Multi-chamber cardioids unravel human heart development and cardiac defects.

The number one cause of human fetal death are defects in heart development. Because the human embryonic heart is inaccessible and the impacts of mutations, drugs, and environmental factors on the specialized functions of different heart compartments are not captured by in vitro models, determining the underlying causes is difficult. Here, we established a human cardioid platform that recapitulates the development of all major embryonic heart compartments, including right and left ventricles, atria, outflow tract, and atrioventricular canal. By leveraging 2D and 3D differentiation, we efficiently generated progenitor subsets with distinct first, anterior, and posterior second heart field identities. This advance enabled the reproducible generation of cardioids with compartment-specific in vivo-like gene expression profiles, morphologies, and functions. We used this platform to unravel the ontogeny of signal and contraction propagation between interacting heart chambers and dissect how mutations, teratogens, and drugs cause compartment-specific defects in the developing human heart.

Discovery of DNA methylation signature in the peripheral blood of individuals with history of antenatal exposure to valproic acid.

PURPOSE: Valproic acid or valproate is an effective antiepileptic drug; however, embryonic exposure to valproate can result in a teratogenic disorder referred to as fetal valproate syndrome (FVS, OMIM #609442). Currently there are no diagnostic biomarkers for the condition. This study aims to define an episignature biomarker for teratogenic antenatal exposure to valproate. METHODS: DNA extracted from peripheral blood of individuals with teratogenic antenatal exposure to valproate was processed using DNA methylation microarrays. Subsequently, methylation profiling and construction of support vector machine classifiers were performed in R. RESULTS: Genomic DNA methylation analysis was applied, and a distinct DNA methylation profile was identified in the majority of affected individuals. This profile was used to develop a diagnostic episignature classifier. The valproate exposure episignature exhibited high sensitivity and specificity relative to a large reference dataset of unaffected controls and individuals with a wide spectrum of syndromic disorders with episignatures. Gene set enrichment analysis demonstrated an enrichment for terms associated with cell adhesion, including significant overrepresentation of the cadherin superfamily. CONCLUSION: This study provides evidence of a robust peripheral blood-based diagnostic epigenetic biomarker for a prenatal teratogenic disorder.

Prescription medication use during pregnancy in the United States from 2011 to 2020: trends and safety evidence.

BACKGROUND: Medication use during pregnancy has increased in the United States despite the lack of safety data for many medications. OBJECTIVE: This study aimed to inform research priorities by examining trends in medication use during pregnancy and identifying gaps in safety information on the most commonly prescribed medications. STUDY DESIGN: We identified population-based cohorts of commercially (MarketScan 2011-2020) and publicly (Medicaid Analytic eXtract/Transformed Medicaid Statistical Information System Analytic Files 2011-2018) insured pregnancies ending in live birth from 2 health care utilization databases. Medication use was based on filled prescriptions between the date of last menstrual period through delivery, as well as the period before the last menstrual period and during specific trimesters. We also included a cross-sectional representative sample of pregnancies ascertained by the National Health and Nutrition Examination Survey (2011-2020), with information on prescription medication use during the preceding month obtained through maternal interviews. Teratogen Information System was used to classify the available evidence on teratogenic risk. RESULTS: Among over 3 million pregnancies, the medications most commonly dispensed at any time during pregnancy were analgesics, antibiotics, and antiemetics. The top medications were ondansetron (16.8%), amoxicillin (13.5%), and azithromycin (12.4%) in MarketScan, nitrofurantoin (22.2%), acetaminophen (21.3%; mostly as part of acetaminophen-hydrocodone products), and ondansetron (19.5%) in Medicaid Analytic eXtract/Transformed Medicaid Statistical Information System Analytic Files, and levothyroxine (5.0%), sertraline (2.9%), and insulin (2.9%) in the National Health and Nutrition Examination Survey group. The most commonly dispensed suspected teratogens during the first trimester were antithyroid medications. The use of antidiabetic and psychotropic medications has continued to increase in the United States during the last decade, opioid dispensation has decreased by half, and antibiotics and antiemetics continue to be common. For one-quarter of medications, there is insufficient evidence available to characterize their safety profile in pregnancy. CONCLUSION: There is a need for more drug research in pregnant patients. Future research should focus on anti-infectives with high utilization and limited level of evidence on safety for use during pregnancy. Although lack of evidence is not evidence of safety concerns, it does not indicate risk either. In many instances, the benefits outweigh the risks when these medications are used clinically, and some of the medications with no proven safety may be necessary to treat patients.

