Development and validation of prediction models for fetal growth restriction and birthweight: an individual participant data meta-analysis.

Background: Fetal growth restriction is associated with perinatal morbidity and mortality. Early identification of women having at-risk fetuses can reduce perinatal adverse outcomes. Objectives: To assess the predictive performance of existing models predicting fetal growth restriction and birthweight, and if needed, to develop and validate new multivariable models using individual participant data. Design: Individual participant data meta-analyses of cohorts in International Prediction of Pregnancy Complications network, decision curve analysis and health economics analysis. Participants: Pregnant women at booking. External validation of existing models (9 cohorts, 441,415 pregnancies); International Prediction of Pregnancy Complications model development and validation (4 cohorts, 237,228 pregnancies). Predictors: Maternal clinical characteristics, biochemical and ultrasound markers. Primary outcomes: fetal growth restriction defined as birthweight <10th centile adjusted for gestational age and with stillbirth, neonatal death or delivery before 32 weeks' gestation birthweight. Analysis: First, we externally validated existing models using individual participant data meta-analysis. If needed, we developed and validated new International Prediction of Pregnancy Complications models using random-intercept regression models with backward elimination for variable selection and undertook internal-external cross-validation. We estimated the study-specific performance (c-statistic, calibration slope, calibration-in-the-large) for each model and pooled using random-effects meta-analysis. Heterogeneity was quantified using τ2 and 95% prediction intervals. We assessed the clinical utility of the fetal growth restriction model using decision curve analysis, and health economics analysis based on National Institute for Health and Care Excellence 2008 model. Results: Of the 119 published models, one birthweight model (Poon) could be validated. None reported fetal growth restriction using our definition. Across all cohorts, the Poon model had good summary calibration slope of 0.93 (95% confidence interval 0.90 to 0.96) with slight overfitting, and underpredicted birthweight by 90.4 g on average (95% confidence interval 37.9 g to 142.9 g). The newly developed International Prediction of Pregnancy Complications-fetal growth restriction model included maternal age, height, parity, smoking status, ethnicity, and any history of hypertension, pre-eclampsia, previous stillbirth or small for gestational age baby and gestational age at delivery. This allowed predictions conditional on a range of assumed gestational ages at delivery. The pooled apparent c-statistic and calibration were 0.96 (95% confidence interval 0.51 to 1.0), and 0.95 (95% confidence interval 0.67 to 1.23), respectively. The model showed positive net benefit for predicted probability thresholds between 1% and 90%. In addition to the predictors in the International Prediction of Pregnancy Complications-fetal growth restriction model, the International Prediction of Pregnancy Complications-birthweight model included maternal weight, history of diabetes and mode of conception. Average calibration slope across cohorts in the internal-external cross-validation was 1.00 (95% confidence interval 0.78 to 1.23) with no evidence of overfitting. Birthweight was underestimated by 9.7 g on average (95% confidence interval -154.3 g to 173.8 g). Limitations: We could not externally validate most of the published models due to variations in the definitions of outcomes. Internal-external cross-validation of our International Prediction of Pregnancy Complications-fetal growth restriction model was limited by the paucity of events in the included cohorts. The economic evaluation using the published National Institute for Health and Care Excellence 2008 model may not reflect current practice, and full economic evaluation was not possible due to paucity of data. Future work: International Prediction of Pregnancy Complications models' performance needs to be assessed in routine practice, and their impact on decision-making and clinical outcomes needs evaluation. Conclusion: The International Prediction of Pregnancy Complications-fetal growth restriction and International Prediction of Pregnancy Complications-birthweight models accurately predict fetal growth restriction and birthweight for various assumed gestational ages at delivery. These can be used to stratify the risk status at booking, plan monitoring and management. Study registration: This study is registered as PROSPERO CRD42019135045. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/148/07) and is published in full in Health Technology Assessment; Vol. 28, No. 14. See the NIHR Funding and Awards website for further award information.

One in ten babies is born small for their age. A third of such small babies are considered to be 'growth-restricted' as they have complications such as dying in the womb (stillbirth) or after birth (newborn death), cerebral palsy, or needing long stays in hospital. When growth restriction is suspected in fetuses, they are closely monitored and often delivered early to avoid complications. Hence, it is important that we identify growth-restricted babies early to plan care. Our goal was to provide personalised and accurate estimates of the mother's chances of having a growth-restricted baby and predict the baby's weight if delivered at various time points in pregnancy. To do so, first we tested how accurate existing risk calculators ('prediction models') were in predicting growth restriction and birthweight. We then developed new risk-calculators and studied their clinical and economic benefits. We did so by accessing the data from individual pregnant women and their babies in our large database library (International Prediction of Pregnancy Complications). Published risk-calculators had various definitions of growth restriction and none predicted the chances of having a growth-restricted baby using our definition. One predicted baby's birthweight. This risk-calculator performed well, but underpredicted the birthweight by up to 143 g. We developed two new risk-calculators to predict growth-restricted babies (International Prediction of Pregnancy Complications-fetal growth restriction) and birthweight (International Prediction of Pregnancy Complications-birthweight). Both calculators accurately predicted the chances of the baby being born with growth restriction, and its birthweight. The birthweight was underpredicted by <9.7 g. The calculators performed well in both mothers predicted to be low and high risk. Further research is needed to determine the impact of using these calculators in practice, and challenges to implementing them in practice. Both International Prediction of Pregnancy Complications-fetal growth restriction and International Prediction of Pregnancy Complications-birthweight risk calculators will inform healthcare professionals and empower parents make informed decisions on monitoring and timing of delivery.

Prioritisation of early pregnancy risk factors for stillbirth: An international multistakeholder modified e-Delphi consensus study.

