Labour and premature delivery differentially affect the expression of the endocannabinoid system in the human placenta.

Plasma concentrations of N-arachidonyletholamine (AEA), N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA) increase at term and can predict when a woman is likely to go into labour. We hypothesised that increased plasma AEA concentrations in women in preterm and term labour might also be increased and have a function in the placenta at the end of pregnancy. Here we examined the expression of the N-acylethanolamine-modulating enzymes fatty acid amide hydrolase (FAAH) and N-acyl-phosphatidylethanolamine-specific phospholipase-D (NAPE-PLD) and of the cannabinoid receptors (CB1 and CB2) in the placenta and their activation in an in vitro model of the third-trimester placenta to determine if those expressions change with labour and have functional significance. Expression of CB1, CB2, FAAH and NAPE-PLD was examined by immunohistochemistry (IHC) and RT-qPCR in placental samples obtained from four patient groups: preterm not in labour (PTNL), term not in labour (TNL), preterm in labour (PTL) and term in labour (TL). Additionally, the effects of AEA on a third-trimester human cell line (TCL-1) were evaluated. All ECS components were present in the third-trimester placenta, with NAPE-PLD and CB2 being the key modulated proteins in terms of expression. Functionally, AEA reduced TCL-1 cell numbers through the actions of the CB2 receptor whilst CB1 maintained placental integrity through the expression of the transcription regulators histone deacetylase 3, thyroid hormone receptor ß 1 and the modulation of 5α reductase type 1. The placenta in the third trimester and at term is different from the placenta in the first trimester with respect to the expression of CB1, CB2, FAAH and NAPE-PLD, and the expression of these proteins is affected by labour. These data suggest that early perturbation of some ECS components in the placenta may cause AEA-induced PTL and thus PTB.

Expression of the putative cannabinoid receptor GPR55 is increased in endometrial carcinoma.

Although the expression of the putative cannabinoid receptor GPR55 has been shown to be involved in the growth of various tumours and is increased in a number of cancers, its expression has not been examined in patients with endometrial cancer (EC). Quantitative RT-PCR (for mRNA levels) and immunohistochemistry (for protein levels) were used to measure GPR55 expression in patients with Type 1 and Type 2 EC and correlated against cannabinoid receptor (CB1 and CB2) protein levels using non-cancerous endometrium as the control tissue. The data indicated that GPR55 transcript and GPR55 protein levels were significantly (p < 0.002 and p < 0.0001, respectively) higher in EC tissues than in control tissues. The levels of immunoreactive GPR55 protein were correlated with GPR55 transcript levels, but not with the expression of CB1 receptor protein, and were inversely correlated with CB2 protein expression, which was significantly decreased. It can be concluded that GPR55 expression is elevated in women with EC, and thus could provide a potential novel biomarker and therapeutic target for this disease.

The levonorgestrel-releasing intrauterine device induces endometrial decidualisation in women on tamoxifen.