Environmental Signals.

Environmental factors have long been known to play a role in the pathogenesis of congenital heart disease (CHD), but this has not been a major focus of research in the modern era. Studies of human exposures and animal models demonstrate that demographics (age, race, socioeconomic status), diseases (e.g., diabetes, hypertension, obesity, stress, infection, high altitude), recreational and therapeutic drug use, and chemical exposures are associated with an increased risk for CHD. Unfortunately, although studies suggest that exposures to these factors may cause CHD, in most cases, the data are not strong, are inconclusive, or are contradictory. Although most studies concentrate on the effects of maternal exposure, paternal exposure to some agents can also modify this risk. From a mechanistic standpoint, recent delineation of signaling and genetic controls of cardiac development has revealed molecular pathways that may explain the effects of environmental signals on cardiac morphogenesis and may provide further tools to study the effects of environmental stimuli on cardiac development. For example, environmental factors likely regulate cellular signaling pathways, transcriptional and epigenetic regulation, proliferation, and physiologic processes that can control the development of the heart and other organs. However, understanding of the epidemiology and risk of these exposures and the mechanistic basis for any effects on cardiac development remains incomplete. Further studies defining the relationship between environmental exposures and human CHD and the mechanisms involved should reveal strategies to prevent, diagnose, and treat CHD induced by environmental signals.

Prescription retinoid and contraception use in women in Australia: A population-based study.

BACKGROUND/OBECTIVES: Oral retinoids are teratogenic, and pregnancy avoidance is an important part of retinoid prescribing. Australia does not have a standardised pregnancy prevention programme for women using oral retinoids, and the contraception strategies for women who use oral retinoids are not well understood. The objectives were to determine trends in the use of prescription retinoids among Australian reproductive-aged women and whether women dispensed oral retinoids used contraception concomitantly. METHODS: This was a population-based study using Australian Pharmaceutical Benefits (PBS) dispensing claims for a random 10% sample of 15-44-year-old Australian women, 2013 - 2021. We described rates and annual trends in dispensing claims for PBS-listed retinoids and contraceptives. We also estimated concomitant oral retinoid and contraceptive use on the day of each retinoid dispensing and determined if there was a period of contraceptive treatment that overlapped. Estimates were then extrapolated to the national level. RESULTS: There were 1,545,800 retinoid dispensings to reproductive-aged women; 57.1% were oral retinoids. The rate of retinoid dispensing to reproductive-aged women increased annually, from 28 dispensings per 1000 population in 2013 to 41 per 1000 in 2021. The rate of oral retinoid dispensing doubled over the study period, from 14 dispensings per 1000 population in 2013 to 28 per 1000 in 2021, while topical retinoid dispensing did not change. Only 25% of oral retinoid dispensings had evidence of concomitant contraceptive use in 2021. CONCLUSIONS: Rates of oral retinoid dispensing have doubled among reproductive-aged women over the past decade. A large percentage of oral retinoid use does not appear to have concomitant contraception use, posing a risk of teratogenic effects in pregnancies.

Anxiety, aggression, reward sensitivity, and forebrain dopamine receptor expression in a laboratory rat model of early-life disadvantage.

