AN INSIGHT ON THE MATERNAL & FETAL OUTCOME OF CRITICALLY ILL PREGNANT WOMEN DURING THE SECOND WAVE OF COVID-19 (preprint)

Objective: To assess and compare the Maternal and fetal outcomes of critically ill pregnant women infected with COVID – 19 cases of pneumonia who required admission to the intensive care unit. Design: A retrospective observational study Settings: Tertiary care hospital settings affiliated with an academic center in UAE. Patients and Methods: A total of 123 patients in their third trimester were included from 1 December 2020 to 31 March 2021 in the study with 30 cases of severe or critical COVID and 93 mild to moderate pregnant COVID patients. The maternal demographic, radiological, and biochemical profile of mothers was noted. Maternal and fetal outcomes were compared. Main outcomes Measured: Maternal and fetal outcomes were compared in severe and mild COVID cases. Result: A total of 30 (24.3%) patients were admitted in ICU and eight required invasive ventilation meaning, Severe COVID was significantly associated with higher mortality (20% vs 0% p-value <0.001), postpartum complications (50% vs 9.67% p-value<0.001) and increased overall hospital stay (p-value<0.001). Neonates born to severe COVID patients had significant higher chances of being born preterm (76.6% vs 35.7% p-value<0.001) and have low birth weight (46.6% vs 13.9% p-value=0.002). There were four cases of stillbirth, two cases of vertical transmission, and no neonatal deaths. Conclusion: Pregnant females with severe COVID have high mortality, peripartum complications; and increased hospital stay. The newborns born to such mothers may be premature, have low birth weights but have comparable mortality

Covid-19 vaccine safety in pregnancy, a nested case-control study in births from April 2021 to March 2022, England (preprint)

Introduction: Vaccine safety in pregnancy is always of paramount importance. Current evidence of COVID-19 vaccine safety in pregnancy has been reassuring with no association found with negative maternal and neonatal outcomes. However, very few safety studies are conducted on a national level and investigate dosage, timing of vaccination as well as vaccine manufacturer. To fill this knowledge gap, we conducted a population based COVID-19 vaccine safety evaluation in England, including timing of vaccination by trimester, dosage and vaccine manufacturer received in pregnancy. Method: A matched case control study nested in a retrospective cohort where adverse maternal and neonatal pregnancy outcomes were compared across several COVID-19 vaccine exposures using conditional multivariable logistic regression, adjusting for a range of demographic and health characteristics. Eligible participants were identified from the national maternity services dataset (MSDS) and records were linked to hospital admission, national COVID-19 vaccine and COVID-19 testing databases. Matching criteria differed by outcome but included participant's age and estimated week of conception. Results: 514,013 pregnant individuals aged between 18 and 50 years were identified during the study period (births from 16th of April 2021- 31st March 2022). Receiving at least one dose of COVID-19 vaccine during pregnancy conferred lower odds of giving birth to a baby who was low birthweight (aOR=0.86, 95% CI: 0.79 - 0.93), preterm (aOR=0.89, 95% CI: 0.85 - 0.92) or who had an Apgar score less than 7 at five mins of age (aOR=0.89, 95% CI: 0.80 - 0.98). There was no association between vaccination in pregnancy and stillbirth (aOR=0.90, 95% CI: 0.76 - 1.07), neonatal death (aOR=1.27, 95% CI: 0.91 - 1.77) perinatal death (aOR=0.98, 95% CI: 0.83 - 1.16), and maternal venous thromboembolism in pregnancy (aOR=0.82, 95% CI: 0.43 - 1.56). The odds of maternal admission to intensive care unit were lower in vaccinated pregnant women (aOR=0.85, 95% CI: 0.76 - 0.95). Conclusion: COVID-19 vaccines are safe to use in pregnancy and they confer protection against SARS-CoV-2 infection which can lead to adverse outcomes for both the mother and the infant. Our findings generated important information to communicate to pregnant women and health professionals to support COVID-19 maternal vaccination programmes.

Changes in stillbirths and child and youth mortality in 2020 and 2021 during the Covid-19 pandemic (preprint)

Background: The COVID-19 pandemic's impact on mortality, especially among the elderly, has been extensively studied. While COVID-19 rarely causes direct mortality in children and youth, the pandemic's indirect effects might harm these age groups. Yet, its influence on stillbirths and mortality rates in neonates, infants, children, and youth remains poorly understood. This study examines disruptions in such trends across 95 countries in 2020 and 72 in 2021, providing the inaugural comprehensive analysis of COVID-19's effect on young mortality and stillbirths. Methods: We estimate expected mortality levels in a non-pandemic setting and calculate relative mortality changes (p-scores) by applying generalized linear models to data from civil registers and vital statistics systems (CRSV) and from the Health Management Information System (HMIS). We then use these estimates to analyze, for each age group, the distribution of country-specific mortality changes and the proportion of countries experiencing mortality deficits, no changes, and excess. Results: For most countries and territories, stillbirths and mortality at ages under 25 did not differ from expected levels in 2020 and 2021. However, when focusing on the countries that did show changes, more countries experienced mortality deficits than excess. The exception was stillbirths in both years and mortality among neonates and those aged 10-24 in 2021, where more countries had an excess rather than a deficit. Overall, a quarter of the countries examined experienced increases in stillbirths and young adult mortality (20-24). Conclusion: Despite global disruptions to essential services, stillbirths and youth mortality were as expected in most countries, defying expectations. However, this doesn't dismiss hypotheses suggesting delayed adverse effects on the youngest that may require more time to be noticeable at the population level. Close and long-term monitoring of health and deaths among children and youth, particularly in low-income and lower-middle-income countries, is required to fully understand the lasting impacts of the COVID-19 pandemic.

