Trends in first-trimester nausea and vomiting of pregnancy and use of select treatments: Findings from the National Birth Defects Prevention Study.

BACKGROUND: Although nausea and vomiting of pregnancy (NVP) is common, the secular and demographic trends of NVP and its treatments are not well-studied. OBJECTIVES: To describe the prevalence and patterns of first-trimester NVP and selected treatments among controls in the National Birth Defects Prevention Study (NBDPS). METHODS: National Birth Defects Prevention Study is a population-based case-control study of birth defects in the United States (1997-2011). We collected self-reported data about NVP and use of commonly reported pharmacological and herbal/natural treatments (ondansetron, promethazine, pyridoxine, metoclopramide, doxylamine succinate, ginger, phosphorated carbohydrate solution, and prochlorperazine) from mothers of non-malformed control infants. We estimated the prevalence of NVP and selected treatments and examined secular and demographic trends (education, race/ethnicity, and maternal age) for such use, adjusting for study centre. RESULTS: Among 10 540 mothers of controls, 7393 women (70.1%) reported first-trimester NVP, and 12.2% of those used one or more of the commonly reported treatments. Specific treatment use varied after adjustment for study centre (ondansetron: 3.4%; promethazine: 4.2%; pyridoxine: 3.2%; metoclopramide: 0.7%; doxylamine succinate: 1.7%; ginger: 1.0%; phosphorated carbohydrate solution: 0.4%; and prochlorperazine: 0.3%). Treatment use increased for each agent over the study period. Women with more years of education reported more NVP and treatment use. White (72%), Hispanic (71%), and other race (73%) women reported more NVP than Black women (67%); White women used selected NVP treatments most frequently, and Black women used them more than Hispanic women. Though women aged 25-34 years reported more NVP (72%) than younger (69%) or older (67%) women, the frequency of medication use was similar among women aged 25-34 and ≥35, and lower among women aged <25 years. CONCLUSIONS: National Birth Defects Prevention Study controls reported NVP at frequencies similar to those previously reported. Of note, we observed an increase in use of selected treatments over time, and variations in NVP and treatments by study site and demographic factors.

Clinical phenotype, biochemical profile, and treatment in 19 patients with arginase 1 deficiency.

BACKGROUND: Arginase 1 (ARG1) deficiency is a rare urea cycle disorder (UCD). This hypothesis-generating study explored clinical phenotypes, metabolic profiles, molecular genetics, and treatment approaches in a cohort of children and adults with ARG1 deficiency to add to our understanding of the underlying pathophysiology. METHODS: Clinical data were retrieved retrospectively from physicians using a questionnaire survey. Plasma aminoacids, guanidinoacetate (GAA), parameters indicating oxidative stress and nitric oxide (NO) synthesis as well as asymmetric dimethylarginine (ADMA) were measured at a single study site. RESULTS: Nineteen individuals with ARG1 deficiency and 19 matched controls were included in the study. In patients, paraparesis, cognitive impairment, and seizures were significantly associated suggesting a shared underlying pathophysiology. In patients plasma GAA exceeded normal ranges and plasma ADMA was significantly elevated. Compared to controls, nitrate was significantly higher, and the nitrite:nitrate ratio significantly lower in subjects with ARG1 deficiency suggesting an advantage for NO synthesis by inducible NO synthase (iNOS) over endothelial NOS (eNOS). Logistic regression revealed no significant impact of any of the biochemical parameters (including arginine, nitrates, ADMA, GAA, oxidative stress) or protein restriction on long-term outcome. CONCLUSION: Three main hypotheses which must be evaluated in a hypothesis driven confirmatory study are delineated from this study: 1) clinical manifestations in ARG1 deficiency are not correlated with arginine, protein intake, ADMA, nitrates or oxidative stress. 2) GAA is elevated and may be a marker or an active part of the pathophysiology of ARG1 deficiency. 3) Perturbations of NO metabolism merit future attention in ARG1 deficiency.