Despite early-life disadvantage (ELD) in humans being a highly heterogenous construct, it consistently predicts negative neurobehavioral outcomes. The numerous environmental contributors and neural mechanisms underlying ELD remain unclear, though. We used a laboratory rat model to evaluate the effects of limited resources and/or heavy metal exposure on mothers and their adult male and female offspring. Dams and litters were chronically exposed to restricted (1-cm deep) or ample (4-cm deep) home cage bedding postpartum, with or without lead acetate (0.1%) in their drinking water from insemination through 1-week postweaning. Restricted-bedding mothers showed more pup-directed behaviors and behavioral fragmentation, while lead-exposed mothers showed more nestbuilding. Restricted bedding-raised male offspring showed higher anxiety and aggression. Either restricted bedding or lead exposure impaired goal-directed performance in a reinforcer devaluation task in females, whereas restricted bedding alone disrupted it in males. Lead exposure, but not limited bedding, also reduced sucrose reward sensitivity in a progressive ratio task in females. D1 and D2 receptor mRNA in the medial prefrontal cortex and nucleus accumbens (NAc) were each affected by the early-life treatments and differently between the sexes. Most notably, adult males (but not females) exposed to both early-life treatments had greatly increased D1 receptor mRNA in the NAc core. These results illuminate neural mechanisms through which ELD threatens neurobehavioral development and highlight forebrain dopamine as a factor.

Association between maternal use of spray formulations and offspring urological anomalies: The Japan Environment and Children's Study.

OBJECTIVE: Concerns exist regarding the effects of maternal inhalation of household products on fetal health. This study aimed to clarify the impact of maternal exposure to household products, including spray formulations, on urological anomalies in offspring up to the age of 1 year. METHODS: This study included data from 84 237 children from the Japan Environment and Children's Study, an ongoing nationwide cohort study. Using maternal self-report questionnaires, information on the use of organic solvents, waterproof sprays, insect-repellent sprays, insecticide sprays, and herbicides from implantation until the second or third trimester of pregnancy and data on urological anomalies were collected 1 year after delivery. RESULTS: Urological anomalies occurred in 799 infants. Multivariate logistic regression analysis adjusted for maternal age, pregnancy body mass index, gestational diabetes, pre-existing maternal kidney disease, and preterm birth revealed no association between maternal exposure to organic solvents and the prevalence of offspring urological anomalies. Nevertheless, we observed significant associations between waterproof spray use during pregnancy and urological anomalies in boys (odds ratio [OR]: 1.28, 95% confidence interval [CI]: 1.03-1.59) and between the use of insecticide spray during pregnancy and urological anomalies in girls (OR: 1.48, 95% CI: 0.98-2.22). Sub-analysis revealed significant associations between waterproof spray use during pregnancy and vesicoureteral reflux in boys (OR: 2.14, 95% CI: 1.02-4.49) and between the use of insecticide spray during pregnancy and hydronephrosis in girls (OR: 2.23, 95% CI: 1.11-4.47). CONCLUSION: Spray formulation use during pregnancy might increase the risk of urological anomalies in the offspring.

Valproate: Not All Boxed Warnings Are Created Equal.

OBJECTIVE: Valproate has undergone significant changes in labeling to the boxed warnings associated with it. This review will analyze evidence regarding the valproate-boxed warnings for teratogenicity, hepatotoxicity, and pancreatitis, with a particular emphasis on the fetal risk. DATA SOURCES: A review of Pubmed, Cochrane Central Register, Google Scholar, manufacturer websites, and product labeling was performed from 1963 to February 2022, using the following search terms: valproate, valproic acid, depakote, teratogenicity, birth defects, fetal risk, hepatotoxicity, and pancreatitis. Relevant English-language studies and those conduced in humans were considered. Product labeling was also reviewed. DATA SYNTHESIS: There is a significant fetal risk following in utero valproate exposure (risk of malformation development: 8.6% in 360 women in North America). Current labeling in the United States recommends co-prescribing effective contraception for women of childbearing age. The risk of hepatotoxicity and pancreatitis is much lower in the general population (1/20 000 and 1/40 000 patients, respectively) compared with those patients with certain risk factors who are taking valproate (1/500). CONCLUSIONS: Overstated monitoring recommendations for the potential risk of hepatotoxicity and pancreatitis distracts from a much more common and severe risk of fetal harm. Clinicians must be diligent about discussing this risk with patients and documenting when this discussion occurs. Changes to the current recommendations for monitoring of the boxed warnings associated with valproate therapy should be considered, such as more stringent monitoring requirements for the inherent fetal risk. This could be accomplished through a Risk Evaluation and Mitigation Strategy program or through institution-based policies and procedures. In addition, monitoring recommendations for the risk of hepatotoxicity and pancreatitis should account for contributing risk factors.

