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Substance use during pregnancy increases risk for a wide range of adverse maternal and neonatal health outcomes. Polysubstance use is common among people who use substances during pregnancy; however, the risks of combined substance exposures during pregnancy are poorly understood. In this report, we provide an overview of the activities of the Centers for Disease Control and Prevention (CDC) and partners and identified gaps related to (1) surveillance, (2) routine screening, and (3) prevention of polysubstance use during pregnancy. Efforts by CDC and other partners to reduce polysubstance use during pregnancy can improve the health of pregnant people and their infants and children.

Background: Hydroxychloroquine is a treatment for rheumatic disease and considered safe during pregnancy. Interest in hydroxychloroquine has increased as it is being examined as a potential treatment and prophylaxis for coronavirus disease 2019. Data on the risks of specific birth defects associated with hydroxychloroquine use are sparse., Methods: Using data from two case-control studies (National Birth Defects Prevention Study and Slone Epidemiology Center Birth Defects Study), we described women who reported hydroxychloroquine use in pregnancy and the presence of specific major birth defects in their offspring. Cases had at least one major birth defect and controls were live-born healthy infants. Women self-reported medication use information in the few months before pregnancy through delivery., Results: In total, 0.06% (19/31,468) of case and 0.04% (5/11,614) of control mothers in National Birth Defects Prevention Study, and 0.04% (11/29,838) of case and 0.05% (7/12,868) of control mothers in Birth Defects Study reported hydroxychloroquine use. Hydroxychloroquine users had complicated medical histories and frequent medication use for a variety of conditions. The observed birth defects among women taking hydroxychloroquine were varied and included nine oral cleft cases; the elevated observed:expected ratios for specific oral cleft phenotypes and for oral clefts overall had 95% confidence intervals that included 1.0., Conclusion: While teratogens typically produce a specific pattern of birth defects, the observed birth defects among the hydroxychloroquine-exposed women did not present a clear pattern, suggesting no meaningful evidence for the risk of specific birth defects. The number of exposed cases is small; results should be interpreted cautiously., (© 2021 Wiley Periodicals LLC.)

Background: Seasonal influenza vaccination rates among pregnant women remain well below the Healthy People 2020 target of 80%. Obstetrician-gynecologist (OB/GYN) recommendations are a critical means of encouraging pregnant women to get vaccinated, but there are limited data about their views. Materials and Methods: A nationally representative survey of 506 practicing OB/GYNs was completed between October 26, 2015, and May 8, 2016. Analyses included univariate distributions and comparisons based on age, size of practice, and academic affiliation using all-pairs, dependent t -tests. Results: A majority of OB/GYNs report they "strongly recommend" seasonal influenza vaccination for their pregnant patients in the first (79%) or second and third trimesters (81%). Among those who do not strongly recommend the flu vaccine in the first trimester, many say this is because of their own concerns (28%) or their patients' concerns (44%) about safety. Older OB/GYNs, those in smaller practices, and those without academic affiliation were less likely to recommend the vaccine and more likely to have safety concerns. For example, 72% of those age 60+ strongly recommended the vaccine in the second and third trimester, compared with 86% of those ages 30-44 and 83% of those ages 45-59 ( p  < 0.05 for all comparisons). Conclusions: OB/GYNs across the country largely support seasonal flu vaccination among pregnant women. Nonetheless, safety is a concern for them and their patients. Outreach to support clinician decisions and conversations with pregnant patients may be most needed among older physicians, those in smaller practices, and those without academic affiliation.

Objective: Examine the relationship between prescription opioid analgesic use during pregnancy and preterm birth or term low birthweight., Design, Setting, and Participants: We analyzed data from the National Birth Defects Prevention Study, a US multisite, population-based study, for births from 1997 to 2011. We defined exposure as self-reported prescription opioid use between one month before conception and the end of pregnancy, and we dichotomized opioid use duration by ≤7 days and >7 days., Main Outcome Measures: We examined the association between opioid use and preterm birth (defined as gestational age <37 weeks) and term low birthweight (defined as <2500 g at gestational age ≥37 weeks)., Results: Among 10,491 singleton mother/infant pairs, 470 (4.5 percent) reported opioid use. Among women reporting opioid use, 236 (50 percent) used opioids for > 7 days; codeine (170, 36 percent) and hydrocodone (163, 35 percent) were the most commonly reported opioids. Opioid use was associated with slightly increased risk for preterm birth [adjusted odds ratio, 1.4; 95 percent confidence interval, 1.0, 1.9], particularly with hydrocodone [1.6; 1.0, 2.6], meperidine [2.5; 1.2, 5.2], or morphine [3.0; 1.5, 6.1] use for any duration; however, opioid use was not significantly associated with term low birthweight., Conclusions: Preterm birth occurred more frequently among infants of women reporting prescription opioid use during pregnancy. However, we could not determine if these risks relate to the drug or to indications for use. Patients who use opioids during pregnancy should be counseled by their practitioners about this and other potential risks associated with opioid use in pregnancy.

Objective: To estimate the annual percentage of women of reproductive age with private insurance or Medicaid who had opioid prescription claims during 2013-2017 and describe trends over time., Design: A secondary analysis of insurance claims data from IBM MarketScan® Commercial and Multi-State Medicaid Databases to assess outpatient pharmacy claims for prescription opioids among women aged 15-44 years during 2013-2017., Participants: Annual cohorts of 3.5-3.8 million women aged 15-44 years with private insurance and 0.9-2.1 million women enrolled in Medicaid., Main Outcome Measure: The percentage of women aged 15-44 years with outpatient pharmacy claims for opioid prescriptions., Results: During 2013-2017, the proportion of women aged 15-44 years with private insurance who had claims for opioid prescriptions decreased by 22.1 percent, and among women enrolled in Medicaid, the proportion decreased by 31.5 -percent., Conclusions: Opioid prescription claims decreased from 2013 to 2017 among insured women of reproductive age. However, opioid prescription claims remained common and were more common among women enrolled in Medicaid than those with private insurance; additional strategies to improve awareness of the risks associated with opioid prescribing may be needed.

