Mary E. D’Alton

Maternal thyroid hypofunction and pregnancy outcome.

OBJECTIVE: To estimate whether maternal thyroid hypofunction is associated with complications. METHODS: A total of 10,990 patients had first- and second-trimester serum assayed for thyroid-stimulating hormone (TSH), free thyroxine (freeT4), and antithyroglobulin and antithyroid peroxidase antibodies. Thyroid hypofunction was defined as 1) subclinical hypothyroidism: TSH levels above the 97.5th percentile and free T4 between the 2.5th and 97.5th percentiles or 2) hypothyroxinemia: TSH between the 2.5th and 97.5th percentiles and free T4 below the 2.5th percentile. Adverse outcomes were evaluated. Patients with thyroid hypofunction were compared with euthyroid patients (TSH and free T4 between the 2.5th and 97.5th percentiles). Patients with and without antibodies were compared. Multivariable logistic regression analysis adjusted for confounders was used. RESULTS: Subclinical hypothyroidism was documented in 2.2% (240 of 10,990) in the first and 2.2% (243 of 10,990) in the second trimester. Hypothyroxinemia was documented in 2.1% (232 of 10,990) in the first and 2.3% (247 of 10,990) in the second trimester. Subclinical hypothyroidism was not associated with adverse outcomes. In the first trimester, hypothyroxinemia was associated with preterm labor (adjusted odds ratio [aOR] 1.62; 95% confidence interval [CI] 1.00–2.62) and macrosomia (aOR 1.97; 95% CI 1.37–2.83). In the second trimester, it was associated with gestational diabetes (aOR 1.7; 95% CI 1.02–2.84). Fifteen percent (1,585 of 10,990) in the first and 14% (1,491 of 10,990) in the second trimester had antithyroid antibodies. When both antibodies were positive in either trimester, there was an increased risk for preterm premature rupture of membranes (P=.002 and P<.001, respectively). CONCLUSION: Maternal thyroid hypofunction is not associated with a consistent pattern of adverse outcomes. LEVEL OF EVIDENCE: II

Racial/ethnic standards for fetal growth: The NICHD Fetal Growth Studies

OBJECTIVE Fetal growth is associated with long-term health yet no appropriate standards exist for the early identification of undergrown or overgrown fetuses. We sought to develop contemporary fetal growth standards for 4 self-identified US racial/ethnic groups. STUDY DESIGN We recruited for prospective follow-up 2334 healthy women with low-risk, singleton pregnancies from 12 community and perinatal centers from July 2009 through January 2013. The cohort comprised: 614 (26%) non-Hispanic whites, 611 (26%) non-Hispanic blacks, 649 (28%) Hispanics, and 460 (20%) Asians. Women were screened at 8w0d to 13w6d for maternal health status associated with presumably normal fetal growth (aged 18-40 years; body mass index 19.0-29.9 kg/m(2); healthy lifestyles and living conditions; low-risk medical and obstetrical history); 92% of recruited women completed the protocol. Women were randomized among 4 ultrasonography schedules for longitudinal fetal measurement using the Voluson E8 (GE Healthcare, Milwaukee, WI). In-person interviews and anthropometric assessments were conducted at each visit; medical records were abstracted. The fetuses of 1737 (74%) women continued to be low risk (uncomplicated pregnancy, absent anomalies) at birth, and their measurements were included in the standards. Racial/ethnic-specific fetal growth curves were estimated using linear mixed models with cubic splines. Estimated fetal weight (EFW) and biometric parameter percentiles (5th, 50th, 95th) were determined for each gestational week and comparisons made by race/ethnicity, with and without adjustment for maternal and sociodemographic factors. RESULTS EFW differed significantly by race/ethnicity >20 weeks. Specifically at 39 weeks, the 5th, 50th, and 95th percentiles were 2790, 3505, and 4402 g for white; 2633, 3336, and 4226 g for Hispanic; 2621, 3270, and 4078 g for Asian; and 2622, 3260, and 4053 g for black women (adjusted global P < .001). For individual parameters, racial/ethnic differences by order of detection were: humerus and femur lengths (10 weeks), abdominal circumference (16 weeks), head circumference (21 weeks), and biparietal diameter (27 weeks). The study-derived standard based solely on the white group erroneously classifies as much as 15% of non-white fetuses as growth restricted (EFW <5th percentile). CONCLUSION Significant differences in fetal growth were found among the 4 groups. Racial/ethnic-specific standards improve the precision in evaluating fetal growth.