A systematic review on the effects of acrylamide and bisphenol A on the development of Drosophila melanogaster.

The current global scenario has instigated a steady upsurge of synthetic chemicals usage thereby creating a toxic environment unsuitable for animals and humans. Acrylamide and bisphenol A are some of the most common toxins found in the atmosphere due to their extensive involvement in numerous industrial processes. Acrylamide, an occupational hazard toxin has been known to cause severe nerve damage and peripheral neuronal damage in both animals and humans. General sources of acrylamide exposure are effluents from textile and paper industries, cosmetics, and thermally processed foods rich in starch. Bisphenol A (BPA) is generally found in food packaging materials, dental sealants, and plastic bottles. It is highly temperature-sensitive that can easily leach into the food products or humans on contact. The genotoxic and neurotoxic effects of acrylamide and bisphenol A have been widely researched; however, more attention should be dedicated to understanding the developmental toxicity of these chemicals. The developmental impacts of toxin exposure can be easily understood using Drosophila melanogaster as a model given considering its short life span and genetic homology to humans. In this review, we have discussed the toxic effects of acrylamide and BPA on the developmental process of Drosophila melanogaster.

[Otorhinolaryngological diseases in pregnancy-which drugs are approved?] / HNO-ärztliche Krankheitsbilder in der Schwangerschaft ­ welche Medikamente sind zulässig?

Between 1958 and 1961 approximately 10,000 children with severe deformities of extremities were born, whose mothers had taken the sedative thalidomide. Since then, drugs in pregnancy are applied with legitimate caution by the pharmaceutical industry, physicians and patients, although often accompanied by irrational panic. The pharmaceutical industry takes a legally safe position noting "contraindication" or at least "strict indication" in the consumer information. This transfers responsibility to the prescribing doctor. Even without drug therapy, the spontaneous malformation rate is approx. 3 to 4%. Concerning expectant mothers, a therapeutic nihilism may lead to a dramatic deterioration of the maternal disease, thereby causing high risks in fetal development. The aim of the present work is to present a structured "Guideline for Practice" of medication that can be used during pregnancy for treating medical conditions of the ear, nose and throat.

Reproductive health in an inpatient psychiatric unit: A retrospective chart review.

OBJECTIVE: The purpose of this study was to evaluate the degree to which reproductive health issues are discussed with women of child-bearing age on an inpatient psychiatric unit. We hypothesized that preconception care is limited, and that contraceptive status of patients is rarely elicited. For this sub-analysis, we focused on counseling related to potential impacts of psychotropic medications on pregnancy, and on contraceptive status, especially when prescribed teratogenic medications. METHODS: A retrospective search was conducted for women between the ages of 18 to 49 years at the time of admission, over a 6-month period. One hundred and forty-eight unique encounters were identified, and electronic charts were reviewed for information regarding: discharge medications, medication counseling, contraceptive use, pregnancy and relationship status, pregnancy history, nature of obstetrics and gynecology consults, substance use, and diagnoses. RESULTS: Almost a fifth (n = 29) of encounters included discharge on at least one potentially teratogenic medication and more than 50% had recent substance use. However, less than 10% of all encounters had documentation of contraceptive status and only one case had documented discussion of reproductive effects of medication; this despite the fact that roughly one third (33.8%) had at least one documented prior pregnancy and two patients were pregnant at the time of admission. CONCLUSION: Few women of reproductive age admitted to the inpatient psychiatric unit had chart-documented counseling on reproductive health, including known side effects of teratogenic medications. This indicates an urgent need for inclusion of reproductive health, including counseling on the risks and benefits of taking psychotropics during the peripartum period, into inpatient mental health care.

Prescription medicines with potential for foetal harm: dispensing before and during pregnancy in New Zealand, 2005-2015.