OBJECTIVE: To identify and prioritise early pregnancy risk factors for stillbirth to inform prognostic factor and model research. STUDY DESIGN: We used a modified e-Delphi method and consultation meeting to achieve consensus. Risk factors for early, late and stillbirth at any gestation identified from an umbrella review of risk factors for stillbirth were entered into a two-stage online Delphi survey with an international group of stakeholders made up of healthcare professionals and researchers. The RAND/ University of California at Los Angeles appropriateness method was used to evaluate consensus. Responders voted on a scale of 1-9 for each risk factor in terms of importance for early, late, and stillbirth at any gestation. Consensus for inclusion was reached if the median score was in the top tertile and at least two thirds of panellists had scored the risk factor within the top tertile. RESULTS: Twenty-six risk factors were identified from an umbrella review and presented to stakeholders in round 1 of our e-Delphi survey. Round 1 was completed by 68 stakeholders, 79% (54/68) of whom went on to complete the second round. Seventeen risk factors were discussed at the consensus meeting. From the twenty-six risk factors identified, fifteen of these were prioritised for stillbirth at any gestation, eleven for early stillbirth, and sixteen for late stillbirth, across three domains of maternal characteristics, ultrasound markers and biochemical markers. The prioritised maternal characteristics common to early, late, and stillbirth at any gestation were: maternal age, smoking, drug misuse, history of heritable thrombophilia, hypertension, renal disease, diabetes, previous stillbirth and multiple pregnancy. Maternal BMI, access to healthcare, and socioeconomic status were prioritised for late stillbirth and stillbirth at any gestation. Previous pre-eclampsia and previous small for gestational age baby were prioritised for late stillbirth. Of the ultrasound markers, uterine artery Doppler pulsatility index and congenital fetal anomaly were prioritised for all. One biochemical marker, placental growth factor, was prioritised for stillbirth at any gestation. CONCLUSIONS: Our prioritised risk factors for stillbirth can inform formal factor-outcome evaluation of early pregnancy risk factors to influence public health strategies on prevention of such risk factors to prevent stillbirth.

Development and validation of a prognostic model to predict birth weight: individual participant data meta-analysis.

Objective: To predict birth weight at various potential gestational ages of delivery based on data routinely available at the first antenatal visit. Design: Individual participant data meta-analysis. Data sources: Individual participant data of four cohorts (237 228 pregnancies) from the International Prediction of Pregnancy Complications (IPPIC) network dataset. Eligibility criteria for selecting studies: Studies in the IPPIC network were identified by searching major databases for studies reporting risk factors for adverse pregnancy outcomes, such as pre-eclampsia, fetal growth restriction, and stillbirth, from database inception to August 2019. Data of four IPPIC cohorts (237 228 pregnancies) from the US (National Institute of Child Health and Human Development, 2018; 233 483 pregnancies), UK (Allen et al, 2017; 1045 pregnancies), Norway (STORK Groruddalen research programme, 2010; 823 pregnancies), and Australia (Rumbold et al, 2006; 1877 pregnancies) were included in the development of the model. Results: The IPPIC birth weight model was developed with random intercept regression models with backward elimination for variable selection. Internal-external cross validation was performed to assess the study specific and pooled performance of the model, reported as calibration slope, calibration-in-the-large, and observed versus expected average birth weight ratio. Meta-analysis showed that the apparent performance of the model had good calibration (calibration slope 0.99, 95% confidence interval (CI) 0.88 to 1.10; calibration-in-the-large 44.5 g, -18.4 to 107.3) with an observed versus expected average birth weight ratio of 1.02 (95% CI 0.97 to 1.07). The proportion of variation in birth weight explained by the model (R2) was 46.9% (range 32.7-56.1% in each cohort). On internal-external cross validation, the model showed good calibration and predictive performance when validated in three cohorts with a calibration slope of 0.90 (Allen cohort), 1.04 (STORK Groruddalen cohort), and 1.07 (Rumbold cohort), calibration-in-the-large of -22.3 g (Allen cohort), -33.42 (Rumbold cohort), and 86.4 g (STORK Groruddalen cohort), and observed versus expected ratio of 0.99 (Rumbold cohort), 1.00 (Allen cohort), and 1.03 (STORK Groruddalen cohort); respective pooled estimates were 1.00 (95% CI 0.78 to 1.23; calibration slope), 9.7 g (-154.3 to 173.8; calibration-in-the-large), and 1.00 (0.94 to 1.07; observed v expected ratio). The model predictions were more accurate (smaller mean square error) in the lower end of predicted birth weight, which is important in informing clinical decision making. Conclusions: The IPPIC birth weight model allowed birth weight predictions for a range of possible gestational ages. The model explained about 50% of individual variation in birth weights, was well calibrated (especially in babies at high risk of fetal growth restriction and its complications), and showed promising performance in four different populations included in the individual participant data meta-analysis. Further research to examine the generalisability of performance in other countries, settings, and subgroups is required. Trial registration: PROSPERO CRD42019135045.

Primary unilateral macronodular adrenal hyperplasia with concomitant glucocorticoid and androgen excess and KDM1A inactivation.