There is conflicting literature on whether the levonorgestrel-releasing intrauterine system (LNG-IUS; Mirena®) induces decidualisation in the tamoxifen-treated endometrium. The expression of the decidualisation marker IGFBP-1 was measured using immunohistochemistry in endometrial biopsies and in serum (using ELISA) of 20 postmenopausal women at the start of tamoxifen-treatment for breast cancer. Ten women were then fitted with LNG-IUS and the other ten received tamoxifen-treatment only and acted as controls. Samples were taken at baseline and after 12 months. At baseline, all endometrial samples were negative for IGFBP-1 and at 12 months, IGFBP-1 was only expressed in the endometria of women fitted with the LNG-IUS, confirming the observed histological features of decidualisation. By contrast, serum IGFBP-1 concentrations were increased by tamoxifen, but not in the group receiving LNG-IUS. In conclusion, tamoxifen induces a rise in serum IGFBP-1 suggesting a systemic, possibly hepatic effect, whilst LNG abrogates this in both the liver and endometrium. Impact statement What is already known on this subject? Previous reports of the use of LNG-IUS in women on tamoxifen have provided conflicting evidence as to whether the endometrium exhibited decidualisation or not. These reports were however based solely on histological examination and lacked supporting biochemical data. What do the results of this study add? After 12 months of treatment with LNG-IUS, the endometria of women on tamoxifen show histological features of decidualisation and the presence of the decidualisation marker IGFBP-1, suggesting that levonorgestrel protects the tamoxifen-treated uterus from additional pathology by causing decidualisation. Serum levels of IGFBP-1 were expected to be a reflection of uterine production, but contrary to expectations, higher levels were identified in women on tamoxifen alone. These data suggest that an inhibition of tamoxifen-induced serum IGFBP-1 production (possibly from a hepatic source) by LNG-IUS occurred and indicates independent systemic effects of both drugs in post menopausal breast cancer patients. What are the implications of these findings for clinical practice and/or further research? This research demonstrated a mechanism for endometrial protection in women on tamoxifen. It also alerts clinicians to the fact that both tamoxifen and LNG-IUS exert systemic effects in this patient group.

Cannabinoid receptor expression in estrogen-dependent and estrogen-independent endometrial cancer.

The lack of good diagnostic/prognostic biomarkers and the often late presentation of endometrial cancer (EC) hinders the amelioration of the morbidity and mortality rates associated with this primarily estrogen-driven disease, a disease that is becoming more prevalent in the population. Previous studies on the expression of the classical cannabinoid receptors, CB1 and CB2, suggest these could provide good diagnostic/prognostic biomarkers for EC but those observations have been contradictory. In this study, we sought to resolve the inconsistency of CB1 and CB2 expression levels in different EC studies. To that end, we used qRT-PCR and immunohistochemistry (IHC) for CB1 and CB2 in endometrial biopsies from women with or without EC and found that transcript levels for both CB1 and CB2 were significantly decreased by 90 and 80%, respectively in EC. These observations were supported by histomorphometric studies where CB1 and CB2 staining intensity was decreased in all types of EC. These data suggest that the loss of both types of CB receptors is potentially involved in the development of or progression of EC and that CB1 and CB2 receptor expression could serve as useful histological markers and therapeutic targets in the treatment of or prevention of EC.

Validation of endogenous control reference genes for normalizing gene expression studies in endometrial carcinoma.

Real-time quantitative RT-PCR (qRT-PCR) is a powerful technique used for the relative quantification of target genes, using reference (housekeeping) genes for normalization to ensure the generation of accurate and robust data. A systematic examination of the suitability of endogenous reference genes for gene expression studies in endometrial cancer tissues is absent. The aims of this study were therefore to identify and evaluate from the thirty-two possible reference genes from a TaqMan(®) array panel their suitability as an internal control gene. The mathematical software packages geNorm qBasePLUS identified Pumilio homolog 1 (Drosophila) (PUM1), ubiquitin C (UBC), phosphoglycerate kinase (PGK1), mitochondrial ribosomal protein L19 (MRPL19) and peptidylpropyl isomerase A (cyclophilin A) (PPIA) as the best reference gene combination, whilst NormFinder identified MRPL19 as the best single reference gene, with importin 8 (IPO8) and PPIA being the best combination of two reference genes. BestKeeper ranked MRPL19 as the most stably expressed gene. In addition, the study was validated by examining the relative expression of a test gene, which encodes the cannabinoid receptor 1 (CB1). A significant difference in CB1 mRNA expression between malignant and normal endometrium using MRPL19, PPIA, and IP08 in combination was observed. The use of MRPL19, IPO8 and PPIA was identified as the best reference gene combination for the normalization of gene expression levels in endometrial carcinoma. This study demonstrates that the arbitrary selection of endogenous control reference genes for normalization in qRT-PCR studies of endometrial carcinoma, without validation, risks the production of inaccurate data and should therefore be discouraged.