Prenatal surgery for myelomeningocele and the need for cerebrospinal fluid shunt placement

OBJECT The Management of Myelomeningocele Study (MOMS) was a multicenter randomized trial comparing the safety and efficacy of prenatal and postnatal closure of myelomeningocele. The trial was stopped early because of the demonstrated efficacy of prenatal surgery, and outcomes on 158 of 183 pregnancies were reported. Here, the authors update the 1-year outcomes for the complete trial, analyze the primary and related outcomes, and evaluate whether specific prerandomization risk factors are associated with prenatal surgery benefit. METHODS The primary outcome was a composite of fetal loss or any of the following: infant death, CSF shunt placement, or meeting the prespecified criteria for shunt placement. Primary outcome, actual shunt placement, and shunt revision rates for prenatal versus postnatal repair were compared. The shunt criteria were reassessed to determine which were most concordant with practice, and a new composite outcome was created from the primary outcome by replacing the original criteria for CSF shunt placement with the revised criteria. The authors used logistic regression to estimate whether there were interactions between the type of surgery and known prenatal risk factors (lesion level, gestational age, degree of hindbrain herniation, and ventricle size) for shunt placement, and to determine which factors were associated with shunting among those infants who underwent prenatal surgery. RESULTS Ninety-one women were randomized to prenatal surgery and 92 to postnatal repair. The primary outcome occurred in 73% of infants in the prenatal surgery group and in 98% in the postnatal group (p < 0.0001). Actual rates of shunt placement were only 44% and 84% in the 2 groups, respectively (p < 0.0001). The authors revised the most commonly met criterion to require overt clinical signs of increased intracranial pressure, defined as split sutures, bulging fontanelle, or sunsetting eyes, in addition to increasing head circumference or hydrocephalus. Using these modified criteria, only 3 patients in each group met criteria but did not receive a shunt. For the revised composite outcome, there was a difference between the prenatal and postnatal surgery groups: 49.5% versus 87.0% (p < 0.0001). There was also a significant reduction in the number of children who had a shunt placed and then required a revision by 1 year of age in the prenatal group (15.4% vs 40.2%, relative risk 0.38 [95% CI 0.22-0.66]). In the prenatal surgery group, 20% of those with ventricle size < 10 mm at initial screening, 45.2% with ventricle size of 10 up to 15 mm, and 79.0% with ventricle size ≥ 15 mm received a shunt, whereas in the postnatal group, 79.4%, 86.0%, and 87.5%, respectively, received a shunt (p = 0.02). Lesion level and degree of hindbrain herniation appeared to have no effect on the eventual need for shunting (p = 0.19 and p = 0.13, respectively). Similar results were obtained for the revised outcome. CONCLUSIONS Larger ventricles at initial screening are associated with an increased need for shunting among those undergoing fetal surgery for myelomeningocele. During prenatal counseling, care should be exercised in recommending prenatal surgery when the ventricles are 15 mm or larger because prenatal surgery does not appear to improve outcome in this group. The revised criteria may be useful as guidelines for treating hydrocephalus in this group.

Thyroid dysfunction in pregnancy: the basic science and clinical evidence surrounding the controversy in management.

Maternal hypothyroidism is known to result in neurodevelopmental disorders in offspring, but whether subclinical hypothyroidism results in lower intelligence quotient (IQ) performance in progeny is an area of debate. Animal studies have shown that fetal thyroxine and triiodothyronine are primarily maternally derived before mid gestation. Other animal data reveal that fetal brain damage at a time that is analogous to the first trimester in humans can be linked to irreversible future brain damage. A large study conducted on an unselected population of pregnant women, both with known diagnosis of hypothyroidism and those who were screened but not diagnosed, found a four-point difference in the IQ levels of the offspring, raising the question of clinical significance. The endocrine community has accepted that subclinical hypothyroidism causes a significant decrease in IQ scores and has advocated for routine screening of pregnant women. However, obstetric authorities have cautioned that more research is needed before a causal relationship between subclinical hypothyroidism and lower IQ performance can be verified. Consequently, the American College of Obstetricians and Gynecologists has stated that routine screening and treatment of subclinical hypothyroidism cannot be recommended. We will review the basic science and clinical evidence for the neurodevelopmental effects of thyroid dysfunction in pregnancy.