BACKGROUND: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. Individuals with PBMAH and glucose-dependent insulinotropic polypeptide (GIP)-dependent Cushing's syndrome due to ectopic expression of the GIP receptor (GIPR) typically harbor inactivating KDM1A sequence variants. Primary unilateral macronodular adrenal hyperplasia (PUMAH) with concomitant glucocorticoid and androgen excess has never been encountered or studied. METHODS: We investigated a woman with a large, heterogeneous adrenal mass and severe adrenocorticotropic hormone-independent glucocorticoid and androgen excess, a biochemical presentation typically suggestive of adrenocortical carcinoma. The patient presented during pregnancy (22nd week of gestation) and reported an 18-month history of oligomenorrhea, hirsutism, and weight gain. We undertook an exploratory study with detailed histopathological and genetic analysis of the resected adrenal mass and leukocyte DNA collected from the patient and her parents. RESULTS: Histopathology revealed benign macronodular adrenal hyperplasia. Imaging showed a persistently normal contralateral adrenal gland. Whole-exome sequencing of 4 representative nodules detected KDM1A germline variants, benign NM_001009999.3:c.136G > A:p.G46S, and likely pathogenic NM_001009999.3:exon6:c.865_866del:p.R289Dfs*7. Copy number variation analysis demonstrated an additional somatic loss of the KDM1A wild-type allele on chromosome 1p36.12 in all nodules. RNA sequencing of a representative nodule showed low/absent KDM1A expression and increased GIPR expression compared with 52 unilateral sporadic adenomas and 4 normal adrenal glands. Luteinizing hormone/chorionic gonadotropin receptor expression was normal. Sanger sequencing confirmed heterozygous KDM1A variants in both parents (father: p.R289Dfs*7 and mother: p.G46S) who showed no clinical features suggestive of glucocorticoid or androgen excess. CONCLUSIONS: We investigated the first PUMAH associated with severe Cushing's syndrome and concomitant androgen excess, suggesting pathogenic mechanisms involving KDM1A.

FERN: is it possible to conduct a randomised controlled trial of intervention or expectant management for early-onset selective fetal growth restriction in monochorionic twin pregnancy - protocol for a prospective multicentre mixed-methods feasibility study.

INTRODUCTION: Selective fetal growth restriction (sFGR) in monochorionic twin pregnancy, defined as an estimated fetal weight (EFW) of one twin <10th centile and EFW discordance ≥25%, is associated with stillbirth and neurodisability for both twins. The condition poses unique management difficulties: on the one hand, continuation of the pregnancy carries a risk of death of the smaller twin, with a high risk of co-twin demise (40%) or co-twin neurological sequelae (30%). On the other, early delivery to prevent the death of the smaller twin may expose the larger twin to prematurity, with the associated risks of long-term physical, emotional and financial costs from neurodisability, such as cerebral palsy.When there is severe and early sFGR, before viability, delivery is not an option. In this scenario, there are currently three main management options: (1) expectant management, (2) selective termination of the smaller twin and (3) placental laser photocoagulation of interconnecting vessels. These management options have never been investigated in a randomised controlled trial (RCT). The best management option is unknown, and there are many challenges for a potential RCT. These include the rarity of the condition resulting in a small number of eligible pregnancies, uncertainty about whether pregnant women will agree to participate in such a trial and whether they will agree to be randomised to expectant management or active fetal intervention, and the challenges of robust and long-term outcome measures. Therefore, the main objective of the FERN study is to assess the feasibility of conducting an RCT of active intervention vs expectant management in monochorionic twin pregnancies with early-onset (prior to 24 weeks) sFGR. METHODS AND ANALYSIS: The FERN study is a prospective mixed-methods feasibility study. The primary objective is to recommend whether an RCT of intervention vs expectant management of sFGR in monochorionic twin pregnancy is feasible by exploring women's preference, clinician's preference, current practice and equipoise and numbers of cases. To achieve this, we propose three distinct work packages (WPs). WP1: A Prospective UK Multicentre Study, WP2A: a Qualitative Study Exploring Parents' and Clinicians' Views and WP3: a Consensus Development to Determine Feasibility of a Trial. Eligible pregnancies will be recruited to WP1 and WP2, which will run concurrently. The results of these two WPs will be used in WP3 to develop consensus on a future definitive study. The duration of the study will be 53 months, composed of 10 months of setup, 39 months of recruitment, 42 months of data collection, and 5 months of data analysis, report writing and recommendations. The pragmatic sample size for WP1 is 100 monochorionic twin pregnancies with sFGR. For WP2, interviews will be conducted until data saturation and sample variance are achieved, that is, when no new major themes are being discovered. Based on previous similar pilot studies, this is anticipated to be approximately 15-25 interviews in both the parent and clinician groups. Engagement of at least 50 UK clinicians is planned for WP3. ETHICS AND DISSEMINATION: This study has received ethical approval from the Health Research Authority (HRA) South West-Cornwall and Plymouth Ethics Committee (REC reference 20/SW/0156, IRAS ID 286337). All participating sites will undergo site-specific approvals for assessment of capacity and capability by the HRA. The results of this study will be published in peer-reviewed journals and presented at national and international conferences. The results from the FERN project will be used to inform future studies. TRIAL REGISTRATION NUMBER: This study is included in the ISRCTN Registry (ISRCTN16879394) and the NIHR Central Portfolio Management System (CPMS), CRN: Reproductive Health and Childbirth Specialty (UKCRN reference 47201).

Diagnosis and management of selective fetal growth restriction in monochorionic twin pregnancies: A cross-sectional international survey.