PURPOSE: This study describes dispensing of potentially teratogenic prescription medicines before and during pregnancy in New Zealand over the period 2005-2015. METHODS: Records in a national dispensing database were linked with the members of the New Zealand Pregnancy Cohort to determine the proportion of pregnancies with at least one dispensing of a Category D or X medicine, using the Australian pregnancy risk categorisation system. Exposure was examined from 270 days prior to conception through to the end of pregnancy. Pregnancy outcomes of D/X-exposed pregnancies were reviewed. RESULTS: In the study, 874,884 pregnancies were included. Overall, Category D and X medicines were dispensed during 4.3% and 0.058% of pregnancies, respectively. After excluding misoprostol, X exposure decreased to 0.035%. Generally, dispensing declined through the 270-day pre-pregnancy period and continued to decline throughout pregnancy. Dispensing of X medicines increased over the study timeframe, whereas dispensing of D medicines increased from 2005 to 2011 then declined slightly. Smokers were more likely than non-smokers to have been dispensed a D/X medicine, and compared with European women, Maori and Pacific women were less likely to have been dispensed a D/X medicine. Excluding misoprostol, pregnancies exposed to an X medicine were more likely than D/X-unexposed pregnancies to have ended in termination. CONCLUSION: Dispensing of potentially harmful medicines in pregnancy in New Zealand was low, particularly for Category X medicines. However, exposure did increase over the study timeframe. The inclusion of pregnancies that did not progress past early pregnancy better reflects population-level pregnancy exposure to potentially teratogenic medicines.

Isotretinoin: Still the cause of anxiety for teratogenicity.

Isotretinoin is known as a potent teratogenic agent. Pregnancy should be ruled out before isotretinoin is prescribed. In this study, we evaluated the fetal outcomes of pregnant women who had inadvertently been exposed to isotretinoin during or before pregnancy. We collected data of pregnant women who had admitted to the Teratology Information Service due to isotretinoin exposure. Data regarding medications and comorbidities were documented. Outcomes were grouped as: live births, stillbirths, live births with congenital malformations, induced abortions (due to fetal abnormalities), spontaneous abortions, and elective abortions. We found that three women had gone to elective abortions. Three babies were live born without birth defects, of which, maternal exposure periods were between 0 and 3 weeks, 9 and 10 weeks before last menstrual period. One woman, exposed to isotretinoin up to the fourth week of gestation, decided ongoing her pregnancy with no current drug-related complications. Although many risk management programs worldwide have been used to prevent isotretinoin-related teratogenicity, the results of the present study showed that women became pregnant during isotretinoin intake and opted for pregnancy termination. Attention should be paid to the risk management programs mandating effective contraceptions, in order to lessen the drug-related terminations.

Utilisation of teratogenic medicines before and during pregnancy in Australian women.

BACKGROUND: Given the potential hazards of teratogenic medicines, to a fetus exposed in utero, monitoring their use around pregnancy is imperative. AIM: To measure utilisation of teratogenic medicines (Therapeutic Goods Administration's category D or X) in women who gave birth in New South Wales, Australia, during pregnancy and the 24 months prior. MATERIALS AND METHODS: We used linked population-based datasets including dispensing and perinatal data for all deliveries in NSW between 2005 and 2012. We included pregnancies among concessional beneficiaries only, with complete ascertainment of dispensing claims. Pre-pregnancy and during-pregnancy periods were based on birth dates and gestational age. We determined prevalence of exposure using percent of pregnancies in which women had at least one dispensed teratogenic medicine in three-month time periods. RESULTS: The study included 191 588 pregnancies (145 419 women). Prevalence of exposure to D/X medicines anytime during pregnancy was 2.0% (<20 pregnancies category X), decreasing from pre-pregnancy (3.8-6.0%) to first trimester (1.5%), further decreasing in second and third trimesters (0.8% and 0.6% respectively). We observed large reductions in antibiotic prevalence but only modest reductions for psychotropics and antilipidemic agents (all category D). Our results suggest higher use of potentially teratogenic medicines (category D) than those strictly contraindicated for use (category X), during pregnancy. Overall, use was higher in the first trimester than the rest of pregnancy. The high prevalence of potentially contraindicated psychotropics in all three trimesters may suggest a higher benefit-to-risk ratio and warrants future research focusing on the reasons for their prescribing to pregnant women.