The impact of the COVID-19 pandemic on adverse fetal outcomes: A cross-sectional study.

The coronavirus disease 2019 (COVID-19) pandemic has been one of the most damaging pandemics in all of human history. Some of the most vulnerable groups within society such as pregnant women and children have also been affected. This observational research, cross-sectional study was conducted to investigate if there was any difference in the incidence of unfavorable outcomes in pregnancy such as miscarriage, intrauterine fetal demise, and early neonatal death during the year prior to the pandemic and the year of the COVID-19 pandemic. This retrospective study was conducted at the University Hospital of Split at the Department of Pathology, Forensic and Cytology and Department of Obstetrics and Gynecology of the same hospital. All data was collected in the time period from March 1st, 2019, to March 1st, 2021. The study included all pregnant women who had an unfavorable pregnancy outcome such as miscarriage and intrauterine fetal demise, as well as early neonatal death at the University Hospital of Split within the time frame mentioned previously. There was no statistically significant difference in the incidence of adverse pregnancy outcomes in the year prior to the pandemic and during the year of the COVID-19 pandemic. Our study showed that the pandemic did not have a negative effect on pregnant women and their fetuses; there was no increase in miscarriage, intrauterine fetal demise, or perinatal death during the year of the pandemic.

Late miscarriage and stillbirth in asymptomatic and symptomatic hospitalised pregnant women in Belgium during the first and second waves of COVID-19: a prospective nationwide population-based study.

BACKGROUND: Stillbirth has been recognized as a possible complication of a SARS-CoV-2 infection during pregnancy, probably due to destructive placental lesions (SARS-CoV-2 placentitis). The aim of this work is to analyse stillbirth and late miscarriage cases in unvaccinated pregnant women infected with SARS-CoV-2 during the first two waves (wild-type period) in Belgium. METHODS: Stillbirths and late miscarriages in our prospective observational nationwide registry of SARS-CoV-2 infected pregnant women (n = 982) were classified by three authors using a modified WHO-UMC classification system for standardized case causality assessment. RESULTS: Our cohort included 982 hospitalised pregnant women infected with SARS-CoV-2, with 23 fetal demises (10 late miscarriages from 12 to 22 weeks of gestational age and 13 stillbirths). The stillbirth rate was 9.5‰ for singleton pregnancies and 83.3‰ for multiple pregnancies, which seems higher than for the background population (respectively 5.6‰ and 13.8‰). The agreement between assessors about the causal relationship with SARS-Cov-2 infection was fair (global weighted kappa value of 0.66). Among these demises, 17.4% (4/23) were "certainly" attributable to SARS-CoV-2 infection, 13.0% (3/23) "probably" and 30.4% (7/23) "possibly". Better agreement in the rating was noticed when pathological examination of the placenta and identification of the virus were available, underlining the importance of a thorough investigation in case of intra-uterine fetal demise. CONCLUSIONS: SARS-CoV-2 causality assessment of late miscarriage and stillbirth cases in our Belgian nationwide case series has shown that half of the fetal losses could be attributable to SARS-CoV-2. We must consider in future epidemic emergencies to rigorously investigate cases of intra-uterine fetal demise and to store placental tissue and other material for future analyses.

Reduction in Spontaneous and Iatrogenic Preterm Births in Twin Pregnancies During COVID-19 Lockdown in Melbourne, Australia: A Multicenter Cohort Study (preprint)

