Detection and evaluation of signals associated with exposure to individual and combination of medications in pregnancy: a signal detection study protocol.

INTRODUCTION: Considering the high prevalence of polypharmacy in pregnant women and the knowledge gap in the risk-benefit safety profile of their often-complex treatment plan, more research is needed to optimise prescribing. In this study, we aim to detect adverse and protective effect signals of exposure to individual and pairwise combinations of medications during pregnancy. METHODS AND ANALYSIS: Using a range of real-world data sources from the UK, we aim to conduct a pharmacovigilance study to assess the safety of medications prescribed during the preconception period (3 months prior to conception) and first trimester of pregnancy. Women aged between 15 and 49 years with a record of pregnancy within the Clinical Practice Research Datalink (CPRD) Pregnancy Register, the Welsh Secure Anonymised Information Linkage (SAIL), the Scottish Morbidity Record (SMR) data sets and the Northern Ireland Maternity System (NIMATS) will be included. A series of case control studies will be conducted to estimate measures of disproportionality, detecting signals of association between a range of pregnancy outcomes and exposure to individual and combinations of medications. A multidisciplinary expert team will be invited to a signal detection workshop. By employing a structured framework, signals will be transparently assessed by each member of the team using a questionnaire appraising the signals on aspects of temporality, selection, time and measurement-related biases and confounding by underlying disease or comedications. Through group discussion, the expert team will reach consensus on each of the medication exposure-outcome signal, thereby excluding spurious signals, leaving signals suggestive of causal associations for further evaluation. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Independent Scientific Advisory Committee, SAIL Information Governance Review Panel, University of St. Andrews Teaching and Research Ethics Committee and Office for Research Ethics Committees Northern Ireland (ORECNI) for access and use of CPRD, SAIL, SMR and NIMATS data, respectively.

The development of a core outcome set for studies of pregnant women with multimorbidity.

BACKGROUND: Heterogeneity in reported outcomes can limit the synthesis of research evidence. A core outcome set informs what outcomes are important and should be measured as a minimum in all future studies. We report the development of a core outcome set applicable to observational and interventional studies of pregnant women with multimorbidity. METHODS: We developed the core outcome set in four stages: (i) a systematic literature search, (ii) three focus groups with UK stakeholders, (iii) two rounds of Delphi surveys with international stakeholders and (iv) two international virtual consensus meetings. Stakeholders included women with multimorbidity and experience of pregnancy in the last 5 years, or are planning a pregnancy, their partners, health or social care professionals and researchers. Study adverts were shared through stakeholder charities and organisations. RESULTS: Twenty-six studies were included in the systematic literature search (2017 to 2021) reporting 185 outcomes. Thematic analysis of the focus groups added a further 28 outcomes. Two hundred and nine stakeholders completed the first Delphi survey. One hundred and sixteen stakeholders completed the second Delphi survey where 45 outcomes reached Consensus In (≥70% of all participants rating an outcome as Critically Important). Thirteen stakeholders reviewed 15 Borderline outcomes in the first consensus meeting and included seven additional outcomes. Seventeen stakeholders reviewed these 52 outcomes in a second consensus meeting, the threshold was ≥80% of all participants voting for inclusion. The final core outcome set included 11 outcomes. The five maternal outcomes were as follows: maternal death, severe maternal morbidity, change in existing long-term conditions (physical and mental), quality and experience of care and development of new mental health conditions. The six child outcomes were as follows: survival of baby, gestational age at birth, neurodevelopmental conditions/impairment, quality of life, birth weight and separation of baby from mother for health care needs. CONCLUSIONS: Multimorbidity in pregnancy is a new and complex clinical research area. Following a rigorous process, this complexity was meaningfully reduced to a core outcome set that balances the views of a diverse stakeholder group.

The burden, prevention and care of infants and children with congenital anomalies in sub-Saharan Africa: A scoping review.

