'An extra level of kind of torment': Views and experiences of recurrent miscarriage care during the initial phases of COVID-19 in Ireland-A qualitative interview study.

INTRODUCTION: Maternity services underwent much change during the COVID-19 pandemic. Research on the impact on miscarriage care and experiences during this time is sparse. Within a national evaluation of recurrent miscarriage care, we qualitatively explored stakeholder views and experiences of recurrent miscarriage services in Ireland. This study describes the impact of the COVID-19 pandemic on those experiences and perceptions of care. METHODS: People with professional and lived experience of recurrent miscarriage and service engagement were actively involved in this qualitative study from idea generation to analysis and reporting. We recruited women and men with two or more consecutive first-trimester miscarriages, and people involved in the management/delivery of recurrent miscarriage services and supports. We used purposive sampling to ensure that perspectives across disciplinary or lived experience, geographical, and health service administrative areas, were included. We conducted semi-structured interviews, virtually all due to COVID-19 restrictions, between June 2020 and February 2021. These were audio-recorded, and data were transcribed, and subsequently analyzed using reflexive thematic analysis. RESULTS: We interviewed 42 service providers and 13 women and 7 men with experience of recurrent miscarriage. We actively generated two central themes during data analysis. The first-'Disconnected'-describes how many women navigated miscarriage diagnosis and management and care in subsequent pregnancies alone; many felt that this resulted in increased trauma. At the same time, men struggled with not being present to support their partners and described feeling disconnected. The second theme highlighted 'The perceived dispensability of recurrent miscarriage services and supports'. Some service providers felt that service reduction and redeployment demonstrated a lack of value in the service. Virtual clinics facilitated access to services, but a preference for in-person care was highlighted. CONCLUSION: Our analysis provides rich insights into the significant impacts that the COVID-19 pandemic has had on the way recurrent miscarriage care is provided and experienced, with important implications for early pregnancy, miscarriage and recurrent miscarriage care. Services have undergone significant changes and, while these may be temporary, how services should be delivered in the future requires consideration, particularly given the deficits in care and care experiences highlighted prepandemic. PATIENT OR PUBLIC CONTRIBUTION: Members of the multidisciplinary RE:CURRENT Project Research Advisory Group (including four parent advocates, two of whom are co-authors on this article) were actively involved throughout the study, including the generation of topic guides and the refining of themes.

The risk of miscarriage following COVID-19 vaccination: a systematic review and meta-analysis.

STUDY QUESTION: What is the risk of miscarriage among pregnant women who received any of the COVID-19 vaccines? SUMMARY ANSWER: There is no evidence that COVID-19 vaccines are associated with an increased risk of miscarriage. WHAT IS KNOWN ALREADY: In response to the COVID-19 pandemic, the mass roll-out of vaccines helped to boost herd immunity and reduced hospital admissions, morbidity, and mortality. Still, many were concerned about the safety of vaccines for pregnancy, which may have limited their uptake among pregnant women and those planning a pregnancy. STUDY DESIGN, SIZE, DURATION: For this systematic review and meta-analysis, we searched MEDLINE, EMBASE, and Cochrane CENTRAL from inception until June 2022 using a combination of keywords and MeSH terms. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included observational and interventional studies that enrolled pregnant women and evaluated any of the available COVID-19 vaccines compared to placebo or no vaccination. We primarily reported on miscarriage in addition to ongoing pregnancy and/or live birth. MAIN RESULTS AND THE ROLE OF CHANCE: We included data from 21 studies (5 randomized trials and 16 observational studies) reporting on 149 685 women. The pooled rate of miscarriage among women who received a COVID-19 vaccine was 9% (n = 14 749/123 185, 95% CI 0.05-0.14). Compared to those who received a placebo or no vaccination, women who received a COVID-19 vaccine did not have a higher risk of miscarriage (risk ratio (RR) 1.07, 95% CI 0.89-1.28, I2 35.8%) and had comparable rates for ongoing pregnancy or live birth (RR 1.00, 95% CI 0.97-1.03, I2 10.72%). LIMITATIONS, REASONS FOR CAUTION: Our analysis was limited to observational evidence with varied reporting, high heterogeneity and risk of bias across included studies, which may limit the generalizability and confidence in our findings. WIDER IMPLICATIONS OF THE FINDINGS: COVID-19 vaccines are not associated with an increase in the risk of miscarriage or reduced rates of ongoing pregnancy or live birth among women of reproductive age. The current evidence remains limited and larger population studies are needed to further evaluate the effectiveness and safety of COVID-19 vaccination in pregnancy. STUDY FUNDING/COMPETING INTEREST(S): No direct funding was provided to support this work. M.P.R. was funded by the Medical Research Council Centre for Reproductive Health Grant No: MR/N022556/1. B.H.A.W. hold a personal development award from the National Institute of Health Research in the UK. All authors declare no conflict of interest. REGISTRATION NUMBER: CRD42021289098.

