Pharmacogenomics of 17-alpha hydroxyprogesterone caproate for recurrent preterm birth: a case-control study.

OBJECTIVE: To compare maternal genotypes between women with and without significant prolongation of pregnancy in the setting of 17-alpha hydroxyprogesterone caproate (17-P) administration for the prevention of recurrent preterm birth (PTB). DESIGN: Case-control. SETTING: Three tertiary-care centres across the USA. POPULATION: Women (n = 99) with ≥ 1 prior singleton spontaneous PTB, receiving 17-P. METHODS: Women were classified as having successful prolongation of pregnancy during the 17-P treated pregnancy, in two ways: (1) Definition A: success/non-success based on difference in gestational age at delivery between 17-P-treated and untreated pregnancies (success: delivered ≥ 3 weeks later with 17-P) and (2) Definition B: success/non-success based on reaching term (success: delivered at term with 17-P). MAIN OUTCOME MEASURES: To assess genetic variation, all women underwent whole exome sequencing. Between-group sequence variation was analysed with the Variant Annotation, Analysis, and Search Tool (VAAST). Genes scored by VAAST with P < 0.05 were then analysed with two online tools: (1) Protein ANalysis THrough Evolutionary Relationships (PANTHER) and (2) Database for Annotation, Visualization, and Integrated Discovery (DAVID). RESULTS: Using Definition A, there were 70 women with successful prolongation and 29 without; 1375 genes scored by VAAST had P < 0.05. Using Definition B, 47 women had successful prolongation and 52 did not; 1039 genes scored by VAAST had P < 0.05. PANTHER revealed key differences in gene ontology pathways. Many genes from definition A were classified as prematurity genes (P = 0.026), and those from definition B as pharmacogenetic genes (P = 0.0018); (P, non-significant after Bonferroni correction). CONCLUSION: A novel analytic approach revealed several genetic differences among women delivering early vs later with 17-P. TWEETABLE ABSTRACT: Several key genetic differences are present in women with recurrent preterm birth despite 17-P treatment.

Lipoprotein particle concentration measured by nuclear magnetic resonance spectroscopy is associated with gestational age at delivery: a prospective cohort study.

OBJECTIVE: To estimate the association between lipoprotein particle concentrations in pregnancy and gestational age at delivery. DESIGN: Prospective cohort study. SETTING: The study was conducted in the USA at the University of North Carolina. POPULATION: We assessed 715 women enrolled in the Pregnancy, Infection, and Nutrition study from 2001 to 2005. METHODS: Fasting blood was collected at two time points (<20 and 24-29 weeks of gestation). Nuclear magnetic resonance (NMR) quantified lipoprotein particle concentrations [low-density lipoprotein (LDL), high-density lipoprotein (HDL), very-low density lipoprotein (VLDL)] and 10 subclasses of lipoproteins. Concentrations were assessed as continuous measures, with the exception of medium HDL which was classified as any or no detectable level, given its distribution. Cox proportional hazards models estimated hazard ratios (HR) for gestational age at delivery adjusting for covariates. MAIN OUTCOME MEASURES: Gestational age at delivery, preterm birth (<37 weeks of gestation), and spontaneous preterm birth. RESULTS: At <20 weeks of gestation, three lipoproteins were associated with later gestational ages at delivery [large LDLNMR (HR 0.78, 95% CI 0.64-0.96), total VLDLNMR (HR 0.77, 95% CI 0.61-0.98), and small VLDLNMR (HR 0.78, 95% CI 0.62-0.98], whereas large VLDLNMR (HR 1.19, 95% CI 1.01-1.41) was associated with a greater hazard of earlier delivery. At 24-28 weeks of gestation, average VLDLNMR (HR 1.25, 95% CI 1.03-1.51) and a detectable level of medium HDLNMR (HR 1.90, 95% CI 1.19-3.02) were associated with earlier gestational ages at delivery. CONCLUSION: In this sample of pregnant women, particle concentrations of VLDLNMR , LDLNMR , IDLNMR , and HDLNMR were each independently associated with gestational age at delivery for all deliveries or spontaneous deliveries <37 weeks of gestation. These findings may help formulate hypotheses for future studies of the complex relationship between maternal lipoproteins and preterm birth. TWEETABLE ABSTRACT: Nuclear magnetic resonance spectroscopy may identify lipoprotein particles associated with preterm delivery.

Use of prophylactic antibiotics in women with previable prelabor rupture of membranes.

OBJECTIVE: To measure the effect of prophylactic antibiotics given at time of previable prelabor rupture of membranes (PROM) on latency. METHODS: Single center, retrospective cohort study of singleton pregnancies with previable (<23 0/7weeks) PROM. Antibiotics were given at clinician discretion. The primary outcome was latency, defined as duration of time between previable PROM and delivery. Secondary outcomes included delivery at ≥ 23weeks, infant survival, and maternal morbidity. Bivariate analysis compared maternal covariates between women who did and did not receive antibiotics. Antibiotic effect on latency was modeled using a Cox proportional hazards ratio. RESULTS: 213 women with previable PROM were identified; 77 (36%) remained pregnant and thus were included in this analysis. Forty (52%) of 77 received antibiotics. Compared to women who did not receive antibiotics, those who did had PROM at a later median (IQR) estimated gestational age, EGA, (22.2weeks [20.7, 22.5] vs. 19.3weeks [18, 20.7], p < 0.01). Median (IQR) latency was not different between women who did and did not receive antibiotics (2.2 [0.7, 3.9] vs. 1.5 [0.5, 4.6] weeks, p = 0.49). More infants survived to discharge among women who received antibiotics compared to those who did not [17(43%) vs. 3(8%), p < 0.01]. When adjusted for EGA at PROM, antibiotics were associated with longer latency (HR 0.57 [95% CI 0.33, 0.97], p = 0.01). Antibiotic use was not associated with differences in maternal morbidity. CONCLUSION: After adjusting for EGA at PROM, antibiotic receipt was associated with longer latency. Larger prospective studies are needed to define the utility of prophylactic antibiotics in previable PROM.

