbirth before 24 weeks’ gestation or “late miscar- between 1984 and 1999, and was no longer apparent in riage” between 16 and 20 weeks also confers an increased risk 2000–2003 (OR = 0.98; 95% CI, 0.91 to 1.05) or 2004–2008 (OR for spontaneous preterm birth after 20 weeks in future pregnan- = 1.02; 95% CI, 0.95 to 1.09). Thus it is possible that more cies.170 This observation is important because these women may modern approaches to abortion, such as medical abortion or be candidates for progesterone prophylaxis, or at least for trans- newer surgical approaches, attenuate the positive relation seen vaginal screening of cervical length.8 in earlier time epochs.176

Pregnancy Termination. Some studies suggest that history of CURRENT PREGNANCY CHARACTERISTICS induced abortion is related to an increased risk for preterm birth in subsequent pregnancies.171-173 Women with more than Bleeding one induced abortion have been found in several studies to have Vaginal bleeding related to placental abruption or placenta a higher risk for subsequent preterm birth, especially for births previa is a recognized cause of preterm delivery, but bleeding before 28 to 32 weeks’ gestation.172-175 A case-control survey of of uncertain origin has also been associated with spontaneous 2938 preterm and 4781 term births in 10 countries reported preterm birth, especially if the bleeding is recurrent or per- that women with a history of induced abortions were sistent.177,178 The mechanism by which bleeding is associated

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The Others have reported a threefold increase in preterm and LBW observation of an increased risk for preterm birth in preg- infants in singletons conceived after controlled stimulation of nancies complicated by an elevated maternal serum alpha ovulation (e.g., with clomiphene as well as gonadotropins).196 fetoprotein not explained by structural fetal anomalies may Notably, a SART study found that extended culture of embryos be related.179-181 First-trimester bleeding in singleton preg- from cleavage stage to blastocyst stage was associated with an nancies after ART has been associated with an increased risk increased risk for preterm birth.193 Singleton IVF births con- for preterm birth. In a review of 1432 singleton pregnancies ceived after blastocyst transfer were at an increased risk for conceived after ART, women with first-trimester bleeding had preterm delivery when compared with births after cleavage- increased rates of pPROM (OR = 2.44; 95% CI, 1.38 to 4.31), stage transfer (18.6% versus 14.4%, respectively; adjusted OR = birth before 37 weeks’ gestation (OR = 1.64; 95% CI, 1.05 to 1.39; P < .001) and very preterm delivery (2.8% versus 2.2%, 2.55), and birth before 32 weeks’ gestation (OR = 3.05; 95% respectively; adjusted OR = 1.35; P < .001). CI, 1.12 to 8.31).182 The rate of preterm birth is also increases Host factors linked to both subfertility and preterm birth, when one fetus in a multifetal gestation is lost, a finding noted and medication effects, are other possible explanations for these among surviving singletons in multifetal gestation conceived associations. by in vitro fertilization (IVF)183 but not in spontaneously conceived pregnancies.184 The risk for preterm birth is increased Multiple Gestation further in higher-order multiple gestations intentionally (See also Chapter 40.) reduced to twins than in gestations of spontaneous twins.185 Multifetal gestations have a sixfold increased risk for preterm These reports suggest that disturbance of the maternal-fetal delivery compared with singleton pregnancies. The risk increases interface in early pregnancy may be associated with risk for with fetal number. In the United States, about 15% to 20% of preterm parturition. all preterm infants are the product of the 3% of pregnancies that are multifetal. More than 50% of twins are born preterm, Assisted Reproductive Technologies most often after spontaneous labor or pPROM before 37 weeks’ Preterm birth is more common in pregnancies conceived after gestation. The remainder deliver preterm because of maternal ovulation induction and ART, including IVF and gamete and or fetal conditions such as preeclampsia or growth restriction. zygote intrafallopian transfer, frozen embryo transfer, and Almost all higher-order multiple gestations deliver before term. donor embryo transfer.186 In the United States in 2014, ART- The risk for early birth rises with the number of fetuses, sug- conceived infants contributed to 4.7% of all preterm (<37 gesting uterine overdistention and fetal signaling as potential weeks’ gestation) infants (range: 1.2% in Puerto Rico to 13.4% pathways to early initiation of labor (Table 41.3). Nevertheless, in Massachusetts). Percentages of preterm births were higher nearly half of women with twins deliver after 37 weeks’ gesta- among infants conceived with ART (33.2%; range: 18.9% in the tion, suggesting that uterine stretch or distention is variably District of Columbia to 45.9% in Puerto Rico) than among all accommodated according to maternal characteristics, including infants born in the total birth population (11.3%; range: 8.5% cervical length, physical activity, uterine tone, and other risk in California to 16.0% in Mississippi).187 factors.197-200 The increased rate of preterm birth after ART is observed in singleton as well as multifetal pregnancies. A review of preg- Uterine Factors nancy outcome of singletons conceived after IVF found Uterine Volume. Increased uterine volume (e.g., polyhydram- increased rates of perinatal mortality (OR = 2.40; 95% CI, 1.59 nios or multiple gestation) is a strong risk factor for preterm to 3.63), preterm birth before 37 weeks’ gestation (OR = 1.93; birth, conferring an RR of 6 or greater.201 95% CI, 1.36 to 2.74), and preterm birth before 33 weeks’ gestation (OR = 2.99; 95% CI, 1.54 to 5.80), as well as increased rates Uterine Contractions. Although uterine contraction fre- of a VLBW infant (OR = 3.78; 95% CI, 4.29 to 5.75), an SGA quency is related to the risk for preterm birth in singletons91,202,203 infant (OR = 1.59; 95% CI, 1.20 to 2.11), and congenital mal- and twins,200 it has not been useful to predict preterm birth formations (OR = 1.41; 95% CI, 1.06 to 1.88), compared with because of wide individual variation in normal pregnancies and spontaneously conceived singleton infants.188 Other meta- the large overlap between women with contractions who do and analyses have drawn similar conclusions: rates of perinatal mor- do not deliver before term.203 tality, preterm birth, LBW and VLBW, and SGA are all increased approximately twofold for singleton infants born after IVF.189-191 Cervical Factors A review of 27 studies found a threefold increased risk for birth Cervical Length. As labor at term approaches, digital exam- before 32 weeks in singleton pregnancies conceived after IVF ination indicates that the cervix shortens, softens, rotates ante- (RR = 3.27; 95% CI, 2.03 to 5.28).192 riorly, and begins to dilate. Softening and shortening are the Potential mechanisms for these associations have been features of the digital examination that most strongly correlate explored in studies from large, prospectively collected data sets with preterm delivery.204 A short cervix measured by transvagi- such as the Society of Assisted Reproductive Technologies nal ultrasound (TVU) is a more reproducible risk factor for (SART) database,193,194 the First- and Second-Trimester Evalua- spontaneous preterm birth.205-208 tion of Risk (FaSTER) study,195 and elsewhere.196 A study of The predictive value of cervical length measurements is FaSTER data found significant associations between ovulation influenced by several factors, including the gestational age induction and placental abruption, fetal loss after 24 weeks, and at measurement. Cervical effacement in normal parturition gestational diabetes, and between IVF and preeclampsia, gesta- begins at about 32 weeks’ gestation, limiting the usefulness of tional hypertension, and placental abruption. LBW, but not cervical length measurements thereafter to excluding preterm preterm birth, was significantly higher in infants born after labor in women with symptoms. Cervical length measurements fresh, compared with frozen and thawed, embryo transfer.194 before 14 to 15 weeks have little relationship to risk for preterm

TABLE Percentages of Preterm and Low-Birth-Weight Births by Order of Gestation 41.3 Births Twin Triplet Quad Quint GESTATIONAL AGE <32 wk 11.8 35.9 64.9 81.4 <37 wk 59.7 93.0 95.9 100 Mean age (±SD) 35.2 ± 3.6 32.1 ± 3.9 29.7 ± 4.5 28.4 ± 2.7 BIRTH WEIGHT <1.5 kg 10.2 33.2 65.1 84.9 <2.5 kg 56.6 94.1 98.4 100 Mean weight (±SD) 2.333 ± 0.634 1.700 ± 0.559 1.276 ± 0.552 1.103 ± 0.383 SD, Standard deviation. Data from Martin JA, Hamilton BE, Sutton PD, et al. Births: final data for 2004.Natl Vital Stat Rep. 2006;55:80–81.

population (see Medical and Surgical Interventions to Prevent Preterm Birth, later). (Fig. 41.11). The RR and positive predictive value of cervical length measurements below the 5th percentile are influenced only slightly by a prior history of preterm birth,214,215 but they are significantly influenced by the gestational age at measurement.216 Table 41.4 displays the likelihood of preterm birth before 35 weeks in women with a previous 1 preterm birth according to cervical length and gestational age at measurement.217 Although short cervix is related to preterm birth, it is not necessarily diagnostic of cervical insufficiency. A short cervix can be viewed as evidence that the process of parturition has begun, but it gives no indication of the cause. Choriodecidual inflammation resulting from infection or hemorrhage, uterine 1 D2 10cm overdistention, and acquired or congenital cervical insufficiency 2 D1 90cm may all appear with short cervix. Traditionally, cervical insuf- Figure 41.10 Endovaginal ultrasound image of a normal cervix at ficiency has been defined by four historical criteria—(1)pain - 24 weeks’ gestation. The closed portion of the cervical canal is mea- less cervical dilation, leading to (2) recurrent, (3) second-trimester sured from the external os, identified as the most distal point at which births in the (4) absence of other causes—in the belief that these anterior and posterior walls of the canal touch, to the internal os, identified as the most proximal point where the walls touch. The cervix in this criteria identified women whose early births were caused solely image is measured in two segments because of the curved canal, a by structural weakness of cervical tissue that could be corrected normal finding. The length is 40 mm, the 75th percentile. The internal by surgical repair. However, it has become clear that these cri- os is closed, forming a “T” relationship to the canal. teria do not distinguish women with structural cervical weakness from those in whom preterm parturition from other causes has begun in the second trimester. Studies of ultrasound images birth.209 Cervical length in the second trimester has been most of cervical changes during pregnancy and related treatment studied. The 50th, 10th, and 3rd percentiles between 16 and 22 trials have altered traditional concepts of cervical insufficiency weeks in studies of women with singleton gestations without a and preterm parturition. Cervical shortening is now under- prior spontaneous preterm birth are approximately 40, 30, and stood to occur often as an early step in parturition rather than 25 mm,207,210 respectively, when measured with a standardized being a hallmark of cervical insufficiency. This conclusion arises TVU technique211 (Fig. 41.10). Between 22 and 32 weeks, these from evidence that progestogen supplementation rather than percentile values are 35, 25, and 15 mm, respectively.206,208 In cerclage is the appropriate initial treatment for short cervix in an observational study of 2915 women,206 a cervical length of women with singleton gestations without a prior spontaneous 25 mm or less (the 10th percentile) at 22 to 24 weeks’ gestation preterm birth.418,419,435 The current challenge is to identify was associated with an RR of 6.5 (CI, 4.5 to 9.3) for preterm women before conception or in early pregnancy who have birth before 35 weeks, and an RR of 7.7 (CI, 4.5 to 13.4) for impaired cervical strength that is best treated surgically, and to preterm birth before 32 weeks. Serial measurements improve distinguish them from women who are best treated medically. predictive value, but additional observations of funneling and The diagnosis of cervical insufficiency is thus one of exclusion, dynamic changes do not.212,213 “Short cervix” has been most to be made in women with risk factors for, or evidence of, ana- often defined as below the 10th percentile (25 mm at 22 to tomic abnormalities, and in whom early parturitional cervical 24 weeks), but the 5th percentile (20 mm) has been another ripening is not present, recognizing that cervical cerclage may useful threshold in clinical practice. Commonly, 25 mm is improve outcomes for the latter as well as the former. used as an action threshold for short cervix among women Cervical Trauma. A cervical laceration may occur during with prior spontaneous preterm birth and 20 mm is used as labor or in the process of delivery, including spontaneous, an action threshold among women in the general obstetric forceps, vacuum, or cesarean birth,26 that might weaken the

TABLE Probability of Preterm Delivery Before Week 35, in Singleton Gestations With Prior Spontaneous Preterm 41.4 Birth, as Predicted by Cervical Length

Week of Pregnancy Cervical Length (mm) 15 16 17 18 19 20 21 22 23 24 25 26 27 28 0 69.8 68.7 67.5 66.3 65.2 64.0 62.7 61.5 60.2 59.0 57.7 56.4 55.1 53.8 5 62.5 61.3 60.0 58.7 57.5 56.2 54.9 53.6 52.2 50.9 49.6 48.3 47.0 45.7 10 54.6 53.3 52.0 50.7 49.4 48.1 46.7 45.4 44.1 42.8 41.6 40.3 39.0 37.8 15 46.5 45.2 43.9 42.6 41.3 40.1 38.8 37.6 36.3 35.1 33.9 32.8 31.6 30.5 20 38.6 37.3 36.1 34.9 33.7 32.5 31.4 30.3 29.2 28.1 27.0 26.0 25.0 24.0 25 31.2 30.1 29.0 27.9 26.9 25.8 24.8 23.9 22.9 22.0 21.1 20.3 19.4 18.6 30 24.7 23.7 22.8 21.8 21.0 20.1 19.3 18.5 17.7 16.9 16.2 15.5 14.8 14.2 35 19.1 18.3 17.5 16.8 16.1 15.4 14.7 14.1 13.4 12.8 12.2 11.7 11.2 10.6 40 14.6 13.9 13.3 12.7 12.1 11.6 11.1 10.6 10.1 9.6 9.2 8.7 8.3 7.9 45 11.0 10.5 10.0 9.6 9.1 8.7 8.3 7.9 7.5 7.2 6.8 6.5 6.2 5.9 50 8.2 7.8 7.4 7.1 6.7 6.4 6.1 5.8 5.5 5.2 5.0 4.7 4.5 4.3 55 6.0 5.7 5.5 5.2 4.9 4.7 4.5 4.3 4.0 3.8 3.7 3.5 3.3 3.1 60 4.4 4.2 4.0 3.8 3.6 3.4 3.3 3.1 3.0 2.8 2.7 2.5 2.4 2.3 Data from Berghella V, Roman A, Daskalakis C, et al. Gestational age at cervical length measurement and incidence of preterm birth. Obstet Gynecol. 2007;110:311–317.

tertiary strategy to reduce perinatal morbidity and mortality regardless of the clinical presentation leading to preterm birth. This section describes clinical management of preterm labor. Chapters 42 and 47 address clinical management of the related 1 conditions of preterm ruptured membranes and fetal growth restriction, respectively. Treatment of symptomatic preterm labor is directed at arresting labor long enough to (1) transfer the mother to an appropriate hospital for delivery and (2) allow administration of corticosteroids; these two interventions have consistently been shown to reduce perinatal mortality and morbidity. Other interventions directed at reducing neonatal and infant morbidity and mortality include predelivery antibiotics and neuroprotectants.