Pregnant women with opioid use disorder (OUD) are at risk of overdose, infectious diseases, and inadequate prenatal care. Additional risks include adverse pregnancy and infant outcomes, such as preterm birth and neonatal abstinence syndrome. Management and treatment of OUD during pregnancy are associated with improved maternal and infant outcomes. Professional organizations, including the American College of Obstetricians and Gynecologists, recommend offering opioid agonist pharmacotherapy ( i.e. , methadone or buprenorphine) combined with behavioral therapy as standard treatment for pregnant women with OUD. Other medications and herbal supplements have also been used by pregnant women for OUD. Determining which OUD treatments optimize maternal and infant outcomes is challenging given the host of potential factors that affect these outcomes. The Centers for Disease Control and Prevention initiated the MATernaL and Infant NetworK to Understand Outcomes Associated with Treatment of Opioid Use Disorder during Pregnancy (MAT-LINK) to monitor more than 2000 mothers and their infants, using data collected from geographically diverse clinical sites. Information learned from MAT-LINK will inform the future management and treatment of pregnant women with OUD.

Background: Medication use among pregnant women is widespread, despite limited evidence about the teratogenicity of most medications. Improved physician-patient communication about pregnancy-related medication safety has been identified as a strategy to address this critical issue; however, little is known about physicians' knowledge, attitudes, and practices that could inform tools for information access and sharing to support such communication. The primary objective of this study is to address gaps in what is known about obstetrician-gynecologist views, practices, and needs related to accessing and sharing pregnancy-related medication safety information with patients. Materials and Methods: The basis for this study is a nationally representative, randomized survey of 506 practicing obstetrician-gynecologists. The survey was completed by mail or online between October 26, 2015 and May 8, 2016 with a 52% response rate. Data were weighted to population parameters to reduce the risk of potential nonresponse biases. Analyses included univariate distributions and comparisons between physicians in different residency cohorts using all-pairs dependent t -tests. Results: Findings point to critical features of obstetrician-gynecologist access and sharing of medication safety information. Obstetrician-gynecologists often retrieve medication safety information during a clinical visit. There is widespread provision of potentially problematic "safe lists" to patients, particularly by younger cohorts, and limited counseling for reproductive-aged patients not actively planning a pregnancy. Conclusions: To improve clinical care, physician-patient communication may be enhanced with technical and policy solutions, including improved digital information tools for retrieving and discussing information in the clinical setting; evidence-based, written information for physicians to share with patients; and encouragement for counseling all women of reproductive age receiving teratogenic medications.

Introduction: Women and healthcare providers lack adequate information on medication safety during pregnancy. While resources describing fetal risk are available, information is provided in multiple locations, often with subjective assessments of available data. We developed a list of medications of greatest concern during pregnancy to help healthcare providers counsel reproductive-aged and pregnant women., Methods: Prescription drug labels submitted to the U.S. Food and Drug Administration with information in the Teratogen Information System (TERIS) and/or Drugs in Pregnancy and Lactation by Briggs & Freeman were included (N = 1,186 medications; 766 from three data sources, 420 from two). We used two supervised learning methods ('support vector machine' and 'sentiment analysis') to create prediction models based on narrative descriptions of fetal risk. Two models were created per data source. Our final list included medications categorized as 'high' risk in at least four of six models (if three data sources) or three of four models (if two data sources)., Results: We classified 80 prescription medications as being of greatest concern during pregnancy; over half were antineoplastic agents (n = 24), angiotensin converting enzyme inhibitors (n = 10), angiotensin II receptor antagonists (n = 8), and anticonvulsants (n = 7)., Discussion: This evidence-based list could be a useful tool for healthcare providers counseling reproductive-aged and pregnant women about medication use during pregnancy. However, providers and patients may find it helpful to weigh the risks and benefits of any pharmacologic treatment for both pregnant women and the fetus when managing medical conditions before and during pregnancy.

Background: The safety profile of antimicrobials used during pregnancy is one important consideration in the decision on how to treat and provide postexposure prophylaxis (PEP) for plague during pregnancy., Methods: We searched 5 scientific literature databases for primary sources on the safety of 9 antimicrobials considered for plague during pregnancy (amikacin, gentamicin, plazomicin, streptomycin, tobramycin, chloramphenicol, doxycycline, sulfadiazine, and trimethoprim-sulfamethoxazole [TMP-SMX]) and abstracted data on maternal, pregnancy, and fetal/neonatal outcomes., Results: Of 13 052 articles identified, 66 studies (case-control, case series, cohort, and randomized studies) and 96 case reports were included, totaling 27 751 prenatal exposures to amikacin (n = 9), gentamicin (n = 345), plazomicin (n = 0), streptomycin (n = 285), tobramycin (n = 43), chloramphenicol (n = 246), doxycycline (n = 2351), sulfadiazine (n = 870), and TMP-SMX (n = 23 602). Hearing or vestibular deficits were reported in 18/121 (15%) children and 17/109 (16%) pregnant women following prenatal streptomycin exposure. First trimester chloramphenicol exposure was associated with an elevated risk of an undescended testis (odds ratio [OR] 5.9, 95% confidence interval [CI] 1.2-28.7). Doxycycline was associated with cardiovascular malformations (OR 2.4, 95% CI 1.2-4.7) in 1 study and spontaneous abortion (OR 2.8, 95% CI 1.9-4.1) in a separate study. First trimester exposure to TMP-SMX was associated with increased risk of neural tube defects (pooled OR 2.5, 95% CI 1.4-4.3), spontaneous abortion (OR 3.5, 95% CI 2.3-5.6), preterm birth (OR 1.5, 95% CI 1.1-2.1), and small for gestational age (OR 1.6, 95% CI 1.2-2.2). No other statistically significant associations were reported., Conclusions: For most antimicrobials reviewed, adverse maternal/fetal/neonatal outcomes were not observed consistently. Prenatal exposure to streptomycin and TMP-SMX was associated with select birth defects in some studies. Based on limited data, chloramphenicol and doxycycline may be associated with adverse pregnancy or neonatal outcomes; however, more data are needed to confirm these associations. Antimicrobials should be used for treatment and PEP of plague during pregnancy; the choice of antimicrobials may be influenced by these data as well as information about the risks of plague during pregnancy., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