Challenges of prenatal diagnosis in obese pregnant women.

Obesity rates are increasing world-wide with most of the increase in women of the reproductive age group. While recognised as an important contributor to non-communicable diseases, pregnant women with obesity are particularly at risk of not only maternal and pregnant complications but also have an increased risk of congenital malformations. Furthermore, pregnant obese women are more likely to be older and therefore at a greater risk of aneuploidy. Prenatal diagnosis in these women especially those who are morbidly obese is challenging due not only to their weight but the implications of the increase adiposity on biochemical markers of aneuploidy. In this review we discuss the current challenges in providing prenatal diagnosis for these women including those related to the ergonomics of ultrasound and those inherent in them because of their obesity. Appropriate counselling for these women should include the lower sensitivity of the tests, the difficulties in performing some of the procedures (imaging and invasive testing) as well as the increased risk of structural abnormalities related to their obesity.

Challenges in timing and mode of delivery in morbidly obese women.

Globally obesity is increasing especially in the reproductive age group. Pregnant women with obesity have higher complication and intervention rates. They are also at increased risk of stillbirth and intrapartum complications. Although organisations like NICE, RCOG, ACOG and WHO have published guidelines and recommendations on care of pregnant women with obesity the evidence from which Grade A recommendations can be made on timing and how to deliver is limited. The current advice is therefore to have discussions with the woman on risks to help her make an informed decision about timing, place, and mode of delivery. Obesity is an independent risk factor for pregnancy complications including diabetes, hypertension and macrosomia. In those with these complications, the timing of delivery is often influenced by the severity of the complication. As an independent factor, population based observational studies in obese women have shown an increase in the risk of stillbirth. This risk increases linearly with weight from overweight through to class II obesity, but then rises sharply in those with class III obesity by at least 10-fold beyond 42 weeks when compared to normal weight women. This risk of stillbirth is notably higher in obese women from 34 weeks onwards compared to normal weight women. One modifiable risk factor for stillbirth as shown from various cohorts of pregnant women is prolonged pregnancy. Research has linked obesity to prolonged pregnancy. Although the exact mechanism is yet unknown some have linked this to maternal dysregulation of the hypothalamic pituitary adrenal axis leading to hormonal imbalance delaying parturition. For these women the two dilemmas are when and how best to deliver. In this review, we examine the evidence and make recommendations on the timing and mode of delivery in women with obesity. For class I obese women there are no differences in outcome with regards to timing and mode of delivery when compared to lean weight women. However, for class II and III obesity, planned induction or caesarean sections may be associated with a lower perinatal morbidity and mortality although this may be associated with an increased in maternal morbidity especially in class III obesity. Studies have shown that delivery by 39 weeks is associated with lower perinatal mortality compared to delivering after in these women. On balance the evidence would favour planned delivery (induction or caesarean section) before 40 weeks of gestation. In the morbidly obese, apart from the standard lower transverse skin incision for CS, there is evidence that a supraumbilical transverse incision may reduce morbidity but is less cosmetic. Irrespective of the option adopted, it is important to discuss the pros and cons of each.

An investigation of endometrial vascularity in normally menstruating women and those in other physiological states using 3D ultrasound imaging.