Figure 41.11 Endovaginal ultrasound image of a cervix at 25 DIAGNOSIS OF PRETERM LABOR weeks’ gestation, showing Y-shaped funneling at the internal os. The cervical length is 21.3 mm, approximately the 5th percentile. Symptoms and Signs Diagnosis of preterm labor is challenging, because the sequence cervix. Examples that suggest cervical trauma include a prior and timing of events that precede preterm labor are incom- pregnancy concluded at term with a prolonged second stage of pletely understood. Because the progression from subclinical labor followed by a difficult vaginal birth, or by a cesarean birth preterm parturition to overt preterm labor is often gradual, the with an extended uterine incision or laceration. traditional criteria for the diagnosis of preterm labor (painful uterine contractions accompanied by cervical change) lack pre- Interventional Strategies for cision. The result is overdiagnosis in as many as 40% to 70% Preterm Labor of women diagnosed with preterm labor, leading to enrollment of women not in labor into trials of agents to arrest Efforts to prevent the morbidity and mortality associated with preterm labor.218 Some women treated to arrest preterm labor preterm birth may be categorized as tertiary (initiated after the who were thought to have been treated successfully may not process of parturition has begun, with a goal of preventing have required treatment at all; the true result of treatment is delivery or improving outcomes for preterm infants), secondary confidently known only for those whose treatment was unsuc- (aimed at eliminating or reducing risk in women with known cessful. Reliable studies of methods to arrest preterm labor risk factors), or primary (directed to all women before or during will not be possible until more accurate diagnostic criteria are pregnancy to prevent and reduce risk). established. Most obstetric care for preterm birth has been focused on Preterm labor must be considered whenever abdominal or tertiary interventions such as regionalized perinatal care, tocol- pelvic symptoms occur after 16 weeks’ gestation. Symptoms ysis, antenatal corticosteroids, antibiotics, and optimal timing including pelvic pressure, increased vaginal discharge, back- of indicated preterm birth. These measures are intended to ache, and menstrual-like cramps occur commonly during reduce the burden of prematurity-related illness and have normal pregnancy, and they suggest preterm labor more by minimal, if any, effect on the incidence of preterm birth. Chapter their persistence than their severity. Contractions may be 36 describes appropriate use of antenatal glucocorticoids as a painful or painless, depending on the resistance offered by the

cervix. Contractions against a closed, uneffaced cervix are likely Symptoms of to be painful, but recurrent pressure or tightening may be the preterm labor only symptoms when cervical effacement precedes the onset of contractions.219 The traditional criteria—persistent uterine contractions accompanied by dilation or effacement of the CL < 20 mm CL > 30 mm cervix (or both)—are reasonably accurate at identifying women CL 20-29 mm at risk for imminent delivery if the contraction frequency is six or more per hour and cervical dilation is 3 cm or greater or effacement is 80% or greater, or if membranes rupture or bleeding occurs.220,221 When lower thresholds for contraction fre- FFN POS FFN NEG Discharge quency and cervical change are used, false-positive diagnosis is common,218,220 but sensitivity does not necessarily increase.222 Accurate diagnosis of early preterm labor is difficult, because 223 91 Treat /MD the symptoms and signs of preterm labor occur commonly discretion in normal women who do not deliver before term, and because digital examination of the cervix in early labor (at <3 cm dila- If contractions persist tion and <80% effacement) is not highly reproducible.224-226 consider observation for 24 hours Tests for Preterm Labor Women with symptoms whose cervical dilation is less than 2 cm or whose effacement is less than 80% present a diagnostic challenge with respect to identifying risk for imminent Not stable Stable delivery. MD discretion Discharge Diagnostic accuracy can be improved by TVU measurement Figure 41.12 Preterm labor evaluation protocol. CL, Cervical of cervical length or by testing for fetal fibronectin in cervico- length; FFN, fetal fibronectin; NEG, negative (<50 ng/dL); POS, positive vaginal fluid.227-232 Both tests improve diagnostic accuracy by (≥50 ng/dL). (From Ness A, Visintine J, Ricci E, Berghella V. Does knowledge of cervical length and fetal fibronectin affect management of reducing the number of false-positive diagnoses. Transabdomi- women with threatened preterm labor? A randomized trial. Am J Obstet nal sonography has poor reproducibility for cervical measure- Gynecol. 2007;197:426.e1–426.e7.) ment and should not be used clinically without confirmation by TVU.233 A cervical length of 30 mm or more by endovaginal sonography suggests, if the examination is properly performed, that preterm labor is unlikely despite symptoms. Similarly, a mothers and infants are designated level I. Larger hospitals that negative fibronectin test in women with symptoms before 34 care for the majority of maternal and infant complications are weeks’ gestation and cervical dilation of less than 3 cm can also designated level II centers; these hospitals have neonatal intensive reduce the rate of false-positive diagnosis if the result is returned care units staffed and equipped to care for most infants with promptly and, importantly, if the clinician is willing to act on birth weights greater than 1500 g. Level III centers typically a negative test result by not initiating treatment.226,228,232 A com- provide care for the sickest and smallest infants, and for maternal monly used algorithm (Fig. 41.12) increased the efficiency of complications requiring intensive care. This approach has been evaluation and reduced the incidence of spontaneous preterm associated with improved outcomes for preterm infants.239,240 birth.234 One key point regarding the utility of the fibronectin test is that the clinician must be willing to avoid treatment in Strategies to Reduce Morbidity and Mortality the setting of a negative test; the more treatment that is pre- Antenatal Corticosteroids. Antenatal corticosteroids (see scribed to women with a negative fibronectin test, the lower the Chapter 36) promote maturation of the developing fetus. In the utility of the test. lung, corticosteroids promote surfactant synthesis, increase Clinical markers for high risk of imminent preterm delivery lung compliance, reduce vascular permeability, and improve the in women with symptoms include ruptured membranes, vaginal postnatal surfactant response. Also, antenatal corticosteroids bleeding, and cervical dilation beyond 2 cm.235 Among women have similar maturational effects on other organs including the with intact membranes, no bleeding, and cervical dilation less brain, kidneys, and gut. than 3 cm, the combination of a positive fibronectin test and a Studies by Liggins and Grieves241 of mechanisms of parturi- sonographic cervical length of less than 30 mm predicted tion in sheep led to the serendipitous discovery of the beneficial increased risk for delivery within 48 hours (26%); the risk was effect of antenatal glucocorticoids on the maturation and per- less than 7% if only one or neither test is positive.236 The pres- formance of the lungs in prematurely born infants. Subsequent ence of debris (or “sludge”) in amniotic fluid near the internal studies have shown conclusively that antepartum administra- os on TVU has also been associated with increased risk for tion of betamethasone or dexamethasone reduces the risk for delivery within 48 hours237 and with intraamniotic infection238 neonatal death, RDS, IVH, patent ductus arteriosus, and NEC. in women with symptoms of preterm labor. Guidelines for appropriate clinical use of antenatal corticosteroids have evolved from initial skepticism and selective use, Management of Preterm Labor through a period of broad and repeated treatment after the first Regionalized Care. Many states have adopted systems of NICHD panel report in 1994, to the practice of a single course regionalized perinatal care in recognition of the advantages of of treatment recommended by the NICHD Consensus Panel in concentrating care for preterm infants, especially those born 2000. More recently, clinical trials support the notion that before 32 weeks. Hospitals and birth centers caring for normal administration of a single rescue course of steroids before 33

Downloaded for Rodrigo Terra ([email protected]) at Clinica Alemana de Santiago - JCon from ClinicalKey.com by Elsevier on October 19, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 694 PART 4 Disorders at the Maternal-Fetal Interface weeks’ gestation improves neonatal outcome (e.g., decreased with pPROM have reduced perinatal morbidity when antepar- RDS, ventilator support, and surfactant use) without an appar- tum antibiotic prophylaxis has been administered (see Chapter ent increase in short-term risk.242A rescue course may be con- 42).26,246 Antibiotic therapy for women with preterm labor and sidered if the initial treatment was given more than 2 weeks with intact membranes has not been effective in prolonging before, and if the gestational age is less than 32 6/7 weeks, in a pregnancy or reducing morbidity247-251 and should be limited to woman judged to be at risk for imminent delivery. However, prophylaxis of GBS transmission or treatment of a specific regularly scheduled repeat courses or multiple courses (more pathogen (e.g., a urinary tract infection).245 than two) are not recommended.243 Betamethasone and dexamethasone, the only drugs found beneficial for this purpose, are Neuroprotectants. Because of the strong association of early potent glucocorticoids with limited if any mineralocorticoid preterm birth with neurodevelopmental morbidity, an antena- effect. A course of treatment consists of two doses of 12 mg of tal or perinatal intervention to reduce this risk has been sought. betamethasone (a combination of 6 mg each of betamethasone Phenobarbital was the first such agent to be studied for this acetate and betamethasone phosphate) administered intramus- purpose, but it did not reduce IVH when given alone or in cularly 24 hours apart, or four doses of 6 mg of dexamethasone combination with vitamin K.252-254 given intramuscularly every 12 hours. Other corticosteroids Reports from observational studies of reduced rates of IVH, (prednisolone, prednisone) and routes of administration (oral) cerebral palsy, and perinatal mortality in premature infants are not suitable alternatives because of reduced placental trans- whose mothers received antenatal magnesium sulfate (MgSO4) fer, lack of demonstrated benefit, and, in the case of oral dexa- prompted large, randomized, placebo-controlled trials of ante- methasone, increased risk for adverse effects when compared natal magnesium. The first trial enrolled 1062 women who with the intramuscular route. We administer steroids if preterm delivered before 30 weeks’ gestation.255 Gross motor dysfunc- birth is expected within 7 days. tion at 2 years of age was significantly reduced, and mortal- Recent data also suggest that betamethasone can be benefi- ity and cerebral palsy were less common among infants born cial in pregnant women at high risk of late preterm birth, to magnesium-treated mothers. No significant adverse effects between 34 0/7 and 36 6/7 weeks’ gestation who have not were noted in infants exposed to antenatal MgSO4. Two sub- received a prior course of antenatal corticosteroids. The Mater- sequent trials256,257 also reported reductions in neurologic mor- nal Fetal Medicine Units Network Antenatal Late Preterm Ster- bidity and cerebral palsy among magnesium-treated infants. 244 oids trial was a double-blind, placebo-controlled, randomized Available evidence suggests that MgSO4 given before antici- clinical trial designed to evaluate the use of antenatal steroids pated early preterm birth reduces the risk for cerebral palsy in for women at high risk for late preterm delivery. Women were surviving infants.258 identified to be at high risk if they presented in preterm labor, The neuroprotective effect of antenatally administered mag- had pPROM, or had a planned delivery in the late preterm nesium was assessed in a meta-analysis of five trials covering period. Tocolysis was not given as a part of this trial, and deliv- two gestational age groups (5235 fetuses at <32 to 34 weeks, and ery was not delayed for obstetric or medical indications. The 3107 fetuses at <30 weeks).258 Major findings were similar for administration of betamethasone led to a significant decrease both gestational age groups: in the need for neonatal respiratory support. A larger decrease • There were statistically significant reductions in the risk was demonstrated for severe respiratory complications, from for “cerebral palsy” (RR = 0.7 for the <32- to 34-week 12.1% in the placebo group to 8.1% in the betamethasone group, and RR = 0.69 for the <30-week group) and in the group (RR = 0.67; 95% CI, 0.53 to 0.84; P < .001). There were risk for “death or moderate to severe cerebral palsy” (RR also significant decreases in the rates of transient tachypnea of = 0.85 for the <32- to 34-week group, and RR = 0.84 for the newborn, bronchopulmonary dysplasia, a composite of the <30-week group). transient tachypnea of the newborn and RDS, and the need for • The largest reduction in risk was for “moderate to severe postnatal surfactant. There was no increase in proven neonatal cerebral palsy”: sepsis, chorioamnionitis, or endometritis with late preterm • <32 to 34 weeks: RR = 0.60 (95% CI, 0.43 to 0.84) betamethasone. Hypoglycemia was more common in the infants • <30 weeks: RR = 0.54 (95% CI, 0.36 to 0.80) exposed to betamethasone (24.0% versus 14.9%; RR = 1.61; • The numbers needed to treat to prevent one case of cere- 95% CI, 1.38 to 1.88). The American Academy of Pediatrics bral palsy in the <32- to 34-week group and in the recommends the monitoring of neonatal blood sugars for late <30-week group were 56 and 46 women, respectively. preterm infants because late preterm birth is a known risk The three trials using MgSO4 for fetal neuroprotection reported factor for hypoglycemia. slightly different administration regimens. All began with an Groups not included in this trial are women with multiple intravenous bolus of MgSO4 (4 or 6 g over 30 minutes), fol- gestations, women with pregestational diabetes, women who lowed by 1 to 2 g per hour for 12 to 24 hours in two trials and previously had received a course of corticosteroids, and women without maintenance doses in the third. The ACOG recom- who gave birth by cesarean at term. Whether or not late preterm mends that hospitals select and adhere to one of the reported corticosteroids provide benefit in these populations is unknown. regimens. Neither the neuroprotective mechanism nor the response Antibiotics. Women with preterm labor should be treated to MgSO4 is well understood. Although it seems likely that with prophylactic antibiotics only if the purpose is to prevent the neuroprotective effects of MgSO4 result from residual neonatal group B Streptococcus (GBS) infection (see Chapter concentrations of the drug in the neonate’s circulation, data 51). Because preterm infants have an increased risk for neonatal are insufficient to determine the maternal dosage that confers GBS infection, compared with infants born at term, intra neonatal benefit. MgSO4 given at doses used for neuropro- partum prophylaxis with penicillin or ampicillin is recom- tection has not been reported to cause neonatal lethargy or mended.245 There is also evidence that infants born to women hypoventilation.256,257