Antenatal Therapy of Smith-Lemli-Opitz Syndrome

Objectives: Smith-Lemli-Opitz syndrome (SLOS) is a recessively inherited disorder caused by an inborn error of cholesterol metabolism that results in deficiency of cholesterol and accumulation of the cholesterol precursor, 7-dehydrocholesterol (DHC) and its epimer, 8-DHC. Affected patients present with congenital anomalies, growth restriction, and mental retardation. Postnatal treatment with cholesterol supplementation has been shown to improve plasma sterol levels and has resulted in improved growth and development in many patients. We hypothesized that prenatal supplementation of cholesterol could potentially arrest some of the adverse consequences of cholesterol deficiency at an earlier stage of development. Methods: SLOS was diagnosed in the third trimester in a fetus initially identified by sonography with intrauterine growth restriction and ambiguous genitalia and confirmed by elevated levels of 7- and 8-DHC in amniotic fluid. Antenatal supplementation of cholesterol was provided by fetal intravenous and intraperitoneal transfusions of fresh frozen plasma (cholesterol level = 219 mg/dl). Results: The in utero transfusions resulted in increased levels of fetal cholesterol, as measured in blood samples obtained by cordocentesis. In addition, fetal red cell mean corpuscular volume rose, which further indicated that the exogenous cholesterol was incorporated into the fetal erythrocytes. Conclusions: Antenatal treatment of SLOS by cholesterol supplementation is feasible and results in improvement in fetal plasma cholesterol levels and fetal red cell volume. SLOS may be added to the growing list of human genetic disorders for which prenatal diagnosis is available and therapeutic intervention may be possible.

Cross-Country Individual Participant Analysis of 4.1 Million Singleton Births in 5 Countries with Very High Human Development Index Confirms Known Associations but Provides No Biologic Explanation for 2/3 of All Preterm Births.

Background Preterm birth is the most common single cause of perinatal and infant mortality, affecting 15 million infants worldwide each year with global rates increasing. Understanding of risk factors remains poor, and preventive interventions have only limited benefit. Large differences exist in preterm birth rates across high income countries. We hypothesized that understanding the basis for these wide variations could lead to interventions that reduce preterm birth incidence in countries with high rates. We thus sought to assess the contributions of known risk factors for both spontaneous and provider-initiated preterm birth in selected high income countries, estimating also the potential impact of successful interventions due to advances in research, policy and public health, or clinical practice. Methods We analyzed individual patient-level data on 4.1 million singleton pregnancies from four countries with very high human development index (Czech Republic, New Zealand, Slovenia, Sweden) and one comparator U.S. state (California) to determine the specific contribution (adjusting for confounding effects) of 21 factors. Both individual and population-attributable preterm birth risks were determined, as were contributors to cross-country differences. We also assessed the ability to predict preterm birth given various sets of known risk factors. Findings Previous preterm birth and preeclampsia were the strongest individual risk factors of preterm birth in all datasets, with odds ratios of 4.6–6.0 and 2.8–5.7, respectively, for individual women having those characteristics. In contrast, on a population basis, nulliparity and male sex were the two risk factors with the highest impact on preterm birth rates, accounting for 25–50% and 11–16% of excess population attributable risk, respectively (p<0.001). The importance of nulliparity and male sex on population attributable risk was driven by high prevalence despite low odds ratios for individual women. More than 65% of the total aggregated risk of preterm birth within each country lacks a plausible biologic explanation, and 63% of difference between countries cannot be explained with known factors; thus, research is necessary to elucidate the underlying mechanisms of preterm birth and, hence, therapeutic intervention. Surprisingly, variation in prevalence of known risk factors accounted for less than 35% of the difference in preterm birth rates between countries. Known risk factors had an area under the curve of less than 0.7 in ROC analysis of preterm birth prediction within countries. These data suggest that other influences, as yet unidentified, are involved in preterm birth. Further research into biological mechanisms is warranted. Conclusions We have quantified the causes of variation in preterm birth rates among countries with very high human development index. The paucity of explicit and currently identified factors amenable to intervention illustrates the limited impact of changes possible through current clinical practice and policy interventions. Our research highlights the urgent need for research into underlying biological causes of preterm birth, which alone are likely to lead to innovative and efficacious interventions.

Underuse of postcesarean thromboembolism prophylaxis.

