Tracy A. Manuck

Prenatal and Perinatal Determinants of Lung Health and Disease in Early Life: A National Heart, Lung, and Blood Institute Workshop Report

Human lung growth and development begins with preconception exposures and continues through conception and childhood into early adulthood. Numerous environmental exposures (both positive and negative) can affect lung health and disease throughout life. Infant lung health correlates with adult lung function, but significant knowledge gaps exist regarding the influence of preconception, perinatal, and postnatal exposures on general lung health throughout life. On October 1 and 2, 2015, the National Heart, Lung, and Blood Institute convened a group of extramural investigators to develop their recommendations for the direction(s) for future research in prenatal and perinatal determinants of lung health and disease in early life and to identify opportunities for scientific advancement. They identified that future investigations will need not only to examine abnormal lung development, but also to use developing technology and resources to better define normal and/or enhanced lung health. Birth cohort studies offer key opportunities to capture the important influence of preconception and obstetric risk factors on lung health, development, and disease. These studies should include well-characterized obstetrical data and comprehensive plans for prospective follow-up. The importance of continued basic science, translational, and animal studies for providing mechanisms to explain causality using new methods cannot be overemphasized. Multidisciplinary approaches involving obstetricians, neonatologists, pediatric and adult pulmonologists, and basic scientists should be encouraged to design and conduct comprehensive and impactful research on the early stages of normal and abnormal human lung growth that influence adult outcome.

Insulin glargine versus neutral protamine Hagedorn insulin for treatment of diabetes in pregnancy.

We compared maternal and neonatal outcomes in diabetic pregnancies treated with either insulin glargine or neutral protamine Hagedorn (NPH) insulin. We performed a retrospective chart review of diabetic pregnant patients using the Diabetes Care Center of Wake Forest University during the years 2000 to 2005. Outcomes of interest included maternal hemoglobin A1C, average fasting and 2-hour postprandial blood sugars, mode of delivery, birth weight, 5-minute Apgar score < 7, umbilical artery pH < 7.20, incidence of neonatal hypoglycemia, and pregnancy complications. A total of 52 diabetic pregnant patients were included in this study. Twenty-seven women used insulin glargine. A total of 13 women used insulin glargine during the first trimester. Glycemic control was similar in women who used NPH insulin and insulin glargine, as determined by hemoglobin A1C levels and mean blood sugar values. There were no differences in mode of delivery, average birth weight, or neonatal outcomes. Maternal and fetal/neonatal outcomes appear similar in pregnant diabetic women who use either NPH insulin or insulin glargine in combination with a short-acting insulin analogue to achieve adequate glycemic control during pregnancy. Insulin glargine appears to be an effective insulin analogue for use in women whose pregnancies are complicated by diabetes.

Antenatal Magnesium Sulfate, Necrotizing Enterocolitis, and Death among Neonates < 28 Weeks Gestation

Objective This study aims to examine the relationship between antenatal magnesium sulfate (MgSO4) and neonatal death and/or severe necrotizing enterocolitis (NEC) among infants < 28 weeks. Methods Secondary analysis of a multicenter randomized trial of antenatal MgSO4 versus placebo administered to women to prevent death and cerebral palsy. Neonates < 28 weeks were included. The primary outcome was neonatal death before NICU discharge, and/or severe NEC (Bell criteria stage II/III). Neonates with and without death/severe NEC were compared. Results A total of 697 neonates met the criteria. Out of which 150 (21.5%) died and/or were diagnosed with severe NEC. Antenatal MgSO4 exposure was not associated with death/severe NEC in infants < 28 weeks. In a subgroup analysis of neonates < 26 weeks, treatment group assignment to antenatal MgSO4 was associated with an increased odds of death/severe NEC (adjusted odds ratio: 1.90, 95% confidence interval: 1.12–3.22, p = 0.017). Conclusions Among neonates < 26 weeks, antenatal MgSO4 was associated with death and severe NEC. Further prospective study in larger populations is needed.