OBJECTIVES: This study aimed to determine the normal vasculature indices of the endometrium and to correlate them with those in various physiological states. METHODS: Women undergoing ultrasound at the Feto-Maternal Center, Qatar in 2020-2021 as part of their gynecologic evaluation were enrolled into the study. They were divided into those with normal menses and no additional pathology, those following spontaneous miscarriage, postpartum and menopausal. Three-dimensional (3D) evaluation of the endometrial vasculature was done and the parameters quantified included vascularization index (VI), flow index (FI), vascularization flow index (VFI), endometrial thickness, endometrial volume and uterine volume. JASP, an open-source statistical analysis software, was used for analysis and an independent t-test to compare the vascularity indices. A multivariate regression analysis was also done to look at the factors affecting the endometrial vascular indices within the luteal phase. RESULTS: A total of 461 women were studied: 122 in the follicular phase, 199 in the luteal phase, 90 after a spontaneous miscarriage, 29 postpartum, and 16 menopausal. The vascularity indices were highest after miscarriage and lowest postnatally. There were no significant effects of age, gravida, para, or abortions on VI and VFI. However, there was a significant positive effect of age on FI (P = 0.019) There was a significant increase in endometrial volume and thickness in the luteal phase as compared to follicular phase (P < 0.01), but there was no difference in the vascularity indices. The uterine and endometrial volume in the postnatal group were nearly double that of the luteal group (P value <0.01 and 0.014, respectively). There was a significant decrease in flow index in the postnatal group compared to the luteal group (P < 0.01), suggesting low flow intensity in the postnatal group. CONCLUSIONS: Endometrial vascular indices measured using 3D Doppler can be used to determine normal vascular indices and vary with physiological states such as after miscarriages, postnatally and in the menopausal states.

Preterm birth in low-middle income Countries.

Preterm birth (PTB), remains a major cause of significant morbidity and mortality world-wide with about 12-15million preterm births occurring every year. Although the overall trend is decreasing, this is mainly in high-income countries (HIC). The rate remains high in low-and middle-income countries (LMIC) varying on average between 10 and 12% compared to 9% in HIC. The pathogenesis of PTB is complex and multifactorial. Attempts to reduce rates that have focused on PTB as a single condition have in general been unsuccessful. However, more recent attempts to phenotype PTB have resulted in targeted preventative approaches which are yielding better results. Prevention (primary or secondary) is the only approach that has been shown to make a difference to rates of PTB. These include identifying risk factors pre-pregnancy and during pregnancy and instituting appropriate measures to address these. In LMIC, although some approaches that have been shown to be effective in some HIC are adaptable, there is a need to involve stakeholders at all levels in utilizing evidence preferrably generated in LMIC to implement strategies that are likely to reduce the rate of PTB. In this review, we focus on prevention and how to involve policy makers in the process of applying evidence into policy that would reduce PTB in LMIC.

Distribution and function of the endocannabinoid system in the rat and human bladder.

INTRODUCTION AND HYPOTHESIS: Our aim was to compare expression and distribution of cannabinoid receptors CB1 and CB2, transient receptor potential vanilloid receptor 1 (TRPV1), and modulating enzymes in human and rat bladder. We also evaluated effects of cannabinoid agonists (ACEA, agonist of CB1; GP1A, agonist of CB2) on contractile responses of rat bladder strips. METHODS: Distribution and expression of CB1, CB2 and TRPV1 receptors and enzymes fatty acid amide hydrolase (FAAH) and N-acyl phosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD) was studied using immunohistochemistry and immunoblotting on human and Wistar rat bladders. The effects of cannabinoid agonists on contractile responses of isolated rat bladder strips to electrical-field stimulation (EFS) or carbachol-evoked responses were determined. RESULTS: Immunoreactivity for CB1 and TRPV1 receptors and FAAH and NAPE-PLD was present in the bladder of both species. CB1 proteins were of different sizes in rat (57 kDa) and human (40 kDa) bladder. CB2 (45 kDa in both species) immunolocalised to both urothelium and detrusor muscle in human bladder but only to detrusor muscle in rat. FAAH proteins were found at 55 kDa for both species. Rat NAPE-PLD protein (44 kDa) was similar in size to that in human bladder (45 kDa). TRPV1 proteins were found at 104 kDa in both species. ACEA (10(-4) M) attenuated bladder contractions by 35 ± 5.4 % (p < 0.001); GP1a had no effect despite the EC50 values for the carbachol dose-response curves for both agonists being significantly shifted to the right. CONCLUSIONS: The endocannabinoid system is functionally expressed in both species, with CB1 receptors showing both pre- and postsynaptic inhibitory effects on rat bladder contraction, whereas CB2 acts only postsynaptically.

