Background The interconception period is considered a time when parents are likely to engage with health messages and are in frequent contact with healthcare professionals. Objectives Through this literature review and policy analysis, we synthesised articles and guidelines on interconception care to provide recommendations to improve health outcomes for parents, infants and future generations. Search Strategy Four databases were searched systematically, using MeSH and free-text terms based on ‘interconception’ and ‘postpartum’. Selection Criteria Selected articles included reviews, pilot studies and guidelines on interconception and postpartum interventions published in English by UK public health organisations and government agencies between 1st January 2010-12th January 2021. Data Collection and Analysis 30% of titles, abstracts and full-text papers were double-screened. The description table of identified guidelines were qualitatively analysed to generate categories, later developed into a framework of six domains. Findings are described using a narrative synthesis approach. Main Results We found 47 documents with guidelines, 29 reviews and six pilot studies on interconception and postpartum care. Interconception care opportunities include the postpartum period, family planning, routine practice, and risk assessments. Health and non-healthcare professionals have a role to play in the interconception period including GPs, health visitors, dieticians, nutritionists, health psychologists, community groups, local authorities and charities such as Tommy’s and First Step Nutrition. Conclusions The interconception and postpartum periods offer crucial opportunities to intervene to reduce possible long-term effects of suboptimal nutrition. Though the policy analysis for this review focused on the UK, the recommendations can have wider implications for other countries.

Objective: To compare emergency department (ED) presentations and hospital admissions for urgent early pregnancy conditions in Victoria before and after the onset of COVID-19 lockdown on 31 March 2020. Design: Population-based retrospective cohort study Setting: Australian state of Victoria Population: Pregnant women presenting to emergency departments or admitted to hospital Methods: We obtained state-wide hospital separation data from the Victorian Emergency Minimum Dataset and the Victorian Admitted Episodes Dataset from January 1, 2018, to October 31, 2020. A linear prediction model based on the pre-COVID period was used to identify the impact of COVID restrictions. Main outcome measures: Monthly ED presentations for miscarriage and ectopic pregnancy, hospital admissions for termination of pregnancy, with subgroup analysis by region, socioeconomic status, disease acuity, hospital type. Results: There was an overall decline in monthly ED presentations and hospital admissions for early pregnancy conditions in metropolitan areas where lockdown restrictions were most stringent. Monthly ED presentations for miscarriage during the COVID period were consistently below predicted, with the nadir in April 2020 (790 observed vs 985 predicted, 95% CI 835-1135). Monthly admissions for termination of pregnancy were also below predicted throughout lockdown, with the nadir in August 2020 (893 observed vs 1116 predicted, 95% CI 905-1326). There was no increase in ED presentations for complications following abortion, ectopic or molar pregnancy during the COVID period. Conclusions: Fewer women in metropolitan Victoria utilized hospital-based care for early pregnancy conditions during the first seven months of the pandemic, without any observable increase in maternal morbidity.

Objective. Clinicians and regulators are receiving reports of changes to menstrual periods following COVID-19 vaccination. However, it is unclear if the two are biologically linked. If they are, people using hormonal contraception are predicted to be less likely to report a change and spontaneously cycling people vaccinated prior to ovulation more likely. The objective was to test these hypotheses. Design. Retrospective cohort study. Setting. UK. Population. 1273 people who had received at least one dose of a COVID-19 vaccination, have periods or withdrawal bleeds and keep a record of the dates of these. Methods. Participants reported whether they use any hormonal contraception and, for each dose of the vaccine, on which day of their menstrual cycle they were vaccinated and details of how the timing and flow of their next period compared to their normal experience. Main outcome measures. Association between 1. the use of hormonal contraception and reported changes to timing or flow of the next menstrual period, and 2. the timing of vaccination within the menstrual cycle and reported changes to timing or flow of the next menstrual period. Results. The data from this cohort did not support the pre-specified hypotheses that people using hormonal contraception would be less likely to report a change, or that spontaneously cycling people vaccinated prior to ovulation would be more likely to report a change. Conclusions. This study did not detect strong signals supporting the idea that COVID-19 vaccination is linked to menstrual changes in most people. Funding. No specific funding.

