Emily DeFranco

Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double‐blind, placebo‐controlled trial

Preterm birth is the leading cause of perinatal morbidity and mortality worldwide. Treatment of preterm labor with tocolysis has not been successful in improving infant outcome. The administration of progesterone and related compounds has been proposed as a strategy to prevent preterm birth. The objective of this trial was to determine whether prophylactic administration of vaginal progesterone reduces the risk of preterm birth in women with a history of spontaneous preterm birth.

Vaginal progesterone is associated with a decrease in risk for early preterm birth and improved neonatal outcome in women with a short cervix: A secondary analysis from a randomized, double-blind, placebo-controlled trial

To investigate the efficacy of vaginal progesterone to prevent early preterm birth in women with sonographic evidence of a short cervical length in the midtrimester.

Short interpregnancy interval: risk of uterine rupture and complications of vaginal birth after cesarean delivery.

OBJECTIVE: To investigate whether short or long interpregnancy interval is associated with uterine rupture and other major maternal morbidities in women who attempt vaginal birth after cesarean delivery (VBAC). METHODS: We performed a secondary analysis of a U.S. multi-center, record-based, retrospective cohort study of 13,331 pregnant women, identified by a validated International Classification of Disease, 9th Revision, code search, with at least one prior cesarean delivery, who attempted VBAC between 1995 and 2000. We performed univariable and multivariable logistic regression analyses to evaluate the association between long or short interpregnancy interval and three maternal outcomes: 1) uterine rupture, 2) composite major morbidity (including rupture, bladder or bowel injury, and uterine artery laceration), and 3) blood transfusion. We evaluated short interpregnancy interval with cutoffs at less than 6, less than 12, and less than 18 months between prior delivery and conception and defined long interval as 60 months or more. RESULTS: A total of 128 cases (0.9%) of uterine rupture occurred, and 286 (2.2%), 1,109 (8.3%), 1,741 (13.1%), and 2,631 (19.7%) women had interpregnancy intervals of less than 6, 6–11, 12–17, and 60 months or more, respectively. An interval less than 6 months was associated with increased risk of uterine rupture (adjusted odds ratio [aOR] 2.66, 95% confidence interval [CI] 1.21–5.82), major morbidity (aOR 1.95, 95% CI 1.04–3.65), and blood transfusion (aOR 3.14, 95% CI 1.42–6.95). Long interpregnancy interval was not associated with an increase in major morbidity. CONCLUSION: Short interpregnancy interval increases risk for uterine rupture and other major morbidities twofold to threefold in VBAC candidates. LEVEL OF EVIDENCE: II

An Evolutionary Genomic Approach to Identify Genes Involved in Human Birth Timing

Coordination of fetal maturation with birth timing is essential for mammalian reproduction. In humans, preterm birth is a disorder of profound global health significance. The signals initiating parturition in humans have remained elusive, due to divergence in physiological mechanisms between humans and model organisms typically studied. Because of relatively large human head size and narrow birth canal cross-sectional area compared to other primates, we hypothesized that genes involved in parturition would display accelerated evolution along the human and/or higher primate phylogenetic lineages to decrease the length of gestation and promote delivery of a smaller fetus that transits the birth canal more readily. Further, we tested whether current variation in such accelerated genes contributes to preterm birth risk. Evidence from allometric scaling of gestational age suggests human gestation has been shortened relative to other primates. Consistent with our hypothesis, many genes involved in reproduction show human acceleration in their coding or adjacent noncoding regions. We screened >8,400 SNPs in 150 human accelerated genes in 165 Finnish preterm and 163 control mothers for association with preterm birth. In this cohort, the most significant association was in FSHR, and 8 of the 10 most significant SNPs were in this gene. Further evidence for association of a linkage disequilibrium block of SNPs in FSHR, rs11686474, rs11680730, rs12473870, and rs1247381 was found in African Americans. By considering human acceleration, we identified a novel gene that may be associated with preterm birth, FSHR. We anticipate other human accelerated genes will similarly be associated with preterm birth risk and elucidate essential pathways for human parturition.

Effect of progesterone on cervical shortening in women at risk for preterm birth: secondary analysis from a multinational, randomized, double-blind, placebo-controlled trial

To determine whether progesterone supplementation alters cervical shortening in women at increased risk for preterm birth.

Heritability of parturition timing: an extended twin design analysis.

OBJECTIVE The objective of the study was to assess relative maternal and paternal genetic influences on birth timing. STUDY DESIGN Utilizing The Netherlands Twin Registry, we examined the correlation in birth timing of infants born to monozygotic (MZ) twins and their first-degree relatives (dizygotic twins and siblings of twins). Genetic models estimated the relative influence of genetic and common environmental factors through model fitting of additive genetic (A), common environmental (C), individual-specific environmental factors, and combinations thereof. RESULTS We evaluated birth timing correlation among the infants of 1390 twins and their 644 siblings. The correlation in MZ female twins (r = 0.330) was greater than MZ male twins (r = -0.096). Positive correlation were also found in sister-sister pairs (r = 0.223) but not in brother-brother (r = -0.045) or brother-sister pairs (r = -0.038). The most parsimonious AE model indicated a significant maternal contribution of genetic and individual-specific environmental factors to birth timing, but no paternal heritability was demonstrated. Heritability of birth timing in women was 34%; and the remaining variance (66%) was caused by individual-specific environmental factors. CONCLUSION Our data implicate a significant contribution of maternal but not paternal genetic influences on birth timing.

