Abstract
Preterm delivery is defined as delivery before 37 weeks’ gestation. It occurs in 5% to 9% of pregnancies in developed countries and is responsible for 75% to 80% of all neonatal deaths and significant neonatal morbidity. The World Health Organization (WHO) and other nongovernmental organizations have identified the frequency of preterm birth as a critical health issue. Worldwide, on a yearly basis, 15 million infants are born preterm. More than 60% of preterm births occur in Africa and South Asia. In lower-income countries, the preterm birth rate is 12% with a neonatal mortality rate greater than 90% in those born extremely preterm (less than 28 weeks). In higher-income countries, the preterm birth rate is 9% with a neonatal mortality rate less than 10%.
In 2006, the Institute of Medicine recommended that investigators focus on (1) better defining the problem; (2) developing treatments to prevent both preterm delivery and morbidity for children born preterm; (3) identifying the causes of preterm birth, including modifiable risk factors and the reasons for disparity among different ethnic, racial, and socioeconomic groups; and (4) developing policies and public programs that can be used to reduce the rate of preterm birth.
Keywords
Preterm labor, Preterm birth, Low birth weight, Tocolysis, Neonatal morbidity and mortality, Preterm premature rupture of membranes
Chapter Outline
Definitions, 799
Neonatal Mortality, 800
Neonatal Morbidity, 801
Preterm Labor, 802
Risk Factors, 802
Prediction of Preterm Labor, 803
Prevention of Preterm Labor, 803
Diagnosis, 804
Assessment and Therapy, 804
The Preterm Infant, 809
Anesthetic Management, 811
Perinatal Effects of Maternal Local Anesthetics, 811
Vaginal Delivery, 812
Cesarean Delivery, 812
Anesthesia for Rescue Cerclage Placement and Cerclage Removal, 813
Venous Thromboembolism Prophylaxis, 813
Interactions between Tocolytic Therapy and Anesthesia, 813
Indications for Anesthesia during and after Tocolytic Therapy, 813
Calcium Entry–Blocking Agents, 813
Cyclooxygenase Inhibitors, 814
Beta-Adrenergic Receptor Agonists, 814
Oxytocin Receptor Antagonists, 815
Magnesium Sulfate, 815
Preterm delivery is defined as delivery before 37 weeks’ gestation. It occurs in 5% to 9% of pregnancies in developed countries and is responsible for 75% to 80% of all neonatal deaths and significant neonatal morbidity. Preterm delivery leads to a large economic burden to society. For example, in 2005, in the United States the cost associated with preterm birth was at least $26.2 billion.
Preterm delivery in the United States increased 20% between 1990 and 2006 (from 10.6% to 12.8%), before declining to 9.9% of all births in 2016 ( Figs. 33.1 and 33.2 ). There is notable racial/ethnic disparity in the frequency of preterm birth. In 2015, 9.0% of non-Hispanic whites, 13.8% of non-Hispanic blacks, and 9.5% of Hispanics delivered preterm. This is not explained by differential use of assisted reproductive technology. Late preterm is defined as 34 0/7 to 36 6/7 completed weeks’ gestation, and early preterm is defined as less than 34 completed weeks’ gestation. Table 33.1 lists subdivisions of early preterm births. In 2016, late preterm deliveries composed 7.1% of all births, and early preterm births composed 2.8% of all births.
| Classification | Gestational Age |
|---|---|
| Extremely preterm | Less than 28 weeks |
| Very preterm | 28 0/7 weeks to 31 6/7 weeks |
| Moderate preterm | 32 0/7 weeks to 33 6/7 weeks |
| Late preterm | 34 0/7 weeks to 36 6/7 weeks |
| Early term | 37 0/7 weeks to 38 6/7 weeks |
| Full term | 39 0/7 weeks to 40 6/7 weeks |
| Late term | 41 0/7 weeks to 41 6/7 weeks |
| Postterm | 42 0/7 weeks and beyond |
The concern about preterm birth is not confined to the United States; the World Health Organization (WHO) and other nongovernmental organizations have identified the frequency of preterm birth as a critical health issue. Worldwide, on a yearly basis, 15 million infants are born preterm. More than 60% of preterm births occur in Africa and South Asia, with Malawi having the highest rate (18.1 per 100 live births). Although truly a global problem, economic disparity exists. In lower-income countries, the preterm birth rate is 12% with a mortality rate greater than 90% in those born extremely preterm (less than 28 weeks). In higher-income countries, the preterm birth rate is 9% with a neonatal mortality rate less than 10%. The global neonatal mortality rate is 19 per 1000 live births. The United States has a slightly higher neonatal mortality rate than Europe (4 versus 3 per 1000 births, respectively), which reflects the higher preterm birth rate in the United States.