The aim of this scoping review was to determine the scope, objectives and methodology of contemporary published research on congenital anomalies (CAs) in sub-Saharan Africa (SSA), to inform activities of the newly established sub-Saharan African Congenital Anomaly Network (sSCAN). MEDLINE was searched for CA-related articles published between January 2016 and June 2021. Articles were classified into four main areas (public health burden, surveillance, prevention, care) and their objectives and methodologies summarized. Of the 532 articles identified, 255 were included. The articles originated from 22 of the 49 SSA countries, with four countries contributing 60% of the articles: Nigeria (22.0%), Ethiopia (14.1%), Uganda (11.7%) and South Africa (11.7%). Only 5.5% of studies involved multiple countries within the region. Most articles included CA as their primary focus (85%), investigated a single CA (88%), focused on CA burden (56.9%) and care (54.1%), with less coverage of surveillance (3.5%) and prevention (13.3%). The most common study designs were case studies/case series (26.6%), followed by cross-sectional surveys (17.6%), retrospective record reviews (17.3%), and cohort studies (17.2%). Studies were mainly derived from single hospitals (60.4%), with only 9% being population-based studies. Most data were obtained from retrospective review of clinical records (56.1%) or via caregiver interviews (34.9%). Few papers included stillbirths (7.5%), prenatally diagnosed CAs (3.5%) or terminations of pregnancy for CA (2.4%).This first-of-a-kind-scoping review on CA in SSA demonstrated an increasing level of awareness and recognition among researchers in SSA of the contribution of CAs to under-5 mortality and morbidity in the region. The review also highlighted the need to address diagnosis, prevention, surveillance and care to meet Sustainable Development Goals 3.2 and 3.8. The SSA sub-region faces unique challenges, including fragmentation of efforts that we hope to surmount through sSCAN via a multidisciplinary and multi-stakeholder approach.

Polypharmacy during pregnancy and associated risk factors: a retrospective analysis of 577 medication exposures among 1.5 million pregnancies in the UK, 2000-2019.

BACKGROUND: The number of medications prescribed during pregnancy has increased over the past few decades. Few studies have described the prevalence of multiple medication use among pregnant women. This study aims to describe the overall prevalence over the last two decades among all pregnant women and those with multimorbidity and to identify risk factors for polypharmacy in pregnancy. METHODS: A retrospective cohort study was conducted between 2000 and 2019 using the Clinical Practice Research Datalink (CPRD) pregnancy register. Prescription records for 577 medication categories were obtained. Prevalence estimates for polypharmacy (ranging from 2+ to 11+ medications) were presented along with the medications commonly prescribed individually and in pairs during the first trimester and the entire pregnancy period. Logistic regression models were performed to identify risk factors for polypharmacy. RESULTS: During the first trimester (812,354 pregnancies), the prevalence of polypharmacy ranged from 24.6% (2+ medications) to 0.1% (11+ medications). During the entire pregnancy period (774,247 pregnancies), the prevalence ranged from 58.7 to 1.4%. Broad-spectrum penicillin (6.6%), compound analgesics (4.5%) and treatment of candidiasis (4.3%) were commonly prescribed. Pairs of medication prescribed to manage different long-term conditions commonly included selective beta 2 agonists or selective serotonin re-uptake inhibitors (SSRIs). Risk factors for being prescribed 2+ medications during the first trimester of pregnancy include being overweight or obese [aOR: 1.16 (1.14-1.18) and 1.55 (1.53-1.57)], belonging to an ethnic minority group [aOR: 2.40 (2.33-2.47), 1.71 (1.65-1.76), 1.41 (1.35-1.47) and 1.39 (1.30-1.49) among women from South Asian, Black, other and mixed ethnicities compared to white women] and smoking or previously smoking [aOR: 1.19 (1.18-1.20) and 1.05 (1.03-1.06)]. Higher and lower age, higher gravidity, increasing number of comorbidities and increasing level of deprivation were also associated with increased odds of polypharmacy. CONCLUSIONS: The prevalence of polypharmacy during pregnancy has increased over the past two decades and is particularly high in younger and older women; women with high BMI, smokers and ex-smokers; and women with multimorbidity, higher gravidity and higher levels of deprivation. Well-conducted pharmaco-epidemiological research is needed to understand the effects of multiple medication use on the developing foetus.

A population-based matched cohort study of major congenital anomalies following COVID-19 vaccination and SARS-CoV-2 infection.