Hydration. In a clinical trial to identify women with true accompanied by maternal hypertension places both mother and preterm labor, 179 women with preterm contractions and fetus at risk for acute hypertensive crises, and it may occur in minimal cervical dilation were randomly assigned to receive response to fetal stress or distress, uterine ischemia, or occult either intravenous hydration and observation without interven- placental abruption. Although vaginal spotting may occur in tion or observation after a single dose of 0.25 mg subcutaneous women with preterm labor because of cervical effacement or terbutaline.259 Intravenous hydration did not decrease preterm dilation, any bleeding beyond light spotting is rarely due to contractions. labor alone. Placenta previa and abruption must be considered, because both may be accompanied by uterine contrac- TOCOLYTIC THERAPY tions. In general, both diagnoses place a woman at greater risk for hemodynamic compromise in the setting of tocolytic Goals of Tocolysis treatment. However, tocolysis in women with these dangerous Because the contracting uterus is the most easily recognized diagnoses may sometimes be considered to allow time for the antecedent of preterm birth, stopping contractions has been administration of corticosteroids (e.g., in the setting of extreme the focus of therapeutic approaches. This strategy is based on prematurity when bleeding is believed to occur in response to the historical belief that clinically apparent contractions are contractions). Such treatment is fraught with difficulty, because commensurate with the initiation of the process of parturition; even low dosages of some tocolytic agents can be hazardous in by logical extension, successfully inhibiting contractions should this situation. β-Mimetic agents and calcium channel block- prevent delivery. The failure of this approach to reduce preterm ers may hamper maternal cardiovascular response to hypoten- birth is evidence of the fallacy of the underlying assumption. sion, and prostaglandin inhibitors may impair platelet function. The inhibition of myometrial contractions is called tocoly- Cardiac disease is a contraindication because of the risks of sis, and an agent administered to that end is referred to as tocolytic drug treatment reported in these patients. Fetal con- a tocolytic. Although no medications are currently approved traindications to tocolysis include gestational age of greater for tocolysis by the US Food and Drug Administration (FDA), than 37 weeks, fetal demise or lethal anomaly, chorioamnionitis, calcium channel blockers, nonsteroidal antiinflammatory drugs and evidence of fetal compromise that requires prompt delivery. (NSAIDs), and β-agonists are the most commonly tocolytics used in practice, and for this purpose are within FDA guidelines Choosing a Tocolytic Agent that allow physicians to prescribe medications for off-label use. The key process in actin-myosin interaction, and thus contrac- The appropriate benchmark to assess the efficacy of tocolytic tion, is myosin light-chain phosphorylation. This reaction is agents is improved health outcome for infants born to women controlled by myosin light-chain kinase. The activity of toco- with preterm parturition, but most studies have insufficient lytic agents can be explained by their effect on the factors regu- power to assess the effect of treatment on this end point. One lating the activity of this enzyme, notably calcium and cyclic placebo-controlled trial of transdermal nitroglycerin treatment adenosine monophosphate. For the myometrium to contract in for preterm labor before 28 weeks’ gestation reported a sig- a coordinated and effective manner (i.e., labor, whether term or nificant decrease in composite neonatal morbidity in infants preterm), individual smooth muscle cells must be functionally born to treated mothers,260 but such trials are uncommon, so interconnected and able to communicate with adjacent cells. meta-analyses and surrogate end points (e.g., delay in deliv- There are no agents used for tocolysis that influence the func- ery) are more commonly used to assess efficacy and safety. The tion or expression of gap junctions. Tocolytic drugs may be Cochrane Collaboration (see http://www.cochrane.org) regu- safely used when standard protocols are followed. Selection of larly conducts meta-analyses of tocolytic drugs; recent Cochrane the appropriate tocolytic requires consideration of the efficacy, reviews concluded that calcium channel blockers such as nife- risks, and side effects to identify the optimal agent for each dipine and the oxytocin antagonist atosiban can delay delivery patient. by 2 to 7 days with a favorable ratio of risk to benefit.261,262 The Cochrane analyses concluded that β-mimetic drugs can Calcium Channel Blockers delay delivery by 48 hours but have greater side effects than Pharmacology. Calcium channel blockers, marketed to treat 263 264 other agents, that MgSO4 is ineffective, and that the data on hypertension, angina, and arrhythmias, are increasingly being cyclooxygenase (COX) inhibitors are not sufficient to support used as tocolytic agents. The pharmacologic effect probably conclusions.265 occurs by inhibition of the voltage-dependent channels of These reviews form the basis for clinical algorithms, but they calcium entry into smooth muscle cells, which results in are limited by the design and size of the original research decreased intracellular calcium and decreased release of stored studies. Because parturition is a gradual process with an acceler- calcium from intracellular storage sites. Nifedipine is the ated phase of active labor that can be difficult to identify until calcium channel blocker most commonly used as a tocolytic well underway, it is extremely difficult for researchers to identify agent. Calcium channel blockers are rapidly absorbed after oral both the appropriate population and the appropriate moment administration. Pharmacokinetics in pregnancy are similar to to use tocolysis. Selection of the best tocolytic drug is less those in the nonpregnant state. Nifedipine appears in plasma important than selecting the patient for whom adjunctive ther- within a few minutes after oral administration, reaches peak apies are appropriate and who would soon progress to delivery concentrations at 15 to 90 minutes, and has a half-life of 81 without tocolysis. minutes.266 Placental transfer occurs within 2 to 3 hours after administration of oral nifedipine. In the mother, the duration Contraindications to Arrest of Labor of action of a single dose is up to 6 hours. Common maternal contraindications to tocolysis include severe preeclampsia or severe gestational hypertension, hemor- Effectiveness. There are no placebo-controlled trials of calcium rhage, and significant maternal cardiac disease. Preterm labor channel blockers as tocolytics. The Cochrane Collaboration

Downloaded for Rodrigo Terra ([email protected]) at Clinica Alemana de Santiago - JCon from ClinicalKey.com by Elsevier on October 19, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 696 PART 4 Disorders at the Maternal-Fetal Interface meta-analyses support the use of calcium channel blockers as convenient. However, efficacy is not established by placebo- short-term tocolytics over other available agents because they controlled trials, and the ideal dosage regimen is not clear. In exhibit greater contraction suppression and fewer side effects general, nifedipine should not be combined with magnesium than other agents in 12 reported trials.267 Rates of birth occur- or β-mimetics, and it should be avoided in women with hyper- ring within 7 days after treatment (RR = 0.76; 95% CI, 0.60 to tension or cardiac disease. 0.97) and before 34 weeks’ gestation (RR = 0.83; 95% CI, 0.69 to 0.99) were significantly reduced with calcium channel block- Cyclooxygenase Inhibitors ers, as were the rates of neonatal morbidities, including RDS Pharmacology. Prostaglandin synthesis is reduced by inhi- (RR = 0.63; 95% CI, 0.46 to 0.88), NEC (RR = 0.21; 95% CI, bition of COX by NSAIDs. Prostaglandins mediate the final 0.05 to 0.96), IVH (RR = 0.59; 95% CI, 0.36 to 0.98), and jaun- pathways of uterine muscle contraction, causing an increase dice (RR = 0.73; 95% CI, 0.57 to 0.93), when compared with in free intracellular calcium levels in myometrial cells and treatment with other tocolytic agents. Fewer women treated increased activation of myosin light-chain kinase. Gap junc- with calcium channel blockers ceased treatment due to adverse tion formation is enhanced by prostaglandins. Prostaglandins drug reactions (RR = 0.14; 95% CI, 0.05 to 0.36). given to pregnant women can ripen the cervix or induce labor, depending on the dosage and route of administration. COX, Maternal Side Effects. Hypotension and headache are the also known as prostaglandin synthase, converts arachidonic most common side effects of nifedipine. Pretreatment with acid to prostaglandin G2. Prostaglandin synthesis is increased fluids may reduce the incidence of maternal side effects such as when the COX-2 form of this enzyme is induced by cytokines, headache (20%), flushing (8%), dizziness, and nausea (6%). bacterial products such as phospholipases and endotoxins, Most side effects are mild, but myocardial infarction was docu- and corticosteroids. NSAIDs vary in activity, potency, and side mented in a healthy young woman 45 minutes after a second effects. Indomethacin, the NSAID most often used as a toco- dose of nifedipine.268 Nifedipine is less likely to be discontinued lytic, crosses the placenta. Unlike aspirin, indomethacin binds because of maternal side effects than either MgSO4 or β-mimetic reversibly to COX, so that inhibition lasts only until the drug is agents.261,269,270 Simultaneous or sequential use of calcium excreted. Umbilical artery serum concentrations equal maternal channel blockers with β-mimetics is not recommended because levels within 6 hours after oral administration. The half-life in of effects on heart rate and blood pressure. Concurrent admin- the mother is 4 to 5 hours; it is 15 hours in a full-term infant istration of magnesium with calcium channel blockers may but significantly longer in preterm infants. cause skeletal muscle blockade.271 As with other tocolytics, maternal pulmonary edema has been reported.272 Effectiveness. A Cochrane review concluded that indomethacin administration was associated with a significant reduction Fetal Side Effects. Early studies in animals reported fetal hypo- in births before the 37th week of gestation, as well as with tension, but a study in women treated with calcium channel increased gestational age at birth and increased birth weight, blockers for preterm labor revealed no changes in the fetal but it noted that there were insufficient data to determine middle cerebral artery, renal artery, ductus arteriosus, umbilical fetal safety.265 artery, or maternal vessels.273 There is one report of fetal death in a patient treated with nifedipine for tocolysis.274 Oei, in sum- Maternal Side Effects. Prostaglandin inhibition has multiple marizing the European experience with nifedipine, advised the side effects because of the abundance of prostaglandin-mediated following precautions: “Calcium channel blockers should not be physiologic functions. Serious maternal side effects are uncom- combined with intravenous β-agonists. Secondly, intravenous mon when the agent is used in a brief course (≤48 hours) of nicardipine or high oral doses of nifedipine (≥150 mg/d) should tocolysis. Gastrointestinal side effects such as nausea, heartburn, be avoided in cases of cardiovascular compromised pregnant and vomiting are common but usually mild. Less common but women and/or multiple gestations. In all cases, blood pressure more serious complications include gastrointestinal bleeding, should be monitored and cardiotocography recorded during the prolonged bleeding time,277 thrombocytopenia, and asthma in administration of immediate release tablets, and patients should aspirin-sensitive patients. Prolonged treatment with NSAIDs can be advised to avoid chewing them.”275 lead to renal injury, especially if other nephrotoxic drugs are used. Hypertensive women uncommonly experience an acute increase Treatment Protocol. When used as a tocolytic, nifedipine in blood pressure after taking indomethacin. The antipyretic is commonly given orally with a 10- to 20-mg initial dose, effect of an NSAID may obscure a clinically significant fever. repeated every 3 to 6 h until contractions are rare, then followed Maternal contraindications to indomethacin tocolysis include by long-acting formulations of 30 or 60 mg every 8 to 12 h for renal or hepatic disease, active peptic ulcer disease, poorly con- 48 h while antenatal steroids are being administered. Serious trolled hypertension, asthma, and coagulation disorders. maternal and fetal side effects are more likely with short-acting preparations when the drug is initiated, and they are more Fetal and Neonatal Side Effects. Although the maternal side likely in women with hypertension or other cardiovascular dis- effect profile is mostly benign, serious fetal and neonatal com- orders. The long-acting preparations have fewer side effects, plications can occur with COX inhibitors if the drugs are used but headache and hypotension still occur. Adverse events are outside established protocols. In actual practice, such complica- highest among women given more than 60 mg (total dosage) of tions are rare, but treatment guidelines must be followed care- nifedipine.276 fully. The major fetal side effects are constriction of the ductus arteriosus, oligohydramnios, and neonatal pulmonary hyper- Calcium Channel Blockers: Summary. Nifedipine has been tension. Ductal constriction may occur because the formation used increasingly as a tocolytic because significant maternal and of prostacyclin and prostaglandin E2, which maintain ductal fetal side effects are uncommon and oral administration is vasodilation, is inhibited by indomethacin.278 Transient ductal

Downloaded for Rodrigo Terra ([email protected]) at Clinica Alemana de Santiago - JCon from ClinicalKey.com by Elsevier on October 19, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 41 Prevention and Management of Preterm Parturition 697 constriction has been reported in as many as 50% of fetuses of if possible. Treatment should be discontinued if delivery is women treated with indomethacin before 32 weeks of preg- imminent. nancy, usually after a week or more of therapy. This typically resolves within 24 hours after the medication is discontinued, Indomethacin: Summary. Indomethacin is an effective toco- without sequelae.279,280 However, persistent ductal constriction lytic agent that is generally well tolerated by the mother. Concern and irreversible right-sided heart failure have been reported about fetal side effects has appropriately limited the use of with continued use.281 indomethacin to brief courses of therapy (48 hours, maximum) Primary pulmonary hypertension in the neonate has been in patients with preterm labor before 32 weeks’ gestation. associated with fetal exposure to NSAIDs,282 including ibupro- fen, naproxen, aspirin, and indomethacin. Although maternal Oxytocin Antagonists indomethacin treatment within 16 hours of birth was blamed Pharmacology. Oxytocin stimulates contractions in labor at for a single case of neonatal pulmonary hypertension,283 neither term by inducing conversion of phosphatidylinositol to inositol a case-control series in which 75 exposed fetuses were matched triphosphate, which binds to a protein in the sarcoplasmic with 150 controls284 nor a systematic review and meta-analysis reticulum, causing release of calcium into the cytoplasm. Oxy- that compared outcomes in 1621 infants treated with indometh- tocin receptor antagonists compete with oxytocin for binding acin in utero with 4387 unexposed infants found significant dif- to receptors in the myometrium and decidua, to prevent or ferences in neonatal morbidity when maternal indomethacin reduce calcium release. The oxytocin receptor antagonist atosi- therapy was used in protocols that limited use to 48 hours ban inhibits spontaneous and oxytocin-induced contractions or less taken before 32 weeks’ gestation.285,286 This reassuring but does not affect prostaglandin-induced contractions. information does not mitigate the potential fetal risks of NSAID treatment for longer than 48 hours before 32 weeks, or for any Maternal and Fetal Side Effects. Maternal side effects are duration after 32 weeks, nor the risks associated with prolonged uncommon, because oxytocin receptors are located only in the or repeated maternal-fetal exposure to NSAIDs at any time uterus and breast. Oxytocin antagonists cross the placenta but during pregnancy. do not affect fetal cardiovascular or acid-base status. Oligohydramnios may accompany indomethacin tocolysis, because indomethacin inhibits the normal prostaglandin inhi- Effectiveness. Atosiban was evaluated in a randomized, bition of antidiuretic hormone and also exerts direct effects on placebo-controlled trial in which 531 women with preterm fetal renal blood flow. These effects are dosage related and labor between 20 0/7 and 33 6/7 gestational weeks were treated reversible, but they are not inconsequential: Neonatal renal with either intravenous and subcutaneous atosiban or intrave- insufficiency and death after several weeks of antenatal mater- nous and subcutaneous placebo.292 Women in either study arm nal treatment has been reported.287 Sulindac is an NSAID that with persistent contractions and progressive cervical change 1 has less placental transfer than indomethacin, but amniotic hour after entry were treated openly with a tocolytic agent of fluid index, hourly fetal urine production, and ductal blood the clinician’s choice. The interval from enrollment to delivery flow were equally reduced in a randomized comparison of did not differ between the two groups (26 versus 21 days; P = sulindac, indomethacin, and nimesulide.288 .6). However, among 424 women who enrolled after 28 weeks’ Other complications, including NEC, small bowel perfora- gestation, those treated with atosiban were more likely to remain tion, patent ductus arteriosus, jaundice, and IVH, have been undelivered without requiring an alternate tocolytic at 24 hours observed when indomethacin was used in a clinical setting only (73% versus 58%; OR = 1.93; 95% CI, 1.30 to 2.86), at 48 hours after other agents had failed and without limit on the duration (67% versus 56%; OR = 1.62; 95% CI, 1.62 to 2.37), and at 7 or gestational age of treatment.289 No association with IVH days (62% versus 49%; OR = 1.70; 95% CI, 1.17 to 2.46). There has been reported in studies in which standard protocols were no differences in pregnancy prolongation for subjects were used.284,285,290 enrolled between 20 and 28 weeks. The FDA did not approve Because of the effect of NSAIDs on fetal urine production atosiban because of an unexpected finding of more perinatal and amniotic fluid volume, indomethacin has been used when deaths among infants born to women enrolled into the atosiban preterm labor is associated with polyhydramnios.291 Uterine arm before 26 weeks. It is not clear whether the difference in activity and pain associated with degenerating uterine fibroids outcomes was related to the drug, or to the larger number of in pregnancy also respond well to indomethacin, but this use women with gestational age less than 26 weeks who were ran- ought to be limited to a duration of 48 hours. domized to the atosiban arm. As in other placebo-controlled Fetal contraindications to the use of indomethacin include tocolytic trials, the rate of “successful” treatment in the placebo renal anomalies, oligohydramnios, ductal-dependent cardiac group was greater than 50%, indicating the difficulty in distin- defects, and twin-twin transfusion syndrome. guishing active preterm labor from preterm parturition. In another trial that compared subcutaneous infusions of Treatment Protocol. Indomethacin is well absorbed orally. atosiban with placebo infusion,293 there were no differences in The usual regimen is a 50-mg oral loading dose followed by 25 the rates of preterm birth before 28, 32, or 37 weeks’ gestation, to 50 mg by mouth every 6 h. Therapy is generally limited to but the interval from the start of maintenance infusion therapy 48 hours and to pregnancies before 32 weeks’ gestation because to the first recurrence of preterm labor was longer for the ato- of concern about the side effects described earlier. siban group. An international study group compared the effi- Amniotic fluid volume and fetal renal anatomy should cacy and side effect profile of atosiban with those of ritodrine.294 be assessed before indomethacin is used for tocolysis. Treat- Efficacies in delaying delivery for 48 hours (about 85% for both ment beyond 48 hours may be considered in extraordinary drugs) and for 7 days (about 75% for both drugs) were similar, circumstances but requires surveillance of amniotic fluid but cardiovascular side effects were much less common for volume and ductal flow. Repeated courses should be avoided atosiban (4%) than for ritodrine (84%).

