Baseline Prevalence of Birth Defects Associated with Congenital Zika Virus Infection - Massachusetts, North Carolina, and Atlanta, Georgia, 2013-2014.

Zika virus infection during pregnancy can cause serious brain abnormalities, but the full range of adverse outcomes is unknown (1). To better understand the impact of birth defects resulting from Zika virus infection, the CDC surveillance case definition established in 2016 for birth defects potentially related to Zika virus infection* (2) was retrospectively applied to population-based birth defects surveillance data collected during 2013-2014 in three areas before the introduction of Zika virus (the pre-Zika years) into the World Health Organization's Region of the Americas (Americas) (3). These data, from Massachusetts (2013), North Carolina (2013), and Atlanta, Georgia (2013-2014), included 747 infants and fetuses with one or more of the birth defects meeting the case definition (pre-Zika prevalence = 2.86 per 1,000 live births). Brain abnormalities or microcephaly were the most frequently recorded (1.50 per 1,000), followed by neural tube defects and other early brain malformations† (0.88), eye abnormalities without mention of a brain abnormality (0.31), and other consequences of central nervous system (CNS) dysfunction without mention of brain or eye abnormalities (0.17). During January 15-September 22, 2016, the U.S. Zika Pregnancy Registry (USZPR) reported 26 infants and fetuses with these same defects among 442 completed pregnancies (58.8 per 1,000) born to mothers with laboratory evidence of possible Zika virus infection during pregnancy (2). Although the ascertainment methods differed, this finding was approximately 20 times higher than the proportion of one or more of the same birth defects among pregnancies during the pre-Zika years. These data demonstrate the importance of population-based surveillance for interpreting data about birth defects potentially related to Zika virus infection.

Birth Defects Among Fetuses and Infants of US Women With Evidence of Possible Zika Virus Infection During Pregnancy.

Importance: Understanding the risk of birth defects associated with Zika virus infection during pregnancy may help guide communication, prevention, and planning efforts. In the absence of Zika virus, microcephaly occurs in approximately 7 per 10 000 live births. Objective: To estimate the preliminary proportion of fetuses or infants with birth defects after maternal Zika virus infection by trimester of infection and maternal symptoms. Design, Setting, and Participants: Completed pregnancies with maternal, fetal, or infant laboratory evidence of possible recent Zika virus infection and outcomes reported in the continental United States and Hawaii from January 15 to September 22, 2016, in the US Zika Pregnancy Registry, a collaboration between the CDC and state and local health departments. Exposures: Laboratory evidence of possible recent Zika virus infection in a maternal, placental, fetal, or infant sample. Main Outcomes and Measures: Birth defects potentially Zika associated: brain abnormalities with or without microcephaly, neural tube defects and other early brain malformations, eye abnormalities, and other central nervous system consequences. Results: Among 442 completed pregnancies in women (median age, 28 years; range, 15-50 years) with laboratory evidence of possible recent Zika virus infection, birth defects potentially related to Zika virus were identified in 26 (6%; 95% CI, 4%-8%) fetuses or infants. There were 21 infants with birth defects among 395 live births and 5 fetuses with birth defects among 47 pregnancy losses. Birth defects were reported for 16 of 271 (6%; 95% CI, 4%-9%) pregnant asymptomatic women and 10 of 167 (6%; 95% CI, 3%-11%) symptomatic pregnant women. Of the 26 affected fetuses or infants, 4 had microcephaly and no reported neuroimaging, 14 had microcephaly and brain abnormalities, and 4 had brain abnormalities without microcephaly; reported brain abnormalities included intracranial calcifications, corpus callosum abnormalities, abnormal cortical formation, cerebral atrophy, ventriculomegaly, hydrocephaly, and cerebellar abnormalities. Infants with microcephaly (18/442) represent 4% of completed pregnancies. Birth defects were reported in 9 of 85 (11%; 95% CI, 6%-19%) completed pregnancies with maternal symptoms or exposure exclusively in the first trimester (or first trimester and periconceptional period), with no reports of birth defects among fetuses or infants with prenatal exposure to Zika virus infection only in the second or third trimesters. Conclusions and Relevance: Among pregnant women in the United States with completed pregnancies and laboratory evidence of possible recent Zika infection, 6% of fetuses or infants had evidence of Zika-associated birth defects, primarily brain abnormalities and microcephaly, whereas among women with first-trimester Zika infection, 11% of fetuses or infants had evidence of Zika-associated birth defects. These findings support the importance of screening pregnant women for Zika virus exposure.