Evidence on associations between COVID-19 vaccination or SARS-CoV-2 infection and the risk of congenital anomalies is limited. Here we report a national, population-based, matched cohort study using linked electronic health records from Scotland (May 2020-April 2022) to estimate the association between COVID-19 vaccination and, separately, SARS-CoV-2 infection between six weeks pre-conception and 19 weeks and six days gestation and the risk of [1] any major congenital anomaly and [2] any non-genetic major congenital anomaly. Mothers vaccinated in this pregnancy exposure period mostly received an mRNA vaccine (73.7% Pfizer-BioNTech BNT162b2 and 7.9% Moderna mRNA-1273). Of the 6731 babies whose mothers were vaccinated in the pregnancy exposure period, 153 had any anomaly and 120 had a non-genetic anomaly. Primary analyses find no association between any vaccination and any anomaly (adjusted Odds Ratio [aOR] = 1.01, 95% Confidence Interval [CI] = 0.83-1.24) or non-genetic anomalies (aOR = 1.00, 95% CI = 0.81-1.22). Primary analyses also find no association between SARS-CoV-2 infection and any anomaly (aOR = 1.02, 95% CI = 0.66-1.60) or non-genetic anomalies (aOR = 0.94, 95% CI = 0.57-1.54). Findings are robust to sensitivity analyses. These data provide reassurance on the safety of vaccination, in particular mRNA vaccines, just before or in early pregnancy.

Breastfeeding, pregnancy, medicines, neurodevelopment, and population databases: the information desert.

BACKGROUND: The pharmacoepidemiology of the long-term benefits and harms of medicines in pregnancy and breastfeeding has received little attention. The impact of maternal medicines on children is increasingly recognised as a source of avoidable harm. The focus of attention has expanded from congenital anomalies to include less visible, but equally important, outcomes, including cognition, neurodevelopmental disorders, educational performance, and childhood ill-health. Breastfeeding, whether as a source of medicine exposure, a mitigator of adverse effects or as an outcome, has been all but ignored in pharmacoepidemiology and pharmacovigilance: a significant 'blind spot'. WHOLE-POPULATION DATA ON BREASTFEEDING: WHY WE NEED THEM: Optimal child development and maternal health necessitate breastfeeding, yet little information exists to guide families regarding the safety of medicine use during lactation. Breastfeeding initiation or success may be altered by medicine use, and breastfeeding may obscure the true relationship between medicine exposure during pregnancy and developmental outcomes. Absent or poorly standardised recording of breastfeeding in most population databases hampers analysis and understanding of the complex relationships between medicine, pregnancy, breastfeeding and infant and maternal health. The purpose of this paper is to present the arguments for breastfeeding to be included alongside medicine use and neurodevelopmental outcomes in whole-population database investigations of the harms and benefits of medicines during pregnancy, the puerperium and postnatal period. We review: 1) the current situation, 2) how these complexities might be accommodated in pharmacoepidemiological models, using antidepressants and antiepileptics as examples; 3) the challenges in obtaining comprehensive data. CONCLUSIONS: The scarcity of whole-population data and the complexities of the inter-relationships between breastfeeding, medicines, co-exposures and infant outcomes are significant barriers to full characterisation of the benefits and harms of medicines during pregnancy and breastfeeding. This makes it difficult to answer the questions: 'is it safe to breastfeed whilst taking this medicine', and 'will this medicine interfere with breastfeeding and/ or infants' development'?

Prevalence and trends of congenital heart defects among live births from 2005 to 2014 in Northern Ireland.

RATIONALE: Congenital heart defects (CHD) are the most frequent group of congenital anomalies representing a significant burden of mortality and morbidity and health service load. OBJECTIVE: In the Northern Ireland population, served by a single paediatric cardiology centre, we determine the prevalence and trends of CHD among live births. METHODS: This is a descriptive cross-sectional population-based study, using the paediatric cardiology database. The study included a total of 245,120 live births representing all children born in Northern Ireland 2005-2014. RESULTS: A total of 11,410 children (4.65% of live births in Northern Ireland) received an echocardiogram for suspected CHD, and 3,059 children were subsequently diagnosed with a major CHD (prevalence = 12.48 per 1,000 live births (95% CI 12.04-12.93)) of whom 490 (16.02%) had genetic or chromosomal disorders including Down syndrome. The prevalence of non-genetic or chromosomal cases was 10.48 per 1,000 live births (95% CI 10.08-10.89) and did not change significantly over time (p = 0.91). The prevalence of CHD diagnosed in the first year of life was 8.46 per 1,000 live births (95% CI 8.10-8.83), which increased over time (p < 0.01). The prevalence of severe CHD was 2.02 per 1,000 live births (95% CI 1.85-2.21). CONCLUSION: Northern Ireland has a high prevalence of CHD among European countries, which may be associated with complete ascertainment of both early and late diagnosed cases recorded in the paediatric cardiology database, as well as being one of the few European countries where terminations of pregnancy for foetal anomaly was illegal during the study period.