Objective No study ever investigated the long-term risk of stroke in women with pre-eclampsia/eclampsia. The purpose of this study is to explore long-term stroke risks, differentiating subtypes and their time trends. Design Nationwide population-based cohort study Methods Between 2000 and 2017, 1,384,427 pregnant women were registered in the National Health Insurance Research Database in Taiwan. After excluding women with previous stroke history and exact matching with all confounders, 6,053 women with pre-eclampsia/eclampsia and 24,212 controls were recruited. Main Outcome Measures Hemorrhagic and ischemic strokes after child-birth Results Over the 17-year follow-up, the adjusted hazard ratio (aHR) for stroke in women with a history of pre-eclampsia/eclampsia was 2.05 (95% confidence interval, CI = 1.67-2.52, p<0.001). The 17 years overall risks of both ischemic and hemorrhagic stroke were 1.98 and 3.45, respectively (p<0.001). The stroke subtypes, hemorrhagic and ischemic, had different time trend risks, and hemorrhagic stroke risks kept higher than that of ischemic stroke. The ischemic stroke risk peaked during 1-3 years after childbirth (aHR=3.09). The hemorrhagic stroke risk peaked during 3-5 years (aHR=7.49). Conclusions Stroke risk persisted even after decades, for both ischemic and hemorrhagic subtypes. Women with pre-eclampsia/eclampsia history should be aware of the long-term risk of stroke. Tweetable abstract Both ischemic and hemorrhagic stroke risks persisted high even after decades, while their time trend risks were different. Keywords: pre-eclampsia/eclampsia; ischemic stroke; hemorrhagic stroke

Objective: Identify the proportion of infants reclassified if sex-specific birthweight charts were used, and if this reclassification has an impact on the correlation between birthweight centile and adverse perinatal outcome. Design: Retrospective cohort study Setting: Victoria, Australia. Population: All infants born from 2005-2015 (529,261) Methods: We applied GROW centiles, either adjusted or unadjusted for fetal sex. We compared proportions of small for gestational age (SGA, <10th centile) infants, then the populations of males considered small only by sex-specific charts and females considered small only by unadjusted charts. Main Outcome Measures: Stillbirth, combined perinatal mortality, NICU admissions, Apgars <7 at 5 minutes, emergency caesarean sections. Results: Of those <10th centile by unadjusted charts, 39.6% were male, and 60.5% female. Using sex-specific charts, 50.3% <10th centile were male and 49.7% female. 9,449 (19.2%) females that were SGA according to unadjusted charts were appropriate for gestational age (AGA,>10th-<90th centile) using sex-specific charts. These reclassified newborn females were not at increased risk of adverse outcomes compared with an AGA infant, but were at increased risk of being iatrogenically delivered for suspected growth restriction (RR 4.90, 95%CI 4.39–5.48). 8,048 male infants were reclassified as SGA by sex-specific charts (25% SGA increase). Compared with AGA infants, these reclassified male newborns were at greater risk of stillbirth (RR 1.94, 95%CI 1.30-2.90) and all other adverse perinatal outcomes. Conclusions: Sex-specific growth standards classify a new high-risk cohort of male infants as SGA, and exclude a cohort of females, whose risk is no greater than appropriately grown infants.

