Issues in Obstetric Management

From Antepartum & Intrapartum Management sponsored by the University of California,
San Francisco, School of Medicine

Ronald Wapner, MD, Professor of Obstetrics and Gynecology; Director, Division of Maternal-Fetal Medicine,
Columbia University Medical Center, New York, NY

Educational Objectives

The goal of this program is to improve maternal-fetal outcomes and to address issues relating to preterm birth. After hearing and assimilating this program, the clinician will be better able to:

1.   Describe the mechanism of action and benefits of antenatal corticosteroids.

2.   Cite recommendations for the appropriate use of antenatal corticosteroids.

3.   Discuss the impact on the neonate of repeat courses of steroids.

4.   Summarize conclusions from Maternal-Fetal Medicine Units (MFMU) Network trials.

5.   Recognize the impact of maternal hypothyroidism in pregnancy.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, Dr. Wapner and the planning committee reported nothing to disclose.

Acknowledgements

Dr. Wapner was recorded at Antepartum & Intrapartum Management, sponsored by the University of California, San Francisco, School of Medicine, and held June 5-7, 2008, in San Francisco. The Audio-Digest Foundation thanks Dr. Wapner and UCSF School of Medicine for their cooperation in the production of this program.

Recommendations for Antenatal Corticosteroids

Discovery: 1968 investigation by Mont Liggins  into factors involved in initiating labor in sheep; observed that ad­ministration of antenatal corticosteroids resulted in preterm labor and relatively advanced maturation of lungs in neonate; proposed that antenatal corticosteroids not only initiated labor in sheep, but accelerated development of lungs; later study (Liggins and Howie) established similar effect in humans treated with antenatal corticosteroids; effects of antenatal corticosteroids  —  studies support significant benefit; reduction in respiratory distress syndrome (RDS) »50% and neonatal mortality ³40%; reduces intraventricular hemorrhage (IVH); Liggins’ original work suggested antenatal corticosteroids most efficacious when neonate delivered £24 hr after administration of antena­tal corticosteroids and £7 days after treatment (effects thought to wear off in ³7 days)

Mechanism of action: induction of proteins and enzymes  —  increase tissue and alveolar surfactant; accelerate anti­oxidant production; induce receptor expression; induced structural changes  —  decrease vascular permeability; effect on lungs of antenatal corticosteroids  —aid in reducing fetal lung fluid by opening epithelial sodium chan­nels (ENaCs) produced by type 1 alveolar cells; EnaCs open naturally close to term; fluid leaves alveoli through channels to interstitial space

Recommended use of antenatal corticosteroids (National Institutes of Health [(NIH)] Consensus Panel 1994): benefits outweigh risks (reduces RDS, mortality, and IVH); all fetuses 24 to 34 wk gestation candidates; decision to use antenatal corticosteroids should not be altered by ethnicity, sex, or surfactant; use betamethasone or dexameth­asone; use with preterm premature rupture of membranes (PPROM); optimal benefit occurs at 24 hr to 7 days after treatment; partial effect with fetuses delivered <24 hr after steroid treatment; quandaries in clinical use  —  benefits and risks of repetitive dosing; treatment at >34 wk and <24 wk; effectiveness of antenatal corticosteroids in condi­tions other than prematurity (eg, twins, ruptured membranes, preeclampsia)

Repetitive dosing: considerations when administering antenatal corticosteroids  —  fetal lungs may mature for period of time, but may not remain mature (rationale for repetitive dosing); antenatal corticosteroids may boost level of lung maturation; animal studies show improvement increases with increased doses (25% improvement with one dose, greater with repetitive doses);  randomized controlled trials in humans demonstrate weekly antenatal cortico­steroids decrease severe RDS and decrease morbidity and mortality; Canadian study found no improvement with repetitive dosing every 14 days, suggesting time from last course until delivery may be more important than total number of courses; hazards to repetitive dosing  —  neonatal Cushing’s syndrome; unlikely in neonate exposed to 3 or 4 courses; one course has effect on both maternal and fetal hypothalamic pituitary adrenal axis; decrease in ma­ternal cortisol levels within 2 hr, nadir at 12 hr, return to normal within 2 days; decrease in neonatal cortisol levels within 6 hr, return to normal by 7 days; repeat (³4) courses reduce maternal adrenal function, with effect lasting ³3 wk, compared to single course; patient and fetus respond well to stress despite baseline adrenal suppression; effect on fetal growth  —  experiments in sheep show »30% reduction in birth weight with exposure to 3 or 4 courses; stud­ies in humans show decreased mean birth weight in neonates exposed to repetitive antenatal corticosteroids; no in­creased risk for intrauterine growth restriction (IUGR) in neonates exposed to 1 to 3 courses of steroids; dramatic increase in small for gestational age (SGA) neonates (less than tenth percentile) in one-third of neonates exposed to ³4 courses; 2-yr follow-up showed no difference in head circumference, or length or weight of children exposed to weekly antenatal corticosteroids; no difference on Bayley Scales of Infant Development between infants exposed to weekly courses and those receiving single course; cerebral palsy (CP)  —  National Institutes of Health (NIH) study showed nonsignificant increase in CP in neonates exposed to ³4 courses (4 appears to be threshold level for risk); increase in rate of CP consistent with animal data showing altered myelination, decreased brain growth, and de­creased number of neurons with repetitive courses; demonstrates need for caution with repetitive courses