Sociodemographic variation in prescriptions dispensed in early pregnancy in Northern Ireland 2010-2016.

AIM: To establish the prevalence of prescriptions dispensed in early pregnancy by maternal age and area deprivation, for women who gave birth in Northern Ireland (NI) 2011-2016. STUDY DESIGN: Population-based linked cohort study. METHODS: The NI Maternity System (NIMATS) database was used to identify all births to resident mothers in NI between 2011 and 2016. Prescriptions dispensed between the last menstrual period (LMP) and the first antenatal care visit (mean 10.7 weeks) (2010-2016) were extracted from the Enhanced Prescribing Database (EPD) which records all prescriptions dispensed by pharmacists in NI. EPD data were linked to NIMATS using the mother's Health and Care Number. Maternal deprivation based on the NI Multiple Deprivation Measure 2017 was linked using the mother's postcode. RESULTS: The cohort included 139,687 pregnancies resulting in live or stillbirths to 106,206 women. A medication was dispensed in 63.5% of pregnancies, and in 48.7% of pregnancies excluding supplements (vitamins, iron, and folic acid). Folic acid was the most commonly dispensed medication (33.1%). Excluding supplements, the mean number of medications was 1.1, with 4.2% having ≥5 medications. The most common non-supplement medications were antibiotics (13.1%), antiemetics (8.7%), analgesics (6.9%), hormonal medications (6.9%) and antidepressants (6.1%). Younger women (<20 years) had more antibiotics while older women (40+ years) had more antidepressants, cardiovascular, antihypertensives, anticoagulant medications and thyroxine. The proportion of women living in the most deprived areas with prescriptions for antidepressants, sedatives, tranquilisers, analgesics, and anti-epileptic medications was double the proportion of women with these medications in the least deprived areas. CONCLUSION: Half of all pregnant women in NI were dispensed a non-supplement medication between LMP and the first antenatal care visit. Younger and older mothers and those living in the most deprived areas were more likely to have medications dispensed. More antidepressants were dispensed in areas of social deprivation.

Surveillance of ARV safety in pregnancy and breastfeeding: towards a new framework.

INTRODUCTION: As new antiretrovirals (ARVs), including long-acting ARVs for treatment and prevention, are approved and introduced, surveillance during pregnancy must become the safety net for evaluating birth outcomes, especially those that are rare and require large numbers of observations. Historically, drug pharmacovigilance in pregnancy has been limited and fragmented between different data sources, resulting in inadequate data to assess risk. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network and World Health Organization convened a Workshop which reviewed strengths and weaknesses of existing programs and discussed an improved framework to integrate existing safety data sources and promote harmonization and digitalization. DISCUSSION: This paper highlights that although robust sources of safety data and surveillance programs exist, key challenges remain, including unknown denominators, reporting bias, under-reporting (e.g. in voluntary registries), few data sources from resource-limited settings (most are in North America and Europe), incomplete or inaccurate data (e.g. within routine medical records). However, recent experiences (e.g. with safety signals) and current innovations (e.g. electronic record use in resource-limited settings and defining adverse outcomes) provide momentum and building blocks for a new framework for active surveillance of ARV safety in pregnancy. A public health approach should be taken using data from existing sources, including registries of pregnancy ARV exposure and birth defects; observational surveillance and cohort studies; clinical trials; and real-world databases. Key facilitators are harmonization and standardization of outcomes, sharing of materials and tools, and data linkages between programs. Other key facilitators include the development of guidance to estimate sample size and duration of surveillance, ensuring strategic geographic diversity, bringing partners together to share information and engaging the community of women living with HIV. CONCLUSIONS: Looking ahead, critical steps to safely introduce new ARVs include (1) adopting harmonized standards for measuring adverse maternal, birth and infant outcomes; (2) establishing surveillance centres of excellence in areas with high HIV prevalence with harmonized data collection and optimized electronic health records linking maternal/infant data; and (3) creating targets and evaluation goals for reporting progress on implementation and quality of surveillance in pregnancy. The platform will be leveraged to ensure that appropriate contributions and strategic actions by relevant stakeholders are implemented.