Objective: Evaluate the impact of the timing of SARS-CoV-2 infection on pregnancy outcomes in a low-middle income setting. Design: two parallel, observational studies. Setting and population: pregnant women or women presenting for labour, enrolled between April-September 2020, in South Africa. Methods: i) longitudinal follow-up study of symptomatic or asymptomatic pregnant women investigated for SARS-CoV-2 infection antenatally, ii) cross-sectional study of SARS-CoV-2 infection at time of labour. SARS-CoV-2 infection was investigated by nucleic acid amplification test (NAAT). Main Outcome Measures: association of SARS-CoV-2 infection on nasal swab and birth outcomes. Results: Antenatally, 793 women were tested for SARS-CoV-2. Overall SARS-CoV-2 infection was confirmed in 138 women, including 119/275 with symptomatic illness (COVID-19) and 19/518 asymptomatic women; 493 women were asymptomatic and SARS-CoV-2 non-reactive. Women with COVID-19 were 1.66-times (95%CI: 1.02, 1.71) more likely to have a low-birthweight newborn (30%) compared to asymptomatic women without SARS-CoV-2 (21%). Overall, 3117 women were tested for SARS-CoV-2 infection at delivery, including 1560 healthy women with an uncomplicated term delivery. Adverse birth outcomes or pregnancy-related complications were not associated with infection at delivery. Among women with SARS-CoV-2 infection at delivery, NAAT was reactive on 6/98 of maternal blood samples, 8/93 of cord-blood, 14/54 of placentas and 3/22 of nasopharyngeal swabs from newborns collected within 72-hours of birth. Conclusions: Antenatal, but not intrapartum, SARS-CoV-2 infection was associated with low-birthweight delivery. Maternal infection at the time of labour was associated with in utero foetal and placental infection, and possible vertical and/or horizontal viral transfer to the newborn.

Objective: To study the effect of a low (0.5g) or a standard (1g) tranexamic acid (TA) dose compared to placebo on clinical and biological endpoints in women experiencing postpartum hemorrhage (PPH) Design: TRACES trial is a double-blind, randomized, placebo-controlled, dose-ranging study Setting: 8 women hospitals in France. Population: Women experiencing PPH > 800 mL during caesarean section. Method: After informed consent, patients were randomized to receive either TA 0.5g (n=57), TA 1g (n=58), or a placebo (n=60). Data were collected at 8 time-points. Main outcome measures: Efficacy: additional blood loss after study drug, maternal morbidity, safety, biology: D-dimers, plasmin-antiplasmin complexes (PAP), simultaneous-generation-thrombin-plasmin-potential. Results: Compared to 1g dose, 0.5g TA was less effective to reduce additional blood loss (300 mL [95% confidence interval (95%CI) 68 to 630] vs 134 mL [95%CI50 to 419] (p=0.042)). Compared to placebo, 1g TA, but not 0.5g, inhibited hyperfibrinolysis as shown by plasmin generation potential, % increase in D-dimers from injection to 120 minutes (93% [95%CI 68 to 118] vs 58% [ 95%CI 32 to 84] (p=0.06) vs 38% [95%CI 13 to 63] (p=0.003) and % increase in PAP from injection to 30 minutes (56% [95%CI 25 to 87] vs 13% [ 95%CI 18 to 43] (p=0,051) vs -2% [95%CI -32 to 28] (p=0.009)). Conclusions: In this study, fibrinolysis inhibition was more sustained after the administration of 1g TA compared to 0.5g TA or a placebo. Further pharmacokinetic-pharmacodynamic modelling will be needed to determine the optimal TA dose to be administered in PPH. NCT 02797119

Objective:Compare the efficacy of intravenous ferric derisomaltose (FDI) with oral iron in pregnant women with persistent iron deficiency. Design:Single-centre, open-labelled, randomised controlled trial. Setting:Danish university hospital. Population:Women 14–21 weeks pregnant with persistent iron deficiency (ferritin <30 µg/L). Methods:Allocation to 1,000 mg intravenous FDI (single-dose) or 100 mg elemental oral iron daily (FA). Assessment of blood tests, patient reported outcomes (fatigue and quality of life) and adverse events throughout eighteen weeks’ follow-up. Main_outcome_measures:Proportion of non-anaemic (haemoglobin ≥11 g/dL) women throughout follow-up (primary endpoint), assessed by Kaplan-Meier estimates compared between groups by risk difference analysis. Change in haematological markers and patient reported outcomes, assessed by restricted maximum likelihood estimates compared between groups by a repeated measures mixed model. Results:From July 2017 through February 2020, 100 women were randomised to FDI and 101 to FA. In the FDI vs. FA group 89% vs. 88% were non-anaemic prior to inclusion. Throughout follow-up, 91% vs. 73% were non-anaemic in favor of FDI (18% difference, 95% CI 0.10–0.25, p<0.001). The haemoglobin least-squares mean increase was significantly greater in the FDI vs. FA group at week six (0.4 vs. -0.2 g/dL, p<0.001), twelve (0.5 vs. 0.1 g/dL, p<0.001) and eighteen (0.8 vs. 0.5 g/dL, p=0.01). Improvements in patient reported fatigue and psychological well-being were greater in the FDI group at weeks three and six. The incidence of treatment related adverse events was comparable across treatments. Conclusions:FDI was superior for avoiding anaemia compared to oral treatment, and biochemical superiority was accompanied by improved fatigue and psychological well-being.