A Cochrane review noted that atosiban treatment was asso- insufficient to assess newborn outcomes.300 A subsequent ran- ciated with an increased number of infants born weighing less domized trial compared β-mimetic tocolysis with GTN plus than 1500 g in the treatment group, compared with the group rescue β-mimetic tocolysis for persistent contractions in 235 receiving placebo (RR = 1.96; 95% CI, 1.15 to 3.35; two trials, women at 24 to 35 weeks’ gestation in whom preterm parturi- 575 infants) but resulted in fewer maternal drug reactions tion was confirmed by a positive finding of cervicovaginal fetal requiring alternative treatment (RR = 0.04; 95% CI, 0.02 to 0.11; fibronectin or ruptured membranes. There was no significant four trials, 1035 women). Evidence for the efficacy of atosiban difference in the time to delivery using Kaplan-Meier curves (P to improve infant outcomes was deemed insufficient.295 = .451).301 In another placebo-controlled trial of NO tocolysis In an open, randomized trial of atosiban compared with before 28 weeks, also published since the Cochrane review, routinely used tocolytic agents conducted in 585 women, pro- composite neonatal morbidity was significantly reduced in longation of pregnancy for 48 hours was equal in both groups, infants born to mothers treated with NO.260 This is one of the but significantly more women receiving atosiban remained few studies to report improved neonatal outcome, but these undelivered at 48 hours without requiring an alternative toco- studies are insufficient to recommend NO donors until addi- lytic (77.6% versus 56.6%; P < .001). Maternal side effects were tional, larger studies are reported. less common in women receiving atosiban.296 Nitric Oxide: Summary. Nitric oxide donors have not been Atosiban: Summary. Atosiban has minimal maternal side widely used for tocolysis but deserve further investigation. effects and efficacy comparable with other tocolytics. Although Current data do not support their use outside clinical trials. it is commonly used in Europe, it was not approved by the FDA because of concerns about fetal outcomes in women treated Magnesium Sulfate before 26 weeks, but those outcomes may not have been related Pharmacology. Magnesium acts by competition with calcium to the drug. either at the motor end plate (reducing excitation by affecting acetylcholine release and sensitivity at the motor end plate)302 Nitric Oxide Donors or at the cell membrane (reducing calcium influx into the cell Pharmacology. Nitric oxide (NO) acts to maintain normal at depolarization). Myometrial contractility is inhibited when smooth muscle tone. It is synthesized during the oxidation of maternal serum levels of magnesium are 5 to 8 mg/dL.303 Deep L-arginine to L-citrulline, a reaction catalyzed by nitric oxide tendon reflexes may be lost when concentrations reach 9 to synthase. The interaction between NO and soluble guanylyl 13 mg/dL, and respiratory depression defects occur at 14 mg/ cyclase links extracellular stimuli of NO formation to synthesis dL. Magnesium is excreted almost entirely by the kidney, with of cyclic guanosine 3′,5′-monophosphate (cGMP) in target at least 75% of the infused dose of magnesium (for the treat- cells. The increase in cGMP content in smooth muscle cells ment of preeclampsia) excreted during the infusion and at least activates myosin light-chain kinase, which causes smooth 90% excreted within 24 hours.304 As magnesium is reabsorbed muscle relaxation. NO donors such as nitroglycerin inhibit in the loop of Henle by a transport-limited mechanism, the spontaneous oxytocin- and prostaglandin-induced activity. glomerular filtration rate affects excretion significantly. Increases Glyceryl trinitrate (GTN) has been studied as an acute in maternal serum magnesium also result in maternal hypocal- uterine relaxant to allow uterine manipulation for external cemia (the total calcium level falling by approximately 25%) cephalic version or ex utero fetal surgery, and also as a tocolytic and an increase in parathyroid hormone, but no change in agent. Studies of GTN as a tocolytic have produced mixed maternal phosphate or calcitonin level. Hypocalcemia is usually results. Intravenous GTN was less effective in arresting contrac- asymptomatic. Magnesium ions cross the placenta rapidly, with tions and had more side effects than MgSO4 in a study of 31 fetal and newborn levels increasing proportionately with mater- subjects.297 nal levels.305 The mean half-life of neonatal hypermagnesemia secondary to maternal therapy may be as long as 40 hours.304 Maternal Side Effects. Headache and hypertension are the most commonly reported maternal side effects. In a random- Maternal Side Effects. Magnesium has a low rate of serious ized trial298 that compared transdermal GTN with ritodrine, maternal side effects, but flushing, nausea, vomiting, dry mouth, treatment was discontinued in 25% of the GTN group because headache, blurred vision, generalized muscle weakness, diplo- of maternal hypotension. Headache was frequent, occurring in pia, and shortness of breath occur, together with maternal sense 30% of GTN-treated women. of loss of control. Chest pain and pulmonary edema have been reported with a frequency similar to that seen with β-mimetics.306 Fetal Side Effects. Fetal side effects are not commonly reported If renal function is impaired (and magnesium excretion is thus but might be expected because of the drug’s effect on maternal reduced), hypermagnesemia leading to respiratory impairment blood pressure. Kahler and colleagues investigated maternal and is more likely. Theoretically, high serum magnesium concentra- fetal blood flow with Doppler ultrasound in women treated for tions could alter the amount of muscle relaxant needed during preterm labor with GTN patches at a dosage of 0.8 mg/h and general anesthesia. Magnesium should not be used as a tocolytic found no effect on blood flow in any fetal organ.299 in women with myasthenia gravis. Hypocalcemia may be asymptomatic, or it may manifest as hand contractures.307 Pro- Effectiveness. In the trial that compared GTN to ritodrine, longed treatment has been associated with maternal osteoporo- 26% of women in both arms delivered before 37 weeks’ gesta- sis.308 Neuromuscular blockade is possible if magnesium is used tion.298 A Cochrane review summarized four randomized trials concurrently with nifedipine tocolysis. that compared NO to placebo, no treatment, or other tocolytics and found that NO treatment of preterm labor was associated Neonatal Side Effects. Magnesium crosses the placenta and with fewer deliveries before 37 weeks, but the data were achieves serum levels comparable to maternal levels, but serious

short-term neonatal complications are uncommon if the dura- serum creatinine levels higher than 0.9 mg/dL. MgSO4 should tion of maternal therapy does not exceed 48 hours. Neona- not be used in women with myasthenia gravis, because the tal lethargy, hypotonia, and respiratory depression may occur. magnesium ion competes with calcium. Prolonged magnesium tocolysis has also been associated with neonatal bone demineralization.309 Large studies (described Magnesium Sulfate: Summary. The tocolytic efficacy of earlier) that demonstrated the neuroprotectant benefits of MgSO4 is not supported by available data. MgSO4 have overcome an early report of possible adverse neonatal and infant effects of antenatal magnesium treatment.310 β-Mimetic Tocolytics Subsequent randomized trials have enrolled more than 30 Pharmacology. β-Sympathomimetic drugs, including terbu- times as many subjects without evidence of increased neona- taline and ritodrine, have been widely used for tocolysis. These tal or infant mortality related to magnesium and have dem- agents act to relax smooth muscle in the bronchial tree, blood onstrated a reduction in moderate to severe cerebral palsy in vessels, and myometrium through stimulation of the β-receptors. 255,309,311-315 surviving infants. β-Receptors are divided into β1 and β2 subtypes. The β1- receptors are largely responsible for the cardiac effects, and Effectiveness. Evidence to support MgSO4 as an effective toco- β2-receptors mediate smooth muscle relaxation, hepatic glyco- lytic is weak.316,317 The Cochrane review found no significant gen production, and islet cell release of insulin. Variable ratios advantage regarding the rates of delivery within 48 hours or of β2- to β1-receptors occur in body tissues. Stimulation of β1- before 34 or 37 weeks’ gestation in studies of women treated receptors in the heart, vascular system, and liver accounts for with magnesium.264 Two small, randomized trials compared the side effects of these drugs. The most commonly used magnesium with nifedipine269 and celecoxib,318 and both found β-mimetic in the United States is terbutaline (marketed as a no difference in the percentage of women who delivered within drug for asthma), but others, including albuterol, fenoterol, 48 hours. hexoprenaline, metaproterenol, nylidrin, orciprenaline, and sal- Despite limited evidence of benefit, magnesium has been butamol, are used in other countries. Although ritodrine was a common choice because of its familiarity and presumed approved by the FDA for tocolysis in 1980, it did not achieve safety relative to β-mimetics and other tocolytics. This ratio- wide use because of frequent maternal side effects, and it is no nale for choosing MgSO4 has been challenged by reviews that longer marketed. Terbutaline has a rapid effect when given sub- emphasized the paucity of data to support any benefit.319-322 cutaneously (3 to 5 minutes). Published protocols often employ Direct evidence of improved fetal, neonatal, or infant out- subcutaneous administration, with a usual dosage of 0.25 mg comes attributable to magnesium tocolysis is absent, and indi- (250 µg) every 4 h.323 rect support from comparative trials and secondary analyses is weak.264,316,319,321,322 Maternal Side Effects. Maternal side effects of the β-mimetic drugs are common and diverse because of the abundance of Treatment Protocol. MgSO4 must be given parenterally to β-receptors in the body. Maternal tachycardia, chest discomfort, achieve serum levels above the normal range. Therapeutic palpitation, tremor, headache, nasal congestion, nausea and dosage regimens are similar to those used for intravenous pro- vomiting, hyperkalemia, and hyperglycemia are significantly phylaxis of seizures in women with preeclampsia. The custom- more common in women treated with β-mimetics.263 Most side ary clinical protocol for MgSO4 begins with a loading dose of 4 effects are mild and of limited duration, but serious maternal to 6 g MgSO4 in a 10% to 20% solution (60 mL of 10% MgSO4 cardiopulmonary and metabolic complications have been in 5% dextrose in 0.9% normal saline) given over 30 min.306 reported. Terbutaline has been the subject of repeated FDA This is followed by a maintenance dose of 2 g/h (40 g of MgSO4 warnings: “Terbutaline administered by injection or through an added to 1 L 5% dextrose in 0.9% normal saline or Ringer infusion pump should not be used in pregnant women for preven- lactate solution at 50 mL/h). The intravenous rate is increased tion or prolonged (beyond 48–72 hours) treatment of preterm by 1 g/h until the patient has less than one contraction per 10 labor due to the potential for serious maternal heart problems and minutes or until a maximal dose of 3 or 4 g/h is reached. Intra- death. In addition, oral terbutaline tablets should not be used venous fluids are restricted to 125 mL/h. Fluid status should be for prevention or treatment of preterm labor” (see https:// followed closely. Deep tendon reflexes and vital signs, includ- www.fda.gov/Drugs/DrugSafety/ucm243539.htm). ing respiratory rate, should be recorded hourly. Magnesium Cardiopulmonary Complications of β-Mimetics. The levels may be obtained to answer safety concerns, but the infu- β-mimetic agents can produce a mild (5 to 10 mm Hg) fall in sion should be reduced or stopped without waiting for drug diastolic blood pressure, and the extensive peripheral vasodi- level results if respiration or urine output declines. Calcium lation may make it difficult for the patient to mount a normal gluconate should be readily available to reverse the effects of response to hypovolemia. Exclusion of women with any history magnesium. of heart disease or significant hemorrhage, and limitation of Once contractions have decreased to less than one every 10 infusion rates to maintain maternal heart rate at less than to 15 minutes, or once they have ceased, the infusion may be 130 beats/min, are important steps to avoid cardiac compli- discontinued without first tapering the infusion rate. Magne- cations. Symptomatic arrhythmias and myocardial ischemia sium is sometimes continued until an arbitrary end point is have occurred during β-agonist tocolytic therapy; myocardial reached (e.g., 12 hours after contractions cease) or until a infarction leading to death has been reported.324 Tocolysis steroid course is completed, but this approach is unsupported should be discontinued and oxygen administered whenever a by data. woman reports chest pain during tocolytic therapy. Premature If renal function is normal, magnesium is excreted rapidly ventricular contractions, premature nodal contractions, and in the urine. Magnesium should be administered cautiously in atrial fibrillation noted in association withβ -mimetic therapy women with evidence of renal impairment, such as oliguria or usually respond to discontinuation of the drug and oxygen

Downloaded for Rodrigo Terra ([email protected]) at Clinica Alemana de Santiago - JCon from ClinicalKey.com by Elsevier on October 19, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 700 PART 4 Disorders at the Maternal-Fetal Interface administration. Baseline or routine electrocardiograms before trials to reduce either prematurity or neonatal morbidity, and or during treatment are not helpful. Nonetheless, an electro- it has notable patient safety concerns. cardiogram is indicated if there is no response to oxygen and cessation of β-mimetic therapy. Pulmonary edema has been Clinical Use of Tocolytic Drugs reported with all tocolytics, including β-mimetic therapy. Tocolytic therapy is used in several clinical circumstances. In Restriction of the duration of treatment to less than 24 hours, caring for a woman with active contractions and advanced cer- careful ongoing attention to fluid status, and detection of com- vical effacement with the goal of arresting labor to allow time plicating conditions such as intrauterine infection may reduce for maternal transfer, administration of antenatal steroids, and this risk. GBS prophylaxis, treatment with oral indomethacin or nifedip- Metabolic Complications. β-Mimetic agents induce tran- ine may stop contractions promptly. Treatment can be contin- sient hyperglycemia and hypokalemia during treatment. Mea- ued at least until contractions occur less frequently than four surement of glucose and potassium before therapy is initiated times per hour without additional cervical change. If labor has and on occasion during the first 24 hours of treatment may be been difficult to stop in a patient with complete cervical efface- appropriate to identify significant hyperglycemia >( 180 mg/dL) ment, acute treatment may be continued for 48 hours while or hypokalemia (<2.5 mEq/L). These metabolic changes are steroid therapy is completed. mild and transient, but prolonged treatment (>24 hours) may If contractions persist despite therapy, the wisdom of toco- induce significant alterations in maternal blood sugar, insulin lytic treatment should be reevaluated. If cervical dilation has levels, and energy expenditure.325 The risk for abnormal glucose progressed beyond 4 cm, treatment should in most instances be metabolism is further increased by simultaneous treatment discontinued. The presence of persistent contractions despite with corticosteroids. Other agents should be chosen for women ongoing tocolysis raises the possibility of placental abruption with pregestational diabetes and gestational diabetes. or intraamniotic infection. Amniocentesis may be considered if there is concern for intraamniotic infection. Neonatal Side Effects. Neonatal hypoglycemia, hypocalcemia, If contractions persist without progressive cervical change, and ileus may occur after treatment with β-mimetics and can the risk for imminent preterm birth should be reevaluated, be clinically significant if the maternal infusion is not discon- remembering that effacement, softness, and development of the tinued 2 hours or more before delivery. lower uterine segment are the features of the digital examination that most reliably indicate preterm labor. If a fibronectin Effectiveness. In a Cochrane Database analysis of 1332 women swab was collected before therapy was begun, it should be sent enrolled into 11 randomized, placebo-controlled trials of for analysis. A positive fibronectin test is not highly predictive, β-mimetic drugs, treated subjects were less likely to deliver but a negative result, if collected before performance of a digital within 48 hours (RR = 0.63; 95% CI, 0.53 to 0.75), but not less examination, suggests that preterm birth is unlikely (4%) within likely to deliver within 7 days.263 Perinatal and neonatal mortal- 2 weeks.228,236 Alternately, a TVU cervical examination may be ity and perinatal morbidity were not reduced by β-mimetic performed. A cervical length of 30 mm or more essentially treatment in this analysis. Side effects requiring change or ces- excludes the diagnosis of preterm labor except in cases of acute sation of treatment were frequent. Other reviews have reported abruption.227 similar conclusions.326 Initiating treatment with a second agent is often considered Because of their potential for clinically significant side effects when contractions persist, but this is not supported by data. and the availability of alternative choices, β-sympathomimetic Serum concentrations of tocolytic drugs are not helpful to agents should not be used in women with known or sus- guide treatment. A change to a second agent or combination pected heart disease, severe preeclampsia or eclampsia, dia- therapy with multiple agents may slow contractions, but this betes, or hyperthyroidism. These drugs are contraindicated approach often results in increased side effects and has not been if suspected preterm labor is complicated by maternal fever, shown to be efficacious. Sustained treatment with multiple fetal tachycardia, leukocytosis, or other signs of possible tocolytics increases the risk for significant side effects and chorioamnionitis. should be avoided. Long-term or maintenance use of β-mimetic drugs was once advocated to suppress contractions, but desensitization of the CARE AFTER TREATMENT FOR adrenergic receptors (tachyphylaxis) occurs after prolonged PRETERM LABOR exposure to β-agonists, so that increasing dosages are required to maintain a response. Continuous subcutaneous infusion of Continued suppression of contractions after acute tocolysis terbutaline has fewer side effects at lower dosages than oral (maintenance tocolysis) does not reduce the rate of preterm administration.327 Although these protocols suppressed con- birth.332-334 Randomized trials comparing maintenance tocolysis tractions, rates of preterm birth or perinatal morbidity were not to placebo or no treatment and meta-analyses of these studies reduced in randomized, placebo-controlled trials,328,329 and sig- found no evidence of prolongation of pregnancy or decline in nificant side effects were reported that led to the aforemen- the frequency of preterm birth.331,335 Outpatient monitoring of tioned FDA warning. Neither the Cochrane review330 nor the uterine contractions and associated care did not improve the most recent ACOG practice bulletin331 supports terbutaline rate of delivery before 37 weeks’ gestation, birth weight, or infusion to prolong pregnancy. gestational age at delivery.336,337 The duration of hospitalization for preterm labor is influ- β-Mimetic Tocolysis: Summary. β-Mimetic drugs were once enced by the dilation, effacement, and sonographic length of commonly used as tocolytics, but they have been replaced by the cervix, ease of tocolysis, gestational age, obstetric history, agents with better safety and side effect profiles. Long-term oral distance from the hospital, and the availability of home and or subcutaneous treatment has not been shown in controlled family supportive care. Risk factors that may complicate or