Objective: To examine the relationship between prenatal diagnostics (ultrasound examination and amniotic fluid Zika virus testing) and postnatal congenital Zika syndrome abnormalities., Data Sources: Systematic searches were performed in 27 databases, including ClinicalTrials.gov, from inception to July 1, 2019, for articles with the keywords "Zika," "prenatal," "ultrasound," and "amniocentesis.", Methods of Study Selection: A total of 3,049 unique records were identified. Two reviewers independently assessed titles, abstracts, and full texts for relevance; 84 articles met the inclusion criteria. These articles describe 402 mother-fetus or mother-neonate dyads; 385 were included in the review of prenatal ultrasound examination, and 56 in the review of amniocentesis (39 in both)., Tabulation, Integration, and Results: Among 195 fetuses with congenital Zika syndrome findings on prenatal ultrasound examination, postnatal congenital Zika syndrome abnormalities were reported for 153 (78%; 95% CI 7-84%). High proportions of microcephaly (76%; 95% CI 69-82%) and brain abnormalities (78%; 95% CI 69-86%) were confirmed postnatally. Among 190 fetuses without congenital Zika syndrome findings on prenatal ultrasound examination, 17% (95% CI 12-24%) had congenital Zika syndrome abnormalities identified postnatally. Structural congenital Zika syndrome abnormalities were identified postnatally in approximately equal proportions among dyads with and without Zika virus RNA detected in an amniotic fluid specimen (68% and 67%; 95% CI 52-82% and 95% CI 38-88%). In six pregnancies, Zika virus RNA was detected in amniotic fluid but not in a subsequent amniocentesis specimen., Conclusion: Prenatal ultrasound examination frequently detects structural findings associated with Zika virus infection; however, not all abnormalities are detected, and some may represent transient findings. As with other congenital infections, prenatal detection may vary with timing of infection, timing of ultrasound examination, technical expertise, and severity of abnormalities. The detection of Zika virus RNA in amniotic fluid in the included studies did not predict the risk for congenital Zika syndrome abnormalities in these cases, and clearance of Zika virus RNA from amniotic fluid appears possible after maternal infection. Diagnostic testing for Zika virus infection remains a shared decision between patients and clinicians, and more data are needed to define clinical predictors that will inform these decisions., Systematic Review Registration: PROSPERO, CRD42018080959.

Objective: The objective of this study was to examine the prevalence of, and maternal characteristics associated with, ADHD medication use before and during pregnancy, and associations between early pregnancy ADHD medication use and risk for 12 selected birth defects. Method: We used data from the National Birth Defects Prevention Study (1998-2011), a U.S. population-based case-control study examining risk factors for major structural birth defects. Results: There was an increase in ADHD medication use from 1998-1999 (0.2%) to 2010-2011 (0.5%; p < .001). Early pregnancy ADHD medication use was more commonly reported by mothers of infants/fetuses with gastroschisis (crude odds ratio [cOR]: 2.9, 95% confidence interval [CI] = [1.2, 6.9]), omphalocele (cOR: 4.0, 95% CI = [1.2, 13.6]), and transverse limb deficiency (cOR: 3.3, 95% CI = [1.1, 9.6]). Conclusion: ADHD medication use before and during pregnancy was rare, but the prevalence of use has increased over time. In this analysis, early pregnancy ADHD medication use was associated with three of 12 selected birth defects.

Purpose: To examine the prevalence of, and factors associated with, atypical antipsychotic use among U.S. pregnant women, and potential associations between early pregnancy atypical antipsychotic use and risk for 14 birth defects., Methods: We analyzed data from the National Birth Defects Prevention Study (1997-2011), a U.S. population-based case-control study examining risk factors for major structural birth defects., Results: Atypical antipsychotic use during pregnancy was more common among women with pre-pregnancy obesity, and women who reported illicit drug use before and during pregnancy, smoking during pregnancy, alcohol use during pregnancy, or use of other psychiatric medications during pregnancy. We observed elevated associations (defined as a crude odds ratio [cOR] ≥2.0) between early pregnancy atypical antipsychotic use and conotruncal heart defects (6 exposed cases; cOR: 2.3, 95% confidence interval [CI]: 0.9-6.1), and more specifically Tetralogy of Fallot (3 exposed cases; cOR: 2.5, 95% CI: 0.7-8.8), cleft palate (4 exposed cases, cOR: 2.5, 95% CI: 0.8-7.6), anorectal atresia/stenosis (3 exposed cases, cOR: 2.8, 95% CI: 0.8-9.9), and gastroschisis (3 exposed cases, cOR: 2.1, 95% CI: 0.6-7.3)., Conclusions: Our findings support the close clinical monitoring of pregnant women using atypical antipsychotics. Women treated with atypical antipsychotics generally access healthcare services before pregnancy; efforts to reduce correlates of atypical antipsychotic use might improve maternal and infant health in this population., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to report., (Published by Elsevier B.V.)