Background: Melbourne, Australia, recorded one of the longest and most stringent pandemic lockdowns in 2020, which was associated with an increase in preterm stillbirths among singleton pregnancies. Twin pregnancies may be particularly susceptible to the impacts of pandemic disruptions to maternity care due to their higher background risk of adverse perinatal outcomes. Objective: To compare the rates of adverse perinatal outcomes in twin pregnancies exposed and unexposed to lockdown restrictions in Melbourne. Study Design: Multicenter retrospective cohort study of all twin pregnancies birthing in public maternity hospitals in Melbourne. We compared perinatal outcomes between a pre-pandemic group ('unexposed') and two lockdown-exposed groups: exposure 1 from 22 March 2020 to 21 March 2021 and exposure 2 from 22 March 2021 to 27 March 2022. We analyzed routinely-collected maternity data on all twin births >20 weeks where outcomes were available for both infants. The primary outcomes were rates of preterm birth<37 weeks and all-cause stillbirth. Multivariable log-binomial regression models were used to compare perinatal outcomes between the pre-pandemic group and women in whom weeks 20+0 to 40+0 of their pregnancy occurred entirely during each lockdown-exposure period. Perinatal outcomes were calculated per infant; maternal outcomes were calculated per pregnancy. Results: We included 2267 women birthing twins. Total preterm births<37 weeks were significantly lower in the exposure 1 group compared with the pre-pandemic group (63.1% vs 68.3% respectively; adjusted risk ratio, aRR 0.92 95% CI 0.87-0.98, p=0.01). This was driven by both fewer iatrogenic preterm births (44.1% vs 48.1%; aRR 0.97 95% CI 0.92-1.03, p=0.39) and fewer spontaneous preterm births (18.9% vs 20.3%; aRR 0.95 95% CI 0.90-0.99, p=0.04). There were also significantly lower rates of preterm birth<34 weeks in the exposure 1 group compared with the pre-pandemic group (19.9% vs 23.0%, aRR 0.93 95% CI 0.89-0.98 p=0.01). Total iatrogenic births for fetal compromise were significantly lower (13.4% vs 20.4%; aRR 0.94 95% CI 0.89-0.98, p=0.01). There were fewer special care nursery admissions (38.5% vs 43.4%; aRR 0.91 95% CI 0.87-0.95, p<0.001). There was no associated difference in all-cause stillbirths (1.5% vs 1.6%; aRR 1.00 95% CI 0.99-1.01, p=0.82), adjusted stillbirths, birthweight<3rd centile (5.7% vs 6.0%; aRR 1.00, 95% CI 0.98-1.02 p=0.74) or neonatal intensive care unit admissions in the exposure 1 group compared to the pre-pandemic group. In contrast, when comparing the pre-pandemic group with exposure 2 group, there was no significant difference in the rates of preterm birth<37 or <34 weeks (p>0.05). However, during exposure 2 the rate of preterm birth<28 weeks was significantly higher (7.2% vs 4.8%; aRR 1.03 95% CI 1.01-1.05, p=0.04) and infants were more likely to be admitted to a neonatal intensive care unit (25.0% vs 19.6%; aRR 1.06 95% CI 1.03-1.10, p<0.0001) compared with the pre-pandemic period. Conclusions: Melbourne's first lockdown-exposure period was associated with fewer twin preterm births<34 and <37 weeks without significant differences in stillbirths or adverse newborn outcomes. These lower rates were not sustained into the second exposure period. Pandemic conditions may provide important lessons for future antenatal care of twin pregnancies, including prevention of preterm birth and optimal timing of birth.

Pregnancy outcomes after SARS-CoV-2 infection in periods dominated by delta and omicron variants in Scotland: a population-based cohort study.

BACKGROUND: Evidence suggests that the SARS-CoV-2 omicron (B.1·1.529) is associated with lower risks of adverse outcomes than the delta (B.1.617.2) variant among the general population. However, little is known about outcomes after omicron infection in pregnancy. We aimed to assess and compare short-term pregnancy outcomes after SARS-CoV-2 delta and omicron infection in pregnancy. METHODS: We did a national population-based cohort study of women who had SARS-CoV-2 infection in pregnancy between May 17, 2021, and Jan 31, 2022. The primary maternal outcome was admission to critical care within 21 days of infection or death within 28 days of date of infection. Pregnancy outcomes were preterm birth and stillbirth within 28 days of infection. Neonatal outcomes were death within 28 days of birth, and low Apgar score (<7 of 10, for babies born at term) or neonatal SARS-CoV-2 infection in births occurring within 28 days of maternal infection. We used periods when variants were dominant in the general Scottish population, based on 50% or more of cases being S-gene positive (delta variant, from May 17 to Dec 14, 2021) or S-gene negative (omicron variant, from Dec 15, 2021, to Jan 31, 2022) as surrogates for variant infections. Analyses used logistic regression, adjusting for maternal age, deprivation quintile, ethnicity, weeks of gestation, and vaccination status. Sensitivity analyses included restricting the analysis to those with first confirmed SARS-CoV-2 infection and using periods when delta or omicron had 90% or more predominance. FINDINGS: Between May 17, 2021, and Jan 31, 2022, there were 9923 SARS-CoV-2 infections in 9823 pregnancies, in 9817 women in Scotland. Compared with infections in the delta-dominant period, SARS-CoV-2 infections in pregnancy in the omicron-dominant period were associated with lower maternal critical care admission risk (0·3% [13 of 4968] vs 1·8% [89 of 4955]; adjusted odds ratio 0·25, 95% CI 0·14-0·44) and lower preterm birth within 28 days of infection (1·8% [37 of 2048] vs 4·2% [98 of 2338]; 0·57, 95% CI 0·38-0·87). There were no maternal deaths within 28 days of infection. Estimates of low Apgar scores were imprecise due to low numbers (5 [1·2%] of 423 with omicron vs 11 [2·1%] of 528 with delta, adjusted odds ratio 0·72, 0·23-2·32). There were fewer stillbirths in the omicron-dominant period than in the delta-dominant period (4·3 [2 of 462] per 1000 births vs 20·3 [13 of 639] per 1000) and no neonatal deaths during the omicron-dominant period (0 [0 of 460] per 1000 births vs 6·3 [4 of 626] per 1000 births), thus numbers were too small to support adjusted analyses. Rates of neonatal infection were low in births within 28 days of maternal SARS-CoV-2 infection, with 11 cases of neonatal SARS-CoV-2 in the delta-dominant period, and 1 case in the omicron-dominant period. Of the 15 stillbirths, 12 occurred in women who had not received two or more doses of COVID-19 vaccination at the time of SARS-CoV-2 infection in pregnancy. All 12 cases of neonatal SARS-CoV-2 infection occurred in women who had not received two or more doses of vaccine at the time of maternal infection. Findings in sensitivity analyses were similar to those in the main analyses. INTERPRETATION: Pregnant women infected with SARS-CoV-2 were substantially less likely to have a preterm birth or maternal critical care admission during the omicron-dominant period than during the delta-dominant period. FUNDING: Wellcome Trust, Tommy's charity, Medical Research Council, UK Research and Innovation, Health Data Research UK, National Core Studies-Data and Connectivity, Public Health Scotland, Scottish Government Health and Social Care, Scottish Government Chief Scientist Office, National Research Scotland.