OBJECTIVE: To identify current practices in the management of selective fetal growth restriction (sFGR) in monochorionic diamniotic (MCDA) twin pregnancies. DESIGN: Cross-sectional survey. SETTING: International. POPULATION: Clinicians involved in the management of MCDA twin pregnancies with sFGR. METHODS: A structured, self-administered survey. MAIN OUTCOME MEASURES: Clinical practices and attitudes to diagnostic criteria and management strategies. RESULTS: Overall, 62.8% (113/180) of clinicians completed the survey; of which, 66.4% (75/113) of the respondents reported that they would use an estimated fetal weight (EFW) of <10th centile for the smaller twin and an inter-twin EFW discordance of >25% for the diagnosis of sFGR. For early-onset type I sFGR, 79.8% (75/94) of respondents expressed that expectant management would be their routine practice. On the other hand, for early-onset type II and type III sFGR, 19.3% (17/88) and 35.7% (30/84) of respondents would manage these pregnancies expectantly, whereas 71.6% (63/88) and 57.1% (48/84) would refer these pregnancies to a fetal intervention centre or would offer fetal intervention for type II and type III cases, respectively. Moreover, 39.0% (16/41) of the respondents would consider fetoscopic laser surgery (FLS) for early-onset type I sFGR, whereas 41.5% (17/41) would offer either FLS or selective feticide, and 12.2% (5/41) would exclusively offer selective feticide. For early-onset type II and type III sFGR cases, 25.9% (21/81) and 31.4% (22/70) would exclusively offer FLS, respectively, whereas 33.3% (27/81) and 32.9% (23/70) would exclusively offer selective feticide. CONCLUSIONS: There is significant variation in clinician practices and attitudes towards the management of early-onset sFGR in MCDA twin pregnancies, especially for type II and type III cases, highlighting the need for high-level evidence to guide management.

Clinical effectiveness and safety of time-lapse imaging systems for embryo incubation and selection in in-vitro fertilisation treatment (TILT): a multicentre, three-parallel-group, double-blind, randomised controlled trial.

BACKGROUND: Time-lapse imaging systems for embryo incubation and selection might improve outcomes of in-vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) treatment due to undisturbed embryo culture conditions, improved embryo selection, or both. However, the benefit remains uncertain. We aimed to evaluate the effectiveness of time-lapse imaging systems providing undisturbed culture and embryo selection, and time-lapse imaging systems providing only undisturbed culture, and compared each with standard care without time-lapse imaging. METHODS: We conducted a multicentre, three-parallel-group, double-blind, randomised controlled trial in participants undergoing IVF or ICSI at seven IVF centres in the UK and Hong Kong. Embryologists randomly assigned participants using a web-based system, stratified by clinic in a 1:1:1 ratio to the time-lapse imaging system for undisturbed culture and embryo selection (time-lapse imaging group), time-lapse imaging system for undisturbed culture alone (undisturbed culture group), and standard care without time-lapse imaging (control group). Women were required to be aged 18-42 years and men (ie, their partners) 18 years or older. Couples had to be receiving their first, second, or third IVF or ICSI treatment and could not participate if using donor gametes. Participants and trial staff were masked to group assignment, embryologists were not. The primary outcome was live birth. We performed analyses using the intention-to-treat principle and reported the main analysis in participants with primary outcome data available (full analysis set). The trial is registered on the International Trials Registry (ISRCTN17792989) and is now closed. FINDINGS: 1575 participants were randomly assigned to treatment groups (525 participants per group) between June 21, 2018, and Sept 30, 2022. The live birth rates were 33·7% (175/520) in the time-lapse imaging group, 36·6% (189/516) in the undisturbed culture group, and 33·0% (172/522) in the standard care group. The adjusted odds ratio was 1·04 (97·5% CI 0·73 to 1·47) for time-lapse imaging arm versus control and 1·20 (0·85 to 1·70) for undisturbed culture versus control. The risk reduction for the absolute difference was 0·7 percentage points (97·5% CI -5·85 to 7·25) between the time-lapse imaging and standard care groups and 3·6 percentage points (-3·02 to 10·22) between the undisturbed culture and standard care groups. 79 serious adverse events unrelated to the trial were reported (n=28 in time-lapse imaging, n=27 in undisturbed culture, and n=24 in standard care). INTERPRETATION: In women undergoing IVF or ICSI treatment, the use of time-lapse imaging systems for embryo culture and selection does not significantly increase the odds of live birth compared with standard care without time-lapse imaging. FUNDING: Barts Charity, Pharmasure Pharmaceuticals, Hong Kong OG Trust Fund, Hong Kong Health and Medical Research Fund, Hong Kong Matching Fund.

External validation of risk prediction model for gestational diabetes: Individual participant data meta-analysis of randomized trials.

BACKGROUND: An original validated risk prediction model with good discriminatory prognostic performance for predicting gestational diabetes (GDM) diagnosis, has been updated for recent international association of diabetes in pregnancy study group (IADPSG) diagnostic criteria. However, the updated model is yet to be externally validated on an international dataset. AIMS: To perform an external validation of the updated risk prediction model to evaluate model indices such as discrimination and calibration based on data from the International Weight Management in Pregnancy (i-WIP) Collaborative Group. MATERIALS AND METHODS: The i -WIP dataset was used to validate the GDM prediction tool across discrimination and model calibration. RESULTS: Overall 7689 individual patient data were included, with 17.4 % with GDM, however only 113 cases were available using IADPSG (International Association of Diabetes and Pregnancy Groups) criteria for 75 g OGTT glucose load and ACOG (American College of Obstetricians and Gynecologists) for 100 g glucose load and having the routine clinical risk factor data. The GDM model was moderately discriminatory (Area Under the Curve (AUC) of 0.67; 95 % CI 0.59 to 0.75), Sensitivity 81.0 % (95 % CI 66.7 % to 90.9 %), specificity 53 % (40.3 % to 65.4 %). The GDM score showed reasonable calibration for predicting GDM (slope = 0.84, CITL = 0.77). Imputation for missing data increased the sample to n = 253, and vastly improved the discrimination and calibration of the model to AUC = 78 (95 % CI 72 to 85), sensitivity (81 %, 95 % CI 66.7 % to 90.9 %) and specificity (75 %, 95 % CI 68.8 % to 81 %). CONCLUSION: The updated GDM model showed promising discrimination in predicting GDM in an international population sourced from RCT individual patient data. External validations are essential in order for the risk prediction area to advance, and we demonstrate the utility of using existing RCT data from different global settings. Despite limitations associated with harmonising the data to the variable types in the model, the validation model indices were reasonable, supporting generalizability across continents and populations.