Use of some medications during pregnancy can be harmful to the developing fetus, and discussion of the risks and benefits with prenatal care providers can provide guidance to pregnant women. We used Pregnancy Risk Assessment Monitoring System data collected for 2015 births aggregated from 34 US states (n = 40,480 women) to estimate the prevalence of self-reported receipt of prenatal care provider counseling about medications safe to take during pregnancy. We examined associations between counseling and maternal characteristics using adjusted prevalence ratios (aPR). The prevalence of counseling on medications safe to take during pregnancy was 89.2% (95% confidence interval [CI]: 88.7-89.7). Women who were nulliparous versus multiparous (aPR 1.03; 95% CI: 1.02-1.04), who used prescription medications before pregnancy versus those who did not, (aPR 1.03; 95% CI: 1.02-1.05), and who reported having asthma before pregnancy versus those who did not, (aPR 1.05; 95% CI: 1.01-1.08) were more likely to report receipt of counseling. There was no difference in counseling for women with pre-pregnancy diabetes, hypertension, and/or depression compared to those without. Women who entered prenatal care after the first trimester were less likely to report receipt of counseling (aPR 0.93; 95% CI: 0.91-0.96). Overall, self-reported receipt of counseling was high, with some differences by maternal characteristics. Although effect estimates were small, it is important to ensure that information is available to prenatal care providers about medication safety during pregnancy, and that messages are communicated to women who are or might become pregnant., (Copyright © 2019. Published by Elsevier Inc.)

Background: Benzodiazepine medications can be used to treat anxiety, a condition affecting 15% of women of childbearing age in the United States. Studies have shown conflicting results for the association between benzodiazepine use during pregnancy and birth defects., Methods: We analyzed 1997-2011 data from the National Birth Defects Prevention Study, a multisite, population-based case-control study. We assessed the prevalence of and factors associated with benzodiazepine use in pregnancy among mothers of live-born infants without a birth defect (control mothers). We used logistic regression to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for the association between specific birth defects and benzodiazepine use; we estimated crude odds ratios (cORs) for defect categories with 3-4 exposed cases., Results: Exposure to benzodiazepines during pregnancy was rare (N = 93/11,614; 0.8%). Benzodiazepine use was more common among control mothers who were ≥30 years, non-Hispanic white, had more education, smoked, and took antidepressant medication. We observed significantly elevated ORs for any benzodiazepine and Dandy-Walker malformation (cOR: 3.1; 95% CI: 1.1, 8.6); for alprazolam and anophthalmia or microphthalmia (cOR: 4.0; 95% CI: 1.2, 13.1) and esophageal atresia or stenosis (aOR: 2.7; 95% CI: 1.2, 5.9); and lorazepam and pulmonary valve stenosis (cOR: 4.1; 95% CI: 1.2, 14.2), but sample sizes were limited and therefore CIs were wide., Conclusions: Our findings suggest that benzodiazepines use is rare and may be associated with risk for certain birth defects. However, these results need replication and should be interpreted with caution., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

We have learned much about the short-term sequelae of congenital Zika virus (ZIKV) infection since the Centers for Disease Control and Prevention activated its ZIKV emergency response in January 2016. Nevertheless, gaps remain in our understanding of the full spectrum of adverse health outcomes related to congenital ZIKV infection and how to optimize health in those who are affected. To address the remaining knowledge gaps, support affected children so they can reach their full potential, and make the best use of available resources, a carefully planned public health approach in partnership with pediatric health care providers is needed. An essential step is to use population-based data captured through surveillance systems to describe congenital Zika syndrome. Another key step is using collected data to investigate why some children exhibit certain sequelae during infancy and beyond, whereas others do not, and to describe the clustering of anomalies and the timing of when these anomalies occur, among other research questions. The final critical step in the public health framework for congenital Zika syndrome is an intervention strategy with evidence-based best practices for longer-term monitoring and care. Adherence to recommended evaluation and management procedures for infants with possible congenital ZIKV infection, including for those with less obvious developmental and medical needs at birth, is essential. It will take many years to fully understand the effects of ZIKV on those who are congenitally infected; however, the lifetime medical and educational costs as well as the emotional impact on affected children and families are likely to be substantial., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects individuals across the lifespan. ADHD medication use among pregnant women is increasing (1), but consensus about the safety of ADHD medication use during pregnancy is lacking. Given that nearly half of U.S. pregnancies are unintended (2), and early pregnancy is a critical period for fetal development, examining trends in ADHD medication prescriptions among reproductive-aged women is important to quantify the population at risk for potential exposure. CDC used the Truven Health MarketScan Commercial Database* for the period 2003-2015 to estimate the percentage of women aged 15-44 years with private employer-sponsored insurance who filled prescriptions for ADHD medications each year. The percentage of reproductive-aged women who filled at least one ADHD medication prescription increased 344% from 2003 (0.9% of women) to 2015 (4.0% of women). In 2015, the most frequently filled medications were mixed amphetamine salts, lisdexamfetamine, and methylphenidate. Prescribing ADHD medications to reproductive-aged women is increasingly common; additional research on ADHD medication safety during pregnancy is warranted to inform women and their health care providers about any potential risks associated with ADHD medication exposure before and during pregnancy., Competing Interests: No conflicts of interest were reported.