SARS-CoV-2 in Pregnancy-The First Wave.

Background and Objectives: COVID-19, a disease caused by SARS-CoV-2, is a public health emergency. Data on the effect of the virus on pregnancy are limited. Materials and Methods: We carried out a retrospective descriptive study, in order to evaluate the obstetric results on pregnant women in which SARS-CoV-2 was detected through RT-PCR of the nasopharyngeal swab, at admission to the maternity hospital. Results: From 16 March to 31 July 2020, 12 SARS-CoV-2 positive pregnant women have been hospitalized. Eleven were hospitalized for initiation or induction of labor, corresponding to 0.64% of deliveries in the maternity hospital. One pregnant woman was hospitalized for threatened abortion, culminating in a stillbirth at 20 weeks of gestation. Regarding the severity of the disease, nine women were asymptomatic and three had mild illness (two had associated cough and one headache). Three had relevant environmental exposure and a history of contact with infected persons. None had severe or critical illness due to SARS-CoV-2. There were no maternal deaths. The following gestational complications were observed: one stillbirth, one preterm labor, one preterm prelabor rupture of membranes, and one fetal growth restriction. Four deliveries were eutocic, two vacuum-assisted deliveries and five were cesarean sections. The indications for cesarean section were obstetric. Conclusions: SARS-CoV-2 infection was found in a minority of hospitalized pregnant women in this sample. Most are asymptomatic or have mild illness, from gestational complications to highlight stillbirth and preterm birth. There were no cases of vertical transmission by coronavirus.

Effects of COVID-19 vaccination during pregnancy on SARS-CoV-2 infection and maternal and neonatal outcomes: A systematic review and meta-analysis.

SARS-CoV-2 infection during pregnancy is associated with adverse maternal and neonatal outcomes, but no systematic synthesis of evidence on COVID-19 vaccination during pregnancy against these outcomes has been undertaken. Thus, we aimed to assess the collective evidence on the effects of COVID-19 vaccination during pregnancy on maternal and neonatal outcomes. PubMed/MEDLINE, CENTRAL, and EMBASE were systematically searched for articles published up to 1 November 2022. A systematic review and meta-analysis were performed to calculate pooled effects size and 95% confidence interval (CI). We evaluated 30 studies involving 862,272 individuals (308,428 vaccinated and 553,844 unvaccinated). Overall pooled analyses in pregnant women during pregnancy showed reduced risks of SARS-CoV-2 infection by 60% (41%-73%), COVID-19 hospitalisation during pregnancy by 53% (31%-69%), and COVID-19 intensive care unit (ICU) admission by 82% (12%-99%). Neonates of vaccinated women were 1.78 folds more likely to acquire SARS-CoV-2 infection during the first 2, 4 and 6 months of life during the Omicron period. The risk of stillbirth was reduced by 45% (17%-63%) in association with vaccination (vs. no vaccination) in pregnancy. A decrease of 15% (3%-25%), 33% (14%-48%), and 33% (17%-46%) in the odds of preterm births before 37, 32 and 28 weeks' gestation were associated with vaccination (vs. no vaccination) in pregnancy, respectively. The risk of neonatal ICU admission was significantly lower by 20% following COVID-19 vaccination in pregnancy (16%-24%). There was no evidence of a higher risk of adverse outcomes including miscarriage, gestational diabetes, gestational hypertension, cardiac problems, oligohydramnios, polyhydramnios, unassisted vaginal delivery, cesarean delivery, postpartum haemorrhage, gestational age at delivery, placental abruption, Apgar score at 5 min below 7, low birthweight (<2500 g), very low birthweight (<1500 g), small for gestational age, and neonatal foetal abnormalities. COVID-19 vaccination during pregnancy is safe and highly effective in preventing maternal SARS-CoV-2 infection in pregnancy, without increasing the risk of adverse maternal and neonatal outcomes, and is associated with a reduction in stillbirth, preterm births, and neonatal ICU admission. Importantly, maternal vaccination did not reduce the risk of neonatal SARS-CoV-2 infection during the first 6 months of life during the Omicron period.