Antidepressant Prescription Claims Among Reproductive-Aged Women With Private Employer-Sponsored Insurance - United States 2008-2013.

Antidepressant medication use during pregnancy has been increasing in the United States (1). Many women require antidepressants on an ongoing basis, and a clear consensus on the safest medication options for both the mother and her fetus does not exist (2). Given that half of all U.S. pregnancies are unplanned (3), antidepressant use will occur during the first weeks of pregnancy, a critical period for fetal development. To understand trends among women of reproductive age, CDC used Truven Health's MarketScan Commercial Claims and Encounters data* to estimate the number of antidepressant prescriptions filled by women aged 15-44 years with private employer-sponsored insurance. During 2008-2013, an average of 15.4% of women aged 15-44 years filled at least one prescription for an antidepressant in a single year. The most frequently filled antidepressants included sertraline, bupropion, and citalopram. Prescribing of antidepressants is common, and research on antidepressant safety during pregnancy needs to be accelerated to provide evidence-based information to health care providers and women about the potential risks for antidepressant exposure before and during pregnancy and between pregnancies.

Using insurance claims data to identify and estimate critical periods in pregnancy: An application to antidepressants.

BACKGROUND: Health insurance claims are a rich data source to examine medication use in pregnancy. Our objective was to identify pregnant women, their pregnancy outcomes, and date of their last menstrual period (LMP), and to estimate antidepressant dispensations in pregnancy. METHODS: From a literature search, we identified diagnosis and procedure codes indicating the end of a pregnancy. Using Truven Health MarketScan® Commercial Claims and Encounters Databases, we identified all inpatient admissions and outpatient service claims with these codes. We developed an algorithm to assign: (1) pregnancy outcome (ectopic pregnancy, induced or spontaneous abortion, live birth, or stillbirth), and (2) estimated gestational age, to each inpatient or outpatient visit. For each pregnancy outcome, we estimated the LMP as the admission (for inpatient visits) or service (for outpatient visits) date minus the gestational age. To differentiate visits associated with separate pregnancies, we required ≥ 2 months between one pregnancy outcomes and the LMP of the next pregnancy. We used this algorithm to identify pregnancies in 2013 and to estimate the proportion of women who filled a prescription for an antidepressant from an outpatient pharmacy at various time points in pregnancy. RESULTS: We identified 488,887 pregnancies in 2013; 79% resulted in a live birth. A prescription for an antidepressant was filled in 6.2% of pregnancies. Dispensations varied throughout pregnancy and were lowest (3.1%) during the second trimester. CONCLUSION: This work will inform future efforts to estimate medication dispensations during critical periods of preconception, interconception, and pregnancy using health insurance claims data. Birth Defects Research (Part A) 106:927-934, 2016. © 2016 Wiley Periodicals, Inc.

Opioid prescription claims among women of reproductive age--United States, 2008-2012.

Prescription opioid use in the United States has become widespread, and studies of opioid exposure in pregnancy suggest increased risk for adverse pregnancy outcomes, including neonatal abstinence syndrome and birth defects (e.g., neural tube defects, gastroschisis, and congenital heart defects). The development of birth defects often results from exposures during the first few weeks of pregnancy, which is a critical period for organ formation. Given that many pregnancies are not recognized until well after the first few weeks and half of all U.S. pregnancies are unplanned, all women who might become pregnant are at risk. Therefore, it is important to assess opioid medication use among all women of reproductive age. CDC used Truven Health's MarketScan Commercial Claims and Encounters and Medicaid data to estimate the number of opioid prescriptions dispensed by outpatient pharmacies to women aged 15-44 years. During 2008-2012, opioid prescription claims were consistently higher among Medicaid-enrolled women when compared with privately insured women (39.4% compared with 27.7%, p<0.001). The most frequently prescribed opioids among women in both groups were hydrocodone, codeine, and oxycodone. Efforts are needed to promote interventions to reduce opioid prescriptions among this population when safer alternative treatments are available.