In 2006, the Institute of Medicine recommended that investigators focus on (1) better defining the problem; (2) developing treatments to prevent both preterm delivery and morbidity for children born preterm; (3) identifying the causes of preterm birth, including modifiable risk factors and the reasons for disparity among different ethnic, racial, and socioeconomic groups; and (4) developing policies and public programs that can be used to reduce the rate of preterm birth.
Definitions
A preterm infant is defined as one who is born between 20 0/7 weeks and 36 6/7 weeks, inclusive, after the first day of the last menstrual period. The American College of Obstetricians and Gynecologists (ACOG) has defined periviable birth as birth between 20 weeks’ and 25 6/7 weeks’ gestation. Further classification of deliveries based on gestational age is outlined in Table 33.1 . If a good basis does not exist for establishing the gestational age from either maternal history or first-trimester ultrasound, the exact gestational age is difficult to determine. A low birth weight (LBW) does not necessarily signify that a neonate has been born preterm, because some newborns have a LBW because they are small for gestational age (SGA) rather than preterm. A neonate who weighs less than 2500 g at birth is considered to have a LBW, regardless of gestational age. Likewise, an infant who weighs less than 1500 g at birth is considered to have a very low birth weight (VLBW), and an infant who weighs less than 1000 g at birth is considered to have an extremely low birth weight (ELBW).
Neonatal Mortality
The survival rate among neonates increases as the birth weight and/or gestational age increases ( Fig. 33.3 ; Table 33.2 ). After data are controlled for gestational age and weight, male infants have a higher mortality than female infants. During the past three decades, there has been a significant improvement in the survival rate for preterm infants, with the greatest improvement occurring in the subgroup with a birth weight between 501 and 1250 g. The rate of neonatal survival now is approximately 94% for infants born at 28 weeks’ gestation.
| Completed Weeks’ Gestation | Percentage of Deaths a |
|---|---|
| 22 | 93 |
| 23 | 68 |
| 24 | 38 |
| 25 | 23 |
| 26 | 15 |
| 27 | 10 |
| 28 | 6 |
a Death rate before discharge by gestational age among all infants born at the Neonatal Research Network Centers between 2008 and 2012.
Infants born at the threshold of viability (22 to 24 weeks’ gestation) continue to have the greatest risk for poor outcome. A retrospective cohort study assessed survival rates for infants delivered between 22 and 28 weeks’ gestation. Neonatal survival was 9% at 22 weeks, 33% at 23 weeks, and then 65%, 81%, and 87% at 24, 25, and 26 weeks’ gestation, respectively. The majority of women received antenatal corticosteroids, and the majority of neonates received exogenous surfactant. A delay in delivery of even 1 week at this time in gestation leads to significantly better outcome and reduced cost.
Younge et al. examined outcomes for infants born between 22 and 24 weeks’ gestation between 2000 and 2011 ( Table 33.3 ). The mortality rate decreased over time overall (72% from 2000 to 2003 to 66% from 2008 to 2011). However, the mortality rate did not change for 22-week infants. As expected, the greatest decrease in mortality was seen in the 24-week group (55% from 2000 to 2003 to 18% from 2008 to 2011). Those born later in the study period were more likely to have been exposed to antenatal maternal corticosteroids, be delivered by cesarean, and be resuscitated at birth, regardless of gestational age. Excess mortality risk for infants born preterm is concentrated in the first year.
| Outcome | Percent |
|---|---|
| |
| 64 |
| 66 |
| 38 |
| 52 |
| 27 |
| 66 |
| 64 |
| 20 |
| 29 |
a Gestational age between 22 and 24 weeks’ gestation, born between 2008 and 2011.
b Neurodevelopmental impairment defined as at least one of the following conditions: moderate or severe cerebral palsy, Gross Motor Function Classification System level 2 or greater, profound hearing loss requiring amplification in both ears, profound visual impairment with visual acuity of less than 20/200 in both eyes, or cognitive impairment.
c Neurosensory impairment defined as moderate or severe cerebral palsy, Gross Motor Function Classification System level 2 or greater, profound hearing loss, or profound visual impairment.