The epidemiology of obesity in reproduction.

Over the last decades, overweight and obesity rates have been rising exponentially and have now reached epidemic proportions. These are significantly higher in women than men, and indeed, data from 2022 show rates varying from the lowest (12%) in the South East Asian Region to the highest (82.8%) in the Western Pacific Region. This rise is mirrored by the increasing health cost of obesity and overweight. Recent estimates put the percentage of medical spending in various countries to vary from 3 to 21%. Obesity is associated with noncommunicable diseases, such as hypertension, diabetes mellitus, and cardiovascular disorders. It is associated with 13 cancers, among which are breast, endometrial, and ovarian. The reproductive consequences of obesity are variable and include but not exclusively menstrual disorders; fertility difficulties; recurrent miscarriages; gestational diabetes, hypertension, and pre-eclampsia; postpartum hemorrhage; and fetal macrosomia. Various factors are responsible for these increasing rates (which are more marked in middle- and low-income countries). These include genetic, epigenetic, environmental, physiologic, cultural, political, and socioeconomic factors that interact in most cases, making it challenging to develop effective interventions on both a local and global scale. In this article, we review the epidemiology of obesity and the factors which modify rates, as well as an overview of the reproductive consequences of obesity. We discuss approaches to reduce the rates and that these should be at three levels: individual, national, and international.

Placental dysfunction in obese women and antenatal surveillance.

Obesity is a significant health concern worldwide and is associated with numerous health complications, including placental dysfunction during pregnancy. Placental dysfunction can lead to adverse outcomes for both the mother and the foetus, such as preeclampsia, gestational diabetes, preterm birth, and foetal growth restriction. Studies have shown that maternal obesity can lead to placental dysfunction through various mechanisms, including chronic inflammation, oxidative stress, and dysregulation of metabolic pathways. These factors can contribute to changes in the placenta's structure and function, impairing nutrient and oxygen exchange between the mother and foetus. Recent research has also suggested that alteration of gene expression in the placenta due to epigenetic changes, such as DNA methylation, may play a role in placental dysfunction associated with maternal obesity. These changes can affect altering foetal growth and development. Prevention and management of maternal obesity are crucial in reducing the risk of placental dysfunction and associated adverse outcomes during pregnancy. This can be achieved through lifestyle modifications, such as diet and exercise, and early detection and management of underlying health conditions. In conclusion, maternal obesity is a significant risk factor for placental dysfunction during pregnancy, which can lead to adverse outcomes for both the mother and the foetus. Further research is needed to understand the relationship and mechanisms to develop effective interventions to prevent and manage placental dysfunction in obese pregnant women.

An overview of contraception in women with obesity.

The use of safe and effective contraception is essential for preventing unplanned pregnancy in women of all body sizes. When counseling women with obesity about contraception, it is important to consider the pharmacokinetic alterations of obesity on various modern contraceptive methods. However, evidence is reassuring that most contraceptive methods are safe and effective in women with obesity. Individual countries and the World Health Organization have published Medical Eligibility Criteria to guide contraceptive selection in women with medical issues including obesity. When choosing contraception, specific risks of the method relative to any underlying medical disorders must also be balanced against the risks of unintended pregnancy in this group.

Obesity and menopause.

The global obesity pandemic continues to rise, with figures from the World Health Organization showing that 13% of the world's adult population was obese in 2016. Obesity has significant implications, with an increased risk of cardiovascular diseases, diabetes mellitus, metabolic syndrome, and several malignancies. The menopausal transition is associated with increased obesity, a transition from a gynecoid to an android body shape, and increased abdominal and visceral fat, which further worsens the associated cardiometabolic risks. Whether this increased obesity is a consequence of menopause, age, genetics, or environmental factors has long been debated. Increasing life expectancy means women spend a significant part of their lives in the menopause. As such, understanding this complex interplay of obesity and menopause is important to providing the right advice/management. We review the current evidence on obesity and menopause, focusing on the implications of increased obesity during menopause, the impact of menopause on obesity, and the effect of available treatments on associated morbidities.