Pharmacogenomics of preterm birth prevention and treatment.

UNLABELLED: 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. TWEETABLE ABSTRACT: Some of the variation to meds for prematurity prevention/treatment may arise from pharmacogenomic effects.

Risk factors associated with preterm birth after a prior term delivery.

OBJECTIVE: The objective of this study was to assess the presence of newly acquired preterm birth (PTB) risk factors among primiparous women with no prior history of PTB. DESIGN: Case-control study. SETTING: Deliveries occurring within a large healthcare system from 2002 to 2012. POPULATION: Women with their first two consecutive pregnancies carried to ≥20(0/7)  weeks' gestation. METHODS: Those delivering the first pregnancy at term and the second preterm ≥20(0/7) and <37(0/7)  weeks (term-preterm cases) were compared with women with a term birth in their first two pregnancies (term-term controls). Social factors with the potential to change between the first and second pregnancies and intrapartum labour characteristics in the first pregnancy were compared between cases and controls. MAIN OUTCOME MEASURES: Risk factors for term-preterm sequence. RESULTS: About 38 215 women met inclusion criteria; 1353 (3.8%) were term-preterm cases. Cases and controls were similar with regard to race/ethnicity and maternal age at the time of the first and second deliveries. Cases delivered their second pregnancy approximately 3 weeks earlier (35.7 versus 39.1, P < 0.001). In multivariable models accounting for known PTB risk factors, women with a caesarean delivery in the first pregnancy [adjusted odds ratio (aOR) = 2.20; 95% confidence interval (CI) 1.57-3.08], new tobacco use (aOR = 2.33; 95% CI 1.61-3.38), and an interpregnancy interval <18 months (aOR = 1.37; 95% CI 1.21-1.55) were at increased risk of term-preterm sequence. CONCLUSION: Caesarean delivery in the first pregnancy, new tobacco use, and short interpregnancy interval <18 months are significant risk factors for term-preterm sequence. Women should receive postpartum counselling regarding appropriate interpregnancy interval and cessation of tobacco use. TWEETABLE ABSTRACT: Caesarean delivery in the 1st pregnancy is a significant risk factor for preterm birth following a term delivery.

Magnesium sulfate, chorioamnionitis, and neurodevelopment after preterm birth.

OBJECTIVE: To assess the neuroprotective effect of magnesium sulfate (MgSO4 ) in preterm children exposed to chorioamnionitis. DESIGN: A secondary analysis of a multicentre randomised controlled trial of antenatal MgSO4 administered to women at risk of preterm birth for the prevention of cerebral palsy (CP). Singleton, non-anomalous pregnancies with clinical chorioamnionitis, delivering at ≥24 weeks of gestation, were selected. Cases were exposed to antepartum MgSO4 ; controls received placebo. SETTING: Multicentre randomised controlled trial. POPULATION: Singleton, non-anomalous pregnancies with clinical chorioamnionitis, delivering at ≥24 weeks of gestation. METHODS: All data were analysed by intention to treat. Univariate and multivariate analyses were performed. MAIN OUTCOME MEASURES: Primary outcome was a composite of stillbirth, death by the age of 1 year, or moderate or severe CP by the age of 2 years. Secondary outcomes included a composite neonatal outcome as well as neurodevelopmental delay, defined as Bayley II mental and psychomotor developmental indices <70 at the age of 2 years. Subgroup analysis assessed these outcomes in children born at <28 weeks of gestation. RESULTS: A total of 396 children were included, with 192 (48.5%) randomised to MgSO4 . Maternal and delivery characteristics were similar between the groups. The primary outcome occurred in 14.1% of children exposed to MgSO4 and 12.7% of children exposed to placebo (relative risk, RR 1.29; 95% CI 0.70-2.38). Rates of stillbirth, death, moderate-severe CP, and neurodevelopmental delay did not differ between groups. In the subgroup analysis of children born at <28 weeks of gestation, there was no difference in the rates of the primary outcome, nor in the secondary outcomes assessed. [Correction added on 02 March 2016 after online publication: There were errors in statistical data analysis and these have been corrected throughout the article.] CONCLUSIONS: Among children at risk for early preterm delivery exposed to chorioamnionitis, antenatal administration of MgSO4 was not associated with improved neurodevelopmental outcome. We do not recommend any change in the guidelines on the administration of MgSO4 for neuroprotection based on this study. TWEETABLE ABSTRACT: MgSO4 was not associated with improved neurodevelopmental outcome in setting of chorioamnionitis.

Congenital pulmonary lymphangiectasia: a case report of thoracic duct agenesis.

We present a 17-year-old Caucasian male with congenital pulmonary lymphangiectasia and an absent thoracic duct. This patient is unique as he did not present with the disorder until age 9.5 years. Since his initial presentation he has had recurrent chylothoraces and has been treated symptomatically. We discuss the possible implications of his disorder as well as some of the limited treatment that is available.