COVID-19 in pregnancy-what study designs can we use to assess the risk of congenital anomalies in relation to COVID-19 disease, treatment and vaccination?

BACKGROUND: The COVID-19 pandemic has accelerated pregnancy outcome research, but little attention has been given specifically to the risk of congenital anomalies (CA) and first trimester exposures. OBJECTIVES: We reviewed the main data sources and study designs used internationally, particularly in Europe, for CA research, and their strengths and limitations for investigating COVID-19 disease, medications and vaccines. POPULATION: We classify research designs based on four data sources: a) spontaneous adverse event reporting, where study subjects are positive for both exposure and outcome, b) pregnancy exposure registries, where study subjects are positive for exposure, c) congenital anomaly registries, where study subjects are positive for outcome and d) population healthcare data where the entire population of births is included, irrespective of exposure and outcome. STUDY DESIGN: Each data source allows different study designs, including case series, exposed pregnancy cohorts (with external comparator), ecological studies, case-control studies and population cohort studies (with internal comparator). METHODS: The quality of data sources for CA studies is reviewed in relation to criteria including diagnostic accuracy of CA data, size of study population, inclusion of terminations of pregnancy for foetal anomaly, inclusion of first trimester COVID-19-related exposures and use of an internal comparator group. Multinational collaboration models are reviewed. RESULTS: Pregnancy exposure registries have been the main design for COVID-19 pregnancy studies, but lack detail regarding first trimester exposures relevant to CA, or a suitable comparator group. CA registries present opportunities for improving diagnostic accuracy in COVID-19 research, especially when linked to other data sources. Availability of inpatient hospital medication use in population healthcare data is limited. More use of ongoing mother-baby linkage systems would improve research efficiency. Multinational collaboration delivers statistical power. CONCLUSIONS: Challenges and opportunities exist to improve research on CA in relation to the COVID-19 pandemic and future pandemics.

Prevalence, determinants and attitude towards herbal medicine use in the first trimester of pregnancy in Cameroon: A survey in 20 hospitals.

To examine the prevalence, determinants and attitude towards herbal medication (HM) use in the first trimester of pregnancy in Cameroon women. Between March to August 2015, we surveyed 795 pregnant women attending 20 randomly selected urban or rural hospitals in South West Cameroon on first trimester orthodox medication (OM) and HM use. Data was obtained by interviews using structured questionnaires. First trimester HM use was reported by 293 (36∙9%) women, 76% of whom used it in combination with OM. The most frequent indication for taking HM was prevention/treatment of anaemia (26∙3%). The HM were usually self-prescribed (33∙3%) or by family (56∙2%), and obtained from the woman's own garden (69∙3%). Twenty percent of women believed that HM was always safe to take in pregnancy, compared to 69.3% for OM. Intake of HM was significantly influenced by women's opinion on OM or HM safety-the odds of taking HM was 3 time higher among women who were unsure about the safety of OM (AOR: 3∙0, 95%CI = 1∙5-6∙1), while women who thought HM were never safe or who were unsure about its safety, were 91% or 84% respectively less likely to take HM compared to women who believed HM were always safe. We identified a high prevalence of HM use and concomitant use with OM, strongly influenced by women's perception of HM and OM safety. These findings indicate the need for WHO to specifically address safety in pregnancy in its policy to integrate traditional medicine use into existing healthcare systems in Africa.

Prevalence of microcephaly: the Latin American Network of Congenital Malformations 2010-2017.

Objective: The Latin American Network of Congenital Malformations: ReLAMC was established in 2017 to provide accurate congenital anomaly surveillance. This study used data from ReLAMC registries to quantify the prevalence of microcephaly from 2010 to 2017 (before, during and after the Zika virus epidemic). Design: Nine ReLAMC congenital anomaly registries provided case-level data or aggregate data for any live births, still births or terminations of pregnancy with microcephaly. Births to pregnant women infected with Zika virus first occurred in Brazil in 2015, and in the remaining registry areas in 2016 with the exception of Chile that did not experience Zika virus. Therefore the prevalence of microcephaly for 2010-2014 and individual years 2015, 2016 and 2017 was estimated using multilevel random effect Poisson models. Clinical classification and characteristics of the cases were compared pre and post Zika for all centres providing individual case-level data. Results: The prevalence of microcephaly for all registries excluding Brazil was 2.3 per 10 000 (95% CI 2.0 to 2.6) for 2010-2014 rising to 5.4 (95% CI 4.8 to 6.0) in 2016 and 5.9 (95% CI 5.3 to 6.6) in 2017. Brazil had a prevalence of 0.6 per 10 000 (95% CI 0.5 to 0.6) in 2010-2014, rising to 5.8 (95% CI 5.6 to 6.1) in 2015, 8.0 (95% CI 7.6 to 8.3) in 2016 and then falling in 2017. Only 29 out of 687 cases of microcephaly were reported as congenital Zika syndrome in countries excluding Brazil. Conclusions: The prevalence of microcephaly was influenced both by Zika causing congenital Zika syndrome and by increased reporting awareness.