Rescue approach: 70% of patients treated with initial dose of antenatal corticosteroids deliver at >32 wk gestation; repetitive weekly dosing exposes 7 in 10 fetuses unnecessarily; data show only 4 in 10 neonates adequately rescued (when patient returns, delivery occurs too rapidly for rescue dose to confer benefit); rescue approach used at speaker’s institution, but witheld second course until delivery clearly imminent; benefit in extremely premature ne­onate (22 to 24-wk gestation)  —data show antenatal corticosteroids decrease death and reduce RDS; speaker be­lieves antenatal corticosteroids should be used if parent desires rescuscitation rather than palliative care of very premature fetus; achieves 1.5 wk of lung maturation at 22 to 24 wk gestation (lungs at 23 wk gestation behave more like those at 25.5 wk)

Twins and PPROM: American College of Obstetricians and Gynecologists (ACOG) practice bulletin suggests ante­natal corticosteroids reduce risk for RDS with PPROM without increasing risk for maternal or neonatal infection, regardless of gestational age; studies have shown no statistical improvement or decrease in RDS in twin gestation; not dose-related

Highlights from the Maternal-Fetal Medicine Units (MFUM) Network

Background: MFUM Network developed by National Institute of Child Health and Human Development (NICHD) 25 yr ago; based on premise that modern obstetric management (especially of high-risk pregnancies) has adopted principles of care, employed pharmaceuticals, and applied methodologies without rigorous use of controlled obser­vation necessary for objective evaluation; modification or replacement followed decades later, after extensive expe­rience failed to support usefulness or showed unexpected consequences; purpose of Network is to prevent adverse outcomes in obstetrics and to respond to need for well-designed clinical trials in maternal-fetal medicine; clinical trials involve large groups of investigators from multiple centers controlling large groups of patients and using com­mon protocol; goals  —  reduce rates of preterm birth, fetal growth abnormalities, neurologic sequelae of newborn, and maternal complications of pregnancy; evaluate maternal and fetal interventions for efficacy, safety, and cost-ef­fectiveness; MFMU Network  —  14 university clinical sites (many with community hospitals functioning as satellite sites); »140,000 deliveries analyzed annually; all data sent to one independent data center; investigators suggest im­portant issues; need two-thirds of group to agree to proceed to study protocol development; each study costs »$1 million annually; 1 to 1.5 yr to identify issue warranting investigation; most studies completed in 2.5 to 3.0 yr (can fast-track if development with potential to change clinical care appears)

Conclusions from completed trials: induction vs monitoring in postterm pregnancies  —  either approach satisfac­tory; speaker believes induction at ³42 wk standard of care in most institutions; low-dose aspirin for prevention of preeclampsia in low-risk nulliparous women  —low-dose aspirin did not reduce incidence of preeclampsia; rather, it increased incidence of placental abruption (negative results prevented change in clinical practice); home uterine ac­tivity monitoring (HUAM)  —  no clinical advantage or decrease in significant outcomes by using HUAM; pregnancy outcomes in women treated for trichomonas vaginalis (TV) or bacterial vaginosis (BV)  —  in low-risk women with BV, antibiotic treatment does not decrease incidence of preterm birth; in asymptomatic women with TV, treatment increased risk for preterm birth (most likely because of change in vaginal flora); 2 additional studies support same conclusion; fetal fibronectin trial  —  antibiotic therapy in fetal fibronectin-positive women of no value; factor V Leiden mutation in pregnancy  —  no increased incidence of poor outcomes (maternal or fetal) in women carrying factor V Leiden mutation without poor obstetric history; presence of factor V Leiden alone does not warrant treat­ment; fetal pulse oximetry  — knowledge of fetal oxygen saturation not associated with reduction in cesarean deliv­eries or improved outcomes; 17 alpha-hydroxyprogesterone caproate for prevention of preterm birth in multiple gestations  —  no advantage; omega-3 supplementation to prevent preterm birth  —  no advantage