Immunisation against COVID-19 in Pregnancy and of Women Planning Pregnancy.

Following reports of the first human SARS-CoV2 infection in December 2019 from Wuhan Province, China, there was such rapid spread that by March 2021, the World Health Organization (WHO) had declared a pandemic. Over 6.5 million people have died from this infection worldwide, although this is most likely an underestimate. Until vaccines became available, mortality and severe morbidity were costly in terms of life lost as well as the cost of supporting the severely and acutely ill. Vaccination changed the landscape, and following worldwide adoption, life has gradually been returning to normal. The speed of production of the vaccines was unprecedented and undoubtedly ushered in a new era in the science of fighting infections. The developed vaccines were on the already known platforms for vaccine delivery: inactivated virus, virus vector, virus-like particles (VLP) subunit, DNA and mRNA. The mRNA platform was used for the first time to deliver vaccines to humans. An understanding of these platforms and the pros and cons of each are important for clinicians who are often challenged by the recipients on the advantages and risks of these vaccines. These vaccines have so far and reassuringly been shown to be safe in reproduction (with no effect on gametes) and pregnancy (not associated with congenital malformations). However, safety remains paramount and continuing vigilance is critical, especially against rare fatal complications such as vaccine-induced thrombocytopenia and myocarditis. Finally, the waning immunity months after vaccination means repeated immunisation is likely to be ongoing, but just how often and how many such revaccinations should be recommended remains uncertain. Research into other vaccines and alternate delivery methods should continue as this infection is likely to be around for a long time.

Prevention of spontaneous preterm delivery - an update on where we are today.

Spontaneous preterm birth (delivery before 37 completed weeks) is the single most important cause of perinatal morbidity and mortality. The rate is increasing world-wide with a great disparity between low, middle and high income countries. It has been estimated that the cost of neonatal care for preterm babies is more than 4 times that of a term neonate admitted into the neonatal care. Furthermore, there are high costs associated with long-term morbidity in those who survive the neonatal period. Interventions to stop delivery once preterm labor starts are largely ineffective hence the best approach to reducing the rate and consequences is prevention. This is either primary (reducing or minimizing factors associated with preterm birth prior to and during pregnancy) or secondary - identification and amelioration (if possible) of factors in pregnancy that are associated with preterm labor. In the first category are optimizing maternal weight, promoting healthy nutrition, smoking cessation, birth spacing, avoidance of adolescent pregnancies and screening for and controlling various medical disorders as well as infections prior to pregnancy. Strategies in pregnancy, include early booking for prenatal care, screening and managing medical disorders and their complications, and identifying predisposing factors to preterm labor such as shortening of the cervix and timely instituting progesterone prophylaxis or cervical cerclage where appropriate. The use of biomarkers such as oncofetal fibronectin, placental alpha-macroglobulin-1 and IGFBP-1 where cervical screening is not available or to diagnosis PPROM would identify those that require close monitoring and allow the institution of antibiotics especially where infection is considered a predisposing factor. Irrespective of the approach to prevention, timing the administration of corticosteroids and where necessary tocolysis and magnesium sulfate are associated with an improved outcome. The role of genetics, infections and probiotics and how these emerging dimensions help in the diagnosis of preterm birth and consequently prevention are exciting and hopefully may identify sub-populations for targeted strategies.

Identification of Potentially Novel Molecular Targets of Endometrial Cancer Using a Non-Biased Proteomic Approach.