Epidemiology of twinning in the National Birth Defects Prevention Study, 1997 to 2007.

BACKGROUND: Our objective was to evaluate associations between twinning and maternal demographic factors and periconceptional exposures among infants with and without orofacial clefts. METHODS: We used data from the National Birth Defects Prevention Study; 228 twins and 8242 singletons without birth defects (controls), and 117 twins and 2859 singletons with orofacial clefts, born 1997 to 2007, were included in the analyses. Because of the occurrence of twinning due to the use of assisted reproductive technologies, logistic regression models were computed to estimate odds ratios and 95% confidence intervals for each exposure, stratified by fertility treatment use. To evaluate factors by zygosity, we used sex-pairing data and a simulation approach to estimate the zygosity of like-sex twin pairs for unassisted conceptions. RESULTS: Among control mothers who did not use fertility treatments, predictors of twinning included non-Hispanic black maternal race (adjusted odds ratio, 1.6; 95% confidence interval, 1.0-2.4), and tobacco smoking (adjusted odds ratio, 1.6; 95% confidence interval, 1.1-2.4). Among control mothers who used fertility treatments, older maternal age, higher income, and state of residence were associated with twinning. Associations were generally stronger among mothers of dizygotic (estimated) twins than monozygotic (estimated) twins. Results for mothers of infants with isolated orofacial clefts were similar to those of controls. CONCLUSION: We observed an increased twinning frequency with increasing maternal age, but factors such as maternal race/ethnicity and socioeconomic status may also contribute. Among women receiving fertility treatments, factors associated with twinning suggested a relation with treatment specifics (e.g., treatment type and number of embryos implanted) and availability of insurance coverage.

Maternal exposures in the National Birth Defects Prevention Study: Time trends of selected exposures.

BACKGROUND: Our objective was to describe time trends in selected pregnancy exposures in the National Birth Defects Prevention Study (NBDPS). METHODS: We analyzed data from the NBDPS, a multi-site case-control study of major birth defects, for mothers of live-born infants without birth defects (controls), with an expected date of delivery (EDD) from 1998 to 2011. Mothers from the 10 participating centers across the United States were interviewed by phone between 6 weeks and 2 years after the EDD. We focused on maternal race/ethnicity and five maternal risk factors: obesity, use of folic acid-containing multivitamins, opioid analgesics, selective serotonin reuptake inhibitors, and loratadine because of their prevalence of use and some reports of associations with major birth defects. Prevalence time trends were examined using the Kendall's τß test statistic. RESULTS: The exposure trend analysis included 11,724 control mothers with EDDs from 1998 to 2011. We observed a significant increase in obesity prevalence among control mothers, as well as use of selective serotonin reuptake inhibitors and loratadine. We also observed an increase in periconceptional use of folic acid-containing multivitamins. Some of the time trends varied by race/ethnicity. No remarkable trend in the overall use of opioid analgesics was observed. The racial/ethnic distribution of mothers changed slightly during the study period. CONCLUSION: Long-term, population-based case-control studies continue to be an effective way to assess exposure-birth defects associations and provide guidance to health care providers. However, investigators examining rare outcomes covering many years of data collection need to be cognizant of time trends in exposures.

Maternal exposure to methotrexate and birth defects: a population-based study.

Methotrexate is an anti-folate medication that is associated with increased risk of multiple birth defects. Using data from the National Birth Defects Prevention Study, a case-control study of major birth defects in the United States, we examined mothers exposed to methotrexate. The study population included mothers of live-born infants without major birth defects (controls) and mothers of fetuses or infants with a major birth defect (cases), with expected dates of delivery between October 1997 and December 2009. Mothers of cases and controls were asked detailed questions concerning pregnancy history, demographic information, and exposures in a telephone interview. Approximately 0.06% (n = 16/27,623) of case and 0.04% (n = 4/10,113) of control mothers reported exposure to methotrexate between 3 months prior to conception through the end of pregnancy. Of the 16 case infants, 11 (68.8%) had a congenital heart defect (CHD). The observed CHDs included atrial septal defects, tetralogy of Fallot, valvar pulmonary stenosis, ventricular septal defects (VSDs), and total anomalous pulmonary venous return. One case infant had microtia in addition to a VSD and another had VACTER association. Exposed cases without a CHD had one of the following birth defects: cleft palate, hypospadias, congenital diaphragmatic hernia, or craniosynostosis. Based on a limited number of methotrexate-exposed mothers, our findings support recent case reports suggesting an association between early pregnancy exposure to methotrexate and CHDs. Because of the rarity of maternal periconceptional exposure to methotrexate, long-term, population-based case-control studies are needed to confirm these findings and better evaluate the association between methotrexate and birth defects.