Maternal race and intergenerational preterm birth recurrence

BACKGROUND: Preterm birth is a complex disorder with a heritable genetic component. Studies of primarily White women born preterm show that they have an increased risk of subsequently delivering preterm. This risk of intergenerational preterm birth is poorly defined among Black women. OBJECTIVE: Our objective was to evaluate and compare intergenerational preterm birth risk among non‐Hispanic Black and non‐Hispanic White mothers. STUDY DESIGN: This was a population‐based retrospective cohort study, using the Virginia Intergenerational Linked Birth File. All non‐Hispanic Black and non‐Hispanic White mothers born in Virginia 1960 through 1996 who delivered their first live‐born, nonanomalous, singleton infant ≥20 weeks from 2005 through 2009 were included. We assessed the overall gestational age distribution between non‐Hispanic Black and White mothers born term and preterm (<37 weeks) and their infants born term and preterm (<37 weeks) using Cox regression and Kaplan‐Meier survivor functions. Mothers were grouped by maternal gestational age at delivery (term, ≥37 completed weeks; late preterm birth, 34‐36 weeks; and early preterm birth, <34 weeks). The primary outcomes were: (1) preterm birth among all eligible births; and (2) suspected spontaneous preterm birth among births to women with medical complications (eg, diabetes, hypertension, preeclampsia and thus higher risk for a medically indicated preterm birth). Multivariable logistic regression was used to estimate odds of preterm birth and spontaneous preterm birth by maternal race and maternal gestational age after adjusting for confounders including maternal education, maternal age, smoking, drug/alcohol use, and infant gender. RESULTS: Of 173,822 deliveries captured in the intergenerational birth cohort, 71,676 (41.2%) women met inclusion criteria for this study. Of the entire cohort, 30.0% (n = 21,467) were non‐Hispanic Black and 70.0% were non‐Hispanic White mothers. Compared to non‐Hispanic White mothers, non‐Hispanic Black mothers were more likely to have been born late preterm (6.8% vs 3.7%) or early preterm (2.8 vs 1.0%), P < .001. Non‐Hispanic White mothers who were born (early or late) preterm were not at an increased risk of early or late preterm delivery compared to non‐Hispanic White mothers born term. The risk of early preterm birth was most pronounced for Black mothers who were born early preterm (adjusted odds ratio, 3.26; 95% confidence interval, 1.77–6.02) compared to non‐Hispanic White mothers. CONCLUSION: We found an intergenerational effect of preterm birth among non‐Hispanic Black mothers but not non‐Hispanic White mothers. Black mothers born <34 weeks carry the highest risk of delivering their first child very preterm. Future studies should elucidate the underlying pathways leading to this racial disparity.

Gestational age at initiation of 17-alpha hydroxyprogesterone caproate and recurrent preterm birth