Downloaded for Rodrigo Terra ([email protected]) at Clinica Alemana de Santiago - JCon from ClinicalKey.com by Elsevier on October 19, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 41 Prevention and Management of Preterm Parturition 701 increase the risk for recurrent preterm labor, such as a positive found modest benefit for antiplatelet drugs, chiefly low-dose genital culture for chlamydia or gonorrhea, urinary tract infec- aspirin: tion, and anemia, should be addressed before the woman is • An 8% reduction in the risk for preterm birth from a discharged from hospital care. Social issues such as homeless- review of 29 trials that enrolled a total of 31,151 women ness, availability of child care, or protection from an abusive (RR = 0.92; 95% CI, 0.88 to 0.97) partner are important determinants of a patient’s ability to • A 10% reduction in SGA infants in a review of 36 comply with medical care and must also be considered before trials that enrolled 23,638 women (RR = 0.90; 95% CI, the patient is released from the hospital. In general, hospitaliza- 0.83 to 0.98) tion for preterm labor for steroids and tocolysis does not last • A 14% reduction in fetal or neonatal deaths in a review of more than 48 hours, but may be extended in the setting of large 40 trials that enrolled 33,098 women (RR = 0.86; 95% CI, distances from patient to hospital, difficulty in transportation, 0.76 to 0.98) or advanced cervical dilation. A Cochrane review found a significant reduction in preeclampsia in women treated with supplemental calcium, with a concomitant reduction in preterm births,350 but there Prevention of Preterm Birth was no independent effect on the incidence of spontaneous 351 STRATEGIES preterm birth. Similar reviews of the use of antioxidants to prevent preeclampsia found a slight decrease in preeclampsia Primary prevention of the morbidity and mortality of preterm but no evidence of a corresponding reduction in the risk for birth is an increasingly compelling strategy as the limitations of preterm birth.352 tertiary care are recognized. Public awareness of the importance of preterm birth as a leading cause of infant mortality remains 338 PREVENTION OF SPONTANEOUS PRETERM low. Care aimed at reducing risk and amelioration of the BIRTH IN PREGNANCY consequences of preterm birth have advanced significantly in recent years, but primary prevention will require increased Efforts to prevent preterm birth after conception have been attention to social as well as biologic pathways that lead to difficult for two reasons. First, because almost all women have prematurity. Systemic approaches to prevention of preterm some risk factor for preterm birth and more than half of preterm birth and improved outcomes for preterm infants include infants are born to women without apparent risk factors,150,353,354 quality improvement initiatives aimed at optimally structured prematurity prevention must be part of prenatal care for every prenatal care,339 avoidance of elective deliveries before 39 woman. Second, because treatment of recognized risk factors weeks,340,341 optimal use of antenatal corticosteroids and proges- (e.g., genitourinary tract infection) does not reduce the inci- terone prophylaxis, promotion of breastfeeding, and optimal dence of preterm birth, criteria for universal screening for interval (e.g., 18 to 24 months) between conceptions. These preterm birth were not met: there were no effective interven- efforts and others are reviewed in the March of Dimes’ publications for women identified as being at risk. These limitations tion, Toward Improving the Outcome of Pregnancy III.342 were decreased by studies demonstrating reduced risk for recur- Meanwhile, attempts to prevent preterm birth must recog- rent preterm birth in women with a prior spontaneous preterm nize that prolongation of pregnancy intended to promote birth treated with progestogens, and they have now been further maturation might in some cases allow continued exposure to reduced by the recognition that short cervix is evidence of the a suboptimal or even hazardous intrauterine environment. early onset of parturition, that it can be detected by TVU, and Indeed, gestational age at birth is only a surrogate end point for that it can be treated with some success with supplemental optimal fetal, infant, and lifelong health.5,343 Indicated preterm progesterone. These findings will require prenatal care provid- birth is by definition intended to improve maternal or fetal (or ers to adopt locally appropriate strategies to identify women both) and neonatal health, in contrast to presumed fetal benefit who are candidates for progesterone prophylaxis because of a by continuing the pregnancy in spontaneous preterm parturi- prior preterm birth or short cervix, or both. Potential strategies tion. However, the distinction between indicated and spontane- are outlined in the following paragraphs. Regardless of the ous preterm birth can be artificial, because factors leading to strategy chosen, limitations remain that relate to three unre- labor and membrane rupture are understood to include intra- solved factors: uterine inflammation related to microbial infection, uterine • The percentage of preterm births that are preceded by vascular compromise, or decidual hemorrhage, all of which may cervical shortening, and how to find and treat those that contribute to neonatal and infant morbidity as much as or more are not than fetal immaturity. • The percentage of preterm births preceded by cervical shortening that are and are not amenable to progestin PREVENTION OF CONDITIONS LEADING TO treatment and prophylaxis, and how to find and treat INDICATED PRETERM BIRTH those that are not • Issues related to training of personnel, ensuring the quality Strategies to prevent indicated preterm births target women of cervical length measurement, cost, and efficient appli- with medical disorders and women with risk factors for pre- cation in practice, which must be addressed to determine eclampsia, such as nulliparity, twin gestation, diabetes, chronic optimal strategies for screening for short cervical length hypertension, and a history of preeclampsia or growth restric- Continued consideration of risk assessment as distinct from tion. Numerous trials of various agents (low-dose aspirin,344,345 treatment remains relevant because risk factors associated with antioxidant vitamins C and E,346 and fish oil347,348) have been preterm birth may still contribute independently to adverse conducted to test their effects on the rates of preeclampsia, fetal outcomes or contribute by accelerating preterm parturition, or growth restriction, and preterm birth. A Cochrane review349 has both (e.g., maternal cigarette smoking). Risk factors may also

Downloaded for Rodrigo Terra ([email protected]) at Clinica Alemana de Santiago - JCon from ClinicalKey.com by Elsevier on October 19, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 702 PART 4 Disorders at the Maternal-Fetal Interface serve as markers to identify candidates for cervical ultrasound significantly reduced in infants born to women cared for in screening for short cervix. Such strategies have not yet been the prematurity clinic. Bastek and coworkers found no differ- tested, but they may appeal to those reluctant to adopt universal ence in the rates of spontaneous preterm birth at less than 37 cervical length screening. The following paragraphs review weeks’ gestation (16.7% versus 16.9%) before and after proges- strategies to reduce risk during pregnancy. tin supplementation was introduced, but the mean gestational age at birth was more than a week longer after progesterone Prenatal Care was adopted.366 This prematurity prevention clinic reported a Preterm birth may be addressed by changes in the structure decline in preterm birth rates associated with progesterone use as well as the content of prenatal care. Removal of economic, only after a policy change was made to identify progestin candi- transportation, and cultural barriers to a first prenatal visit, dates among women with a prior preterm birth before 14 weeks’ accelerated first visits for women with risk, geographic iden- gestation, so as to overcome barriers to initiating treatment tification of risk zones, group prenatal care, alternative care at 16 weeks. providers, and alteration of the traditional preeclampsia detection–based schedule of visits have been considered as Modification of Maternal Activity potential pathways to reduce prematurity. The content and pace Restriction of physical activity, including bed rest, limited of prenatal care will probably require revision to incorporate work, and reduced sexual activity, is frequently recommended historical and ultrasound screening, as well as prophylaxis for to reduce the likelihood of preterm birth in pregnancies at preterm birth. risk for indicated and spontaneous preterm birth, despite the absence of benefit and considerable evidence of maternal risk Access. Early entry into care is associated with low rates of in the literature.367 Yost and colleagues found no relation- preterm birth, but the relationship is more likely related to the ship between coitus and risk for recurrent preterm birth.92 high rate of preterm birth among women who receive no pre- However, limitation of physical activity has not been studied natal care than to the content of early prenatal care. For example, in women with short cervix. Of note, in a secondary analysis early access to prenatal care did not influence the rate of preterm of a randomized trial of progestogen for prevention of recur- births among women enrolled in the FaSTER study of prenatal rent preterm birth, Grobman and associates noted that preterm diagnostic techniques in the first and second trimesters.355 Rates birth at less than 37 weeks’ gestation was more common among of preterm birth remained notably high among African- women placed on activity restriction (37% compared with American women in this study despite early prenatal care. 17%, P < .001). After controlling for potential confounding However, early care can create opportunities to identify risk factors, preterm birth remained more common among those factors and overcome obstacles to performing cervical sonog- placed on activity restriction (adjusted OR = 2.37; 95% CI, raphy or beginning progesterone prophylaxis. Accelerated entry 1.60 to 3.53).368 into care for women with risk factors for preterm birth is important. Nutritional Supplements Vitamins. Rates of spontaneous preterm birth before 37, 34, Enhanced Care for Women With Risk. Enhanced prenatal and 28 weeks’ gestation were not improved by supplemental care, including social support, home visits, and education, has vitamin C and vitamin E given to prevent preeclampsia in a not been an effective strategy to decrease preterm births.356-360 randomized trial conducted in 1877 healthy women.369 Another A Cochrane analysis found no benefit for enhanced prenatal randomized trial in 9968 nulliparous women concluded that care in women with increased risk.361 However, these efforts supplementation with vitamins C and E beginning at 9 to 16 antedate application of cervical ultrasound, prophylactic pro- weeks’ gestation did not reduce spontaneous preterm births gestogens, and group prenatal care to women at risk. appearing with either preterm labor or ruptured membranes.370 Group prenatal care, in which traditional and enhanced pre- There is insufficient evidence to determine the effect, if any, of natal care are provided in a supportive learning group of women supplemental vitamin D.371 with similar gestational age and demography led by a nurse or Prolonged preconception folic acid supplementation was other health professional, has been associated with lower rates associated with a lower risk for preterm birth in a study based of preterm birth in studies of women who self-selected this on maternal recall of prenatal vitamin intake,372 with precon- approach362 and in a randomized trial.363 This is a subject of ceptional use ranging from 6 months to 2 years prior to preg- active investigation. nancy. Importantly, this observation was made in a low-risk Preterm birth rates reported from prematurity preven- population and has not been confirmed in prospective studies. tion clinics have been inconclusive. A multicenter randomized trial that compared intensive patient education and frequent Minerals. As noted, calcium supplementation reduces the inci- visits to routine care in more than 3000 high-risk women dence of preterm birth related to preeclampsia, but Cochrane reported no significant differences in preterm birth rates,358 Reviews discerned no effect on spontaneous preterm birth.350,351 but a single-site study reported a 19% reduction in preterm Studies of other micronutrient minerals are limited but suggest birth rates in high-risk women who received increased educa- that benefit, if any, of supplementation is limited to populations tion and more frequent obstetric visits.364 Results from studies with dietary deficiencies. evaluating the effect of progestogen supplementation in clinical practice are few and inconsistent. Manuck and colleagues Polyunsaturated Fatty Acids. The preterm birth rate is low in reported a recurrent spontaneous preterm (<37 weeks’ gesta- populations with a high dietary intake of ω-3 polyunsaturated tion) birth rate of 48.6% in 70 women seen in a prematu- fatty acids (PUFAs), which reduce levels of proinflammatory rity clinic, compared with 63.4% in 153 women who received cytokines. Dietary supplementation with PUFAs has been asso- routine prenatal care.365 Composite neonatal morbidity was ciated with reduced production of inflammatory mediators