The timing, duration, and severity of nausea and vomiting of pregnancy and adverse birth outcomes among controls without birth defects in the National Birth Defects Prevention Study.

BACKGROUND: Nausea and vomiting of pregnancy (NVP) occurs in approximately 70% of pregnant people, with varying severity and duration. Treatments include pharmacologic and herbal/natural medications. The associations between NVP and birth outcomes, including preterm birth, small for gestational age (SGA), and low birth weight are inconclusive. OBJECTIVE: To determine whether NVP and reported medications are associated with adverse birth outcomes. METHODS: We used data from the population-based, multisite National Birth Defects Prevention Study (1997-2011) to evaluate whether self-reported NVP according to timing, duration, and severity or its specific treatments were associated with preterm birth, SGA, and low birth weight among controls without birth defects. Odds ratios (aOR) and 95% confidence intervals (CI) were adjusted for sociodemographic, reproductive, and medical factors. For any NVP, duration, treatment use, and severity score analyses, the comparison group was participants with no reported NVP. For timing analyses, the comparison group was women with no reported NVP in the same trimester of pregnancy. RESULTS: Among 6018 participants, 4339 (72.1%) reported any NVP. Among those with NVP, moderate or severe symptoms were more common than mild symptoms. Any versus no NVP was not associated with any of the outcomes of interest. NVP in months 4-6 (aOR 1.21, 95% CI: 1.00, 1.47) and 7-9 (aOR 1.57, 95% CI: 1.22, 2.01) of pregnancy were associated with an increase in the risk of preterm birth. NVP lasting one trimester in duration was associated with decrease in risk of SGA (aOR: 0.74, 95% CI: 0.58, 0.95), and NVP present in every trimester of pregnancy had a 50% increase in risk of preterm birth (aOR: 1.50, 95% CI: 1.11, 2.05). For NVP in months 7-9 and preterm birth, ORs were elevated for moderate (aOR: 1.82, 95% CI: 1.26, 2.63), and severe (aOR: 1.53, 95% CI: 1.06, 2.19) symptoms. NVP was not significantly associated with low birth weight. Our analyses of medications were limited by small numbers, but none suggested increased risk of adverse outcomes associated with use of the medication. CONCLUSION: Mild NVP and NVP limited to early pregnancy appear to have no effect or a small protective effect on birth outcomes. Long-lasting NVP, severe NVP, and NVP later in pregnancy may increase risk of preterm birth and SGA.

Neurologic and neurodevelopmental phenotypes in young children with early-treated combined methylmalonic acidemia and homocystinuria, cobalamin C type.

Abnormal neurodevelopment has been widely reported in combined methylmalonic aciduria (MMA) and homocystinuria, cblC type (cblC disease), but neurodevelopmental phenotypes in cblC have not previously been systematically studied. We sought to further characterize developmental neurology in children with molecularly-confirmed cblC. Thirteen children at our center with cblC, born since implementation of expanded newborn screening in New York State, undertook standard-of-care evaluations with a pediatric neurologist and pediatric ophthalmologist. At most recent follow-up (mean age 50 months, range 9-84 months), of twelve children with early-onset cblC, three (25%) had a history of clinical seizures and two (17%) meet criteria for microcephaly. A majority of children had hypotonia and nystagmus. Twelve out of thirteen (92%) underwent neurodevelopmental evaluation (mean age 41 months; range 9-76 months), each child tested with standardized parental interviews and, where possible, age- and disability-appropriate neuropsychological batteries. All patients showed evidence of developmental delay with the exception of one patient with a genotype predictive of attenuated disease and near-normal biochemical parameters. Neurodevelopmental deficits were noted most prominently in motor skills, with relative preservation of socialization and communication skills. Nine children with early-onset cblC underwent magnetic resonance imaging and spectroscopy (MRI/MRS) at mean age of 47 months (range 6-81 months); common abnormalities included callosal thinning, craniocaudally short pons, and increased T2 FLAIR signal in periventricular and periatrial white matter. Our study further characterizes variable neurodevelopmental phenotypes in treated cblC, and provides insights into the etiopathogenesis of disordered neurodevelopment frequently encountered in cblC. Plasma homocysteine and MMA, routinely measured at clinical follow-up, may be poor predictors for neurodevelopmental outcomes. Additional data from large, prospective, multi-center natural history studies are required to more accurately define the role of these metabolites and others, as well as that of other genetic and environmental factors in the etiopathogenesis of the neurologic components of this disorder.