Objective To explore women's perceptions of the risks and benefits associated with medication use during pregnancy and to better understand how women make decisions related to medication use in pregnancy. Methods We conducted online focus groups with 48 women who used medication during pregnancy or while planning a pregnancy, and 12 in-depth follow-up interviews with a subset of these women. Results We found that women were aware of general risks associated with medication use but were often unable to articulate specific negative outcomes. Women were concerned most about medications' impact on fetal development but were also concerned about how either continuing or discontinuing medication during pregnancy could affect their own health. Women indicated that if the risk of a given medication were unknown, they would not take that medication during pregnancy. Conclusion This formative research found that women face difficult decisions about medication use during pregnancy and need specific information to help them make decisions. Enhanced communication between patients and their providers regarding medication use would help address this need. We suggest that public health practitioners develop messages to (1) encourage, remind, and prompt women to proactively talk with their healthcare providers about the risks of taking, not taking, stopping, or altering the dosage of a medication while trying to become pregnant and/or while pregnant; and (2) encourage all women of childbearing age to ask their healthcare providers about medication use.

Our study sought to explore the actual and potential roles of patients, physicians, and pharmacists, as well as their shared challenges and opportunities, in improving the safety of medication use during pregnancy. We conducted virtual focus groups with 48 women and in-depth interviews with nine physicians and five pharmacists. Qualitative analysis revealed that all three groups of participants reported "playing it safe," the need for an engaged patient making informed decisions, challenges surrounding communication about pregnancy status, and a lack of patient-centric resources. Patients, physicians, and pharmacists are highly motivated to protect developing babies from potential harms of medication use during pregnancy while maintaining the patient's health. Strategic messaging could maximize the effectiveness of these interactions by helping physicians discuss the benefits and risks of medication use during pregnancy, pharmacists screen for pregnancy and counsel on medication safety, and patients using medications to share pregnancy intentions with their providers pre-pregnancy.

Purpose: To compare the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and/or opioids to the use of acetaminophen without NSAIDs or opioids with respect to associations with birth defects., Methods: We used data from the National Birth Defects Prevention Study (1997-2011). Exposure was self-reported maternal analgesic use from the month before through the third month of pregnancy (periconceptional). Adjusted odds ratios (aORs) were calculated to examine associations with 16 birth defects., Results: Compared to acetaminophen, mothers reporting NSAIDs were significantly more likely to have offspring with gastroschisis, hypospadias, cleft palate, cleft lip with cleft palate, cleft lip without cleft palate, anencephaly, spina bifida, hypoplastic left heart syndrome, pulmonary valve stenosis, and tetralogy of Fallot (aOR range, 1.2-1.6). Opioids were associated with tetralogy of Fallot, perimembranous ventricular septal defect, and ventricular septal defect with atrial septal defect (aOR range, 1.8-2.3), whereas use of both opioids and NSAIDs was associated with gastroschisis, cleft palate, spina bifida, hypoplastic left heart syndrome, and pulmonary valve stenosis (aOR range, 2.0-2.9)., Conclusions: Compared to periconceptional use of acetaminophen, selected birth defects occurred more frequently among infants of women using NSAIDs and/or opioids. However, we could not definitely determine whether these risks relate to the drugs or to indications for treatment., (Published by Elsevier Inc.)

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., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2017 by the American Academy of Pediatrics.)

Neonatal abstinence syndrome (NAS) is a drug withdrawal syndrome that most commonly occurs in infants after in utero exposure to opioids, although other substances have also been associated with the syndrome (1). NAS usually appears within 48-72 hours of birth with a constellation of clinical signs, including central nervous system irritability (e.g., tremors), gastrointestinal dysfunction (e.g., feeding difficulties), and temperature instability (1) (Box 1). Opioid exposure during pregnancy might result from clinician-approved use of prescription opioids for pain relief; misuse or abuse of prescription opioids; illicit use (e.g., heroin); or medication-assisted treatment (MAT) of opioid use disorder (2) (Box 2).