Evidence-based surgical procedures to optimize caesarean outcomes: an overview of systematic reviews.

Background: Caesarean section (CS) is the most performed major surgery worldwide. Surgical techniques used for CS vary widely and there is no internationally accepted standardization. We conducted an overview of systematic reviews (SR) of randomized controlled trials (RCT) to summarize the evidence on surgical techniques or procedures related to CS. Methods: Searches were conducted from database inception to 31 January 2024 in Cochrane Database of Systematic Reviews, PubMed, EMBASE, Lilacs and CINAHL without date or language restrictions. AMSTAR 2 and GRADE were used to assess the methodological quality of the SRs and the certainty of evidence at outcome level, respectively. We classified each procedure-outcome pair into one of eight categories according to effect estimates and certainty of evidence. The overview was registered at PROSPERO (CRD 42023208306). Findings: The analysis included 38 SRs (16 Cochrane and 22 non-Cochrane) published between 2004-2024 involving 628 RCT with a total of 190,349 participants. Most reviews were of low or critically low quality (AMSTAR 2). The SRs presented 345 procedure-outcome comparisons (237 procedure versus procedure, 108 procedure versus no treatment/placebo). There was insufficient or inconclusive evidence for 256 comparisons, clear evidence of benefit for 40, possible benefit for 17, no difference of effect for 13, clear evidence of harm for 14, and possible harm for 5. We found no SRs for 7 pre-defined procedures. Skin cleansing with chlorhexidine, Joel-Cohen-based abdominal incision, uterine incision with blunt dissection and cephalad-caudal expansion, cord traction for placental extraction, manual cervical dilatation in pre-labour CS, changing gloves, chromic catgut suture for uterine closure, non-closure of the peritoneum, closure of subcutaneous tissue, and negative pressure wound therapy are procedures associated with benefits for relevant outcomes. Interpretation: Current evidence suggests that several CS surgical procedures improve outcomes but also reveals a lack of or inconclusive evidence for many commonly used procedures. There is an urgent need for evidence-based guidelines standardizing techniques for CS, and trials to fill existing knowledge gaps. Funding: UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), a cosponsored programme executed by the World Health Organization (WHO).

Effectiveness and safety of COVID-19 vaccines on maternal and perinatal outcomes: a systematic review and meta-analysis.

OBJECTIVE: To assess the effects of COVID-19 vaccines in women before or during pregnancy on SARS-CoV-2 infection-related, pregnancy, offspring and reactogenicity outcomes. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Major databases between December 2019 and January 2023. STUDY SELECTION: Nine pairs of reviewers contributed to study selection. We included test-negative designs, comparative cohorts and randomised trials on effects of COVID-19 vaccines on infection-related and pregnancy outcomes. Non-comparative cohort studies reporting reactogenicity outcomes were also included. QUALITY ASSESSMENT, DATA EXTRACTION AND ANALYSIS: Two reviewers independently assessed study quality and extracted data. We undertook random-effects meta-analysis and reported findings as HRs, risk ratios (RRs), ORs or rates with 95% CIs. RESULTS: Sixty-seven studies (1 813 947 women) were included. Overall, in test-negative design studies, pregnant women fully vaccinated with any COVID-19 vaccine had 61% reduced odds of SARS-CoV-2 infection during pregnancy (OR 0.39, 95% CI 0.21 to 0.75; 4 studies, 23 927 women; I2=87.2%) and 94% reduced odds of hospital admission (OR 0.06, 95% CI 0.01 to 0.71; 2 studies, 868 women; I2=92%). In adjusted cohort studies, the risk of hypertensive disorders in pregnancy was reduced by 12% (RR 0.88, 95% CI 0.82 to 0.92; 2 studies; 115 085 women), while caesarean section was reduced by 9% (OR 0.91, 95% CI 0.85 to 0.98; 6 studies; 30 192 women). We observed an 8% reduction in the risk of neonatal intensive care unit admission (RR 0.92, 95% CI 0.87 to 0.97; 2 studies; 54 569 women) in babies born to vaccinated versus not vaccinated women. In general, vaccination during pregnancy was not associated with increased risk of adverse pregnancy or perinatal outcomes. Pain at the injection site was the most common side effect reported (77%, 95% CI 52% to 94%; 11 studies; 27 195 women). CONCLUSION: COVID-19 vaccines are effective in preventing SARS-CoV-2 infection and related complications in pregnant women. PROSPERO REGISTRATION NUMBER: CRD42020178076.

Maternal and perinatal outcomes in twin pregnancies following assisted reproduction: a systematic review and meta-analysis involving 802 462 pregnancies.