Predictive factors for severe placental damage in pregnant women with SARS-CoV-2 infection.

INTRODUCTION: SARS-Cov-2 infection during pregnancy can lead to severe placental lesions characterized by massive perivillous fibrin deposition, histiocytic intervillositis and trophoblast necrosis. Diffuse placental damage of this kind is rare, but can sometimes lead to obstetric complications, such as intrauterine fetal death (IUFD). The objectives of this study were to identify possible predictors of severe placental lesions. METHODS: We retrospectively studied 96 placentas from SARS-Cov-2 positive pregnant women who gave birth between March 2020 and March 2022. Cases with and without severe placental lesions were compared in terms of clinical and laboratory findings. RESULTS: Twelve of the 96 patients had severe placental lesions. There was no significant association with diabetes, obesity or severe clinical maternal disease. In contrast, presence of severe placental lesions was significantly associated with neonatal intensive care, cesarean section, prematurity, IUFD, intrauterine growth restriction (IUGR), gestational age, maternal hypofibrinogenemia and thrombocytopenia. No cases of severe placental lesions were observed in vaccinated patients or in those with the Omicron variant. DISCUSSION: In these patients, severe placental lesions due to SARS-Cov-2 were significantly associated with the presence of coagulation abnormalities (hypofibrinogenemia and thrombocytopenia), IUGR and gestational age. These results support laboratory and ultrasound monitoring of these parameters in pregnant women with SARS-Cov-2 infection, especially during the second trimester, to predict potential negative fetal outcomes.

The impact of COVID-19 vaccinations on stillbirth rates among pregnant women in the Metro-Detroit area.

Infection by COVID-19 increases maternal morbidity and mortality prompting both the American College of Obstetrics and Gynecology and the Society of Maternal Fetal Medicine to strongly recommend vaccination during pregnancy. Limited data exist assessing the risk of intrauterine fetal death (IUFD) associated with COVID vaccination during pregnancy. This was a retrospective chart review at a large multisite hospital system in Metro Detroit which reviewed data from 13,368 pregnancies. We compared IUFD rates between vaccinated and unvaccinated patients. The rate of stillbirths among unvaccinated women (0.75%) was not statistically different from those who were vaccinated (0.60%). Individuals with government insurance were less likely to be vaccinated and more likely to have IUFD in comparison to patients with private insurance. The rate of stillbirths among Black women was significantly higher than among White women at a rate of 1.1% compared to 0.53% (p=0.008) with no difference in stillbirth rates among vaccinated vs unvaccinated racial distribution. Lastly, it is worth noting that the overall vaccination rate at our healthcare system in pregnancy was very poor (0.26%). In conclusion, this is a large population of highly diverse patients which indicates that COVID-19 vaccination does not lead to IUFD. We plan to use this data to help drive an educational vaccination campaign to try to increase our COVID-19 vaccination rate in our pregnant patients. Systemic racism and social determinants of health have played a large factor in COVID-19 outcomes, and our data highlights that this is the case for IUFD in Black women. Improvements must be made to identify barriers for these women to allow for better pregnancy outcomes. We acknowledge that individuals with government insurance may also have other barriers to healthcare or face healthcare inequity which leaves room for improvement on getting these individuals vaccinated and getting the resources they need to have better pregnancy outcomes.

Impact of COVID-19 pandemic on preterm delivery.

OBJECTIVE: Controversies exist on whether the pandemic lockdown has resulted in a lower rate of preterm deliveries. A higher stillbirth rate was also reported. This retrospective observational study aimed to examine the rate of preterm delivery and stillbirth in a tertiary hospital in Hong Kong during COVID-19 pandemic. METHODS: Data from 8787 singleton pregnancies at Queen Mary Hospital between April 2018 to September 2021 were retrieved from the clinical management system and obstetric database. Rates of preterm delivery (<37 weeks), low birth weight infants (<2500 g), and stillbirth in the pre-pandemic (April 2018 to September 2019) and pandemic (April 2020 to September 2021) periods were compared. RESULTS: Total numbers of singleton deliveries during the pre-pandemic and pandemic periods were 5064 and 3723, respectively. Background demographics were comparable, except 3 were higher rates of cesarean sections (30.7% vs. 25.8%; p < 0.05) and hypertensive disorders (1.4% vs. 0.7%; p < 0.05) in the pandemic cohort. Moreover, more women with a spontaneous onset of labor had a history of preterm delivery (3.5% vs. 2.4%; p < 0.05) during the pandemic. Rates of low birth weight infants (8.7% vs. 7.4%; p = 0.03) and spontaneous preterm deliveries (2.6% vs. 1.7%; p = 0.01), particularly spontaneous moderate-to-late preterm delivery (32-36 weeks) (1.9% vs. 1.2%; p = 0.01) were significantly higher during COVID-19. However, no statistical difference was found in stillbirth rates (0.2% vs. 0.4%; p = 0.17). CONCLUSIONS: Rates of spontaneous preterm delivery and low birth weight babies increased significantly during the COVID-19 pandemic. This could be related to an increase in maternal stress, or a change in behavioral patterns for pregnant women.