Hypothyroidism in pregnancy: increased risk for stillbirth, preterm birth, IUGR and other adverse pregnancy out­comes; subclinical hypothyroidism  —  elevated thyrotropin (TSH), but normal thyroxine (free T₄); hypothyroxinemia  —  normal TSH but low T₄; placental transfer of thyroid hormones  —fetus begins to form T₄ at 14 to 16 wk gestation; thyroid hormone crosses placenta; mother serves as source of thyroid hormone for fetus early in pregnancy; studies show increase in T₃ receptors in fetal brain by 10 wk gestation (increasing 10-fold from 10-16 wk gestation); fetus dependent on thyroid hormones of maternal origin during period of maximum growth velocity of developing brain; impact of subclinical hypothyroidism during pregnancy (Haddow et al)  —  TSH mea­sured in stored samples from >25,000 pregnant women; 62 women with high TSH levels and 124 controls; evalu­ated children (now 7-9 yr old) with 15 tests for intelligence, attention, language, reading ability, school performance, and visual motor performance; study showed full-scale IQ 4 points lower in children of hypothyroid women; 15% had IQ <85, compared to only 5% in euthyroid women; IQ averaged 7 points lower than controls in 48 women not treated for hypothyroidism; significant evidence suggesting hypothyroidism may cause underdevel­opment of fetal brain; impact of hypothyroxinemia throughout pregnancy (Pop et al)  —  woman with low T₄ 5 times more likely to have infant with IQ <85 than mother with normal T₄ (many of these women had normal TSH); evi­dence that subclinical hypothyroidism has potential to cause underdevelopment of fetal neurocognitive ability; data show infants of mothers hypothyroxinemic at 12 wk gestation, and whose levels subsequently dropped further, had lowest developmental scores; evidence suggests that continuous exposure to thyroid during pregnancy, not just early exposure, most important; children did not show any developmental delay if free T₄ increased during preg­nancy; correction of maternal hypothyroxinemia by 24 wk gestation prevented impaired neurodevelopment; evi­dence supports prevention of significant neurodevelopmental problems if subclinical hypothyroidism treated early in pregnancy; position of ACOG  —  premature to recommend universal screening for hypothyroidism in pregnancy (supported by the American Thyroid Association, the Endocrine Society, and the American Association of Clinical Endocrinologists); meta-analysis showed insufficient evidence to recommend for or against routine determination of TSH levels in pregnant women or women planning to become pregnant; MFMU Network TSH study  —  currently screening pregnant women in first trimesters for subclinical hypothyroidism; 50% of patients with disease random­ized to treatment with thyroxine; children will be followed until 5 yr of age; will undergo yearly evaluation of neu­rocognitive development; research questions to be answered in 9 yr

Antenatal corticosteroid therapy at >34 wk gestation: increasing incidence of late preterm birth (currently 9% of all births); late preterm infants populate neonatal intensive care units (NICUs); not all respiratory distress in late preterm infants benign; cesarean deliveries and inductions in late preterm period increasing; obstetricians more comfortable delivering late preterm infants than in past; at speaker’s institution, »42% of late preterm infants deliv­ered for preterm labor and PPROM, »28% had acute problem (eg, non-reassuring fetal heart tracing, severe pre­eclampsia), but »30% were planned deliveries (eg, repeat cesarean section, IUGR with normal fluid and testing, mild oliguria with reassuring testing); surfactant deficiency not only cause of respiratory distress in newborns (fluid retention major contributor)

Rate of NICU admissions with and without antenatal corticosteroid therapy: study compared corticosteroid-ex­posed infants delivered at <34 wk with corticosteroid-unexposed infants delivered 34 to 37 wk; 8 of 10 NICU ad­missions steroid-unexposed infants; 1 of 4 steroid exposed; full-term births and antenatal corticosteroids  —significantly lower NICU admissions, lower respiratory distress, and transient tachypnea of the newborn and RDS in women having cesarean delivery at ³37 wk gestation who were exposed to antenatal corticosteroids; MFMU Network initiating clinical trial  —  to determine whether antenatal corticosteroids beneficial at >34 wk; »5000 in­fants with delivery expected in 34 to 37 wk window; 50% randomized to betamethasone, 50% to antenatal cortico­steroids; trial fast-tracked

Suggested Reading

Andrews WW et al: What we have learned from an antibiotic trial in fetal fibronectin positive women. Semin Perina­tol 27:231, 2003; Garite TJ et al: Impact of a “rescue course” of antenatal corticosteroids: a multicenter randomized placebo-controlled trial. Am J Obstet Gynecol 200:248, 2009;  Haddow JE et al: Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 341:549, 1999; Kooistra L et al: Neonatal effects of maternal hypothyroxinemia during early pregnancy. Pediatrics 117:161, 2006; Pop VJ et al: Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor devel­opment in infancy. Clin Endocrinol 50:149, 1999; Stutchfield P et al: Antenatal betamethasone and incidence of neonatal respiratory distress after elective caesarean section: pragmatic randomized trial. BMJ 331:662, 2005; Surks MI et al: Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 291:228, 2004; Wapner RJ: Long-term outcomes after repeat doses of antenatal corticosteroids. N Engl J Med 357:1190, 2007; Wapner RJ: Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy. Am J Obstet Gynecol 195:633, 2006.