Area-level poverty and preterm birth risk: A population-based multilevel analysis

BackgroundPreterm birth is a complex disease with etiologic influences from a variety of social, environmental, hormonal, genetic, and other factors. The purpose of this study was to utilize a large population-based birth registry to estimate the independent effect of county-level poverty on preterm birth risk. To accomplish this, we used a multilevel logistic regression approach to account for multiple co-existent individual-level variables and county-level poverty rate.MethodsPopulation-based study utilizing Missouris birth certificate database (1989–1997). We conducted a multilevel logistic regression analysis to estimate the effect of county-level poverty on PTB risk. Of 634,994 births nested within 115 counties in Missouri, two levels were considered. Individual-level variables included demographics factors, prenatal care, health-related behavioral risk factors, and medical risk factors. The area-level variable included the percentage of the population within each county living below the poverty line (US census data, 1990). Counties were divided into quartiles of poverty; the first quartile (lowest rate of poverty) was the reference group.ResultsPTB < 35 weeks occurred in 24,490 pregnancies (3.9%). The rate of PTB < 35 weeks was 2.8% in counties within the lowest quartile of poverty and increased through the 4th quartile (4.9%), p < 0.0001. High county-level poverty was significantly associated with PTB risk. PTB risk (< 35 weeks) was increased for women who resided in counties within the highest quartile of poverty, adjusted odds ratio (adjOR) 1.18 (95% CI 1.03, 1.35), with a similar effect at earlier gestational ages (< 32 weeks), adjOR 1.27 (95% CI 1.06, 1.52).ConclusionWomen residing in socioeconomically deprived areas are at increased risk of preterm birth, above other underlying risk factors. Although the risk increase is modest, it affects a large number of pregnancies.

Mother's Genome or Maternally-Inherited Genes Acting in the Fetus Influence Gestational Age in Familial Preterm Birth

Objective: While multiple lines of evidence suggest the importance of genetic contributors to risk of preterm birth, the nature of the genetic component has not been identified. We perform segregation analyses to identify the best fitting genetic model for gestational age, a quantitative proxy for preterm birth. Methods: Because either mother or infant can be considered the proband from a preterm delivery and there is evidence to suggest that genetic factors in either one or both may influence the trait, we performed segregation analysis for gestational age either attributed to the infant (infant’s gestational age), or the mother (by averaging the gestational ages at which her children were delivered), using 96 multiplex preterm families. Results: These data lend further support to a genetic component contributing to birth timing since sporadic (i.e. no familial resemblance) and nontransmission (i.e. environmental factors alone contribute to gestational age) models are strongly rejected. Analyses of gestational age attributed to the infant support a model in which mother’s genome and/or maternally-inherited genes acting in the fetus are largely responsible for birth timing, with a smaller contribution from the paternally-inherited alleles in the fetal genome. Conclusion: Our findings suggest that genetic influences on birth timing are important and likely complex.

The Genetics of Birth Timing: Insights into a Fundamental Component of Human Development

The timing of birth necessitates the coupling of fetal maturation with the onset of parturition, and occurs at characteristic, but divergent gestations between mammals. Preterm birth in humans is an important but poorly understood outcome of pregnancy that uncouples fetal maturation and birth timing. The etiology of preterm birth is complex, involving environmental and genetic factors whose underlying molecular and cellular pathogenic mechanisms remain poorly understood. Animal models, although limited by differences with human physiology, have been crucial in exploring the role of various genetic pathways in mammalian birth timing. Studies in humans of both familial aggregation and racial disparities in preterm birth have contributed to the understanding that preterm birth is heritable. A significant portion of this heritability is due to polygenic causes with few true Mendelian disorders contributing to preterm birth. Thus far, studies of the human genetics of preterm birth using a candidate gene approach have met with limited success. Emerging research efforts using unbiased methods may yield promising results if concerns about study design can be adequately addressed. The findings from this frontier of research may have direct implications for the allocation of public health and clinical resources as well as spur the development of more effective therapeutics.

Serum PBDEs and Age at Menarche in Adolescent Girls: Analysis of the National Health and Nutrition Examination Survey 2003–2004

BACKGROUND Polybrominated diphenyl ethers (PBDEs), widely used as flame retardants since the 1970s, have exhibited endocrine disruption in experimental studies. Tetra- to hexa-BDE congeners are estrogenic, while hepta-BDE and 6-OH-BDE-47 are antiestrogenic. Most PBDEs also have antiandrogenic activity. It is not clear, however, whether PBDEs affect human reproduction. OBJECTIVES The analysis was designed to investigate the potential endocrine disruption of PBDEs on the age at menarche in adolescent girls. METHODS We analyzed the data from a sample of 271 adolescent girls (age 12-19 years) in the National Health and Nutrition Examination Survey (NHANES), 2003-2004. We estimated the associations between individual and total serum BDEs (BDE-28, -47, -99, -100, -153, and -154, lipid adjusted) and mean age at menarche. We also calculated the risk ratios (RRs) and 95% confidence intervals (CI) for menarche prior to age 12 years in relation to PBDE exposure. RESULTS The median total serum BDE concentration was 44.7ng/g lipid. Higher serum PBDE concentrations were associated with slightly earlier ages at menarche. Each natural log unit of total BDEs was related to a change of -0.10 (95% CI: -0.33, 0.13) years of age at menarche and a RR of 1.60 (95% CI: 1.12, 2.28) for experiencing menarche before 12 years of age, after adjustment for potential confounders. CONCLUSION These data suggest high concentrations of serum PBDEs during adolescence are associated with a younger age of menarche.