Changes in preterm birth and stillbirth during COVID-19 lockdowns in 26 countries.

Preterm birth (PTB) is the leading cause of infant mortality worldwide. Changes in PTB rates, ranging from -90% to +30%, were reported in many countries following early COVID-19 pandemic response measures ('lockdowns'). It is unclear whether this variation reflects real differences in lockdown impacts, or perhaps differences in stillbirth rates and/or study designs. Here we present interrupted time series and meta-analyses using harmonized data from 52 million births in 26 countries, 18 of which had representative population-based data, with overall PTB rates ranging from 6% to 12% and stillbirth ranging from 2.5 to 10.5 per 1,000 births. We show small reductions in PTB in the first (odds ratio 0.96, 95% confidence interval 0.95-0.98, P value <0.0001), second (0.96, 0.92-0.99, 0.03) and third (0.97, 0.94-1.00, 0.09) months of lockdown, but not in the fourth month of lockdown (0.99, 0.96-1.01, 0.34), although there were some between-country differences after the first month. For high-income countries in this study, we did not observe an association between lockdown and stillbirths in the second (1.00, 0.88-1.14, 0.98), third (0.99, 0.88-1.12, 0.89) and fourth (1.01, 0.87-1.18, 0.86) months of lockdown, although we have imprecise estimates due to stillbirths being a relatively rare event. We did, however, find evidence of increased risk of stillbirth in the first month of lockdown in high-income countries (1.14, 1.02-1.29, 0.02) and, in Brazil, we found evidence for an association between lockdown and stillbirth in the second (1.09, 1.03-1.15, 0.002), third (1.10, 1.03-1.17, 0.003) and fourth (1.12, 1.05-1.19, <0.001) months of lockdown. With an estimated 14.8 million PTB annually worldwide, the modest reductions observed during early pandemic lockdowns translate into large numbers of PTB averted globally and warrant further research into causal pathways.

Study protocol: examining the impacts of COVID-19 mitigation measures on pregnancy and birth outcomes in Scotland-a linked administrative data study.

INTRODUCTION: This protocol outlines aims to test the wider impacts of the COVID-19 pandemic on pregnancy and birth outcomes and inequalities in Scotland. METHOD AND ANALYSIS: We will analyse Scottish linked administrative data for pregnancies and births before (March 2010 to March 2020) and during (April 2020 to October 2020) the pandemic. The Community Health Index database will be used to link the National Records of Scotland Births and the Scottish Morbidity Record 02. The data will include about 500 000 mother-child pairs. We will investigate population-level changes in maternal behaviour (smoking at antenatal care booking, infant feeding on discharge), pregnancy and birth outcomes (birth weight, preterm birth, Apgar score, stillbirth, neonatal death, pre-eclampsia) and service use (mode of delivery, mode of anaesthesia, neonatal unit admission) during the COVID-19 pandemic using two analytical approaches. First, we will estimate interrupted times series regression models to describe changes in outcomes comparing prepandemic with pandemic periods. Second, we will analyse the effect of COVID-19 mitigation measures on our outcomes in more detail by creating cumulative exposure variables for each mother-child pair using the Oxford COVID-19 Government Response Tracker. Thus, estimating a potential dose-response relationship between exposure to mitigation measures and our outcomes of interest as well as assessing if timing of exposure during pregnancy matters. Finally, we will assess inequalities in the effect of cumulative exposure to lockdown measures on outcomes using several axes of inequality: ethnicity/mother's country of birth, area deprivation (Scottish Index of Multiple Deprivation), urban-rural classification of residence, number of previous children, maternal social position (National Statistics Socioeconomic Classification) and parental relationship status. ETHICS AND DISSEMINATION: NHS Scotland Public Benefit and Privacy Panel for Health and Social Care scrutinised and approved the use of these data (1920-0097). Results of this study will be disseminated to the research community, practitioners, policy makers and the wider public.

Pregnancy and neonatal outcomes of COVID-19: The PAN-COVID study.