The present study was aimed at identifying novel proteins in endometrial cancer (EC), employing proteomic analysis of tissues obtained after surgery. A differential MS-based proteomic analysis was conducted from whole tissues dissected from biopsies from post-menopausal women, histologically confirmed as endometrial cancer (two endometrioid and two serous; n = 4) or normal atrophic endometrium (n = 4), providing 888 differentially expressed proteins with 246 of these previously documented elsewhere as expressed in EC and 372 proteins not previously demonstrated to be expressed in EC but associated with other types of cancer. Additionally, 33 proteins not recorded previously in PubMed as being expressed in any forms of cancer were also identified, with only 26 of these proteins having a publication associated with their expression patterns or putative functions. The putative functions of the 26 proteins (GRN, APP, HEXA, CST3, CAD, QARS, SIAE, WARS, MYH8, CLTB, GOLIM4, SCARB2, BOD1L1, C14orf142, C9orf142, CCDC13, CNPY4, FAM169A, HN1L, PIGT, PLCL1, PMFBP1, SARS2, SCPEP1, SLC25A24 and ZC3H4) in other tissues point towards and provide a basis for further investigation of these previously unrecognised novel EC proteins. The developmental biology, disease, extracellular matrix, homeostatic, immune, metabolic (both RNA and protein), programmed cell death, signal transduction, molecular transport, transcriptional networks and as yet uncharacterised pathways indicate that these proteins are potentially involved in endometrial carcinogenesis and thus may be important in EC diagnosis, prognostication and treatment and thus are worthy of further investigation.

Bariatric surgery and reproduction-implications for gynecology and obstetrics.

As the rates of obesity continue to rise across the world, there has been an increasing resort to bariatric surgery amongst the options for treatment. Through the reproductive lifespan, between menarche and menopause, women might benefit from this surgical intervention, which may have a bearing on other aspects of their health. The consequences of bariatric surgery have been reported and evaluated from various perspectives in obstetrics and gynecology. Fertility and sexuality are enhanced, but not all gynecological diseases are ameliorated. There are also psychological and behavioral sequelae to be cognizant of. With multi-disciplinary and responsive care, most post-bariatric pregnancies have satisfactory outcomes. The effects of bariatric surgery on the babies conceived thereafter remains a subject of interest, whereas the possible effect on the climacteric is speculative.

A Meta-Analysis of the Global Stillbirth Rates during the COVID-19 Pandemic.

COVID-19 has been shown to have variable adverse effects on pregnancy. Reported data on stillbirth rates during the pandemic have, however, been inconsistent-some reporting a rise and others no change. Knowing the precise impact of COVID-19 on stillbirths should help with the planning and delivery of antenatal care. Our aim was, therefore, to undertake a meta-analysis to determine the impact of COVID-19 on the stillbirth rate. Databases searched included PubMed, Embase, Cochrane Library, ClinicalTrials.gov, and Web of Science, with no language restriction. Publications with stillbirth data on women with COVID-19, comparing stillbirth rates in COVID-19 and non-COVID-19 women, as well as comparisons before and during the pandemic, were included. Two independent reviewers extracted data separately and then compared them to ensure the accuracy of extraction and synthesis. Where data were incomplete, authors were contacted for additional information, which was included if provided. The main outcome measures were (1) stillbirth (SB) rate in pregnant women with COVID-19, (2) stillbirth rates in pregnant women with and without COVID-19 during the same period, and (3) population stillbirth rates in pre-pandemic and pandemic periods. A total of 29 studies were included in the meta-analysis; from 17 of these, the SB rate was 7 per 1000 in women with COVID-19. This rate was much higher (34/1000) in low- and middle-income countries. The odds ratio of stillbirth in COVID-19 compared to non-COVID-19 pregnant women was 1.89. However, there was no significant difference in population SB between the pre-pandemic and pandemic periods. Stillbirths are an ongoing global concern, and there is evidence that the rate has increased during the COVID-19 pandemic, but mostly in low- and middle-income countries. A major factor for this is possibly access to healthcare during the pandemic. Attention should be focused on education and the provision of high-quality maternity care, such as face-to-face consultation (taking all the preventative precautions) or remote appointments where appropriate.