BACKGROUND: ART is associated with higher rates of twin pregnancies than singleton pregnancies. Whether twin pregnancies conceived following ART have additional maternal and neonatal complications compared with non-ART twin pregnancies is not known. OBJECTIVE AND RATIONALE: The objective was to quantify the risk of adverse maternal and perinatal outcomes among twin pregnancies conceived following ART compared with non-ART and natural conception. Existing reviews vary in the reported outcomes, with many studies including triplet pregnancies in the study population. Therefore, we aimed to perform an up-to-date review with an in-depth analysis of maternal and perinatal outcomes limited to twin pregnancies. SEARCH METHODS: We searched electronic databases MEDLINE and EMBASE from January 1990 to May 2023 without language restrictions. All cohort studies reporting maternal and perinatal outcomes following ART compared with non-ART twin pregnancies and natural conception were included. Case-control studies, case reports, case series, animal studies, and in vitro studies were excluded. The Newcastle-Ottawa Scale was used to assess the methodological quality of the studies. Using random-effects meta-analysis, the estimates were pooled and the findings were reported as odds ratios (OR) with 95% CI. OUTCOMES: We included 111 studies (802 462 pregnancies). Twin pregnancies conceived following ART were at higher risk of preterm birth at <34 weeks (OR 1.33, 95% CI 1.14-1.56, 29 studies, I2 = 73%), <37 weeks (OR 1.26, 95% CI 1.19-1.33, 70 studies, I2 = 76%), hypertensive disorders in pregnancy (OR 1.29, 95% CI 1.14-1.46, 59 studies, I2 = 87%), gestational diabetes mellitus (OR 1.61, 95% CI 1.48-1.75, 51 studies, I2 = 65%), and caesarean delivery (OR 1.80, 95% CI 1.65-1.97, 70 studies, I2 = 89%) compared with non-ART twins. The risks for the above maternal outcomes were also increased in the ART group compared with natural conception. Of the perinatal outcomes, ART twins were at significantly increased risk of congenital malformations (OR 1.17, 95% CI 1.05-1.30, 39 studies, I2 = 59%), birthweight discordance (>25% (OR 1.31, 95% CI 1.05-1.63, 7 studies, I2 = 0%)), respiratory distress syndrome (OR 1.32, 95% CI 1.09-1.60, 16 studies, I2 = 61%), and neonatal intensive care unit admission (OR 1.24, 95% CI 1.14-1.35, 32 studies, I2 = 87%) compared with non-ART twins. When comparing ART with natural conception, the risk of respiratory distress syndrome, intensive care admissions, and birthweight discordance >25% was higher among the ART group. Perinatal complications, such as stillbirth (OR 0.83, 95% CI 0.70-0.99, 33 studies, I2 = 49%), small for gestational age <10th centile (OR 0.90, 95% CI 0.85-0.95, 26 studies, I2 = 36%), and twin-twin transfusion syndrome (OR 0.45, 95% CI 0.25-0.82, 9 studies, I2 = 25%), were reduced in twin pregnancies conceived with ART versus those without ART. The above perinatal complications were also fewer amongst the ART group than natural conception. WIDER IMPLICATIONS: ART twin pregnancies are associated with higher maternal complications than non-ART pregnancies and natural conception, with varied perinatal outcomes. Women seeking ART should be counselled about the increased risks of ART twin pregnancies and should be closely monitored in pregnancy for complications. We recommend exercising caution when interpreting the study findings owing to the study's limitations.

Vulnerabilities and reparative strategies during pregnancy, childbirth, and the postpartum period: moving from rhetoric to action.

Maternal outcomes throughout pregnancy, childbirth, and the postnatal period are influenced by interlinked and interdependent vulnerabilities. A comprehensive understanding of how various threats and barriers affect maternal and perinatal health is critical to plan, evaluate and improve maternal health programmes. This paper builds on the introductory paper of the Series on the determinants of maternal health by assessing vulnerabilities during pregnancy, childbirth, and the postnatal period. We synthesise and present the concept of vulnerability in pregnancy and childbirth, and map vulnerability attributes and their dynamic influence on maternal outcomes in early and late pregnancy and during childbirth and the postnatal period, with a particular focus on low-income and middle-income countries (LMICs). We summarise existing literature and present the evidence on the effects of various reparative strategies to improve pregnancy and childbirth outcomes. Lastly, we discuss the implications of the identified vulnerability attributes and reparative strategies for the efforts of policymakers, healthcare professionals, and researchers working towards improving outcomes for women and birthing people in LMICs.

Association between pregnancy-related complications and development of type 2 diabetes and hypertension in women: an umbrella review.

BACKGROUND: Despite many systematic reviews and meta-analyses examining the associations of pregnancy complications with risk of type 2 diabetes mellitus (T2DM) and hypertension, previous umbrella reviews have only examined a single pregnancy complication. Here we have synthesised evidence from systematic reviews and meta-analyses on the associations of a wide range of pregnancy-related complications with risk of developing T2DM and hypertension. METHODS: Medline, Embase and Cochrane Database of Systematic Reviews were searched from inception until 26 September 2022 for systematic reviews and meta-analysis examining the association between pregnancy complications and risk of T2DM and hypertension. Screening of articles, data extraction and quality appraisal (AMSTAR2) were conducted independently by two reviewers using Covidence software. Data were extracted for studies that examined the risk of T2DM and hypertension in pregnant women with the pregnancy complication compared to pregnant women without the pregnancy complication. Summary estimates of each review were presented using tables, forest plots and narrative synthesis and reported following Preferred Reporting Items for Overviews of Reviews (PRIOR) guidelines. RESULTS: Ten systematic reviews were included. Two pregnancy complications were identified. Gestational diabetes mellitus (GDM): One review showed GDM was associated with a 10-fold higher risk of T2DM at least 1 year after pregnancy (relative risk (RR) 9.51 (95% confidence interval (CI) 7.14 to 12.67) and although the association differed by ethnicity (white: RR 16.28 (95% CI 15.01 to 17.66), non-white: RR 10.38 (95% CI 4.61 to 23.39), mixed: RR 8.31 (95% CI 5.44 to 12.69)), the between subgroups difference were not statistically significant at 5% significance level. Another review showed GDM was associated with higher mean blood pressure at least 3 months postpartum (mean difference in systolic blood pressure: 2.57 (95% CI 1.74 to 3.40) mmHg and mean difference in diastolic blood pressure: 1.89 (95% CI 1.32 to 2.46) mmHg). Hypertensive disorders of pregnancy (HDP): Three reviews showed women with a history of HDP were 3 to 6 times more likely to develop hypertension at least 6 weeks after pregnancy compared to women without HDP (meta-analysis with largest number of studies: odds ratio (OR) 4.33 (3.51 to 5.33)) and one review reported a higher rate of T2DM after HDP (hazard ratio (HR) 2.24 (1.95 to 2.58)) at least a year after pregnancy. One of the three reviews and five other reviews reported women with a history of preeclampsia were 3 to 7 times more likely to develop hypertension at least 6 weeks postpartum (meta-analysis with the largest number of studies: OR 3.90 (3.16 to 4.82) with one of these reviews reporting the association was greatest in women from Asia (Asia: OR 7.54 (95% CI 2.49 to 22.81), Europe: OR 2.19 (95% CI 0.30 to 16.02), North and South America: OR 3.32 (95% CI 1.26 to 8.74)). CONCLUSIONS: GDM and HDP are associated with a greater risk of developing T2DM and hypertension. Common confounders adjusted for across the included studies in the reviews were maternal age, body mass index (BMI), socioeconomic status, smoking status, pre-pregnancy and current BMI, parity, family history of T2DM or cardiovascular disease, ethnicity, and time of delivery. Further research is needed to evaluate the value of embedding these pregnancy complications as part of assessment for future risk of T2DM and chronic hypertension.