Downloaded for Rodrigo Terra ([email protected]) at Clinica Alemana de Santiago - JCon from ClinicalKey.com by Elsevier on October 19, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 41 Prevention and Management of Preterm Parturition 703 thought to participate in inflammation-driven parturition. A consistent reductions in the incidence of preterm birth despite randomized trial of ω-3 supplements conducted in women at eradication of the target organism. In some studies, antibiotic risk for preterm birth reported a 50% reduction in preterm treatment of screen-positive women increased the risk for births.347 A subsequent randomized trial of supplemental fish preterm birth.122,383,384 oil also reported a significant reduction in recurrent preterm Routine screening of all pregnant women for BV, with treat- birth (RR = 0.54; 95% CI, 0.30 to 0.98),348 but a randomized, ment intended to reduce preterm birth, has been extensively placebo-controlled trial of supplemental ω-3 PUFAs in 852 studied, with mixed results.115,119,385,386 BV carriage has been women with a prior preterm birth found no effect of ω-3 sup- associated with a positive screening test for fetal fibronec- plementation on birth or spontaneous birth before 37 or 35 tin.124,387 Although a secondary analysis suggested that antibiotic weeks (RR = 0.91; 95% CI, 0.77 to 1.07). Treatment groups did treatment might reduce the rate of preterm birth in women not differ when stratified by fish intake (RR= 0.92; 95% CI, with BV who also have a positive fibronectin screen,388 the rate 0.78 to 1.08). In this study, all participants in both arms were of preterm birth was not reduced by antibiotic treatment of treated with 17-OHPC.373 In a secondary analysis of data from women with a positive fetal fibronectin result in a randomized this study, women who ate fish at least once a month had a trial.389 Therefore despite the consistent linkage of maternal significantly reduced rate of spontaneous preterm birth com- BV to risk for preterm birth, and despite the ability of antimi- pared with women who consumed fish less than once a month crobial therapy to eradicate BV, screening and treatment for (RR = 0.62; 95% CI, 0.45 to 0.86), regardless of their study BV does not reliably reduce the occurrence of preterm birth assignment. in low-risk women115,386 and is not recommended for these patients.229,390 Proteins and Calories. The effects of protein and calorie sup- Antibiotic treatment for women with a prior preterm birth plementation during pregnancy are less clear.374 Although who also have BV was suggested by secondary analyses of data nutritional advice was associated with improved rates of from two trials, one that enrolled women at risk for preterm preterm birth, energy and protein supplementation were not, birth,391 in which benefit was found only in women with BV, and high-protein supplementation was linked to increased risk and another that enrolled women with BV,392 in which benefit for SGA infants. was limited to women with a prior preterm birth. Other trials of treatment for BV-positive women have produced conflicting Smoking Cessation results, perhaps because of variations in the timing, dosage, and Smoking cessation programs are more likely to be well received antibiotic employed.384,393-395 among pregnant than non-pregnant women.375 A brief (<15 Lamont and colleagues396,397 argued that clindamycin used minutes) counseling session with a trained provider offering before 22 weeks’ gestation to treat women with abnormal pregnancy-specific counseling was found to reduce smoking vaginal flora can reduce the incidence of preterm birth, but rates in pregnant women.376 The reduction was modest but others express concern about higher rates of preterm birth clinically significant (RR= 1.7; 95% CI, 1.3 to 2.2). Smoking in women treated with metronidazole122,384,389 and about the reduction and cessation in prenatal visits are persistently negative results of a Cochrane review of 15 trials involving emphasized in most programs. Smoking cessation in pregnancy 5888 women.115 may be more successful when specific funding for this service Data produced by these trials suggest that the contribution is available.376 One program reported successful results in 3569 to preterm birth of microorganisms colonizing and infecting indigent women who received care coordination, nutritional the genital tract varies significantly between women, probably counseling, or psychosocial counseling to address specific risks, because of genetic and environmental exposures that must be including smoking and inadequate weight gain.377 Women who further elucidated before antimicrobial agents can be used stopped smoking had fewer LBW infants than women who effectively and safely to prevent preterm birth. The appropriate continued to smoke (8.5% versus 13.7%). The rate of LBW role for antimicrobial therapy to reduce the risk for preterm infants was lower in women who achieved adequate weight gain birth cannot be determined until questions about the roles of than in those who did not (6.7% versus 17.2%). A Cochrane concurrent exposures (e.g., smoking), host factors influencing review concluded that smoking cessation programs in preg- immune defenses, and selection and timing of treatment are nancy can produce modest reductions in preterm birth (RR = answered.134,398,399 0.94; 95% CI, 0.93 to 0.96).378 Screening to Assess Risk of Preterm Birth Screening for Infection Tests to assess risk for preterm birth may be useful when effec- Asymptomatic Bacteriuria. Screening and treatment for tive treatment is available for a positive test, or when a negative asymptomatic bacteriuria prevents pyelonephritis379 and test result may safely avoid an intervention that has risk, incon- has been reported to reduce the rate of preterm birth, but venience, high cost, or limited circumstances for use. Appropri- the optimal screening and treatment protocols to prevent ate use of antenatal corticosteroids and tocolytic drugs are good preterm birth have not been studied recently.126,380 While the examples. Assessment of the risk for imminent preterm birth optimal protocol has yet to be defined, we recommend the may also be helpful when maternal transport to a tertiary care use of a screening and treatment protocol for asymptomatic center is considered. bacteriuria. Scoring Systems and Biomarkers. Biologic markers of partu- Genital Infections. Genital tract colonization and infection rition have been studied as potential screening tests, alone and are consistently associated with risk for preterm birth, but trials in combination with clinical risk factors, to create scoring of screening and treatment for organisms including U. urealyti- systems that have had limited sensitivity, and, until recently, did cum,381 GBS,382 and T. vaginalis122,383 have not demonstrated not identify women for whom an effective intervention was

Downloaded for Rodrigo Terra ([email protected]) at Clinica Alemana de Santiago - JCon from ClinicalKey.com by Elsevier on October 19, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 704 PART 4 Disorders at the Maternal-Fetal Interface available. Clinical characteristics such as a maternal BMI of less to predict preterm birth is modest—35% to 40%. In addition than 19.6 kg/m2, African-American ethnicity, social depriva- to measurement of cervical length, TVU can detect other signs tion, and genitourinary colonization have been studied together of pathologic parturition, such as the presence of debris (or with markers of parturition in maternal serum (alpha fetopro- sludge), a sign of intrauterine microbial colonization,414 and tein, alkaline phosphatase, corticotropin-releasing hormone, membrane edema or separation from the decidua. relaxin) and cervical fluid (fetal fibronectin, granulocyte colony- stimulating factor, interleukins),150,387,400,401 but clinical utility Combined Testing. A comparison of digital examination, fetal has not been proven. fibronectin testing, and cervical sonography to predict birth Uterine contraction frequency was studied extensively as a before 35 weeks’ gestation in nulliparous and low-risk multipa- screen for risk for preterm birth and as a marker of impending rous women reported low sensitivity for all three tests: less than preterm labor.402 Although contraction frequency is associated 25% each for digital examination and fibronectin, and 39% for with preterm birth, it did not prove to be an efficient screening cervical sonography.415 Sequential use of digital examination or test because of the wide variation in contraction frequency in fibronectin screening followed by cervical ultrasound had very normal and complicated pregnancies.200,202,203 low sensitivity. In a US-based multicenter, prospective, observational cohort study of 9410 nulliparous women, among Fetal Fibronectin. Fetal fibronectin, a glycoprotein thought women who experienced spontaneous preterm birth, cervical to act as an adherent at the maternal-fetal interface, is length of 25 mm or less occurred in 35 of 439 women (8.0%) uncommonly present in cervicovaginal secretions in the late at 16 to 22 weeks’ gestation and in 94 of 403 (23.3%) at 22 to second and early third trimesters.387,403 Although the risk 30 weeks’ gestation.416 Fetal fibronectin levels of 50 ng/mL or for preterm birth increases as the level of fetal fibronectin greater at 16 to 22 weeks identified 30 of 410 women (7.3%) rises,404 it has been evaluated only as a qualitative test, with with spontaneous preterm birth and 31 of 384 (8.1%) at 22 to a value of 50 ng/dL or greater being called positive. A posi- 30 weeks. The area under the receiver operating characteristic tive test is believed to indicate disruption of the maternal- curve for screening between 22 and 30 weeks for fetal fibronec- fetal decidual attachment.405 Asymptomatic women with tin level alone was 0.59 (95% CI, 0.56 to 0.62), for transvaginal a positive fetal fibronectin test have an increased risk for cervical length alone was 0.67 (95% CI, 0.64 to 0.70), and for preterm birth before 35 weeks’ gestation, especially within 2 the combination as continuous variables was 0.67 (95% CI, 0.64 weeks of a positive result.387,406 Although the sensitivity of the to 0.70). This study demonstrated that, among nulliparous fibronectin test at 22 to 24 weeks for all spontaneous births women with singleton pregnancies, quantitative vaginal fetal before 35 weeks was only 25%, sensitivity for births before fibronectin and serial TVU cervical length had low predictive 28 weeks was 65% in one study.342 Placebo-controlled trials accuracy for spontaneous preterm birth. These findings do not of antibiotics in women with a positive fibronectin result,389 support routine use of these tests in such women, although the and in women with historical risk and a positive fibronectin issue remains controversial. result,384 were disappointing. Preterm birth rates were not Because preterm birth occurs in only 35% to 40% of all improved by antibiotic treatment in either trial, and in fact women with untreated short cervix206 and in 25% to 30% of were slightly higher in women who received antibiotics. No women with a positive fetal fibronectin test in the second tri- other interventions for women with a positive fetal fibronec- mester,124 many women apparently experience the initial phases tin test have been evaluated in controlled trials. Screening of preterm parturition but do not progress to preterm birth. of asymptomatic women with fetal fibronectin testing is not recommended.407 Medical and Surgical Interventions to Prevent Preterm Birth Cervical Examination Medical and surgical interventions to prevent preterm birth Digital Examination of the Cervix. Recent emphasis on were, until recently, largely ineffective, but this is no longer TVU measurement of cervical length does not make digital true. Randomized trials have shown reduced rates of preterm assessment of the cervix obsolete but rather informs the digital birth in women treated medically with progestational agents examination by placing emphasis on the changes in cervical (collectively referred to here as progesterone, recognizing the dif- effacement, consistency, and position that precede dilation. ferent pharmacologic properties of the agents studied)156,417-419 Digital examination should document the position, consistency, and surgically with cerclage.420,421 Women who benefit from length, and dilation of the cervix along the lateral fornix to either treatment share one common characteristic: short cervi- generate a Bishop pelvic score,408 where a score of 4 or greater cal length demonstrated by TVU. Progesterone treatment does indicates cervical ripening has occurred. The cervical score (cal- not reduce the risk for preterm birth in women with a prior culated by subtracting the cervical dilation in centimeters from preterm birth who do not have a short cervix,157 or in nul- the cervical length in centimeters, and ranging from +4 to −4), liparous women with a moderately short cervix.422 Similarly, had a clinical usefulness similar to that of sonographic cervical cervical cerclage for women with a prior preterm birth reduces length in judging risk for preterm birth.409 the risk for recurrent preterm birth in women whose cervix is Cervical Ultrasound. Changes in the cervix preceding short (<25 mm), and it is especially effective in women with a myometrial activation may be used to identify women in very short cervix (≤15 mm) (see Cervical Cerclage to Prevent whom the parturitional process has begun. Evaluation of the Preterm Birth, later).421 In contrast, the risk for preterm birth cervix by TVU measurement of cervical length (Boxes 41.2 in women with multifetal gestation is not reduced by proges- and 41.3) identifies women with increased risk for preterm terone supplementation423,424 or by cervical cerclage, suggesting birth.205-208,226,410-413 However, because preterm cervical ripening a different pathway to preterm birth in multifetal pregnancies. occurs at variable rates over a period of weeks and does not When considered together with ultrasound studies of cervi- always progress to early birth, the sensitivity of cervical length cal shortening in pregnancy,414,425,426 the results of these trials

BOX 41.2 TRANSVAGINAL ULTRASOUND (TVU) MEASUREMENT OF CERVICAL LENGTH TECHNIQUE OF TVU MEASUREMENT OF CERVICAL LENGTH the notches made by the internal os and the external os. If TVU is the most reproducible technique for cervical assess- the internal os is open, cervical length is measured from the ment. Its technical aspects are important. Ultrasound images of tip of the funnel, where the mucosal surfaces touch, to the the cervix using transabdominal and transperineal sonography external os. are more difficult to obtain and are less reproducible than trans- • Cervical length should be determined only from images in vaginal images.410-412 A standardized protocol is used to ensure which the lower-most edge of the empty maternal bladder reproducibility.206 and the internal and external os are visible, and when the • First, the maternal bladder is emptied before initiating the exam- anterior and posterior lips of the cervix are of about equal ination. Ultrasound gel is placed on a transvaginal probe before thickness (Fig. 41.14). If the cervix appears asymmetric, thin covering it with a condom or specialized probe cover. Sterile anteriorly and thicker posteriorly, excessive probe pressure ultrasound gel is then placed on the cover. If the membranes is likely. are ruptured, both the cover and the gel should be sterile. • When the cervical canal is curved (Fig. 41.15), the length of the • With the real-time image in view, the transducer is gently cervix should be measured by a single straight line from the advanced into the anterior vaginal fornix until the amniotic internal to the external os, and also by the sum of two or more fluid and cervix are visualized. It is important to avoid excessive separate straight lines along each segment of the curved cervix. pressure on the anterior cervical lip. The image is enlarged to If the difference between the straight line and the point of maximal separation exceeds 3 mm, the sum of the segmental fill at least two-thirds of the ultrasound screen and oriented so 212 that cephalad is to the left of the screen on a midsagittal image. measurements is used. A curved cervix is usually long, • The examiner first identifies the amniotic fluid and then the whereas a short cervix is more often straight. Tracing the cervi- lowest edge of the empty maternal bladder. The internal cervical canal should be avoided because it introduces unpredict- cal os is then located, often just below the bladder edge. able operator variation. • The appropriate sagittal view for measuring cervical length • Before a final determination of cervical length is recorded, includes the usually T- or V-shaped appearance of the inter- gentle manual pressure should be applied by the sonographer to the fundus or suprapubic area to elicit the true cervical nal os, the triangular area of echodensity at the external os, 413 and the endocervical canal, which appears as a faint line of length. echodensity or echolucency between the two, surrounded by • The examination is performed over at least 3 to 5 minutes, a zone of cervical glands inside the cervical stroma (Fig. allowing time after the application of fundal pressure to observe 41.13). Excess pressure on the cervix can artificially increase development of pressure-elicited changes in the cervix. After its apparent length. This can be avoided by first obtaining an pressure has been applied, and three measurements that fully apparently satisfactory image, withdrawing the probe until satisfy the criteria in this box have been obtained that vary by the image blurs, and then reapplying only enough pressure less than 10%, the shortest of these is chosen and recorded as to restore the image. the “shortest best.” Reporting the average and the range of • Cervical length is measured along the line made by the cervical length measurements is not useful and may be mislead- interface of the mucosal surfaces (the closed portion of the ing. Choosing the shortest of three excellent images reduces cervix). It is usually the distance between calipers placed at interobserver and intraobserver variation.