Background Preterm birth is the leading cause of neonatal morbidity and mortality in nonanomalous neonates in the United States. Women with a previous early spontaneous preterm birth are at highest risk for recurrence. Weekly intramuscular 17‐alpha hydroxyprogesterone caproate reduces the risk of recurrent prematurity. Although current guidelines recommend 17‐alpha hydroxyprogesterone caproate initiation between 16 and 20 weeks, in clinical practice, 17‐alpha hydroxyprogesterone caproate is started across a spectrum of gestational ages. Objective The objective of the study was to examine the relationship between the gestational age at 17‐alpha hydroxyprogesterone caproate initiation and recurrent preterm birth among women with a prior spontaneous preterm birth 16–28 weeks’ gestation. Study Design This was a retrospective cohort study of women from a single tertiary care center, 2005–2016. All women with ≥1 singleton preterm births because of a spontaneous onset of contractions, preterm prelabor rupture of membranes, or painless cervical dilation between 16 and 28 weeks followed by a subsequent singleton pregnancy treated with 17‐alpha hydroxyprogesterone caproate were included. Women were grouped based on quartiles of gestational age of 17‐alpha hydroxyprogesterone caproate initiation (quartile 1, 140/7 to 161/7; quartile 2, 162/7 to 170/7; quartile 3, 171/7 to 186/7; and quartile 4, 190/7 to 275/7). Women with a gestational age of 17‐alpha hydroxyprogesterone caproate initiation in quartiles 1 and 2 were considered to have early‐start 17‐alpha hydroxyprogesterone caproate; those in quartiles 3 and 4 were considered to have late‐start 17‐alpha hydroxyprogesterone caproate. The primary outcome was recurrent preterm birth <37 weeks’ gestation. Secondary outcomes included recurrent preterm birth <34 and <28 weeks’ gestation and composite major neonatal morbidity (diagnosis of grade III or IV intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia, necrotizing enterocolitis stage II or III, or death). Gestational age at delivery was compared by quartile of 17‐alpha hydroxyprogesterone caproate initiation using Kaplan‐Meier survival curves and the log‐rank test. Logistic regression models estimated odds ratios for the association between gestational age at 17‐alpha hydroxyprogesterone caproate initiation and preterm birth <37 weeks’ gestation, adjusting for demographics, prior pregnancy and antenatal characteristics. Results A total of 132 women met inclusion criteria; 52 (39.6%) experienced recurrent preterm birth <37 weeks in the studied pregnancy. 17‐Alpha hydroxyprogesterone caproate was initiated at a mean 176/7 ± 2.5 weeks. Demographic and baseline characteristics were similar between women with early‐start 17‐alpha hydroxyprogesterone caproate (quartiles 1 and 2) compared with those with late‐start 17‐alpha hydroxyprogesterone caproate (quartiles 3 and 4). Women with early‐start 17‐alpha hydroxyprogesterone caproate trended toward lower rates of recurrent preterm birth <37 weeks compared with those with late‐start 17‐alpha hydroxyprogesterone caproate (41.3% vs 57.7%, P = .065). Delivery gestational age was inversely proportional to gestational age at 17‐alpha hydroxyprogesterone caproate initiation (quartile 1, 374/7 weeks vs quartile 2, 365/7 vs quartile 3, 361/7 weeks vs quartile 4, 340/7, P = .007). In Kaplan‐Meier survival analyses, these differences in delivery gestational age by 17‐alpha hydroxyprogesterone caproate initiation quartile persisted across pregnancy (log‐rank P < .001). In regression models, later initiation of 17‐alpha hydroxyprogesterone caproate was significantly associated with increased odds of preterm birth <37 weeks. Women with early 17‐alpha hydroxyprogesterone caproate initiation also had lower rates of major neonatal morbidity than those with later 17‐alpha hydroxyprogesterone caproate initiation (1.5% vs 14.3%, P = .005). Conclusion Rates of recurrent preterm birth among women with a prior spontaneous preterm birth 16–28 weeks are high. Women beginning 17‐alpha hydroxyprogesterone caproate early deliver later and have improved neonatal outcomes. Clinicians should make every effort to facilitate 17‐alpha hydroxyprogesterone caproate initiation at 16 weeks.

The association among cytochrome P450 3A, progesterone receptor polymorphisms, plasma 17-alpha hydroxyprogesterone caproate concentrations, and spontaneous preterm birth