Neonatal Morbidity
Approximately 84% of preterm births occur between 32 0/7 and 36 6/7 weeks’ gestation. Compared with earlier gestational ages, mortality is less common, but morbidity is a relatively greater concern in this gestational age range. Researchers have examined the association between late preterm birth and neurocognitive performance in late adulthood; 919 Finnish men and women were evaluated at a mean age of 68.2 years. When controlling for confounders, those who were born between 34 and 37 weeks’ gestation had lower scores on tests evaluating neurocognitive performance than those born after 37 weeks’ gestation.
As with mortality, most morbidity decreases in frequency as gestational age increases. For example, the incidence of high-grade (III or IV) intraventricular hemorrhage diminishes rapidly after 27 weeks’ gestation, and grade III or IV intraventricular hemorrhages are very rare after 32 weeks’ gestation. Likewise, neonatal morbidity from patent ductus arteriosus and necrotizing enterocolitis diminishes significantly after 32 weeks’ gestation. Data from the National Institute of Child Health and Development (NICHD) Neonatal Research Network sites from 1997 to 2002 indicate that survival without complications (e.g., bronchopulmonary dysplasia, severe intraventricular hemorrhage, necrotizing enterocolitis, or a combination of these disorders) ranged from 20% for infants with a birth weight between 501 and 750 g to 89% for those with a birth weight between 1251 and 1500 g.
Piecuch et al. reported data for a cohort of 138 nonanomalous infants delivered between 24 and 26 weeks’ gestation between 1990 and 1994. The incidence of cerebral palsy did not differ significantly among the three groups born at 24, 25, and 26 weeks’ gestation (11%, 20%, and 11%, respectively). However, the incidence of normal cognitive outcome rose with increasing gestational age at birth (28%, 47%, and 71% at 24, 25, and 26 weeks’ gestation, respectively).
The EPICure study group assessed the association between extreme preterm delivery and long-term physical and mental disability in a cohort of infants delivered between 22 and 25 weeks’ gestation during a 10-month period in 1995. These investigators noted rates of severe disability of 54%, 52%, and 45% among infants delivered at 23, 24, and 25 weeks’ gestation, respectively. In a later cohort of infants, born between 1997 and 2002, the rates of severe disability were 33%, 21%, and 12% for infants delivered at 23, 24, and 25 weeks’ gestation, respectively. A 6-year follow-up to the EPICure study cohort reported persistent severe disability in 25%, 29%, and 18% of infants born at 23, 24, and 25 weeks’ gestation, respectively.
Hack et al. monitored a cohort of ELBW infants born between 1992 and 1995 until they were 8 years of age. The mean birth weight was 810 g, and the mean gestational age at delivery was 26 weeks. Compared with a cohort of age-matched children of normal birth weight, the ELBW group had a higher incidence of significant neurosensory impairment (16% versus 0%, respectively) and asthma (21% versus 9%). The ELBW children differed significantly from the cohort with normal birth weight in rates of suboptimal intelligence, academic achievement, motor skills, and adaptive functioning. These data underscore the long-term medical, educational, and social services required by these children.
The economic costs for the care of surviving preterm infants (especially VLBW infants) can be enormous. A conservative estimate is that 7.7% of insured infants born preterm accounted for 37% of $2.0 billion spent by participating plans on the care of infants born during 2013. With a mean difference in plan expenditures between preterm and term infants of approximately $47,100 per infant, preterm births cost the included plans an extra $600 million during the first year of life. These figures likely will continue to rise with the escalating cost of health care.