Signal Detection in EUROmediCAT: Identification and Evaluation of Medication-Congenital Anomaly Associations and Use of VigiBase as a Complementary Source of Reference.

INTRODUCTION: Knowledge on the safety of medication use during pregnancy is often sparse. Pregnant women are generally excluded from clinical trials, and there is a dependence on post-marketing surveillance to identify teratogenic medications. AIMS: This study aimed to identify signals of potentially teratogenic medications using EUROmediCAT registry data on medication exposure in pregnancies with a congenital anomaly, and to investigate the use of VigiBase reports of adverse events of medications in the evaluation of these signals. METHODS: Signals of medication-congenital anomaly associations were identified in EUROmediCAT (21,636 congenital anomaly cases with 32,619 medication exposures), then investigated in a subset of VigiBase (45,749 cases and 165,121 exposures), by reviewing statistical reporting patterns and VigiBase case reports. Evidence from the literature and quantitative and qualitative aspects of both datasets were considered before recommending signals as warranting further independent investigation. RESULTS: EUROmediCAT analysis identified 49 signals of medication-congenital anomaly associations. Incorporating investigation in VigiBase and the literature, these were categorised as follows: four non-specific medications; 11 likely due to maternal disease; 11 well-established teratogens; two reviewed in previous EUROmediCAT studies with limited additional evidence; and 13 with insufficient basis for recommending follow-up. Independent investigations are recommended for eight signals: pregnen (4) derivatives with limb reduction; nitrofuran derivatives with cleft palate and patent ductus arteriosus; salicylic acid and derivatives with atresia or stenosis of other parts of the small intestine and tetralogy of Fallot; carbamazepine with atrioventricular septal defect and severe congenital heart defect; and selective beta-2-adrenoreceptor agonists with posterior urethral valve and/or prune belly. CONCLUSION: EUROmediCAT data should continue to be used for signal detection, accompanied by information from VigiBase and review of the existing literature to prioritise signals for further independent evaluation.

Global birth defects app: An innovative tool for describing and coding congenital anomalies at birth in low resource settings.

BACKGROUND: Surveillance programs in low- and middle-income countries (LMICs) have difficulty in obtaining accurate information about congenital anomalies. METHODS: As part of the ZikaPLAN project, an International Committee developed an app for the description and coding of congenital anomalies that are externally visible at birth, for use in low resource settings. The "basic" version of the app was designed for a basic clinical setting and to overcome language and terminology barriers by providing diagrams and photos, sourced mainly from international Birth Defects Atlases. The "surveillance" version additionally allows recording of limited pseudonymized data relevant to diagnosis, which can be uploaded to a secure server, and downloaded by the surveillance program data center. RESULTS: The app contains 98 (88 major and 10 minor) externally visible anomalies and 12 syndromes (including congenital Zika syndrome), with definitions and International Classification of Disease v10 -based code. It also contains newborn examination videos and links to further resources. The user taps a region of the body, then selects among a range of images to choose the congenital anomaly that best resembles what they observe, with guidance regarding similar congenital anomalies. The "basic" version of the app has been reviewed by experts and made available on the Apple and Google Play stores. Since its launch in November 2019, it has been downloaded in 39 countries. The "surveillance" version is currently being field-tested. CONCLUSION: The global birth defects app is a mHealth tool that can help in developing congenital anomaly surveillance in low resource settings to support prevention and care.

Macrolide and lincosamide antibiotic exposure in the first trimester of pregnancy and risk of congenital anomaly: A European case-control study.