Aberrant DNA methylation as a diagnostic biomarker of diabetic embryopathy.

PURPOSE: Maternal diabetes is a known teratogen that can cause a wide spectrum of birth defects, collectively referred to as diabetic embryopathy (DE). However, the pathogenic mechanisms underlying DE remain uncertain and there are no definitive tests to establish the diagnosis. Here, we explore the potential of DNA methylation as a diagnostic biomarker for DE and to inform disease pathogenesis. METHODS: Bisulfite sequencing was used to identify gene regions with differential methylation between DE neonates and healthy infants born with or without prenatal exposure to maternal diabetes, and to investigate the role of allele-specific methylation at implicated sites. RESULTS: We identified a methylation signature consisting of 237 differentially methylated loci that distinguished infants with DE from control infants. These loci were found proximal to genes associated with Mendelian syndromes that overlap the DE phenotype (e.g., CACNA1C, TRIO, ANKRD11) or genes known to influence embryonic development (e.g., BRAX1, RASA3). Further, we identified allele-specific methylation (ASM) at 11 of these loci, within which 61.5% of ASM single-nucleotide variants are known expression quantitative trait loci (eQTLs). CONCLUSIONS: Our study suggests a role for aberrant DNA methylation and cis-sequence variation in the pathogenesis of DE and highlights the diagnostic potential of DNA methylation for teratogenic birth defects.

Vaginal antimycotics and the risk for spontaneous abortions.

BACKGROUND: Spontaneous abortions are the most common complication of pregnancy. Clotrimazole and miconazole are widely used vaginal-antimycotic agents used for the treatment of vulvovaginal candidiasis. A previous study has suggested an increased risk of miscarriage associated with these azoles, which may lead health professionals to refrain from their use even if clinically indicated. OBJECTIVE: The aim of the current study was to assess the risk for spontaneous abortions following first trimester exposure to vaginal antimycotics. STUDY DESIGN: A historical cohort study was conducted including all clinically apparent pregnancies that began from January 2003 through December 2009 and admitted for birth or spontaneous abortion at Soroka Medical Center, Clalit Health Services, Beer-Sheva, Israel. A computerized database of medication dispensation was linked with 2 computerized databases containing information on births and spontaneous abortions. Time-varying Cox regression models were constructed adjusting for mother's age, diabetes mellitus, hypothyroidism, obesity, hypercoagulable or inflammatory conditions, recurrent miscarriages, intrauterine contraceptive device, ethnicity, tobacco use, and the year of admission. RESULTS: A total of 65,457 pregnancies were included in the study: 58,949 (90.1%) ended with birth and 6508 (9.9%) with a spontaneous abortion. Overall, 3246 (5%) pregnancies were exposed to vaginal antimycotic medications until the 20th gestational week: 2712 (4.2%) were exposed to clotrimazole and 633 (1%) to miconazole. Exposure to vaginal antimycotics was not associated with spontaneous abortions as a group (crude hazard ratio, 1.11; 95% confidence interval, 0.96-1.29; adjusted hazard ratio, 1.11; 95% confidence interval, 0.96-1.29) and specifically for clotrimazole (adjusted hazard ratio, 1.05; 95% confidence interval, 0.89-1.25) and miconazole (adjusted hazard ratio, 1.34; 95% confidence interval, 0.99-1.80). Furthermore, no association was found between categories of dosage of vaginal antimycotics and spontaneous abortions. CONCLUSION: Exposure to vaginal antimycotics was not associated with spontaneous abortions.

Drug safety in pregnancy: the German Embryotox institute.