Objective We report our experience with a transvaginal approach with overlapping AS repair. The aim of this study was to evaluate long term functional outcomes. Design Retrospective Cohort study. Setting and Population Women who had undergone AS surgery for anal incontinence from July 2005 to July 2020. were included. The patients included attended the Mercy Hospital Perineal clinic a multidisciplinary team of urogynecologists and colorectal surgeons. Private patients from the surgeons in Perineal clinic were also included. Methods Overall 107 women were included in the study with a median follow up of 57.5 months. Main Outcome Measure We analysed outcomes by comparing patients St marks score difference before and after surgery. Meaningful clinical difference (MID) was set at 5 points as per previous validation studies, complications and patient demographics were recorded along with a question if they would recommend this treatment to a friend. Results An improvement exceeding the minimal clinical difference (MID) was seen in 69.3% of women. With a marked improvement in 46.5% of patients. Furthermore 70% of our patients would recommend the procedure to a friend, if they were in a similar situation. Wound infection or perineal breakdown occurred in 45% of women but did not significantly impact on outcomes. Conclusion Transvaginal AS repair is associated with significant improvements in patients’ St. Marks score. Our data shows that the long-term success rate of transvaginal AS repair may be better than previously reported in the literature using a transvaginal approach. Funding This study received no funding or sponsorship

Background Parental abnormal chromosomal karyotypes are considered as reasons for recurrent pregnancy loss. Objective This systematic meta-analysis evaluated the current evidence on pregnancy outcomes amongst couples with abnormal versus normal chromosomal karyotypes. Search strategy Two independent reviewers screened titles and abstracts identified in EMBASE and PubMed from inception to January 2021. Selection criteria Studies were included if they provided a description of pregnancy outcomes of parental chromosomal abnormality. Data collection and analysis Random effects meta-analysis was used to compare odds of pregnancy outcomes associated with noncarriers and carriers. Main results A significantly lower first pregnancy live birth rate (FPLBR) was found in carriers than in noncarriers with RPL (OR: 0.55; 95% CI: 0.46-0.65; p<0.00001). Regarding FPLBR between translocation or inversion carriers and noncarriers, a markedly decreased FPLBR was found in translocation (OR: 0.44; 95% CI: 0.31–0.61; p<0.00001) but not inversion carriers. The accumulated live birth rate (ALBR) (OR: 0.96; 95% CI: 0.90–1.03; p=0.26) was similar, while the miscarriage rate (MR) of accumulated pregnancies (OR: 2.21; 95% CI: 1.69–2.89; p<0.00001) was significantly higher in the carriers than in noncarriers with RPL. The ALBR was not significant (OR: 1.82; 95% CI: 0.38–8.71; p=0.45) but the MR (OR: 5.75; 95% CI: 2.57–12.86; p<0.0001) was markedly lower for carriers who choose PGD than natural conception. Conclusions Carriers with RPL had higher risk of miscarriage but obtained a satisfying pregnancy outcome through multiple attempts. No sufficient evidence was found PGD could enhance the ALBR but it was an alternative to decrease the MR.