This study investigated the risk of congenital heart defects (CHD) and other congenital anomalies (CA) associated with first trimester use of macrolide antibiotics (mainly erythromycin, spiramycin, clarithromycin and azithromycin) and lincosamides (clindamycin) using a case-malformed control design. Data included 145,936 babies with a CA diagnosis (livebirths, stillbirths and terminations of pregnancy for CA) from 15 population-based EUROCAT registries in 13 European countries, covering 9 million births 1995-2012. Cases were babies with CHD, anencephaly, orofacial clefts, genital and limb reduction anomalies associated with antibiotic exposure in the literature. Controls were babies with other CA or genetic conditions. Main outcomes were odds ratios adjusted (AOR) for maternal age and registry, with 95 % Confidence Intervals (95 %CI). Macrolide and lincosamide exposure was recorded for 307 and 28 cases, 72 and 4 non-genetic controls, 57 and 7 genetic controls, respectively. AOR for CHD was not significantly raised (AOR 0.94, 95 %CI: 0.70-1.26 vs non-genetic controls; AOR 1.01, 95 %CI: 0.73-1.41 vs genetic controls), nor significantly raised for any specific macrolide. The risk of atrioventricular septal defect was significantly raised with exposure to any macrolide (AOR 2.98; 95 %CI: 1.48-6.01), erythromycin (AOR 3.68, 95 %CI: 1.28-10.61), and azithromycin (AOR 4.50, 95 %CI: 1.30-15.58). Erythromycin, clarithromycin, azithromycin, and clindamycin were associated with an increased risk of at least one other CA. Further research is needed on the risk of specific CA associated with macrolide and lincosamide use in the first trimester, particularly relevant for the potential use of azithromycin in the treatment of COVID-19.

The legacy of ZikaPLAN: a transnational research consortium addressing Zika.

Global health research partnerships with institutions from high-income countries and low- and middle-income countries are one of the European Commission's flagship programmes. Here, we report on the ZikaPLAN research consortium funded by the European Commission with the primary goal of addressing the urgent knowledge gaps related to the Zika epidemic and the secondary goal of building up research capacity and establishing a Latin American-European research network for emerging vector-borne diseases. Five years of collaborative research effort have led to a better understanding of the full clinical spectrum of congenital Zika syndrome in children and the neurological complications of Zika virus infections in adults and helped explore the origins and trajectory of Zika virus transmission. Individual-level data from ZikaPLAN`s cohort studies were shared for joint analyses as part of the Zika Brazilian Cohorts Consortium, the European Commission-funded Zika Cohorts Vertical Transmission Study Group, and the World Health Organization-led Zika Virus Individual Participant Data Consortium. Furthermore, the legacy of ZikaPLAN includes new tools for birth defect surveillance and a Latin American birth defect surveillance network, an enhanced Guillain-Barre Syndrome research collaboration, a de-centralized evaluation platform for diagnostic assays, a global vector control hub, and the REDe network with freely available training resources to enhance global research capacity in vector-borne diseases.

Use of infectious disease surveillance reports to monitor the Zika virus epidemic in Latin America and the Caribbean from 2015 to 2017: strengths and deficiencies.

OBJECTIVES: To summarise the occurrence of congenital Zika syndrome (CZS) in Latin America and the Caribbean from 2015 to 2017 using two outcome measures derived from infectious disease surveillance reports and to assess the completeness of these reports. DESIGN: Surveillance study. SETTING: Pan American Health Organization (PAHO)/WHO epidemiology reports on confirmed and suspected Zika virus infection and cases of CZS. PARTICIPANTS: Populations of 47 countries in the South and Central Americas, Mexico and the Caribbean. PRIMARY AND SECONDARY OUTCOME MEASURES: The number of CZS cases per 1000 births (using 2016-2017 births as a denominator) and the number of CZS cases per 1000 births in women with Zika virus infection during pregnancy. RESULTS: By 4 January 2018, 548623 suspected and 239063 confirmed Zika virus infections had been reported to PAHO/WHO from 47 countries. In 25 countries, over 80% of infections were reported as suspected. There were 3617 confirmed CZS cases in 25 countries; 2952 (82%) had occurred in Brazil. The number of CZS cases per 1000 births varied considerably with Brazil and several Caribbean island communities (Puerto Rico, St Martin, Martinique, Guadeloupe and Grenada) having the highest CZS prevalence above 0.5 per 1000 births. Analysing the number of CZS cases per 1000 births in women infected with Zika virus during their pregnancy highlighted the inaccuracies of the data, with Venezuela likely to have had severe under-reporting of CZS. CONCLUSIONS: Expressing data on CZS in relation to total births, rather than as absolute numbers, better illustrates the burden of disease, providing that under-reporting of CZS is not too severe. Data on infections in pregnant women enable potential under-reporting of CZS to be identified. Both measures are recommended for future PAHO/WHO publications. Evidence of severe under-reporting of Zika virus infections and CZS makes interpretation of the data and comparisons between countries challenging.