Persistent organic pollutant exposure as a risk factor of gestational diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND: Findings related to the association between persistent organic pollutants (POPs) and gestational diabetes mellitus (GDM) are inconclusive. OBJECTIVES: To estimate the strength of the association between POP exposure and GDM in a systematic review with meta-analysis. SEARCH STRATEGY: MEDLINE, Scopus and Web of Science were searched until July 2023. SELECTION CRITERIA: Cohort and case-control studies analysing the association between POPs and GDM. DATA COLLECTION AND ANALYSIS: We assessed the risk of bias using the Quality in Prognosis Studies scale (QUIPS). Standardised mean differences were pooled using random-effect models. MAIN RESULTS: Sixteen articles including 12 216 participants were selected. The risk of bias was high in four articles (25%), moderate in 11 (68.75%) and low in one (6.25%). Small mean difference between GDM cases and controls was observed for PFHpA (0.26, 95% confidence interval [CI] 0.1-0.35, I2 = 0.0%), PCB180 (0.37, 95% CI 0.19-0.56; I2 = 25.3%), BDE47 (0.23, 95% CI 0.0-0.45, I2 = 0%), BDE99 (0.36, 95% CI 0.14-0.59; I2 = 0%), BDE100 (0.42, 95% CI 0.19-0.64; I2 = 0%) and HCB (0.22, 95% CI 0.01-0.42, I2 = 39.6%). No considerable difference was observed for the rest of POPs. CONCLUSION: Small mean differences between GDM cases and controls were observed for some POPs. However, evidence shows mostly moderate quality and results were heterogeneous. Improved research methodology is needed to assess POPs and GDM risk.

Neglected medium-term and long-term consequences of labour and childbirth: a systematic analysis of the burden, recommended practices, and a way forward.

Over the past three decades, substantial progress has been made in reducing maternal mortality worldwide. However, the historical focus on mortality reduction has been accompanied by comparative neglect of labour and birth complications that can emerge or persist months or years postnatally. This paper addresses these overlooked conditions, arguing that their absence from the global health agenda and national action plans has led to the misconception that they are uncommon or unimportant. The historical limitation of postnatal care services to the 6 weeks after birth is also a contributing factor. We reviewed epidemiological data on medium-term and long-term complications arising from labour and childbirth beyond 6 weeks, along with high-quality clinical guidelines for their prevention, identification, and treatment. We explore the complex interplay of human evolution, maternal physiology, and inherent predispositions that contribute to these complications. We offer actionable recommendations to change the current trajectories of these neglected conditions and help achieve the targets of Sustainable Development Goal 3. This paper is the third in a Series of four papers about maternal health in the perinatal period and beyond.

COVID-19 in pregnant women: a systematic review and meta-analysis on the risk and prevalence of pregnancy loss.

BACKGROUND: Pregnant women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are more likely to experience preterm birth and their neonates are more likely to be stillborn or admitted to a neonatal unit. The World Health Organization declared in May 2023 an end to the coronavirus disease 2019 (COVID-19) pandemic as a global health emergency. However, pregnant women are still becoming infected with SARS-CoV-2 and there is limited information available regarding the effect of SARS-CoV-2 infection in early pregnancy on pregnancy outcomes. OBJECTIVE AND RATIONALE: We conducted this systematic review to determine the prevalence of early pregnancy loss in women with SARS-Cov-2 infection and compare the risk to pregnant women without SARS-CoV-2 infection. SEARCH METHODS: Our systematic review is based on a prospectively registered protocol. The search of PregCov19 consortium was supplemented with an extra electronic search specifically on pregnancy loss in pregnant women infected with SARS-CoV-2 up to 10 March 2023 in PubMed, Google Scholar, and LitCovid. We included retrospective and prospective studies of pregnant women with SARS-CoV-2 infection, provided that they contained information on pregnancy losses in the first and/or second trimester. Primary outcome was miscarriage defined as a pregnancy loss before 20 weeks of gestation, however, studies that reported loss up to 22 or 24 weeks were also included. Additionally, we report on studies that defined the pregnancy loss to occur at the first and/or second trimester of pregnancy without specifying gestational age, and for second trimester miscarriage only when the study presented stillbirths and/or foetal losses separately from miscarriages. Data were stratified into first and second trimester. Secondary outcomes were ectopic pregnancy (any extra-uterine pregnancy), and termination of pregnancy. At least three researchers independently extracted the data and assessed study quality. We calculated odds ratios (OR) and risk differences (RDs) with corresponding 95% CI and pooled the data using random effects meta-analysis. To estimate risk prevalence, we performed meta-analysis on proportions. Heterogeneity was assessed by I2. OUTCOMES: We included 120 studies comprising a total of 168 444 pregnant women with SARS-CoV-2 infection; of which 18 233 women were in their first or second trimester of pregnancy. Evidence level was considered to be of low to moderate certainty, mostly owing to selection bias. We did not find evidence of an association between SARS-CoV-2 infection and miscarriage (OR 1.10, 95% CI 0.81-1.48; I2 = 0.0%; RD 0.0012, 95% CI -0.0103 to 0.0127; I2 = 0%; 9 studies, 4439 women). Miscarriage occurred in 9.9% (95% CI 6.2-14.0%; I2 = 68%; 46 studies, 1797 women) of the women with SARS CoV-2 infection in their first trimester and in 1.2% (95% CI 0.3-2.4%; I2 = 34%; 33 studies; 3159 women) in the second trimester. The proportion of ectopic pregnancies in women with SARS-CoV-2 infection was 1.4% (95% CI 0.02-4.2%; I2 = 66%; 14 studies, 950 women). Termination of pregnancy occurred in 0.6% of the women (95% CI 0.01-1.6%; I2 = 79%; 39 studies; 1166 women). WIDER IMPLICATIONS: Our study found no indication that SARS-CoV-2 infection in the first or second trimester increases the risk of miscarriages. To provide better risk estimates, well-designed studies are needed that include pregnant women with and without SARS-CoV-2 infection at conception and early pregnancy and consider the association of clinical manifestation and severity of SARS-CoV-2 infection with pregnancy loss, as well as potential confounding factors such as previous pregnancy loss. For clinical practice, pregnant women should still be advised to take precautions to avoid risk of SARS-CoV-2 exposure and receive SARS-CoV-2 vaccination.