Bladder Ext os

Int os

Fetal head

Posterior cervical lip

Figure 41.13 Ultrasound image, sagittal view of cervix. The image Figure 41.14 Ultrasound image of normal cervix. When measuring used for measuring cervical length includes the usually T- or V-shaped cervical length, the relationship of the maternal bladder, the internal appearance of the internal os, the triangular area of echodensity at the and the external os, and the anterior and posterior lips of the cervix external os, and the endocervical canal. should be visible. Ext os, External os; Int os, internal os. have advanced our understanding of the origins and progress shortening occurs despite prophylaxis. The following section of preterm parturition and have the potential to reduce the describes the basis for this strategy and outline remaining incidence and ultimately the morbidity and mortality of uncertainties about its application. preterm birth. Short cervix is now understood to represent evidence of preterm parturition in most instances rather than Progestational Agents to Prevent Preterm Birth. Progester- a structural deficit (see Cervical Cerclage to Prevent Preterm one supplementation for women at risk for preterm birth was Birth, later). Progesterone is a medical prophylactic treatment investigated with regard to several plausible mechanisms of that can be supplemented by cervical cerclage when progressive action, including reduced gap junction formation and oxytocin

BOX 41.3 PITFALLS TO AVOID WHEN MEASURING CERVICAL LENGTH WITH TRANSVAGINAL ULTRASOUND (TVU) • Putting excess pressure on the cervix during the examination • Contractions during the examination can cause a false impres- is a common error that creates an artificially longer cervix as a sion of a long cervix. If the internal os is not clearly visualized result of compression of the anterior cervical lip and lower and a contraction is present, one needs to wait until the con- uterine segment. This can be avoided by withdrawing the traction resolves before the cervical length can accurately be probe when the internal and external os are visualized, until measured. slight blurring occurs, and then reinserting it slightly until a clear • A common problem is measuring the cervical length too image returns. quickly, without allowing adequate time for any effects on the • The anterior and posterior lips of the cervix should be of cervix to resolve. approximately equal thicknesses. • If the image remains suboptimal, the cervix is often easier to • If the lower uterine segment is underdeveloped, it can be dif- locate sonographically if a digital examination is performed, as ficult to identify the true internal os so that myometrium may gel from the examiner’s glove left in the cervical canal makes be included in the cervical length measurement. This should be the external os more echogenic. In addition, digital examina- suspected when the cervix appears longer than 50 mm, or tion aids in the assessment of risk for premature delivery by when the internal os is cephalad above the bladder reflection.29 determining dilation, position, and consistency, features not A difference in echotexture between myometrium and true optimally assessed by ultrasound. cervical stroma can often be appreciated during real-time scan- To obtain adequate measurements of cervical length, TVU should ning, and this provides a way to differentiate between the two be performed in accordance with these technical steps. At least 20 structures. Before 14 weeks, it is particularly difficult to differ- cervical ultrasound examinations performed under supervision are entiate between the lower uterine segment and the cervix. typically necessary before reproducible TVU cervical length images Nonetheless, in some particularly high-risk pregnancies, such are obtained without supervision. The increased use of cervical as those with prior second-trimester losses or large (or multiple) sonography as a screening test will lead to standardized credential- cone biopsies, cervical shortening has been seen as early as 10 ing to perform this examination. Tutorials and credentials can be to 13 weeks of gestation.23 Placenta previa may also create this obtained from the Perinatal Quality Foundation’s Cervical Length same phenomenon, resulting in an apparent but artificially Education and Review (CLEAR) program (available at https://clear increased cervical length. .perinatalquality.org) and from the Fetal Medicine Foundation • Uneven placement of lubricant into the transducer cover may (https://fetalmedicine.com/fmf-certification/certificssates-of-compe generate small air bubbles that create a poor image. tence/cervical-assessment-1).

placebo.156 Women treated with 17-OHPC were significantly less likely to deliver before 37, 35, and 32 weeks. Secondary analyses of this study revealed a stronger beneficial effect for women whose qualifying preterm birth was less than 34 weeks429 and for women with more than one prior preterm birth.430 The rate of preterm birth before 37 weeks in the placebo group was deemed by some to be higher than expected,431 but the recurrence rate was not surprising given the demographics and obstetric history of the women enrolled: 59% of subjects in both groups were African Americans, the mean gestational age of the qualifying preterm birth was 31 weeks in both groups, and 32% of women enrolled had more than one prior preterm birth—all factors that increase the risk for recurrence beyond the usual twofold risk associated with a prior preterm birth. The groups differed in the mean number of previous preterm deliveries (1.6 in the placebo group versus 1.4 in the 17-OHPC Figure 41.15 Ultrasound image of a curved cervical canal. group; P = .007), a difference that might have influenced the recurrence rate of 55%. Subsequent trials that enrolled women with short cervix antagonism leading to relaxation of smooth muscle, mainte- report significant reductions in preterm birth in women treated nance of cervical integrity, and antiinflammatory effects.427 with vaginal progesterone compared with those treated with Small trials performed in women with recurrent miscarriage placebo, but only when short cervix was defined as less than the and preterm birth were reviewed by Keirse, who concluded that 3rd percentile.417,418 Fonseca and associates417 enrolled women 17-OHPC does not protect against miscarriage but reduces the with cervical length of less than 15 mm (1.7% of more than occurrence of preterm birth.428 This observation prompted two 24,000 women screened), and found significantly lower rates of randomized trials of progestational agents in women with risk preterm birth before 34 weeks’ gestation (19% versus 44%; RR factors for preterm birth.156,419 In a trial that enrolled 142 women = 0.56; 95% CI, 0.36 to 0.86) in those treated with 200-mg with a history of preterm birth or other risk factors to receive vaginal progesterone suppositories daily. Hassan and col- placebo or 100-mg progesterone suppositories daily beginning leagues418 enrolled women with cervical length measurements at 24 weeks’ gestation, birth before 37 weeks occurred in 28.5% between 10 and 20 mm (2.3% of more than 32,000 women of women in the placebo arm as opposed to 13.5% in the pro- screened) and found similar results: Among 465 women ran- gesterone arm.419 In a second, larger placebo-controlled trial, domized, those who received 90 mg vaginal progesterone gel 459 women with a prior spontaneous preterm birth received daily until 36 6/7 weeks had lower rates of preterm birth before weekly intramuscular injections of 250 mg 17-OHPC or 28 weeks (5.1% versus 10.3%; RR = 0.50; 95% CI, 0.25 to 0.97),

33 weeks (8.9% versus 16.1%; RR = 0.55; 95% CI, 0.33 to 0.92), with the failure of progesterone to prevent preterm birth in all and 35 weeks (14.5% versus 23.3%; RR = 0.62; 95% CI, 0.42 to women with a very short cervix,417,418 suggests that the effect may 0.92). Neonatal morbidity or mortality was also significantly be related to modulation of inflammation or cervical ripening lower in treated patients (7.7% versus 13.5%; RR = 0.57; 95% more than an effect on uterine contractility. CI, 0.33 to 0.99).418 There is growing evidence of neonatal benefit and safety for In contrast, preterm birth rates were not reduced by proges- progesterone supplementation. In a meta-analysis of five high- terone supplementation in two other randomized, placebo- quality trials that included a total of 775 women and 827 infants, controlled trials that enrolled women with cervical length treatment with vaginal progesterone was associated with a signifi- measurements well above the 3rd percentile.157,422 O’Brien and cant reduction in preterm birth before 33 weeks (RR = 0.58; 95% colleagues157 found no effect of progesterone vaginal gel on the CI, 0.42 to 0.80), 35 weeks (RR = 0.69; 95% CI, 0.55 to 0.88), and preterm birth rate in 659 women with a prior preterm birth 28 weeks’ gestation (RR = 0.50; 95% CI, 0.30 to 0.81).435 RDS (RR (women likely to receive a cerclage were specifically excluded). = 0.48; 95% CI, 0.30 to 0.76), composite neonatal morbidity and Cervical length was measured at entry to characterize the a mortality (RR = 0.57; 95% CI, 0.40 to 0.81), birth weight below priori risk of women enrolled; mean cervical length of enrollees 1500 g (RR = 0.55; 95% CI, 0.38 to 0.80), admission to a neonatal was 37 mm at 18 to 20 weeks’ gestation, indicating a population intensive care unit (RR = 0.75; 95% CI, 0.59 to 0.94), and need with relatively longer cervical length.350 Grobman and cowork- for mechanical ventilation (RR = 0.66; 95% CI, 0.44 to 0.98) were ers422 enrolled nulliparous women with a singleton gestation all significantly less frequent in infants of treated women. There between 16 and 22 3/7 weeks with cervical length less than were no significant differences between the vaginal progesterone 30 mm (the 10th percentile in this population) who were ran- and placebo groups in the rate of adverse maternal events or domly assigned to receive weekly intramuscular injections of congenital anomalies. The safety of progesterone supplementa- 17-OHPC (250 mg) or placebo until 36 weeks. Birth before 37 tion is further supported by a review of outcomes of pregnancies weeks did not differ between women who received 17-OHPC treated before 1990,436 by a review of animal studies,437 and by a (n = 327) and those who received placebo (n = 330) (25.1% thorough neurodevelopmental evaluation of children at 4 years versus 24.2%; RR = 1.03; 95% CI, 0.79 to 1.35). Composite of age born to women treated in the NICHD trial.438 Studies to adverse neonatal outcome was not different (7.0% versus 9.1%; date have not shown increased rates of fetal growth restriction or RR = 0.77; 95% CI, 0.46 to 0.30). stillbirth, but because progesterone prophylaxis may act through Progesterone supplementation is not effective as prophy- antiinflammatory effects, potential risks related to that action laxis or as treatment in women with multiple gestations when remain a concern.439 multifetal gestation is the only risk factor. In randomized Current evidence supports offering 17-OHPC to women trials conducted in women with twin pregnancies, neither with a history of prior spontaneous preterm birth and vaginal 17-OHPC424,432 nor vaginal progesterone433 reduced the rate of progesterone to women with a cervical length of 20 to 25 mm preterm birth. Results in triplet gestations were no different.423 or less before 25 weeks’ gestation. Use of progesterone for indi- Uncertainty persists, however, about the effect of progester- cations other than prior preterm birth and short cervix is not one supplementation in three circumstances involving multi- supported by available evidence. Small studies suggest that ini- fetal gestation that lack adequate literature: Care for women tiation of prophylaxis after 20 weeks may be beneficial,440 that with twins who also have short cervix or a previous singleton discontinuation of prophylaxis may increase the risk for preterm preterm birth, as well as for women with a singleton pregnancy birth,441 and that treatment after an episode of preterm labor with a prior preterm birth of twins, is currently based on inad- for women with short cervix might be helpful.442 None of these equate direct evidence, aided by interpretation of the literature studies were large enough to influence current practice, but they in singletons. When progesterone data are considered in toto, support further investigation to define the appropriate role for progesterone prophylaxis is effective when a very short cervix this treatment. represents the early onset of parturition, but it is not effective Whether the various progestational agents are similarly effective when short cervix is the result of other causes (e.g., uterine for either indication is not known, but is suggested by the results of stretch), as might be the case for most women with multifetal the O’Brien trial,157 in which progestin treatment was ineffective pregnancies. Thus women with twins and short cervix but with in women with a history of preterm birth whose cervical length no other risk factors are unlikely to benefit from progesterone at entry averaged 37 mm, and by an analysis of data from women supplementation, as is suggested by the limited available lit- with a previous preterm birth in the Preterm Prediction Study,443 erature.434 We do not offer progesterone treatment to women which showed recurrent preterm birth rates of less than 10% when with twins or triplets, regardless of cervical length, unless there the cervical length was 35 mm or more at 22 to 24 weeks. is a documented history of a prior spontaneous preterm birth. Although the benefit of progesterone supplementation has Women with a previous spontaneous birth of twins before 32 been observed in multiple research trials, the optimal clinical to 34 weeks’ gestation have an increased risk for spontane- protocols for progesterone have not yet been developed. Wide ous preterm birth in future singleton pregnancies,163-165 as do clinical use of progesterone supplementation for women with a women with a prior singleton preterm birth, regardless of fetal prior spontaneous preterm birth has been estimated to result number in future pregnancies. We offer progesterone prophy- in savings of more than $2 billion annually in the United laxis to these women, although this is not based on quality States.444-446 Two cost-effectiveness studies support universal evidence. A history of preterm birth in a triplet pregnancy does cervical length screening with TVU for all pregnant women not constitute an indication for progesterone prophylaxis. between 18 and 24 weeks, but they rely on assumptions that A beneficial effect of supplemental progesterone is not univer- have not been tested in practice.447,448 sally observed in women with a prior preterm birth, indicating Discussions of how best to integrate comprehensive obstetric that some pathways to recurrent preterm birth are not affected by history and cervical TVU into clinical practice to detect candi- this therapy. The absence of effect in multiple gestations, coupled dates for progesterone are underway, driven by recent practice

Initial Prenatal Visit Comprehensive Obstetrical History Ultrasound Confirmation of Dates and Plurality

Is There a History of Spontaneous Preterm Birth? Defined as a singleton birth (live or stillborn) at 160/7–366/7 weeks presenting as labor, ruptured membranes, or advanced cervical dilation or effacement

Yes No

Rx Is this a singleton 17-OHPC 250 mg IM gestation? weekly from 150/7 to 360/7 weeks’ gestation Yes

TV CL Q 14 days Universal Indicated TV CL between 16-24 weeks TV CL at - Symptoms—persistent Q 7 days if cervix <25 mm 18-24 wk pressure, cramps, increased vag dischg - Transabdominal US suggests short CL - Risk factors for PTB

Perform TV CL TV CL >25 mm

If TV CL TV CL ≤25 mm ≤20 mm

TV CL 21-25 mm Routine * Consider cerclage, especially if Repeat x 1 in 7-10 d care cervical length <15 mm or multiple prior 2nd trimester losses * Continue progesterone Vaginal Progesterone Daily 200 mg (suppositories or capsules) or 90 mg gel until 360/7 weeks

Figure 41.16 Algorithm for identification and treatment of candidates for progesterone supplementation. Algorithm is based on Practice Guidelines published by the Society for Maternal-Fetal Medicine and the American College of Obstetricians and Gynecologists. IM, Intramuscularly; 17-OHPC, 17α-hydroxyprogesterone caproate; PTB, preterm birth; Q, every; TV CL, transvaginal ultrasound measurement of cervical length; US, ultrasound; vag dischg, vaginal discharge. (Society for Maternal-Fetal Medicine Publications Committee. Progesterone and preterm birth prevention: translating clinical trials data into clinical practice. Am J Obstet Gynecol. 2012;206:376–386; and Committee on Practice Bulletins—Obstetrics, American College of Obstetricians and Gynecologists. Practice bulletin no. 130: prediction and prevention of preterm birth. Obstet Gynecol. 2012;120:964–973.) guidelines from the Society for Maternal-Fetal Medicine449 and screening may become standard for all pregnancies. It is likely that the ACOG407 that support 17-OHPC prophylaxis for women the optimal protocol or protocols will be identified by population- with a history of preterm birth, and vaginal progesterone for based observational reports, as was the case for GBS screening. Evi- short cervix of 20 mm or less before 24 weeks. Both documents dence for a population-level effect of progestogen prophylaxis on include care algorithms that are integrated in Fig. 41.16. the rate of early premature births has been reported from Ohio, Discussions of prevention strategies are currently focused on where aggressive statewide promotion of both 17-OHPC and whether all women should undergo transvaginal cervical ultra- vaginal progesterone was accompanied by a significant 6.6% sound examination to measure cervical length, or whether an algo- decline in births before 32 weeks over 24 months.15 rithm can be devised that can identify women for whom it is unnecessary. The best care path is uncertain, but nevertheless, con- Cervical Cerclage to Prevent Preterm Birth. Cervical cer- sideration of cervical ultrasound surveillance has entered routine clage has been the treatment of choice for patients with pre- prenatal care, and with it, some form of prematurity prevention sumed weakness of the cervix. When preterm birth is predicted,

TABLE Indications for Cerclage 41.5 Accepted Cerclage Gestational Age at Nomenclature Definition of Indicationa Placement (wk) Former Nomenclature