Background Infants born <37 weeks’ gestation are of public health concern since complications associated with preterm birth are the leading cause of mortality in children <5 years of age and a major cause of morbidity and lifelong disability. The administration of 17‐alpha hydroxyprogesterone caproate reduces preterm birth by 33% in women with history of spontaneous preterm birth. We demonstrated previously that plasma concentrations of 17‐alpha hydroxyprogesterone caproate vary widely among pregnant women and that women with 17‐alpha hydroxyprogesterone caproate plasma concentrations in the lowest quartile had spontaneous preterm birth rates of 40% vs rates of 25% in those women with higher concentrations. Thus, plasma concentrations are an important factor in determining drug efficacy but the reason 17‐alpha hydroxyprogesterone caproate plasma concentrations vary so much is unclear. Predominantly, 17‐alpha hydroxyprogesterone caproate is metabolized by CYP3A4 and CYP3A5 enzymes. Objective We sought to: (1) determine the relation between 17‐alpha hydroxyprogesterone caproate plasma concentrations and single nucleotide polymorphisms in CYP3A4 and CYP3A5; (2) test the association between progesterone receptor single nucleotide polymorphisms and spontaneous preterm birth; and (3) test whether the association between plasma concentrations of 17‐alpha hydroxyprogesterone caproate and spontaneous preterm birth varied by progesterone receptor single nucleotide polymorphisms. Study Design In this secondary analysis, we evaluated genetic polymorphism in 268 pregnant women treated with 17‐alpha hydroxyprogesterone caproate, who participated in a placebo‐controlled trial to evaluate the benefit of omega‐3 supplementation in women with history of spontaneous preterm birth. Trough plasma concentrations of 17‐alpha hydroxyprogesterone caproate were measured between 25‐28 weeks of gestation after a minimum of 5 injections of 17‐alpha hydroxyprogesterone caproate. We extracted DNA from maternal blood samples and genotyped the samples using TaqMan (Applied Biosystems, Foster City, CA) single nucleotide polymorphism genotyping assays for the following single nucleotide polymorphisms: CYP3A4*1B, CYP3A4*1G, CYP3A4*22, and CYP3A5*3; and rs578029, rs471767, rs666553, rs503362, and rs500760 for progesterone receptor. We adjusted for prepregnancy body mass index, race, and treatment group in a multivariable analysis. Differences in the plasma concentrations of 17‐alpha hydroxyprogesterone caproate by genotype were evaluated for each CYP single nucleotide polymorphism using general linear models. The association between progesterone receptor single nucleotide polymorphisms and frequency of spontaneous preterm birth was tested using logistic regression. A logistic model also tested interaction between 17‐alpha hydroxyprogesterone caproate concentrations with each progesterone receptor single nucleotide polymorphism for the outcome of spontaneous preterm birth. Results The association between CYP single nucleotide polymorphisms *22, *1G, *1B, and *3 and trough plasma concentrations of 17‐alpha hydroxyprogesterone caproate was not statistically significant (P = .68, .44, .08, and .44, respectively). In an adjusted logistic regression model, progesterone receptor single nucleotide polymorphisms rs578029, rs471767, rs666553, rs503362, and rs500760 were not associated with the frequency of spontaneous preterm birth (P = .29, .10, .76, .09, and .43, respectively). Low trough plasma concentrations of 17‐alpha hydroxyprogesterone caproate were statistically associated with a higher frequency of spontaneous preterm birth (odds ratio, 0.78; 95% confidence ratio, 0.61–0.99; P = .04 for trend across quartiles), however no significant interaction with the progesterone receptor single nucleotide polymorphisms rs578029, rs471767, rs666553, rs503362, and rs500760 was observed (P = .13, .08, .10, .08, and .13, respectively). Conclusion The frequency of recurrent spontaneous preterm birth appears to be associated with trough 17‐alpha hydroxyprogesterone caproate plasma concentrations. However, the wide variation in trough 17‐alpha hydroxyprogesterone caproate plasma concentrations is not attributable to polymorphisms in CYP3A4 and CYP3A5 genes. Progesterone receptor polymorphisms do not predict efficacy of 17‐alpha hydroxyprogesterone caproate. The limitations of this secondary analysis include that we had a relative small sample size (n = 268) and race was self‐reported by the patients.