Preterm Labor
Risk Factors
Box 33.1 lists factors associated with preterm labor. These associations do not necessarily indicate cause-and-effect relationships. Significant risk factors include a history of preterm delivery, non-Hispanic black race (irrespective of socioeconomic status), and multiple gestation.
Demographic and Medical Characteristics
Non-Caucasian race
Extremes of age (less than 17 or greater than 35 years)
Low socioeconomic status
Low prepregnancy body mass index
History of preterm delivery
Interpregnancy interval less than 6 months
Periodontal disease
Abnormal uterine anatomy (e.g., myomas)
Trauma
Abdominal surgery during pregnancy
Behavioral Factors
Tobacco use
Substance abuse
Obstetric Factors
Previous preterm birth
Vaginal bleeding
Infection (systemic, genital tract, periodontal)
Short cervical length
Multiple gestation
Assisted reproductive technologies
Preterm premature rupture of membranes
Polyhydramnios
The process of normal parturition involves anatomic, physiologic, and biochemical changes that lead to (1) greater uterine contractility, (2) cervical ripening, and (3) membrane/decidual activation. The fetus also appears to play a role in parturition. It is hypothesized that the mature fetal hypothalamus secretes more corticotropin-releasing hormone (CRH), which in turn stimulates fetal adrenal production of adrenocorticotropic hormone (ACTH) and cortisol. Preterm labor results from the pathologic activation of one or more of these components ( Fig. 33.4 ). Preterm delivery results from (1) preterm premature rupture of membranes (preterm PROM) in approximately 25% of cases; (2) spontaneous preterm labor in approximately 45% of cases; and (3) maternal or fetal indications for early delivery in approximately 30% of cases. However, the “spontaneous” causes do not have a uniform underlying pathophysiology, and it appears that preterm labor is a syndrome with multiple causes influenced by a number of genetic, biologic, biophysical, psychosocial, and environmental factors.
Two factors of interest are the influences of infection and uterine distention on initiation of myometrial contractility. Infection is thought to be present in up to 40% of preterm deliveries. Commonly identified organisms include Ureaplasma urealyticum, Bacteroides species, Neisseria gonorrhoeae, Chlamydia trachomatis, group B streptococci, Staphylococcus aureus, Treponema pallidum, and enteropharyngeal bacteria. Although approximately 50% of preterm deliveries occur in women with no apparent risk factors, subclinical infection may precipitate preterm labor in some of these cases. In addition, infection compounds the effects of preterm birth with increased rates of neurologic injury.
Multiple gestation accounts for 21.6% of all preterm births. In the past three decades, there was a significant rise in the incidence of multiple gestation (see Chapter 34 ), attributed to a shift toward older maternal age at conception, and to increased use of assisted reproductive technology (ART). The twinning rate (births in twin deliveries per 1000 total births) rose 76% from 1980 to 2009 (from 18.9 to 33.2 per 1000). Recently, rates of multifetal pregnancies have started to decline. The twin birth rate peaked at 33.9 twins per 1000 births in 2014, and has since decreased to 33.4 in 2016. Likewise, the triplet and higher-order multiple birth rate has fallen 48% since the 1998 peak (193.5) to a rate of 101.4 multiples per 100,000 births in 2016.
Modifications in ART may be contributing to changes in the preterm birth rate and recent declines in multiple gestation. In 2015, ART contributed to 1.7% of all infants born in the United States and 17.0% of all multiple-birth infants, including 16.8% of all twin infants and 22.2% of all triplets and higher-order infants. Risk for preterm birth is elevated even for singleton pregnancies conceived by ART. A 2004 meta-analysis of 15 studies that compared outcomes for 12,283 ART singleton pregnancies with outcomes for 1.9 million spontaneously conceived singleton pregnancies demonstrated a higher risk for preterm and SGA deliveries in the ART group. Placenta previa, gestational diabetes, preeclampsia, and neonatal intensive care unit admission were also more prevalent in the ART group.