Objectives: In July 2017, Victoria’s largest maternity service implemented a new clinical guideline aimed to reduce the rates of stillbirth at term for South Asian-born women. Here we present the evaluation of the change in care on rates of stillbirth, neonatal and obstetric interventions. Design: Cohort Study Setting: Victoria’s largest metropolitan university-affiliated teaching hospital. Population: All women receiving antenatal care who gave birth in the term period between January 2016 and December 2020. Methods: Differences in rates of stillbirths, neonatal deaths, perinatal morbidities, and interventions after July 2017 were determined. Multigroup interrupted time-series analysis was used to assess changes in rates of induction of labour. Main Outcome Measures: Rates of stillbirths, neonatal deaths, perinatal morbidities, and obstetric interventions. Results: 3506 south Asian-born women gave birth prior to, and 8532 after the change. There was a 64% reduction in term stillbirth (95%CI 87% to 2%; p=0.047) for south Asian-born women after the change in practice from 2.3 per 1000 births to 0.8 per 1000 births. The rates of early neonatal death (3.1 per 1000 vs 1.3 per 1000; p=0.03) and SCN admission (16.5% vs 11.1%; p<0.001) also decreased. There were no significant differences in admission to NICU, Apgar<7 at 5 minutes, birthweight or differences in the trends of induction of labour per month. Conclusions: Fetal monitoring from 39 weeks’ may offer an alternative to routine earlier induction of labour to reduce the rates of stillbirth without causing an increase in neonatal morbidity or obstetric interventions.

Background: Although women are encouraged to achieve good diet quality in preconception and pregnancy, the benefits on perinatal outcomes have not been established. Objective: To systematically review and quantify the association between diet quality and adverse perinatal outcomes. Search strategy: Medline, Embase, Food Science and Technology Abstracts and CINAHL were searched up to 5th March 2020. Selection criteria: Two authors independently screened, selected and coded relevant prospective cohort studies. Data collection and analysis: Thirty-three studies (315,431 participants) were included in the meta-analysis. Odds ratios and mean differences from individual studies were pooled using random-effects models. Main Results: The pooled results for the association between diet quality and excessive (OR: 0.91; 95 CI: 0.76, 1.10) or inadequate (OR: 0.90; 95 CI: 0.70, 1.17) gestational weight gain were not statistically significant. Women in the top tertile of diet quality scores during prepregnancy or pregnancy had a lower risk of gestational diabetes (OR: 0.77; 95 CI: 0.65, 0.90), hypertensive disorders of pregnancy (OR: 0.87; 95 CI: 0.83, 0.92), preterm birth (OR: 0.77; 95 CI: 0.66, 0.89), small for gestational age (OR: 0.88; 95 CI: 0.79, 0.99) and low birth weight (OR: 0.60; 95 CI: 0.37, 0.99) compared to those in the bottom tertile. No studies were found for delivery mode. Conclusions: Data from prospective cohort studies support the potential of improving maternal diet quality in the effort to prevent adverse perinatal outcomes. Funding: Canadian Institutes of Health Research HLT 151517, National Natural Sciences Foundation of China No. 81661128010 Keywords: Diet quality, perinatal outcomes.

Abstract Objective:Evaluate deformable slice-to-volume registration (DSVR) to calculate 3D-segmented total lung volume (TLV) in fetuses with congenital diaphragmatic hernia, congenital lung lesions and healthy controls, with comparison to 2D-manual segmentation. Design:Pilot study Setting:Regional fetal medicine referral centre Sample:Fetal MRIs performed for clinical indications (abnormal cases) or as research participants (healthy controls) Methods:Sixteen MRI datasets of fetuses (22-32 weeks GA). Diagnosis: CDH(n=5), CPAM(n=2), CDH with BPS(n=1) and healthy control(n=8). DSVR was used for reconstruction of 3D isotropic (0.85 mm) volumes of fetal body followed by semi-automated lung segmentation. The resulting 3D TLV were compared to the traditional 2D-based volumetry, and a normogram of DSVR-derived fetal lung volumes from 100 cases was produced. Main Outcome Measures:Concordance with 2D-volumetry assessed with Bland-Altman analysis, results of segmentations presented visually. Observed/Expected values were calculated for abnormal cases based upon the normogram. Results:DSVR-derived TLV values have high correlation with the 2D-based measurements but with a consistently lower volume; bias -1.44cm3 [95% limits: -2.6 to -0.3] with improved resolution able to exclude hilar structures even in severe motion corruption or in cases of lung hypoplasia. Conclusions:Application of DSVR for fetal MRI provides a solution for analysis of motion corrupted scans and does not suffer from the interpolation error inherent in 2D-segmentation as per current clinical practice. It increases information content of acquired data in terms of visualising organs in 3D space and quantification of volumes, which we believe will have important value for counselling and surgical planning. Keywords:Fetal MRI; congenital diaphragmatic hernia; CPAM; lung volume