History-indicated Historical criteria (e.g., recurrent [≥3] early 12–14 Prophylactic, elective PTBs or second-trimester losses) Ultrasound-indicated Short CL (<25 mm) before 24 weeks’ gestation 14–23 Therapeutic, salvage in singleton gestations with prior SPTB Physical examination–indicated Cervical changes (e.g., ≥1 cm dilated, or 16–23 Rescue, emergency, urgent prolapsed membranes) detected on physical examination Transabdominal Prior history-indicated cerclage that resulted 11–12 — in PTB at <33 weeks aFor singleton gestations only. CL, Cervical length; PTB, preterm birth; SPTB, spontaneous preterm birth. there are four main indications for cerclage (Table 41.5). The first is based solely on poor obstetric history, which should BOX 41.4 CERVICAL INSUFFICIENCY: RISK FACTORS include at least one prior early preterm birth. The second, ultrasound-indicated cerclage, is based on the TVU finding of a ACQUIRED short (i.e., ≤25 mm) cervical length before 24 weeks in a woman • Cervical laceration or obstetric injury with a singleton gestation and a prior spontaneous preterm • Cervical instrumentation birth. The third indication for cerclage is the finding of an open • Dilation and evacuation (D&E) • Dilation and curettage (D&C) cervix by manual or speculum examination before 24 weeks. • Elective abortion The fourth cerclage nomenclature is transabdominal, which • Loop electrosurgical excision procedure (LEEP) may be indicated in the setting of a prior history-indicated cer- • Cold-knife conization clage that resulted in preterm birth at less than 33 weeks. • Laser conization • Hysteroscopy In assessing the efficacy of cerclage, singleton gestations • Prior second-trimester birth (at <28 weeks) should be assessed separately from multiple gestations, because efficacies appear to differ in these populations. CONGENITAL History-Indicated Cerclage. Historically, the decision to • Collagen disorders (e.g., Ehlers-Danlos) perform cerclage was based solely on a poor obstetric history. • Uterine anomalies • In utero exposure to diethylstilbestrol (DES) In current practice, history-indicated cerclage has become less common because of TVU surveillance450,451 of cervical length. In a meta-analysis of four trials involving singleton gestations with a prior spontaneous preterm birth, TVU screening of cervical BOX 41.5 CERVICAL INSUFFICIENCY: length with the option of cerclage if the cervical length became DIFFERENTIAL DIAGNOSIS less than 25 mm before 24 weeks’ gestation was compared with routine placement of history-indicated cerclage; outcomes were • Maternal or fetal infection similar.450 Short cervix was detected by TVU screening in only • Uterine distention (e.g., hydramnios, multiple gestation) • Bleeding or placental disease about 40% of singleton gestations with a prior early preterm • Other fetal disease associated with preterm birth (e.g., struc- birth, thus avoiding cerclage in the 60% who did not manifest tural or karyotypic anomaly) short cervix.450 These percentages, recorded before progesterone • Other maternal disease associated with preterm birth (e.g., treatment for short cervix was widely used, may change. poorly controlled diabetes) Based on trials of the efficacy of cerclage indicated by history These disorders precede cervical changes. alone,452 we limit consideration to women with either of the following: • Multiple prior second-trimester (14 to 28 weeks’ gestation) pregnancy losses, when risk factors for cervical insuf- Singletons Without a Prior Preterm Birth. Ultrasound- ficiency (Box 41.4) are present and other differential indicated cerclage has not been shown to be beneficial in single- diagnoses (Box 41.5) have been ruled out ton gestations when a short cervix was identified before 24 • A prior singleton pregnancy with a short cervix (<25 mm) weeks’ gestation but there was no prior preterm birth. A meta- before 24 weeks that led to preterm birth at less than 32 analysis of four trials of singleton pregnancies screened with weeks even with intervention (e.g., cerclage),453 when risk cervical ultrasound, found to have a short (>25-mm) cervix, factors for cervical insufficiency are present and other dif- and randomly assigned to cerclage or no cerclage showed a ferential diagnoses have been ruled out nonsignificant (24%) reduction in preterm birth at less than 35 Ultrasound-Indicated Cerclage. The effectiveness of weeks in the cerclage group if the patients had no risk factors ultrasound-indicated cerclage, placed because of the finding for preterm birth—26%, compared with 33% in the group of a short cervix on second-trimester TVU, has depended without cerclage (RR = 0.76; 95% CI, 0.52 to 1.15).454 This on the population studied, even within singleton gestations. nonsignificant decrease in preterm birth deserves further study These trials were performed before progesterone therapy was in women whose cervix shortens despite progesterone prophy- employed. laxis. Unfortunately, in women without a prior preterm birth,

Downloaded for Rodrigo Terra ([email protected]) at Clinica Alemana de Santiago - JCon from ClinicalKey.com by Elsevier on October 19, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 710 PART 4 Disorders at the Maternal-Fetal Interface but with other risk factors such as prior cervical surgery, intraamniotic infection, ruptured membranes, advanced labor, ultrasound-indicated cerclage has been insufficiently studied to or significant hemorrhage is present, delivery is indicated. Sus- make a recommendation. picion for intraamniotic infection is increased by the presence The effect of cerclage in women with singleton gestations, no of an otherwise-unexplained fever or by uterine tenderness. In history of preterm birth, and a short cervix (≤25 mm) who are the absence of indications for delivery, the gestational age and treated with progesterone has not been adequately investigated. degree of cervical dilation need to be determined. Prior to fetal Singletons With Prior Preterm Birth. On the other hand, viability, management is usually aimed at prolonging the preg- ultrasound-indicated cerclage has been associated with benefit nancy, but allowing or promoting delivery may be appropriate when performed in women with a prior preterm birth who have in some circumstances, such as previable pPROM or advanced a short cervix by TVU. Between 30% and 40% of women with cervical dilation (>4 cm). If viability has been reached, the singleton gestations who had a prior spontaneous preterm birth goal is to both prolong the pregnancy and improve neonatal will develop a short cervix (<25 mm) before 24 weeks’ gesta- outcome in the event of preterm birth. tion.450,455 In these cases, ultrasound-indicated cerclage has been Data from several studies459 suggest that a dilated cervix with shown to decrease the incidence of preterm birth, confirming the visible membranes may be an appropriate indication for cer- diagnosis of cervical insufficiency. In the largest trial, 302 women clage placement in some cases. Placement of a cerclage when a with a prior spontaneous preterm birth between 16 and 34 weeks dilated cervix and visible membranes are detected on digital (mean, 24 weeks) and a cervical length of less than 25 mm were examination at less than 24 weeks’ gestation appeared to prolong randomly assigned to receive cerclage or no cerclage.455 Cerclage pregnancy by about 1 month and to improve pregnancy was associated with a significant reduction in perinatal deaths outcome, compared with expectant management.459 (8.8% versus 16%), and in births at less than 24 weeks (6.1% We suggest considering amniocentesis to check for infection versus 14%) and less than 37 weeks (45% versus 60%).455 In a in women with visible membranes and no clinical signs of meta-analysis involving 504 singleton pregnancies with prior infection, especially when the cervix is dilated 2 cm or more, or spontaneous preterm birth occurring at less than 34 weeks and when there are ultrasound findings suggestive of inflammation: having a cervical length of less than 25 mm before 24 weeks’ membrane edema, separation of membranes from the decidua, gestation, cerclage was associated with a significant (30%) reduc- or debris (sludge) in the amniotic fluid. Cerclage can be con- tion in the risk for preterm birth at less than 35 weeks (28% sidered in these women only in the absence of infection, labor, versus 41%; RR = 0.70; 95% CI, 0.55 to 0.89) and a 36% reduc- and vaginal bleeding. tion in composite perinatal mortality and morbidity (16% versus 25%; RR = 0.64; 95% CI, 0.45 to 0.91).454 Benefit from cerclage Cervical Pessary. A cervical pessary was first reported as a pos- was seen at all cervical length cutoffs between 0 and 24 mm.455 sible intervention to prevent preterm birth in the 1950s.461 The Therefore TVU screening for cervical length in women with precise mechanism of action by which a cervical pessary may singleton gestations who had prior spontaneous preterm birth, prevent preterm birth is largely unknown. One potential mecha- starting at about 16 weeks and then every 2 weeks until 23 nism is to influence cervical biomechanical loading. Another sug- weeks, is suggested so that cerclage can be offered to those who gested mechanism is that, by encompassing the cervix and develop a cervical length of less than 25 mm despite progester- compressing the cervical canal, a pessary might protect cervical one prophylaxis.456–458 mucus integrity and function. Meta-analysis of three trials (1412 According to current recommendations from the American women) showed that cervical pessary placement did not reduce College of Obstetricians and Gynecologists and the Society for the risk of spontaneous preterm birth (<34 weeks’ gestation) in Maternal-Fetal Medicine, all women with a history of spontane- these women (RR, 0.71; 95% CI, 0.21 to 2.43, P = .59; heterogene- ous preterm birth should be offered progesterone prophylaxis, ity [I2] = 90%).462 This meta-analysis also showed that a cervical regardless of cervical length.457–459 Cerclage is beneficial in these pessary did not prevent preterm birth at less than 34 weeks, 30 women if sonographic short cervix (<25 mm) develops.451,455 A weeks, or 28 weeks and was not associated with RDS, NEC, IVH, recent meta-analysis involving 169 singleton gestations with a neonatal sepsis, retinopathy of prematurity, fetal death, neonatal prior preterm birth and a cervical length of 25 mm or less, most death, perinatal death, birth weight less than 1500 g or less than before 25 weeks’ gestation, revealed that vaginal progesterone 2500 g, pPROM, corticosteroid treatment for fetal maturation, or was associated with a significant reduction in preterm birth at admission to neonatal intensive care unit. Although this meta- less than 33 weeks (RR = 0.54; 95% CI, 0.30 to 0.98) and in analysis showed that cervical pessary placement did not reduce composite neonatal morbidity and mortality (RR = 0.41; 95% the risk of preterm birth in women with a singleton pregnancy CI, 0.17 to 0.98).456 and a short cervix, further data in this regard will be forthcoming Interestingly, ultrasound-indicated cerclage was associated from large-scale randomized controlled trials. with the lowest risk ratios for preterm birth in women with a cervical length of less than 15 mm. In fact, in the meta-analysis, PREMATURITY PREVENTION BEFORE the lowest risk ratio was for a cervical length of 15.9 mm or less: PREGNANCY preterm birth occurred at less than 35 weeks with or without cerclage (35.0% and 58.1%, respectively; RR = 0.59; 95% CI, Preconception interventions are attractive because many risk 0.42 to 0.83).460 factors are difficult to address successfully during pregnancy. Physical Examination–Indicated Cerclage. Rarely, a woman presents before 24 weeks’ gestation with minimal or Public Education Interventions no symptoms and speculum or digital examination reveals The public inaccurately perceives that the problems of preterm cervical dilation of 1 to 4 cm. Occasionally, such a finding infants have been overcome by improved neonatal care.338 follows the identification of a very short cervix (e.g.,< 5 mm) Increased awareness of preterm birth as the leading cause of detected by TVU (see Ultrasound-Indicated Cerclage, earlier). If infant mortality offers an opportunity to raise public awareness

Downloaded for Rodrigo Terra ([email protected]) at Clinica Alemana de Santiago - JCon from ClinicalKey.com by Elsevier on October 19, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 41 Prevention and Management of Preterm Parturition 711 of avoidable risk factors.3 For example, greater public and with the least amount of education (0 to 11 years) had the professional knowledge of evidence suggesting that repeated highest prevalence of maternal smoking during pregnancy and uterine instrumentation may confer an increased risk for sub- the poorest birth outcomes, but the strongest reduction in sequent preterm birth might affect decision making about these smoking in response to higher cigarette taxes. procedures.142,172,173,463 The use of laminaria has been reported to reduce the risk for subsequent preterm birth in women under- Preconception Care for Women With Risk going second-trimester dilation and evacuation.464 Preconception interventions to reduce risk for preterm birth Similarly, broader public knowledge of the increased risk for typically target women with a previous preterm birth.477 The preterm birth in singleton gestations conceived with ART upper gestational age boundary for a preterm birth is com- might, if coupled with information about the consequences of monly 37 weeks, and the risk of recurrence declines as the ges- prematurity, influence fertility care.465-467 Such educational tational age of the index preterm birth approaches 37 weeks.146 efforts could be modeled after successful efforts to reduce the The lowest gestational age for which an increased risk for prevalence of smoking. preterm birth is observed in subsequent pregnancies is optimal for clinical use and was determined to be 17 to 18 weeks for Public and Professional Policies spontaneous preterm births in studies of data from the Preterm In contrast to public education strategies, policies adopted by Prediction Study.146 Previous births before 17 weeks did not governmental or medical bodies can have a more immedi- confer an increased risk for recurrent preterm delivery.146,155,477 ate effect. Policies adopted to reduce the risk of higher-order As noted earlier, the risk of recurrence is increased for both multiple gestation have been successful in Europe, Australia, spontaneous and indicated preterm births.152,159,166 Risk increases and the United States. Rates of triplet and higher-order mul- as the gestational age of the previous preterm birth declines, tiple pregnancies were rising rapidly in the United States until and as the number of preterm births increases.146 Careful review 1998, when voluntary adoption of limitations on the number of records from prior pregnancies may be helpful to establish of embryos transferred was promoted by professional groups. the gestational age of the index birth, estimate the recurrence The rate of higher-order multiples then fell by 50% between risk, and identify risks amenable to intervention, including 1996 and 2003.468,469 some that may require preconception intervention (e.g., correc- Social policies to improve pregnancy outcomes have been tion of müllerian anomalies)478 and others that could determine adopted by many European countries.470 Minimal paid preg- care choices during pregnancy (e.g., prophylactic progesterone nancy leave of 14 weeks, time off for prenatal visits, exemption or cerclage). Prepregnancy medical risk factors have been iden- from night shifts, and protection from workplace hazards, tified in as many as 40% of preterm births,479 suggesting that including complete work leave if necessary, are among the strat- women with these risks might benefit from preconception egies used. control of diabetes, seizures, asthma, or hypertension. Interconception care for women with prior preterm birth Systemic Interventions has been proposed,480 but evidence that these steps can actually Prenatal care can be considered as part of a continuum of care influence the preterm birth rate is lacking. A randomized trial that begins long before women reach reproductive age. Preven- of interconception home visits and counseling by midwives did tion of risks associated with adverse pregnancy outcome can not reduce preterm birth and LBW infants in a study of 1579 begin in the preadolescent period with attention to nutrition, women.481 On the basis of the hypothesis that preconception sexually transmitted infection, timing of desired pregnancies, microbial colonization of the endometrium might increase the and general health education.342 risk for preterm birth, a randomized, placebo-controlled trial of interconception antimicrobial treatment was performed in Nutritional Supplements women with a prior early preterm birth.482 Study participants Women considering a pregnancy are routinely advised to initi- received metronidazole and azithromycin or placebo at 3-month ate supplementation with prenatal vitamins before conception, intervals until their next pregnancy occurred. The rate of recur- chiefly to reduce the risk for birth defects.471 A randomized, rent preterm birth was not influenced by antibiotic treatment. placebo-controlled trial of vitamin supplementation that The proportion of women enrolled in this study whose qualify- enrolled women before conception and continued through the ing preterm birth was related to infection is not known.398 first 2 months of pregnancy found no effect of vitamins on the Preconception strategies to reduce the risk for preterm preterm birth rate.472 birth may be applied to populations as well as to individuals. Population-based strategies include prevention of unplanned Smoking and potentially unwanted pregnancies because both are asso- The attributable risk of cigarette smoking exceeds 25% for ciated with increased rates of preterm birth. Such strategies preterm birth473 and approximates 5% for infant mortality.474 include programs to promote continued school attendance An overall decrease in maternal smoking before conception through high school, education about contraception and sexu- might be expected to reduce preterm births, but preterm birth ally transmitted infection (e.g., use of condoms and long-acting rate in the United States rose from 11.6% to 12.5% between contraceptives), and community efforts to promote social and 2000 and 2004, a time when smoking among women ages 18 to economic security. Provision of long-acting reversible con- 44 years declined from 25.5% to 21.7%.475 Reduced prevalence traception among women at risk for unplanned pregnancy of smoking would nevertheless have multiple health benefits for was successful in reducing unplanned births in a community pregnant women and infants. Increases in the cigarette tax were program in St. Louis and could be expected to contribute to a associated with improved health outcomes related to smoking reduction in preterm births as well.483 among the highest-risk mothers and infants in an analysis of 476 more than 16 million singleton births in 28 states. Mothers A full reference list is available online at ExpertConsult.com.

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