Prediction of Preterm Labor
The ability to prevent spontaneous preterm birth would be facilitated if it were possible to intervene prophylactically to prevent preterm labor or to effectively treat preterm labor once it occurs. Both prophylaxis and treatment would require the ability to accurately predict which asymptomatic or symptomatic patients will go on to have spontaneous preterm delivery. Several methods of predicting preterm delivery have been proposed, including home uterine activity monitoring and fetal fibronectin screening. However, available interventional studies based on the use of these tests for screening asymptomatic women have not demonstrated improved perinatal outcomes. Thus, these methods are not recommended as screening strategies.
Novel biomarkers are being investigated for their ability to predict preterm birth. A recent study found that two serum proteins (insulin-like growth factor–binding protein 4 [IBP4] and sex hormone–binding globulin [SHBG]) identified asymptomatic pregnant women at risk for spontaneous preterm delivery. Although promising, these markers have yet to be used in clinical practice.
Short cervical length, as assessed by transvaginal ultrasonography, is associated with a greater risk for preterm delivery. In a 2006 systematic analysis, Kagan et al. concluded that cervical length is associated with preterm delivery (i.e., the shorter the cervix the greater the risk for preterm delivery) in symptomatic women. Further, multiple studies have shown an increased risk for preterm delivery in asymptomatic women with a shortened cervix. A Maternal-Fetal Medicine Units Network study of nearly 3000 women found that the risk for spontaneous preterm delivery is increased in women with evidence of a short cervix detected by transvaginal ultrasonography between 24 and 28 weeks’ gestation. A cervical length below the 10th percentile had a sensitivity of 37% and a specificity of 92% in predicting preterm birth before 35 weeks’ gestation, with a corresponding positive predictive value of 18% and a negative predictive value of 97%. The cervix appears to shorten at a similar rate before preterm birth whether the presentation is preterm labor (–0.96 mm/week) or rupture of membranes (–0.82 mm/week).
A history of cervical surgery, including conization and loop electrosurgical excision procedure, traditionally has been thought to be a risk factor for preterm birth because of associated cervical injury. However, this relationship may be related to environmental factors and/or behavioral factors that underlie the progression of cervical dysplasia. Uterine instrumentation, such as dilation and curettage, also has been associated with an increased risk for preterm birth in some, but not all, studies; the mechanism is unclear, but it may be a result of intrauterine microbial colonization, injury to the endometrium, or both, together with host and environmental factors.
Prevention of Preterm Labor
Screening for any disease is of greatest benefit when there are interventions available to decrease the incidence of said disease. Unfortunately, few if any interventions have been shown to definitively reduce the incidence of preterm labor and delivery. Interventions that have been studied include detection and suppression of uterine contractions, antimicrobial therapy, prophylactic cervical cerclage, maternal nutritional supplements, and reduction of maternal stress. It is not surprising that most of these simple interventions have not been shown to alter outcome, given that preterm labor is increasingly understood to be a complex syndrome with multiple, overlapping causes.
Prophylactic cervical cerclage in the early second trimester has been performed to prevent preterm birth, typically in women with a history of mid-trimester pregnancy loss. Evidence supporting the efficacy of this practice is weak. There remains controversy with regard to whether cerclage should be placed in response to transvaginal ultrasonographic evidence of a short cervix in the second half of the mid-trimester. Data do not support such a practice in the general population, but there is some evidence that the practice may be beneficial among high-risk women, such as those with a prior preterm birth.
Evidence does not support the administration of prophylactic antibiotics in asymptomatic women at risk for preterm labor. Likewise, evidence does not support the prophylactic use of beta-adrenergic receptor agonists to prevent preterm labor in high-risk women.
By contrast, evidence suggests that progesterone therapy may be effective in reducing the rate of preterm birth in some patient populations. The Maternal-Fetal Medicine Units Network performed a randomized controlled trial that compared prophylactic intramuscular 17α-hydroxyprogesterone caproate (17P) (250 mg weekly beginning at 16 to 20 weeks’ gestation, and continued until delivery or 36 weeks’ gestation) with placebo in women with a history of spontaneous preterm delivery. The risk for delivery before 37 weeks’ gestation was reduced in the 17P group (relative risk [RR], 0.66; 95% confidence interval [CI], 0.54 to 0.81). A systematic review of 11 randomized controlled trials ( n = 2425) also concluded that progesterone administration was associated with a significant reduction in recurrent preterm birth in women with a history of spontaneous preterm delivery.