Background: Little is known about the association between maternal autoimmune disease or its treatment and the risk of birth defects. We examined these associations using data from the National Birth Defects Prevention Study, a multi-site, population-based, case-control study., Methods: Analyses included 25,116 case and 9897 unaffected control infants with estimated delivery dates between 1997 and 2009. Information on autoimmune disease, medication use, and other pregnancy exposures was collected by means of telephone interview. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for birth defects with five or more exposed cases; crude ORs and exact 95% CIs were estimated for birth defects with three to four exposed cases., Results: Autoimmune disease was reported by 373 mothers (279 case and 94 control mothers). The majority of birth defects evaluated were not associated with autoimmune disease; however, a statistically significant association between maternal autoimmune disease and encephalocele was observed (OR, 4.64; 95% CI, 1.95-11.04). Eighty-two mothers with autoimmune disease used an immune modifying/suppressing medication during pregnancy; this was associated with encephalocele (OR, 7.26; 95% CI, 1.37-24.61) and atrial septal defects (OR, 3.01; 95% CI, 1.16-7.80)., Conclusion: Our findings suggest maternal autoimmune disease and treatment are not associated with the majority of birth defects, but may be associated with some defects, particularly encephalocele. Given the low prevalence of individual autoimmune diseases and the rare use of specific medications, we were unable to examine associations of specific autoimmune diseases and medications with birth defects. Other studies are needed to confirm these findings. Birth Defects Research (Part A) 106:950-962, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: Previous studies noted associations between birth defects and some antibiotics (e.g., nitrofurantoin, sulfonamides) but not others (e.g., penicillins). It is unclear if previous findings were due to antibiotic use, infections, or chance. To control for potential confounding by indication, we examined associations between antibiotic use and birth defects, among women reporting urinary tract infections (UTIs)., Methods: The National Birth Defects Prevention Study is a multi-site, population-based case-control study. Case infants/fetuses have any of over 30 major birth defects and controls are live-born infants without major birth defects. We analyzed pregnancies from 1997 to 2011 to estimate the association between maternally reported periconceptional (month before conception through the third month of pregnancy) use of nitrofurantoin, trimethoprim-sulfamethoxazole, or cephalosporins and specific birth defects, among women with periconceptional UTIs. Women with periconceptional UTIs who reported penicillin use served as the comparator., Results: Periconceptional UTIs were reported by 7.8% (2029/26,068) of case and 6.7% (686/10,198) of control mothers. Most (68.2% of case, 66.6% of control mothers) also reported antibiotic use. Among 608 case and 231 control mothers reporting at least one periconceptional UTI and certain antibiotic use, compared with penicillin, nitrofurantoin use was associated with oral clefts in the offspring (adjusted odds ratio, 1.97 [95% confidence interval, 1.10-3.53]), trimethoprim-sulfamethoxazole use with esophageal atresia (5.31 [1.39-20.24]) and diaphragmatic hernia (5.09 [1.20-21.69]), and cephalosporin use with anorectal atresia/stenosis (5.01 [1.34-18.76])., Conclusion: Periconceptional exposure to some antibiotics might increase the risk for certain birth defects. However, because individual birth defects are rare, absolute risks should drive treatment decisions.Birth Defects Research (Part A) 106:940-949, 2016.© 2016 Wiley Periodicals, Inc., Competing Interests: None of the authors have any conflicts of interest to disclose., (© 2016 Wiley Periodicals, Inc.)

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.

Background: When making decisions about medication use in pregnancy, women consult many information sources, including the Internet. The aim of this study was to assess the content of publicly accessible YouTube videos that discuss medication use in pregnancy., Methods: Using 2023 distinct combinations of search terms related to medications and pregnancy, we extracted metadata from YouTube videos using a YouTube video Application Programming Interface. Relevant videos were defined as those with a medication search term and a pregnancy-related search term in either the video title or description. We viewed relevant videos and abstracted content from each video into a database. We documented whether videos implied each medication to be "safe" or "unsafe" in pregnancy and compared that assessment with the medication's Teratogen Information System (TERIS) rating., Results: After viewing 651 videos, 314 videos with information about medication use in pregnancy were available for the final analyses. The majority of videos were from law firms (67%), television segments (10%), or physicians (8%). Selective serotonin reuptake inhibitors (SSRIs) were the most common medication class named (225 videos, 72%), and 88% of videos about SSRIs indicated that they were unsafe for use in pregnancy. However, the TERIS ratings for medication products in this class range from "unlikely" to "minimal" teratogenic risk., Conclusion: For the majority of medications, current YouTube video content does not adequately reflect what is known about the safety of their use in pregnancy and should be interpreted cautiously. However, YouTube could serve as a platform for communicating evidence-based medication safety information., (Copyright © 2015 John Wiley & Sons, Ltd.)

Many prescription medications have limited information regarding safety for use during pregnancy. In order to inform research on safer medication use during pregnancy, we examined prescription medication use among women in the United States. We analyzed data from the 1999-2006 National Health and Nutrition Examination Survey (NHANES) to estimate the prevalence of prescription medication use in the past 30 days among pregnant women and non-pregnant women of childbearing age (15-44 years) and to ascertain the most commonly reported prescription medications by women in these groups. We assessed how the most commonly reported medications differed among groups defined by selected demographic characteristics, including age, race/ethnicity, and markers of socioeconomic status. Prescription medication use in the past 30 days was reported by 22 % of pregnant women and 47 % of non-pregnant women of childbearing age. The most commonly reported prescription medications by NHANES participants differed somewhat by pregnancy status; allergy and anti-infective medications were more common among pregnant women, while oral contraceptives were more common among non-pregnant women. Use of prescription medication for asthma and thyroid disorders was reported by both groups. Although prescription medication use in the previous 30 days was less common among pregnant women than non-pregnant women, its use was reported among almost 1 in 4 pregnant women. Many of the most common medications reported were for the treatment of chronic medical conditions. Given the potential impact of medications on the developing fetus, our data underscore the importance of understanding the safety of these medications during pregnancy.

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.

To address information gaps that limit informed clinical decisions on medication use in pregnancy, the Centers for Disease Control and Prevention (CDC) solicited expert input on a draft prototype outlining a systematic approach to evaluating the quality and strength of existing evidence for associated risks. The draft prototype outlined a process for the systematic review of available evidence and deliberations by a panel of experts to inform clinical decision making for managing health conditions in pregnancy. At an expert meeting convened by the CDC in January 2013, participants divided into working groups discussed decision points within the prototype. This report summarizes their discussions of best practices for formulating an expert review process, developing evidence summaries and treatment guidance, and disseminating information. There is clear recognition of current knowledge gaps and a strong collaboration of federal partners, academic experts, and professional organizations willing to work together toward safer medication use during pregnancy., (Published by Elsevier Inc.)

