Nonimmune hydrops fetalis: identifying the underlying genetic etiology.

PURPOSE: Numerous etiologies may lead to nonimmune hydrops fetalis (NIHF), and the underlying cause often remains unclear. We aimed to determine the proportion of NIHF cases in which the etiology was clearly determined in a large, contemporary, and diverse cohort, as well as to describe the etiologies with a focus on genetic causes. METHODS: Retrospective review of NIHF cases between 2015 and 2017 from the five University of California Fetal-Maternal Consortium sites. Singleton pregnancies with prenatally diagnosed NIHF were included, and cases with maternal alloimmunization were excluded. Cases were categorized as being of confirmed, suspected, or unknown etiology. RESULTS: Sixty-five NIHF cases were identified. Forty-six percent (30/65) remained of unknown etiology, while 9.2% (6/65) had a suspected etiology and 44.6% (29/65) were of confirmed etiology. Among confirmed cases, 11 resulted from aneuploidy; 7 from fetal structural anomalies; 2 each from fetal arrhythmia, Noonan syndrome, and generalized lymphatic dysplasia; and 1 each from arthrogryposis, parvovirus, neonatal alloimmune thrombocytopenia, fetal goiter, and Kasabach-Merritt syndrome. CONCLUSION: In this contemporary, multicenter study, the cause of prenatally diagnosed NIHF was confirmed in only 44% of cases, and a genetic etiology was found in only 25% of those that received standard of care genetic testing.

The association of single-nucleotide polymorphisms in the oxytocin receptor and G protein-coupled receptor kinase 6 (GRK6) genes with oxytocin dosing requirements and labor outcomes.

BACKGROUND: Oxytocin is a potent uterotonic agent that is widely used for induction and augmentation of labor. Oxytocin has a narrow therapeutic index and the optimal dosing for any individual woman varies widely. OBJECTIVE: The objective of this study was to determine whether genetic variation in the oxytocin receptor (OXTR) or in the gene encoding G protein-coupled receptor kinase 6 (GRK6), which regulates desensitization of the oxytocin receptor, could explain variation in oxytocin dosing and labor outcomes among women being induced near term. STUDY DESIGN: Pregnant women with a singleton gestation residing in Durham County, NC, were prospectively enrolled as part of the Healthy Pregnancy, Healthy Baby cohort study. Those women undergoing an induction of labor at 36 weeks or greater were genotyped for 18 haplotype-tagging single-nucleotide polymorphisms in OXTR and 7 haplotype-tagging single-nucleotide polymorphisms in GRK6 using TaqMan assays. Linear regression was used to examine the relationship between maternal genotype and maximal oxytocin infusion rate, total oxytocin dose received, and duration of labor. Logistic regression was used to test for the association of maternal genotype with mode of delivery. For each outcome, backward selection techniques were utilized to control for important confounding variables and additive genetic models were used. Race/ethnicity was included in all models because of differences in allele frequencies across populations, and Bonferroni correction for multiple testing was used. RESULTS: DNA was available from 482 women undergoing induction of labor at 36 weeks or greater. Eighteen haplotype-tagging single-nucleotide polymorphisms within OXTR and 7 haplotype-tagging single-nucleotide polymorphisms within GRK6 were examined. Five single-nucleotide polymorphisms in OXTR showed nominal significance with maximal infusion rate of oxytocin, and two single-nucleotide polymorphisms in OXTR were associated with total oxytocin dose received. One single-nucleotide polymorphism in OXTR and two single-nucleotide polymorphisms in GRK6 were associated with duration of labor, one of which met the multiple testing threshold (P = .0014, rs2731664 [GRK6], mean duration of labor, 17.7 hours vs 20.2 hours vs 23.5 hours for AA, AC, and CC genotypes, respectively). Three single-nucleotide polymorphisms, two in OXTR and one in GRK6, showed nominal significance with mode of delivery. CONCLUSION: Genetic variation in OXTR and GRK6 is associated with the amount of oxytocin required as well as the duration of labor and risk for cesarean delivery among women undergoing induction of labor near term. With further research, pharmacogenomic approaches may potentially be utilized to develop personalized treatment to improve safety and efficacy outcomes among women undergoing induction of labor.