Hospitalizations and associated costs in a population-based study of children with Down syndrome born in Florida.

BACKGROUND: Our objective was to examine differences in hospital resource usage for children with Down syndrome by age and the presence of other birth defects, particularly severe and nonsevere congenital heart defects (CHDs). METHODS: This was a retrospective, population-based, statewide study of children with Down syndrome born 1998 to 2007, identified by the Florida Birth Defects Registry (FBDR) and linked to hospital discharge records for 1 to 10 years after birth. To evaluate hospital resource usage, descriptive statistics on number of hospitalized days and hospital costs were calculated. Results were stratified by isolated Down syndrome (no other coded major birth defect); presence of severe and nonsevere CHDs; and presence of major FBDR-eligible birth defects without CHDs. RESULTS: For 2552 children with Down syndrome, there were 6856 inpatient admissions, of which 68.9% occurred during the first year of life (infancy). Of the 2552 children, 31.7% (n = 808) had isolated Down syndrome, 24.0% (n = 612) had severe CHDs, 36.3% (n = 927) had nonsevere CHDs, and 8.0% (n = 205) had a major FBDR-eligible birth defect in the absence of CHD. Infants in all three nonisolated DS groups had significantly higher hospital costs compared with those with isolated Down syndrome. From infancy through age 4, children with severe CHDs had the highest inpatient costs compared with children in the other sub-groups. CONCLUSION: Results support findings that for children with Down syndrome the presence of other anomalies influences hospital use and costs, and children with severe CHDs have greater hospital resource usage than children with other CHDs or major birth defects without CHDs.

Maternal Use of Opioids During Pregnancy and Congenital Malformations: A Systematic Review.

CONTEXT: Opioid use and abuse have increased dramatically in recent years, particularly among women. OBJECTIVES: We conducted a systematic review to evaluate the association between prenatal opioid use and congenital malformations. DATA SOURCES: We searched Medline and Embase for studies published from 1946 to 2016 and reviewed reference lists to identify additional relevant studies. STUDY SELECTION: We included studies that were full-text journal articles and reported the results of original epidemiologic research on prenatal opioid exposure and congenital malformations. We assessed study eligibility in multiple phases using a standardized, duplicate review process. DATA EXTRACTION: Data on study characteristics, opioid exposure, timing of exposure during pregnancy, congenital malformations (collectively or as individual subtypes), length of follow-up, and main findings were extracted from eligible studies. RESULTS: Of the 68 studies that met our inclusion criteria, 46 had an unexposed comparison group; of those, 30 performed statistical tests to measure associations between maternal opioid use during pregnancy and congenital malformations. Seventeen of these (10 of 12 case-control and 7 of 18 cohort studies) documented statistically significant positive associations. Among the case-control studies, associations with oral clefts and ventricular septal defects/atrial septal defects were the most frequently reported specific malformations. Among the cohort studies, clubfoot was the most frequently reported specific malformation. LIMITATIONS: Variabilities in study design, poor study quality, and weaknesses with outcome and exposure measurement. CONCLUSIONS: Uncertainty remains regarding the teratogenicity of opioids; a careful assessment of risks and benefits is warranted when considering opioid treatment for women of reproductive age.

Twinning and major birth defects, National Birth Defects Prevention Study, 1997-2007.