Objective: Characterize the presentation of vulvar lichen scleorsus (LS) among premenopausal women. Design: Cross-sectional study. Setting: An international web-based survey distributed on social media support groups and in two urban gynecology offices specializing in LS. Population: A total of 503 premenopausal women with biopsy-confirmed vulvar LS between the ages of 18-50. Methods: Participants completed an anonymous 28-question web-based survey between January to March 2021. Main Outcome Measures: Symptoms, timing and accuracy of diagnosis, and presence of concomitant autoimmune conditions. Results: Symptoms reported to be most present and affect the individual were dyspareunia (68%; 44%) and tearing with intercourse or vaginal insertion (63%; 39%). Symptoms that most frequently prompted patients to seek medical attention were dyspareunia (35%), pruritus (31%), and tearing with intercourse or vaginal insertion (26%). Most common skin changes included hypopigmentation (81%), vulvar fissures (72%) and labial resorption (60%), with fissures affecting the individual the most (48%). There was a 4-year delay in diagnosis with an average age of symptom onset of 27 years and average age of diagnosis of 32 years. Sixty-six percent of respondents initially received an alternative diagnosis, most commonly vulvovaginal yeast infection (49%). There is an increased incidence of hypothyroidism, vitiligo, pernicious anemia, and celiac disease. Conclusion: Premenopausal women with vulvar LS more commonly present with dyspareunia and tearing with intercourse, less often than vulvar pruritis. This condition should be considered and evaluated in women of all ages presenting with vulvar symptoms and sexual pain. Funding: None Keywords: lichen sclerosus; vulvar dermatoses; vulvar pruritis; dyspareunia

Objective: To characterise placental gene expression at term to evaluate sex-specific genetic changes that occur in small for gestational age (SGA) infants. Design: Case control study. Setting: Australian hospitals. Samples: Twelve human placental samples from pregnancies that were either SGA or appropriate for gestational age (AGA). Methods: RNA-sequencing of term placental tissue from both SGA and AGA infants. Candidate genes associated with fetal size and fetal sex were identified using differential gene expression and weighted gene co-expression network analyses. Single-cell sequencing data was used for candidate validation and to estimate candidate transcript expression in specific placental cell populations. Main outcome measures: Functions of differentially expressed genes in the placenta of SGA infants that differed by fetal sex. Results: Differential gene expression and weighted gene co-expression network analyses identified 403 candidate transcripts associated with SGA infants. One hundred and three of these transcripts showed sex-specific expression. Sex-independent transcript expression for genes involved in protein synthesis, and sex-dependent transcript expression for genes involved in cell cycle processes in males and endoplasmic reticulum stress in females was validated (17 and 7 transcripts for females and males) in published placental RNA-sequencing datasets. Conclusions: Sexual dimorphism is an important consideration when examining placental dysfunction and poor fetal growth. This study identified activation of shared and divergent molecular mechanisms (i.e., cell cycle and endoplasmic reticulum stress), in response to an adverse environmental stressor.