Purpose: To investigate associations between maternal use of common medications and herbals during early pregnancy and risk for hypospadias in male infants., Methods: We used data from the National Birth Defects Prevention Study, a multi-site, population-based, case-control study. We analyzed data from 1537 infants with second-degree or third-degree isolated hypospadias and 4314 live-born male control infants without major birth defects, with estimated dates of delivery from 1997 to 2007. Exposure was reported use of prescription or over-the-counter medications or herbal products, from 1 month before to 4 months after conception. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression, adjusting for maternal age, race/ethnicity, education, pre-pregnancy body mass index, previous live births, maternal subfertility, study site, and year., Results: We assessed 64 medication and 24 herbal components. Maternal uses of most components were not associated with an increased risk of hypospadias. A new associations was observed for venlafaxine (aOR 2.4; 95%CI 1.0, 6.0) [Correction made here after initial online publication.]. The previously reported association for clomiphene citrate was confirmed (aOR 1.9; 95%CI 1.2, 3.0). Numbers were relatively small for exposure to other specific patterns of fertility agents, but elevated aORs were observed for the most common of them., Conclusions: Overall, findings were reassuring that hypospadias is not associated with most medication components examined in this analysis. New associations will need to be confirmed in other studies. Increased risks for hypospadias associated with various fertility agents raise the possibility of confounding by underlying subfertility., (Copyright © 2013 John Wiley & Sons, Ltd.)

Purpose: Medication use during pregnancy is common and increasing. Women are also increasingly getting healthcare information from sources other than their physicians., Methods: This report summarizes an environmental scan that identified 25 active Internet sites that list medications reported to be safe for use in pregnancy and highlights the inadequate evidence base and inconsistent guidance provided by these sites., Results: These lists included 245 different products, of which 103 unique components had been previously evaluated in terms of fetal risk by the Teratogen Information System (TERIS), a resource that assesses risk of birth defects after exposure under usual conditions by consensus of clinical teratology experts. For 43 (42%) of the 103 components that were listed as 'safe' on one or more of the Internet sites surveyed, the TERIS experts were unable to determine the fetal risk based on published scientific literature. For 40 (93%) of these 43, either no data were available to assess human fetal risk or the available data were limited., Conclusions: Women who see a medication on one of these 'safe' lists would be led to believe that there is no increased risk of birth defects resulting from exposure. Thus, women are being reassured that fetal exposure to these medications is safe even though a sufficient evidence base to determine the relative safety or risk does not exist., (Copyright © 2013 John Wiley & Sons, Ltd.)

Objective: Birth defects are a leading cause of infant mortality in the United States. Previous reports have highlighted black-white differences in overall infant mortality and infant mortality attributable to birth defects (IMBD). We evaluated the impact of gestational age on US racial/ethnic differences in IMBD., Methods: We estimated the rate of IMBD as the underlying cause of death using the period-linked birth/infant death data for US residents for January 2003 to December 2006. We excluded infants with missing gestational age, implausible values based on Alexander's index of birth weight for gestational age norms, or gestational ages <20 weeks or >44 weeks; we categorized gestational age into 3 groups: 20 to 33, 34 to 36, and 37 to 44 weeks. Using Poisson regression, we compared neonatal and postneonatal IMBD for infants of non-Hispanic black and Hispanic mothers with that for infants of non-Hispanic white mothers stratified by gestational age., Results: IMBD occurred in 12.2 per 10 000 live births. Among infants delivered at 37 to 44 weeks, blacks (and Hispanics, to a lesser degree) had significantly higher neonatal and postneonatal IMBD than whites; however, among infants delivered at 20 to 33 or 34 to 36 weeks, neonatal (but not postneonatal) IMBD was significantly lower among blacks compared with whites., Conclusions: Racial/ethnic differences in IMBD were not explained in these data by differences in gestational age. Further investigation should include an assessment of possible racial/ethnic differences in severity and/or access to timely diagnosis and management of birth defects.

Selected antiepileptic drugs (AEDs) increase the risk of birth defects. To assess the impact of influencing AED prescribing practices on spina bifida and cleft palate we searched the literature for estimates of the association between valproic acid or carbamazepine use during pregnancy and these defects and summarized the associations using meta-analyses. We estimated distributions of the prevalence of valproic acid and carbamazepine use among women of childbearing age based on analyses of four data sets. We estimated the attributable fractions and the number of children born with each defect that could be prevented annually in the United States if valproic acid and carbamazepine were not used during pregnancy. The summary odds ratio estimate for the association between valproic acid and spina bifida was 11.9 (95% uncertainty interval (UI): 4.0-21.2); for valproic acid and cleft palate 5.8 (95% UI: 3.3-9.5); for carbamazepine and spina bifida 3.6 (95% UI: 1.3-7.8); and for carbamazepine and cleft palate 2.4 (95% UI: 1.1-4.5) in the United States. Approximately 40 infants (95% UI: 10-100) with spina bifida and 35 infants (95% UI: 10-70) with cleft palate could be born without these defects each year if valproic acid were not used during pregnancy; 5 infants (95% UI: 0-15) with spina bifida and 5 infants (95% UI: 0-15) with cleft palate could be born without these defects each year if carbamazepine were not used during pregnancy. This modeling approach could be extended to other medications to estimate the impact of translating pharmacoepidemiologic data to evidence-based prenatal care practice., (Published 2011 Wiley-Liss, Inc.)

Objective: We examined whether maternal opioid treatment between 1 month before pregnancy and the first trimester was associated with birth defects., Study Design: The National Birth Defects Prevention Study (1997 through 2005) is an ongoing population-based case-control study. We estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIS) for birth defects categories with at least 200 case infants or at least 4 exposed case infants., Results: Therapeutic opioid use was reported by 2.6% of 17,449 case mothers and 2.0% of 6701 control mothers. Treatment was statistically significantly associated with conoventricular septal defects (OR, 2.7; 95% CI, 1.1-6.3), atrioventricular septal defects (OR, 2.0; 95% CI, 1.2-3.6), hypoplastic left heart syndrome (OR, 2.4; 95% CI, 1.4-4.1), spina bifida (OR, 2.0; 95% CI, 1.3-3.2), or gastroschisis (OR, 1.8; 95% CI, 1.1-2.9) in infants., Conclusion: Consistent with some previous investigations, our study shows an association between early pregnancy maternal opioid analgesic treatment and certain birth defects. This information should be considered by women and their physicians who are making treatment decisions during pregnancy., (Published by Mosby, Inc.)