OBJECTIVE: To assess perinatal outcomes for pregnancies affected by suspected or confirmed SARS-CoV-2 infection. METHODS: Prospective, web-based registry. Pregnant women were invited to participate if they had suspected or confirmed SARS-CoV-2 infection between 1st January 2020 and 31st March 2021 to assess the impact of infection on maternal and perinatal outcomes including miscarriage, stillbirth, fetal growth restriction, pre-term birth and transmission to the infant. RESULTS: Between April 2020 and March 2021, the study recruited 8239 participants who had suspected or confirmed SARs-CoV-2 infection episodes in pregnancy between January 2020 and March 2021. Maternal death affected 14/8197 (0.2%) participants, 176/8187 (2.2%) of participants required ventilatory support. Pre-eclampsia affected 389/8189 (4.8%) participants, eclampsia was reported in 40/ 8024 (0.5%) of all participants. Stillbirth affected 35/8187 (0.4 %) participants. In participants delivering within 2 weeks of delivery 21/2686 (0.8 %) were affected by stillbirth compared with 8/4596 (0.2 %) delivering ≥ 2 weeks after infection (95 % CI 0.3-1.0). SGA affected 744/7696 (9.3 %) of livebirths, FGR affected 360/8175 (4.4 %) of all pregnancies. Pre-term birth occurred in 922/8066 (11.5%), the majority of these were indicated pre-term births, 220/7987 (2.8%) participants experienced spontaneous pre-term births. Early neonatal deaths affected 11/8050 livebirths. Of all neonates, 80/7993 (1.0%) tested positive for SARS-CoV-2. CONCLUSIONS: Infection was associated with indicated pre-term birth, most commonly for fetal compromise. The overall proportions of women affected by SGA and FGR were not higher than expected, however there was the proportion affected by stillbirth in participants delivering within 2 weeks of infection was significantly higher than those delivering ≥ 2 weeks after infection. We suggest that clinicians' threshold for delivery should be low if there are concerns with fetal movements or fetal heart rate monitoring in the time around infection. The proportion affected by pre-eclampsia amongst participants was not higher than would be expected, although we report a higher than expected proportion affected by eclampsia. There appears to be no effect on birthweight or congenital malformations in women affected by SARS-CoV-2 infection in pregnancy and neonatal infection is uncommon. This study reflects a population with a range of infection severity for SARS-COV-2 in pregnancy, generalisable to whole obstetric populations.

SARS Cov2 Infection and Preeclampsia. How an Infection Can Help Us To Know More About an Obstetric Condition (preprint)

In this review, we aimed to understand the relationship between SARS-CoV-2 infection and preeclampsia severity in infected pregnant women. Pregnant women with SARS- CoV-2 infection have been shown to have a significantly increased risk of maternal death, ICU admission, preterm delivery, and stillbirth compared with those without infection. The risk of preeclampsia also increases in pregnant women infected with SARS-CoV-2, particularly in those with severe symptoms. We emphasize the im-portance of specialized clinical management to prevent poor pregnancy outcomes in this situation. The association between COVID-19 and preeclampsia (PE) is likely due to multiple mechanisms, including the direct effects of the virus on trophoblast function and the arterial wall, acute atherosis, local inflammation leading to pla-cental ischemia, exaggerated inflammatory responses in pregnant women, SARS-CoV-2-related myocardial injury, cytokine storm, and thrombotic microan-giopathy. Emphasis has been placed on the potential impact of COVID-19 on pregnant women, specifically in relation to thrombotic complications, placental dysfunction, and cardiovascular dysfunction. Undoubtedly, one of the diagnostic tools to differentiate between COVID-19-induced preeclampsia-like syndrome and true preeclampsia is the use of biomarkers, such as the sFlt-1/PlGF ratio. We wish to highlight the potential for COVID-19-induced myocardial injury in pregnant women and the associated in-crease in maternal mortality rate. Vaccination against COVID-19 in the general population and in pregnant women in particular, drastically reduced the severity of the disease. There is an urgent need to continue the follow-up of these women and their children to detect the appearance of sequelae of the disease or peristent COVID 19

Preterm birth and stillbirth rates associated with socioeconomic disparities during COVID-19 pandemic: a population-based cross-sectional study.