The association of nausea and vomiting of pregnancy, its treatments, and select birth defects: Findings from the National Birth Defect Prevention Study.

BACKGROUND: Nausea and vomiting of pregnancy (NVP) occurs in approximately 70% of pregnant people. Treatments include pharmacologic and herbal/natural products. Research on the associations between NVP and its treatments and birth defects is limited. METHODS: We used data from the case-control National Birth Defects Prevention Study (1997-2011) to examine whether first-trimester NVP or its specific treatments were associated with 37 major birth defects. Odds ratios (aOR) and 95% confidence intervals (CIs) were adjusted for sociodemographic and reproductive factors. RESULTS: Mothers of 66.6% of 28,628 cases and 69.9% of 11,083 controls reported first-trimester NVP. Compared to no NVP, mothers with NVP had ≥10% reduction in risk of cardiac and noncardiac defects overall, and of 18 specific defects. Over-the-counter antiemetic use, compared to untreated NVP, was associated with ≥10% increase in risk for nine defect groups (heterotaxy, hypoplastic left heart syndrome [HLHS], aortic stenosis, cataracts, anophthalmos/microphthalmos, biliary atresia, transverse limb deficiency, omphalocele, and gastroschisis), whereas use of prescription antiemetics increased risk ≥10% for seven defect groups (tetralogy of Fallot, HLHS, spina bifida, anopthlamos/microphthalmos, cleft palate, craniosynostosis, and diaphragmatic hernia). We observed increased risks for promethazine and tetralogy of Fallot (aOR: 1.49, 95% CI: 1.05-2.10), promethazine and craniosynostosis (1.44, 1.08-1.92), ondansetron and cleft palate (1.66, 1.18-2.31), pyridoxine and heterotaxy (3.91, 1.49-10.27), and pyridoxine and cataracts (2.57, 1.12-5.88). CONCLUSIONS: NVP does not increase risks of birth defects. Our findings that some treatments for NVP increase risk of specific birth defects should be investigated further before clinical recommendations are made.

Association of income and education with fecundability in a North American preconception cohort.

PURPOSE: The purpose of this study is to evaluate socioeconomic determinants of fecundability. METHODS: Among 8654 female pregnancy planners from Pregnancy Study Online, a North American prospective cohort study (2013-2019), we examined associations between socioeconomic status and fecundability (the per-cycle probability of conception). Information on income and education was collected via baseline questionnaires. Bimonthly follow-up questionnaires were used to ascertain pregnancy status. We estimated fecundability ratios (FRs) and 95% confidence intervals (CIs) using proportional probabilities regression, controlling for potential confounders. RESULTS: Relative to an annual household income of greater than or equal to $150,000, adjusted FRs were 0.91 (95% CI: 0.83-1.01) for less than $50,000, 0.99 (95% CI: 0.92-1.07) for $50,000-$99,000, and 1.09 (95% CI: 1.01-1.18) for $100,000-$149,000. FRs for less than 12, 13-15, and 16 years of education, relative to greater than or equal to 17 years, were 0.90 (95% CI: 0.76-1.08), 0.84 (95% CI: 0.78-0.91), and 0.89 (95% CI: 0.84-0.95), respectively. Slightly stronger associations for income and education were seen among older women. CONCLUSIONS: Lower levels of education and income were associated with modestly reduced fecundability. These results demonstrate the presence of socioeconomic disparities in fecundability.