Objective: The goal was to compare the frequency of children's antibiotic intake, emphasizing antibiotics with anti-Helicobacter pylori effects, in El Paso, Texas, and Juarez, Mexico., Methods: Hispanic children were enrolled prenatally at mother-child clinics in El Paso, and Juarez, in 1998-2000, to identify determinants of H pylori infection. During follow-up examinations targeted every 6 months from 6 to 84 months of age, caretakers reported medication use during the preceding interval. Courses of any systemic and H pylori-effective antibiotics were compared for US and Mexican children., Results: Antibiotic data were available for 602 children, from 2938 follow-up visits. Overall antibiotic intake was higher in Juarez, where 84% of children received > or = 1 course during the follow-up period (52% of visits), compared with El Paso, where 76% of children received > or = 1 course (40% of visits). In contrast, the intake of H pylori-effective antibiotics was higher in El Paso, where 65% of children received > or = 1 course during the follow-up period (27% of visits), compared with Juarez, where 44% of children received > or = 1 course (16% of visits). Of H pylori-effective courses, 94% contained amoxicillin and 2% each clarithromycin, metronidazole, and furazolidone; uses were primarily for throat and ear infections, diarrhea, and cold/flu., Conclusions: Pediatric antibiotic use was higher in Mexico than on the US side of the border. Apparent misuse of H pylori-effective antibiotics was more frequent in Juarez but also occurred in El Paso. Such misuse of antibiotics may lead to drug resistance and may impair the control of H pylori infection in this region.

Objective: We estimated the prevalence and patterns of herbal use among US women before and during pregnancy., Study Design: The National Birth Defects Prevention Study is an ongoing, population-based, case-control study. This analysis included 4239 women from 10 centers in the United States who delivered infants without major birth defects from 1998-2004., Results: The prevalence of reported herbal use 3 months before or during pregnancy was 10.9%. During pregnancy, prevalence was 9.4% and was highest in the first trimester. Higher prevalence was associated with age greater than 30 years and education greater than 12 years. Use varied considerably by state (5-17%). Ginger and ephedra were the most commonly reported products early in pregnancy; teas and chamomile were most commonly reported throughout pregnancy., Conclusion: Potentially 395,000 US births annually involve antenatal exposure to herbal products. Health care providers should inquire routinely about herbal use and educate patients about what little is known regarding risks of these products.

Purpose: Factors that determine persistence of untreated Helicobacter pylori (H. pylori) infection in childhood are not well understood. We estimated risk differences for the effect of incidental antibiotic exposure on the probability of a detected clearance at the next test after an initial detected H. pylori infection., Methods: The Pasitos Cohort Study (1998-2005) investigated predictors of H. pylori infection in children from El Paso, Texas, and Juarez, Mexico. Children were screened for infection at 6-month target intervals from 6 to 84 months of age, using the 13C-urea breath test corrected for body-size-dependent variation in CO2 production. Exposure was defined as courses of any systemic antibiotic (systemic) or those with anti-H. pylori action (HP-effective) reported for the interval between initial detected infection and next test. Binomial regression models included country of residence, mother's education, adequacy of prenatal care, age at infection, and interval between tests., Results: Of 205 children with a test result and antibiotic data following a detected infection, the number of children who took > or =1 course in the interval between tests was 74 for systemic and 33 for HP-effective. The proportion testing negative at the next test was 66% for 0 courses, 72% for > or =1 systemic course, and 79% for > or =1 HP-effective course. Adjusted risk differences (95%CI) for apparent clearance, comparing > or =1 to 0 courses were 10% (1-20%) for systemic and 11% (0-21%) for HP-effective., Conclusions: Incidental antibiotic exposure appears to influence the duration of childhood H. pylori infection but seems to explain only a small portion of spontaneous clearance., (Copyright 2009 John Wiley & Sons, Ltd.)

Orofacial clefts are among the most common types of birth defects, but their clinical presentation has not been well described in a geographically diverse US population. To describe the birth prevalence and phenotype of nonsyndromic clefts, we used data from the National Birth Defects Prevention Study (NBDPS), a multi-site, population-based, case-control study aimed at identifying genetic and environmental risk factors for birth defects. Included in the study were infants born during 1997-2004 with a cleft lip (CL), cleft lip with cleft palate (CLP), or cleft palate (CP). Infants with clefts associated with recognized single-gene disorders, chromosome abnormalities, holoprosencephaly, or amniotic band sequence were excluded. A total of 3,344 infants with nonsyndromic orofacial clefts were identified, including 751 with CL, 1,399 with CLP, and 1,194 with CP, giving birth prevalence estimates of 0.3, 0.5, and 0.4/1,000 live births, respectively. Among infants with CLP where cleft laterality was specified, about twice as many had unilateral vs. bilateral involvement, while for CL there were over 10 times as many with unilateral versus bilateral involvement. Involvement was most often left-sided. About one-quarter of infants with CP had Pierre Robin sequence. Over 80% of infants had an isolated orofacial cleft. Among infants with CL or CLP, heart, limb, and other musculoskeletal defects were most commonly observed, while heart, limb, and central nervous system defects were most common among infants with CP. Better understanding of the birth prevalence and phenotype may help guide clinical care as well as contribute to an improved understanding of pathogenesis.