BACKGROUND: Twinning has been associated with many types of birth defects, although previous studies have had inconsistent findings. Many studies lack information about potential confounders, particularly use of fertility treatment. Our objective was to assess the association between twinning and birth defects in the National Birth Defects Prevention Study (NBDPS). METHODS: We used data from the NBDPS, a population-based, case-control study of major birth defects in the USA, to evaluate associations between twinning and birth defects. The study population included mothers of twin and singleton controls (live-born infants without major birth defects), and cases (fetuses or infants with a major birth defect) born October 1997-December 2007. Adjusted ORs and 95% CIs were estimated using multivariable logistic regression stratified by use of fertility treatment. Twin sex-pairing data and a simulation approach were used to estimate the zygosity of twins. RESULTS: In the unassisted conception stratum, we observed significant positive associations between twinning and 29 of 45 defect groups. The largest effect estimates were observed for multiple ventricular septal defects and cloacal exstrophy. Among mothers reporting any use of fertility treatments, we observed a significant association with twinning for 5 of 25 defect groups, with the largest effect estimates for hypoplastic left heart syndrome and omphalocele. OR estimates in the estimated monozygotic stratum were generally further from the null than in the dizygotic stratum. CONCLUSIONS: Compared with singletons, a wide range of birth defects are significantly more common among twins. Birth defect risk in twins may be differential by use of fertility treatment.

Relationship between resource utilization and length of stay following tetralogy of Fallot repair.

BACKGROUND: The relationship between resource utilization and postoperative length of stay (PLOS) following congenital heart disease surgery is unknown. METHODS: We performed a retrospective cohort study using data from the Pediatric Health Information Systems database. We included subjects 1 month to 1 year of age with a PLOS of ≤ 1 month following elective, complete repair of tetralogy of Fallot (TOF) during 2004-2008 at children's hospitals that performed ≥ 10 such surgeries during the study period. We constructed three generalized linear models to assess the relationships of total costs, laboratory costs, and imaging costs during the first three postoperative days with overall PLOS. Race/ethnicity, insurance type, sex, and presence of a genetic syndrome (by ICD-9 codes) were included in the models as fixed effects; hospital of surgery was included as a random effect. RESULTS: For 1161 eligible surgical encounters at 36 children's hospitals, mean PLOS was 7.1 days (median = 6 days). Mean total, laboratory, and imaging costs for the first three postoperative days were $26,455, $2941, and $813, respectively. Most subjects were male (58.9%), did not have a genetic syndrome (88.3%), were non-Hispanic white (58.3%), and had either public or private insurance (41.0% and 39.1%, respectively). An estimated increase in total costs of $4600 or laboratory costs of $700 in the first three postoperative days was associated with a 1-day increase in PLOS. Imaging costs were not associated with PLOS. CONCLUSIONS: Increased resource utilization is not associated with a shorter PLOS following elective TOF repair, and it may be associated with longer PLOS.

Factors associated with late detection of critical congenital heart disease in newborns.

OBJECTIVES: Critical congenital heart disease (CCHD) was recently added to the US Recommended Uniform Screening Panel for newborns. This study assessed whether maternal/household and infant characteristics were associated with late CCHD detection. METHODS: This was a statewide, population-based, retrospective, observational study of infants with CCHD born between 1998 and 2007 identified by using the Florida Birth Defects Registry. We examined 12 CCHD conditions that are primary and secondary targets of newborn CCHD screening using pulse oximetry. We used Poisson regression models to analyze associations between selected characteristics (eg, CCHD type, birth hospital nursery level [highest level available in the hospital]) and late CCHD detection (defined as diagnosis after the birth hospitalization). RESULTS: Of 3603 infants with CCHD and linked hospitalizations, CCHD was not detected during the birth hospitalization for 22.9% (n = 825) of infants. The likelihood of late detection varied by CCHD condition. Infants born in a birth hospital with a level I nursery only (adjusted prevalence ratio: 1.9 [95% confidence interval: 1.6-2.2]) or level II nursery (adjusted prevalence ratio: 1.5 [95% confidence interval: 1.3-1.7]) were significantly more likely to have late-detected CCHD compared with infants born in a birth hospital with a level III (highest) nursery. CONCLUSIONS: After controlling for the selected characteristics, hospital nursery level seems to have an independent association with late CCHD detection. Thus, perhaps universal newborn screening for CCHD could be particularly beneficial in level I and II nurseries and may reduce differences in the frequency of late diagnosis between birth hospital facilities.