BACKGROUND: Conflicting evidence exists on the impact of the COVID-19 pandemic restrictions on preterm birth (PTB) and stillbirth rates. We aimed to evaluate changes in PTB and stillbirth rates before and during the pandemic period and assess the potential effect modification of socioeconomic status (SES). METHODS: Using the linked administrative health databases from Manitoba, Canada, we conducted a cross-sectional study among all pregnant women, comparing 3.5 years pre-pandemic (1 October 2016 to 29 February 2020) to the first year of the pandemic (1 March 2020 to 31 March 2021). We used generalised linear models to assess the quarterly rates of PTB (<37 weeks) and stillbirths. We calculated the predicted trends based on pre-pandemic period data. Finally, we evaluated the PTB and stillbirth rates among lower and higher SES pregnant women (average annual household income) using subgroup analysis and interaction models. RESULTS: We examined 70 931 pregnancies in Manitoba during the study period. The risk of PTB increased by 7.7% (95%CI 1.01 to 1.13) and stillbirths by 33% (95% CI 1.08 to 1.64) during the pandemic period. Following COVID-19 restrictions implemented in March 2020, there were increases in the quarterly rates of both PTB (immediate increase (ß2)=1.37; p=0.0247) and stillbirths (immediate increase (ß2)=0.12; p=0.4434). Among the lower income groups, the pandemic restrictions resulted in an immediate relative increase in PTB and stillbirth rates by 20.12% (immediate increase (ß2)=3.17; p=0.0057) and 27.19% (immediate increase (ß2)=0.48; p=0.0852). However, over the pandemic, the overall PTB rate significantly decreased as a rebound effect by 0.85% per quarter (p=0.0004), whereas the overall stillbirth rate did not decrease significantly (slope decrease (ß3) =-0.01; p=0.8296) compared with the pre-pandemic period. The quarterly rates during the pandemic among the higher income group decreased by 0.39% (p=0.1296) for PTB and increased by 0.07% (p=0.1565) for stillbirth. We observed an effect modification by SES for PTB rates (p=0.047). CONCLUSION: While the onset of COVID-19 pandemic restrictions was not associated with significant effects on stillbirth rates, we observed an immediate and rebound effect on PTB rates. The impact of COVID-19 on preterm birth was dependent on SES, with higher influence on families with lower SES. Further studies are needed to detect future trend changes during pandemic waves after 2021 and assess potential underlying mechanisms.

Health and economic benefits of achieving contraceptive and maternal health targets in Small Island Developing States in the Pacific and Caribbean.

INTRODUCTION: Reducing unmet need for modern contraception and expanding access to quality maternal health (MH) services are priorities for improving women's health and economic empowerment. To support investment decisions, we estimated the additional cost and expected health and economic benefits of achieving the United Nations targets of zero unmet need for modern contraceptive choices and 95% coverage of MH services by 2030 in select Small Island Developing States. METHODS: Five Pacific (Kiribati, Samoa, Solomon Islands, Tonga and Vanuatu) and four Caribbean (Barbados, Guyana, Jamaica and Saint Lucia) countries were considered based on population survey data availability. For each country, the Lives Saved Tool was used to model costs, health outcomes and economic benefits for two scenarios: business-as-usual (BAU) (coverage maintained) and coverage-targets-achieved, which scaled linearly from 2022 (following COVID-19 disruptions) coverage of evidence-based family planning and MH interventions to reach United Nations targets, including modern contraceptive methods and access to complete antenatal, delivery and emergency care. Unintended pregnancies, maternal deaths, stillbirths and newborn deaths averted by the coverage-targets-achieved scenario were converted to workforce, education and social economic benefits; and benefit-cost ratios were calculated. RESULTS: The coverage-targets-achieved scenario required an additional US$12.6M (US$10.8M-US$15.9M) over 2020-2030 for the five Pacific countries (15% more than US$82.4M to maintain BAU). This additional investment was estimated to avert 126 000 (40%) unintended pregnancies, 2200 (28%) stillbirths and 121 (29%) maternal deaths and lead to a 15-fold economic benefit of US$190.6M (US$67.0M-US$304.5M) by 2050. For the four Caribbean countries, an additional US$17.8M (US$15.3M-US$22.4M) was needed to reach the targets (4% more than US$405.4M to maintain BAU). This was estimated to avert 127 000 (23%) unintended pregnancies, 3600 (23%) stillbirths and 221 (25%) maternal deaths and lead to a 24-fold economic benefit of US$426.2M (US$138.6M-US$745.7M) by 2050. CONCLUSION: Achieving full coverage of contraceptive and MH services in the Pacific and Caribbean is likely to have a high return on investment.

The dose- and time-dependent effectiveness and safety associated with COVID-19 vaccination during pregnancy: a systematic review and meta-analysis.

OBJECTIVES: This study aimed to provide guidance for clinical treatment and increase public confidence in COVID-19 vaccines. METHODS: The Cochrane Library, Embase, PubMed, Web of Science, ClinicalKey, and other COVID-19 datasets were searched from December 2019 to May 2022. Case-control studies and prospective cohort studies of COVID-19 vaccine effectiveness and safety in pregnant women were included. RESULTS: From day 11 to day 13, after the first dose of the COVID-19 messenger RNA vaccine, the effectiveness was 54% (95% confidence interval: 0.33-0.69). On days 14 to 27, the effectiveness was 59%. There was a 14% increase in vaccine effectiveness 28 days after the first dose was given. The inactivated vaccines showed similar effectiveness. The proportions of placental abruptions, postpartum hemorrhages, miscarriages, stillbirths, premature births, and small for gestational age infants were not significantly different between vaccinated and nonvaccinated pregnant women. Fatigue and fever were also not associated with pregnancy. CONCLUSION: Our findings affirm that the effectiveness varies for different types of vaccines and is significantly and positively correlated with time in the pregnant population. COVID-19 vaccines have also been deemed safe for pregnant women. Thus, we developed a comprehensive understanding of the role of vaccines in pregnant women.