Since 1988, the German Embryotox institute combines individual counselling of pregnant women and their health care providers (HCP) with research on drug safety in pregnancy. In addition, Embryotox offers web-based information which covers the most important and most frequently requested pharmaceutical substances. In contrast to ready-made drug risk information in package leaflets and other product information, individual counselling considers different clinical settings such as (1) looking for a drug of choice or planning pregnancy under medication, (2) risk assessment of a particular drug that has already been taken during an (unplanned) pregnancy and (3) evaluation of an adverse pregnancy outcome in association with a particular medication. Using the three established developmental toxicants valproic acid, isotretinoin, and renin-angiotensin-aldosterone system (RAAS) inhibitors as an example, the need of detailed information is illustrated. Through the risk communication process, pregnancy outcome data are routinely collected by Embryotox. This approach uses the advantages of a pre-existing communication structure and of dealing with motivated responders. Engagement in the treatment plan facilitates receiving reliable data on drug exposure as well as detailed follow-up data. Based on these patient records, prospective datasets are evaluated in observational cohort studies in comparison to non-exposed control cohorts. In addition, retrospective datasets received as suspected adverse drug reactions from multiple German sources allow a screening for signals of teratogenicity and distinct patterns of developmental toxicity. Clinical expertise in specialties such as teratology, paediatrics, embryology, obstetrics and human genetics are required to ensure high-quality assessment of drug safety in pregnancy.

Drug prescribing during pregnancy in a central region of Italy, 2008-2012.

BACKGROUND: Drug consumption during pregnancy is a matter of concern, especially regarding drugs known or suspected to be teratogens. Little is known about drug use in pregnant women in Italy. The present study is aimed at examining the prevalence, and to detect potential inappropriateness of drug prescribing among pregnant women in Latium, a region of central Italy. METHODS: This retrospective study was conducted on a cohort of women aged 18-45 years who delivered between 2008 and 2012 in public hospitals. Women were enrolled through the Regional Birth Register. After linking the regional Health Information Systems and the Regional Drug Claims Register, women's clinical data and prescribed medications were analyzed. Italian Medicine Agency (AIFA) and US Food and Drug Administration (FDA) evidence were used to investigate inappropriate prescribing and teratogenic risk. RESULTS: Excluding vitamins and minerals, 80.6% (n = 153,079) of the women were prescribed at least one drug during pregnancy, with an average of 4.6 medications per pregnancy. Drugs for blood and hematopoietic organs were the most commonly prescribed (53.0%,), followed by anti-infectives for systemic use (50.7%). Among the inappropriate prescriptions, progestogen supplementation was given in 20.1% of pregnancies; teratogen drugs were prescribed in 0.8%, mostly angiotensin co-enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) (0.3%). CONCLUSIONS: In Latium, drugs are widely used in pregnancy. Prescriptions of inappropriate drugs are observed in more than a fifth of pregnancies, and teratogens are still used, despite their known risk. Continuous updates of information provided to practitioners and an increased availability of information to women might reduce inappropriate prescribing.

Patterns of Orofacial Clefting in New York City From 1983 to 2010: Trends by Racial Background, Birthplace, and Public Health Strategies.

OBJECTIVE: To determine the role of racial background, public health initiatives, and residence on the prevalence of orofacial clefts (OFCs) in New York City (NYC). DESIGN/METHODS: Retrospective review of OFC cases from the New York State Congenital Malformations Registry. PATIENTS/PARTICIPANTS: Patients born with an OFC and all live births to mothers residing in NYC between 1983 and 2010. MAIN OUTCOME MEASURES: Orofacial cleft birth prevalence by cleft type, race, and borough of maternal residence for each year and by time period around the implementation of public health interventions including folate supplementation. RESULTS: A total of 3557 cases were reviewed. The prevalence remained stable for cleft palate and cleft lip with or without cleft palate (CL ± P) in sequential time periods of the study. Among CL ± P cases, cleft lip prevalence decreased early in the study compared to increases in cleft lip and palate prevalence. For most years, the prevalence of OFCs was lower among African Americans than whites. A total of 12% to 26% of mothers in 4 of the NYC boroughs deliver outside of their borough of residence, choosing to give birth in Manhattan most often. No difference in OFC prevalence was shown in any of the 5 NYC boroughs. CONCLUSIONS: The period prevalence remained relatively stable during the time periods before and after the implementation of folate supplementation for OFCs in NYC. Prevalence of OFC subtypes was lower for most time periods during this study among African Americans compared to whites. Several factors may explain the choice of birthplace outside of the mother's borough of residence.