Title:Ondansetron in pregnancy revisited: Assessment and pregnancy labelling by the European Medicines Agency (EMA) & Pharmacovigilance Risk Assessment Committee (PRAC).Running title:Ondansetron in pregnancyPer DamkierMD, PhDDepartment of Clinical Biochemistry & Pharmacology Odense University Hospital, DenmarkDepartment of Clinical research University of Southern Denmark, DenmarkMail:pdamkier@health.sdu.dkPhone: +45 65 50 37 90Ondansetron is an effective antiemetic that is being widely used as a second-line treatment option for severe Nausea and Vomiting of Pregnancy (NVP) in accordance with clinical guidelines (1–4).In July 2019, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) released updated comprehensive assessment report on the use of ondansetron in first trimester (5). This report is a detailed assessment of the available published data on the subject, including responses to supplementary questions posed to the Marking Authorization Holder (MAH), and the authors to the two central publications discussed below. The ensuing Summary of product Characteristics (SmPC) was updated in November 2019 with important changes to section 4.6 “Fertility, pregnancy and lactation” (6), which now state that ondansetron should not be used in first trimester of pregnancy.We acknowledge that the EMA SmPC in principal only frames the way that the MAH are legally allowed to market their product within the EU. It does not bind the physician as such; they must act and adhere with reference to the legal framework of their respective countries. We also acknowledge that EMA operates within a given formalized set of options on SmPC phrasings. In everyday practice however, the wording of the SmPC has consequences for treatment options and decision support beyond those formal to the legal ramifications of the SmPC.We applaud the EMA for the following nuanced phrasings in the SmPC:Based on human experience from epidemiological studies, ondansetron is suspected to cause orofacial malformations when administered during the first trimester of pregnancy.In one cohort study including 1.8 million pregnancies, first trimester ondansetron use was associated with an increased risk of oral clefts (3 additional cases per 10 000 women treated; adjusted relative risk, 1.24, (95% CI 1.03-1.48)).The available epidemiological studies on cardiac malformations show conflicting results. We believe that data from animal studies are of less relevance in these and analogue situations with an abundance of human data available:“Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.”We do not believe that the most important sentence therein is appropriately substantiated or justified:“Ondansetron should not be used during the first trimester of pregnancy.”The latter statement comes with very clear and immediate consequences to clinical practice and pregnant women suffering from NVP. Previous somewhat contradictory data notwithstanding (7), the core of the discussion is down to the interpretation of two extraordinarily large sets of data. These are recent publications each comprising 80.000+ first-trimester exposed liveborn children. Previous studies with somewhat contradictory results comprise cumulated first trimester exposures less than 10% of these new data.Huybrechts et al., a well-established research group within studies of adverse pregnancy outcome following drug exposure during pregnancy with an elite publication track-record, published their large study in December 2018 (8). In this meticulously designed, conducted and reported study comprising 88.000 liveborn children exposed to ondansetron in first trimester, they reported no increased overall risk of malformations and null associations for any or cardiac malformations and a small increased risk for oral cleft. Compared to 1,727.000 unexposed liveborn, propensity score adjusted relative risks were 1.01 (95% CI 0.98-1.05), 0.99 (95% CI 0.93-1.06) and 1.24 (95% CI 1.03-1.48) for any, cardiac and oral cleft malformations, respectively. The increased risk of oral clefts corresponds to about 3 additional cases for every 10.000-liveborn children exposed to ondansetron in first trimester.Zambelli-Weiner et al. published their findings from a large study in January 2019 (9). This triggered controversy and extensive discussions among clinicians and researchers within the field.They reported data on 82.000 liveborn children exposed to ondansetron in first trimester. Compared to about 780.000 unexposed liveborn, their overall analysis identified a weak but no clinically meaningful association with cardiac effects, aOR 1.04 (95% CI 1.00-1.08) and a weak association to orofacial clefts, aOR 1.12 (95% CI: 0.95-1.33). Ade facto subgroup analysis – defined by the authors as “primary analysis” - restricted exposure to 5.500 women who were administered ondansetron in hospitals (“medical administration”). The inferential analysis substantially reinforced the overall weak signal for cardiac effects (aOR 1.43; 95% CI 1.28-1.61) but not orofacial clefts, (aOR 1.30; 95% CI: 0.75-2.25). The technical analysis appears suboptimal as adjustments were made as by a crude approach; i.e. the selection of confounder variables was