Progesterone therapy also has been shown to be beneficial in reducing the incidence of preterm delivery in the subset of women with a sonographically identified short cervix. In two double-blind, placebo-controlled trials, women with a mid-trimester diagnosis of a short cervix (less than 15 mm in one trial and 10 to 20 mm in the other ) were randomized to receive either vaginal progesterone or placebo. Women who received vaginal progesterone experienced a significant reduction in the frequency of preterm delivery before 33 weeks’ gestation. By contrast, in a trial that enrolled nulliparous women with a cervical length less than 30 mm, women randomized to receive 17P did not experience a reduction in preterm delivery compared with women who received placebo.
A number of studies have examined whether progesterone is efficacious in reducing preterm birth among women with multiple gestation. A recent meta-analysis comparing progesterone (both intramuscular and vaginal preparations), pessary, and cerclage found that vaginal progesterone may be beneficial in twin pregnancy.
Even among women for whom progesterone is thought to be indicated, the optimal type, timing, and dosing of progesterone is unclear. Based on existing evidence, the ACOG has concluded that vaginal progesterone should be offered to asymptomatic women with a singleton gestation without a previous preterm delivery, who have a very short cervical length (i.e., less than or equal to 20 mm at or before 24 weeks’ gestation).
Diagnosis
Determining whether a woman is in early preterm labor or in false labor is often difficult. Criteria for the diagnosis of preterm labor include gestational age between 20 0/7 and 36 6/7 weeks’ gestation and regular uterine contractions accompanied by a change in cervical dilation, effacement, or both (or initial presentation with regular contractions and cervical dilation of 2 cm or more). Less than 10% of women with the clinical diagnosis of preterm labor actually give birth within 7 days of presentation.
Assessment and Therapy
Initial assessment of the patient with possible preterm labor includes physical examination and external monitoring of contractions with a tocodynometer (and fetal heart rate if indicated by gestational age). Acute conditions associated with preterm labor should be considered, including infection and placental abruption. Maternal physical examination may include a sterile speculum examination to exclude preterm PROM if symptoms or signs indicate this possibility. In many women who have preterm uterine contractions, these contractions will cease spontaneously. In the past, clinicians assumed that intravenous hydration was a useful component of therapy. However, there is no evidence that intravenous hydration reduces the chance of preterm delivery.
Once the diagnosis of preterm labor is established, the obstetric care provider must decide whether intervention is warranted. The administration of antenatal corticosteroids for fetal lung maturation and magnesium sulfate for fetal neuroprotection are associated with improved neonatal outcomes. Although widely used before 34 weeks’ gestation, acute tocolytic therapy remains a source of controversy. Tocolysis is currently recommended between 24 and 34 weeks’ gestation. However, certain clinical scenarios may be favorable for administration of this intervention between 23 and 24 weeks’ gestation as well. There is no consistent evidence that the use of acute tocolysis reduces the chance of preterm birth or improves neonatal outcome. However, because acute tocolysis has been associated with a short (approximately 48-hour) prolongation of pregnancy, it may be used to facilitate transfer of the patient from a community hospital to a tertiary care facility that can provide optimal care for the preterm neonate. Moreover, a short course of tocolytic therapy may delay delivery for 24 to 48 hours, allowing maternal administration of (1) a corticosteroid to accelerate fetal lung maturity and (2) antibiotic therapy to prevent neonatal group B streptococcal infection. Thus, the ACOG supports the use of acute tocolysis to allow administration of a complete course of antenatal corticosteroids, but discourages the continued use of tocolysis after corticosteroid administration is complete.
Criteria for the use of tocolytic therapy include (1) gestational age after viability (23 weeks) and before 34 weeks’ gestation, (2) reassuring fetal status, and (3) no overt clinical signs of infection. The potential benefits of delaying delivery of the preterm infant (i.e., decreased neonatal morbidity and mortality) must be weighed against the maternal and fetal risks (e.g., maternal side effects of tocolytic drugs, deterioration of a compromised fetus). Box 33.2 lists contraindications to inhibiting labor.
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