OBJECTIVE: To characterize contemporary practice patterns for postcesarean thromboembolism prophylaxis and determine whether opportunities to substantially decrease maternal mortality and morbidity in this clinical setting are being missed. METHODS: A commercial hospitalization database that includes procedure and diagnosis codes, health care provider and hospital information, and patient demographic data were used to analyze use of venous thromboembolism prophylaxis after cesarean delivery in the United States between 2003 and 2010. The analysis evaluated whether patients received pharmacologic prophylaxis, mechanical prophylaxis, combined prophylaxis, or no prophylaxis. Hospital-level factors and patient characteristics were included in multivariable regression models evaluating prophylaxis administration. RESULTS: We identified 1,263,205 women who underwent cesarean delivery. Within the cohort, 75.7% (n=955,787) received no thromboembolism prophylaxis, 22.1% (n=278,669) received mechanical prophylaxis alone, 1.3% (n=16,639) received pharmacologic prophylaxis, and 1.0% (n=12,110) received combination prophylaxis. The rate of prophylaxis increased from 8.4% in 2003 to 41.6% in 2010. Prophylaxis rates varied significantly by geographic region. Medical risk factors for thromboembolism were associated with only modest increases in prophylaxis. CONCLUSION: Although our findings demonstrated increased adoption of postcesarean venous thromboembolism prophylaxis, fewer than half of patients received recommended care as of 2010, and significant variation was present. Thromboembolism prophylaxis is underused and represents a major opportunity to reduce maternal morbidity and mortality. Risk assessment tools and thromboprophylaxis guidelines are needed to assure high-quality, uniform care. LEVEL OF EVIDENCE: III

Management of single fetal demise in a multiple gestation.

Intrauterine fetal demise of 1 twin in a multiple gestation is a complex clinical situation. Chorionicity, gestational age at diagnosis, problems specific to the pregnancy, and the emotional needs of the patient can impact management. Strategies to optimize outcomes may include a multidisciplinary team approach and fetal surveillance. The following article reviews (1) adverse fetal and neonatal outcomes associated with intrauterine fetal demise of 1 twin, (2) the potential maternal impact, and (3) the strategies to possibly prevent poor outcomes. It is important to remember that even the most vigilant care may not avoid adverse sequelae in a portion of at-risk pregnancies. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to outline the factors that impact outcome in patients with multiples complicated by a single IUFD, to describe the pathophysiology of adverse outcomes associated with IUFD of one twin, and to list potential strategies for twin pregnancies at risk for IUFD.

Variation in and Factors Associated With Use of Episiotomy

Episiotomy is a common obstetric procedure, estimated to be performed in 25% of vaginal deliveries in the United States in 2004.1 Restrictive use of episiotomy has been recommended given the risks of the procedure and unclear benefits of routine use. In 2006, the American Congress of Obstetricians and Gynecologists recommended against routine episiotomy,2 and, in 2008, the National Quality Forum recognized limiting routine episiotomy as an important measure of quality and patient safety, noting increased risks of pain, laceration, and anal incontinence with the procedure.

Proposed diagnostic criteria for the case definition of amniotic fluid embolism in research studies

Amniotic fluid embolism is a leading cause of maternal mortality in developed countries. Our understanding of risk factors, diagnosis, treatment, and prognosis is hampered by a lack of uniform clinical case definition; neither histologic nor laboratory findings have been identified unique to this condition. Amniotic fluid embolism is often overdiagnosed in critically ill peripartum women, particularly when an element of coagulopathy is involved. Previously proposed case definitions for amniotic fluid embolism are nonspecific, and when viewed through the eyes of individuals with experience in critical care obstetrics, would include women with a number of medical conditions much more common than amniotic fluid embolism. We convened a working group under the auspices of a committee of the Society for Maternal-Fetal Medicine and the Amniotic Fluid Embolism Foundation whose task was to develop uniform diagnostic criteria for the research reporting of amniotic fluid embolism. These criteria rely on the presence of the classic triad of hemodynamic and respiratory compromise accompanied by strictly defined disseminated intravascular coagulopathy. It is anticipated that limiting research reports involving amniotic fluid embolism to women who meet these criteria will enhance the validity of published data and assist in the identification of risk factors, effective treatments, and possibly useful biomarkers for this condition. A registry has been established in conjunction with the Perinatal Research Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development to collect both clinical information and laboratory specimens of women with suspected amniotic fluid embolism in the hopes of identifying unique biomarkers of this condition.