Sex-Specific Obesity and Cardiometabolic Disease Risks in Low- and Middle-Income Countries: A Meta-Analysis Involving 3 916 276 Individuals.

CONTEXT: There is limited knowledge about the disparities between the sexes in obesity prevalence and associated cardiovascular complications in low- and middle-income countries (LMICs). OBJECTIVE: We undertook a systematic review and meta-analysis to assess sex-specific disparities in the prevalence of obesity and cardiometabolic diseases in LMICs, the burden in women, and variations by region, country's income status, setting, and time. METHODS: We searched major databases from inception to March 2023. Two independent reviewers selected the studies, assessed their quality, and extracted data. We used DerSimonian and Laird random-effects models to obtain pooled estimates of odds ratios and 95% CI for the association between sex and obesity and cardiometabolic diseases, and multilevel random-effects logistic regression models to estimate the prevalence of relevant outcomes (PROSPERO CRD42019132609). RESULTS: We included 345 studies (3 916 276 individuals). The odds of obesity were 2.72-fold higher in women than men (OR 2.72; 95% CI, 2.54-2.91). The sex-specific disparities varied by region, with the greatest disparities in Sub-Saharan Africa (OR 3.91; 95% CI, 3.49-4.39). Among women in LMICs, 23% (95% CI, 21%-25%) had obesity, 27% (95% CI, 24%-29%) had hypertension, and 7% (95% CI, 6%-9%) had type 2 diabetes. The prevalence of obesity and type 2 diabetes in women varied by region, country's income, and setting, with the highest prevalence in the Middle East and North Africa, upper-middle-income countries and urban settings. The odds of hypertension (OR 2.41; 95% CI, 1.89-3.08) and type 2 diabetes (OR 2.65; 95% CI, 1.76-3.98) were doubled in women with vs without obesity. CONCLUSION: There is an urgent need for a women-centred and region-stratified approach to tackle obesity awareness, treatment, and prevention in women in LMICs.

Factors affecting the implementation of calcium supplementation strategies during pregnancy to prevent pre-eclampsia: a mixed-methods systematic review.

OBJECTIVES: Daily calcium supplements are recommended for pregnant women from 20 weeks' gestation to prevent pre-eclampsia in populations with low dietary calcium intake. We aimed to improve understanding of barriers and facilitators for calcium supplement intake during pregnancy to prevent pre-eclampsia. DESIGN: Mixed-method systematic review, with confidence assessed using the Grading of Recommendations, Assessment, Development and Evaluations-Confidence in the Evidence from Reviews of Qualitative research approach. DATA SOURCES: MEDLINE and EMBASE (via Ovid), CINAHL and Global Health (via EBSCO) and grey literature databases were searched up to 17 September 2022. ELIGIBILITY CRITERIA: We included primary qualitative, quantitative and mixed-methods studies reporting implementation or use of calcium supplements during pregnancy, excluding calcium fortification and non-primary studies. No restrictions were imposed on settings, language or publication date. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and assessed risk of bias. We analysed the qualitative data using thematic synthesis, and quantitative findings were thematically mapped to qualitative findings. We then mapped the results to behavioural change frameworks to identify barriers and facilitators. RESULTS: Eighteen reports from nine studies were included in this review. Women reported barriers to consuming calcium supplements included limited knowledge about calcium supplements and pre-eclampsia, fears and experiences of side effects, varying preferences for tablets, dosing, working schedules, being away from home and taking other supplements. Receiving information regarding pre-eclampsia and safety of calcium supplement use from reliable sources, alternative dosing options, supplement reminders, early antenatal care, free supplements and support from families and communities were reported as facilitators. Healthcare providers felt that consistent messaging about benefits and risks of calcium, training, and ensuring adequate staffing and calcium supply is available would be able to help them in promoting calcium. CONCLUSION: Relevant stakeholders should consider the identified barriers and facilitators when formulating interventions and policies on calcium supplement use. These review findings can inform implementation to ensure effective and equitable provision and scale-up of calcium interventions. PROSPERO REGISTRATION NUMBER: CRD42021239143.