The genomics of prematurity in an era of more precise clinical phenotyping: A review

Spontaneous preterm birth is a major public health problem, with a clear genetic component. Genetic association studies have evolved substantially in recent years, moving away from the traditional candidate gene analyses to newer approaches utilizing sophisticated analysis platforms to examine sequencing data, and shifting towards functional studies including methylation analysis. It is becoming increasingly evident that careful clinical phenotyping is crucial to high quality genetic association studies regardless of the assay or platform being used. Nonetheless, genetic studies of prematurity are hampered by numerous challenges including small sample sizes, incomplete phenotying, population stratification, and multiple comparisons. As the costs of sequencing and functional analyses continue to decrease, unbiased genome-wide assays will be more widely available. Researchers have met improved success recently when critically applying clinical phenotyping knowledge to group women prior to analyzing genotyping results. Eventually, as the analytic approaches evolve, it is likely that this methodology (combining precisely clinically phenotyped subjects with genome-wide data) will provide key information regarding the pathophysiology of prematurity, and provide potential new avenues for exploring innovative therapeutic strategies.

Pharmacogenomics of preterm birth prevention and treatment

Pharmacogenomics and personalised medicine incorporate genetic factors, historical data, and environmental exposures to predict individual variation in response to medications. The study of pharmacology and pharmacogenomics is challenging in obstetrics, and our knowledge in this area lags behind other disciplines of medicine. Some preliminary data, however, suggest that some of the interindividual variation seen in response to medications given for the prevention (progesterone) and the treatment (nifedipine, terbutaline, and others) of preterm labour may be caused by pharmacogenomic effects. A comprehensive approach, integrating clinical data, environmental factors, including concomitant medications and genotype, to optimise the prevention and treatment strategies for preterm birth, is urgently needed.

Genomics of Preterm Birth-Evidence of Association and Evolving Investigations

Preterm birth (PTB) is a large public health problem in the United States and worldwide. There is a clear genetic component to the pathogenesis of PTB, as evidenced by twin studies, heritability studies, and investigations from large population databases. Although numerous single nucleotide polymorphisms have been associated with PTB, results have been inconsistent and overall disappointing. With recent advances in genetic technology, investigations are moving beyond simple, more traditional candidate gene studies, and have expanded to encompass more exploratory analyses using high-throughput genetic techniques. Care should be taken to consider the potential impact of fetal genotype, the environment, and gene-drug interactions (pharmacogenomics) in addition to maternal genotype. Future research should capitalize on evolving analytic techniques, including pathway analyses and correlation of genetic and functional data to optimize discovery, increase knowledge regarding prematurity pathogenesis, and begin to develop novel therapeutic strategies.

Maternal super obesity and neonatal morbidity after term cesarean delivery

Objective To estimate the association between maternal super obesity (body mass index [BMI] ≥ 50 kg/m(2)) and neonatal morbidity among neonates born via cesarean delivery (CD). Methods Retrospective cohort of singleton neonates delivered via CD ≥ 37 weeks in the Maternal-Fetal Medicine Unit Cesarean Registry. Maternal BMI at delivery was stratified as 18.5 to 29.9 kg/m(2), 30 to 39.9 kg/m(2), 40 to 49.9 kg/m(2), and ≥ 50 kg/m(2). Primary outcomes included acute (5-minute Apgar score < 5, cardiopulmonary resuscitation and ventilator support < 24 hours, neonatal injury, and/or transient tachypnea of the newborn) and severe (grade 3 or 4 intraventricular hemorrhage, necrotizing enterocolitis, seizure, respiratory distress syndrome, hypoxic ischemic encephalopathy, meconium aspiration, ventilator support ≥ 2 days, sepsis and/or neonatal death) neonatal morbidity. Odds of neonatal morbidity were estimated for each BMI category adjusting for clinical and operative characteristics. Results Of 41,262 maternal-neonatal dyads, 36% of women were nonobese, 49% had BMI of 30 to 39.9 kg/m(2), 12% had BMI of 40 to 49.9 kg/m(2), and 3% were super obese. Compared with nonobese women, super obese women had twofold odds of acute (5 vs. 10%; adjusted odds ratio [aOR]: 1.81, 95% confidence interval [CI]: 1.59-2.73) and severe (3 vs. 6%; aOR: 2.08; 95% CI: 1.59-2.73) neonatal morbidity. Conclusion Among term infants delivered via CD, maternal super obesity is associated with increased risk of neonatal morbidity.