based on these resulting in at least 10% change in effect estimates rather than simply including all selected confounders in the model.It appears plausible that this subpopulation of pregnant women in whom hospital treatment was deemed necessary, suffered from a more severe presentation of NVP, a confounder that they did not accounted for. The sensitivity analysis performed in patients assigned a diagnosis of NVP or hyperemesis gravidarum does not satisfactorily account for this. In almost all exposed cases, the exposure comprised a single intravenous dose of ondansetron. It is biologically counterintuitive that a causal relation to cardiac malformations be present based on such exposure. The paper reports extraordinarily high rates of congenital cardiac malformations be it among unexposed (3.7%) or exposed (5.5 and 4.1% for intravenous and any exposure, respectively) liveborn children. These observations are incompatible with all other reported data on the rate of congenital cardiac malformations. The external validity of the study findings is therefore less convincing and compromises comparisons to other findings.The authors did not provide satisfactory responses to additional questions poses by PRAC during the assessment process. Five specific questions were posed, and the authors did not address any of these. They provided a short narrative statement that did not serve to clarify or advance understanding of their findings (5). Not least, this paper is severely compromised by an initially undisclosed serious conflict of interest. The formal COI disclosure in the paper state: ”As an organization, TTi reports receiving funds from plaintiff law firms involved in ondansetron litigation…” The extent of this COI was only revealed during a litigation process. The specific study received substantial funding ($ 210.000) from plaintiffs’ representation who was pursuing litigative damage by claiming malformations from ondansetron use in pregnancy (10). It is the position of the undersigned and ENTIS Scientific Committee that this study is methodologically and ethically compromised to an extent that the results thereof cannot be considered when assessing the totality of evidence on the safety of ondansetron in pregnancy.Since the PRAC recommendation two additional studies have been published that should be considered in the overall assessment of the risk during pregnancy.In January 2020, Huybrechts et al. published an additional study on intravenous administration of ondansetron in early pregnancy and risk of congenital malformations (11). In this study, the authors revisited the study population from their original paper, but restricted their analysis to those women who received intravenous ondansetron in first trimester (8). The resulting propensity-score adjusted inferential analysis of about 24.000 pregnancies exposed to intravenous ondansetron did not result in increased risk of cardiac malformations (RR 0.97; 95% CI 0.86-1.10), oral clefts (RR 0.95; 95% CI 0.63-1.43), or any congenital malformation(RR 1.02; 95% CI 0.96-1.08). Unadjusted analyses suggested a small increased risk for cardiac and any malformation (11). These data strongly mitigate the previous data on intravenous ondansetron (9).Lemon and colleagues reported a small increased risk of ventricular septal defect (VSD) following first trimester exposure to intravenous or oral ondansetron in first trimester among 3700 pregnancies (12). Across various methodological approaches the adjusted risk ratio varied between 1.7 and 2.1 with 95% CI ranging between 1.0 and 4.0. In an overall analysis though there was no increased risk for any birth defect or any heart defect, illustrating the dilemma of splitting versus lumping in such analyses (13). In this study, there may be an issue of ascertainment bias. Women exposed to ondansetron likely suffered from more severe NVP and thus may have been be subject to more attention and their newborn babies to a greater extent are subject to an echocardiograph evaluation. VSDs may be clinically asymptomatic and ”Up to 80% of small, muscular VSDs and 30%-50% of perimembranous defects will close spontaneously” (14).In summary, we believe that the abundance of most methodologically convincing data on cardiovascular malformations is reasonably reassuring. Even if a small excess risk may still be present, ondansetron in first trimester should remain an option for pregnant women with severe NVP.It is the opinion of ENTIS that the EMA decision to explicitly discourage first trimester treatment with ondansetron puts pregnant women with severe NVP, physicians and health care professionals between a rock and a hard place. We do not agree that the specific wording against the use of ondansetron in first trimester is justified and we do not support the conclusion of EMA/PRAC assessment report and this section of the SmPC.We urge the EMA/PRAC to carefully consider everyday clinical consequences of formal regulatory decisions. In cases with likely widespread clinical consequences, we suggest that EMA/PRAC consult liberally with relevant patient organizations, clinicians and health care professionals before final adoption of a recommendation.