The Latin American network for congenital malformation surveillance: ReLAMC.

The early detection of congenital anomaly epidemics occurs when comparing current with previous frequencies in the same population. The success of epidemiologic surveillance depends on numerous factors, including the accuracy of the rates available in the base period, wide population coverage, and short periodicity of analysis. This study aims to describe the Latin American network of congenital malformation surveillance: ReLAMC, created to increase epidemiologic surveillance in Latin America. We describe the main steps, tasks, strategies used, and preliminary results. From 2017 to 2019, five national registries (Argentina [RENAC], Brazil [SINASC/SIM-BRS], Chile [RENACH], Costa Rica [CREC], Paraguay [RENADECOPY-PNPDC]), six regional registries (Bogotá [PVSDC-Bogota], Cali [PVSDC-Cali], Maule [RRMC SSM], Nicaragua [SVDC], Nuevo-León [ReDeCon HU], São Paulo [SINASC/SIM-MSP]) and the ECLAMC hospital network sent data to ReLAMC on a total population of 9,152,674 births, with a total of 101,749 malformed newborns (1.1%; 95% CI 1.10-1.12). Of the 9,000,651 births in countries covering both live and stillbirths, 88,881 were stillborn (0.99%; 95% CI 0.98-0.99), and among stillborns, 6,755 were malformed (7.61%; 95% CI 7.44-7.79). The microcephaly rate was 2.45 per 10,000 births (95% CI 2.35-2.55), hydrocephaly 3.03 (2.92-3.14), spina bifida 2.89 (2.78-3.00), congenital heart defects 15.53 (15.27-15.79), cleft lip 2.02 (1.93-2.11), cleft palate and lip 2.77 (2.66-2.88), talipes 2.56 (2.46-2.67), conjoined twins 0.16 (0.14-0.19), and Down syndrome 5.33 (5.18-5.48). Each congenital anomaly showed heterogeneity in prevalence rates among registries. The harmonization of data in relation to operational differences between registries is the next step in developing the common ReLAMC database.

Risk factors for congenital heart disease: The Baby Hearts Study, a population-based case-control study.

We investigated the role of maternal environmental factors in the aetiology of congenital heart disease (CHD). A population-based case-control study (242 CHD cases, 966 controls) was conducted using an iPad questionnaire for mother with linkage to maternity and first trimester prescription records. Risk of CHD was associated with low maternal education (OR adjusted for confounders 1.59; 95% confidence interval [CI], 1.02-2.49), pregestational diabetes (OR 4.04; 95% CI 1.00-16.28), self-reported maternal clotting disorders (adjOR 8.55, 95%CI 1.51-48.44), prescriptions for the anticlotting medication enoxaparin (adjOR 3.22, 95%CI 1.01-10.22) and self-reported vaginal infections (adjOR 1.69, 95%CI 1.01-2.80). There was no strong support for the hypothesis that periconceptional folic acid supplements have a protective effect, but there was a protective effect of frequent consumption of folate rich fruits (adjOR 0.64, 95%CI 0.47-0.89). Compared to the most common pre-pregnancy dietary pattern, CHD risk was associated with a poor diet low in fruit and vegetables (adjOR 1.56, 95%CI 1.05-2.34). Mothers of cases reported more pregnancy related stress (adjOR 1.69; 95% CI 1.22-2.34) and multiple stressors (adjOR 1.94, 95%CI 0.83-4.53). We found no supportive evidence for CHD risk being associated with obesity, smoking, depression or antidepressant use in this population. Our findings add to the previous evidence base to show potential for public health approaches to help prevent CHD in future by modifying environmental factors. Independent confirmation should be sought regarding elevated CHD risk associated with maternal blood clotting disorders and their treatment, since we are the first to report this.