The COVID-19 Pandemic Impact on the Outcome of Medically Assisted Reproduction Pregnancies.

Background: The impact of the Coronavirus Disease-2019 (COVID-19) pandemic on pregnancy is not well-understood. During the outbreak, the initial approach suggested by the major societies was to postpone all non-urgent assisted reproductive technology (ART) treatments. Nevertheless, the Italian Society of Fertility and Sterility and Reproductive Medicine considered ethically correct to proceed with ART treatments, as the infertility rate is increasing over time, with a consistent decline in the live birth rate. The objective of our study was to assess the impact of the COVID-19 pandemic on the outcomes of ART pregnancies, in terms of early pregnancy loss, overall success rate, and live birth rate. Methods: We conducted a single-center retro-prospective cohort study. Patients who underwent ART treatments from 1 March 2020 to 28 February 2021 (pandemic ART cohort, pART; n = 749) and from 1 March 2019 to 29 February 2020 (control cohort, CTR; n = 844) were enrolled. The study had a duration of 24 months. Patients underwent baseline severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) nasopharyngeal swab; quantitative serum beta human chorionic gonadotropin (ß-hCG) to assess pregnancy; pelvic transvaginal ultrasound; and follow-up until delivery. The study took place at the ART Center of the University Hospital in Florence, Italy. Results: There were not statistically significant differences on implantation rate (pART 0.348 ± 0.034 vs. CTR 0.365 ± 0.033, CI = 95%, p = 0.49), clinical pregnancy rate (pART 0.847 ± 0.044 vs. CTR 0.864 ± 0.038, CI = 95%, p = 0.56), and ectopic pregnancy rate (pART 0.008 ± 0.011 vs. CTR 0.01 ± 0.011, CI = 95%, p = 0.79). Neither first trimester miscarriage rate was different between the groups (pART 0.224 ± 0.056 vs. CTR 0.213 ± 0.05, CI = 95%, p = 0.77) nor second trimester miscarriage rate (pART 0.018 ± 0.018 vs. CTR 0.019 ± 0.017, CI = 95%, p = 0.95). Live birth rate remained unchanged during the pandemic (pART 0.22 ± 0.03 vs. CTR 0.239 ± 0.029, CI = 95%, p = 0.37) and stable even when compared to our center rate between 2015 and 2019 (pART 0.222 ± 0.03 vs. general rate 0.224 ± 0.014, CI = 95%, p = 0.83). Conclusion: The COVID-19 pandemic did not cause a statistically significant change in the live birth rate and in the pregnancy loss rate. ART during the COVID-19 pandemic can be considered fair and safe, ethically and medically appropriate. Patients and physicians should be reassured that ART pregnancy outcomes do not seem to be jeopardized by the pandemic state.

SARS-CoV-2 infection in the first trimester and the risk of early miscarriage: a UK population-based prospective cohort study of 3041 pregnancies conceived during the pandemic.

STUDY QUESTION: Does maternal infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the first trimester affect the risk of miscarriage before 13 week's gestation? SUMMARY ANSWER: Pregnant women with self-reported diagnosis of SARS-CoV-2 in the first trimester had a higher risk of early miscarriage. WHAT IS KNOWN ALREADY: Viral infections during pregnancy have a broad spectrum of placental and neonatal pathology. Data on the effects of the SARS-CoV-2 infection in pregnancy are still emerging. Two systematic reviews and meta-analyses reported an increased risk of preterm birth, caesarean delivery, maternal morbidity and stillbirth. Data on the impact of first trimester infection on early pregnancy outcomes are scarce. This is the first study, to our knowledge, to investigate the rates of early pregnancy loss during the SARS-CoV-2 outbreak among women with self-reported infection. STUDY DESIGN, SIZE, DURATION: This was a nationwide prospective cohort study of pregnant women in the community recruited using social media between 21 May and 31 December 2020. We recruited 3545 women who conceived during the SARS-CoV-2 pandemic who were <13 week's gestation at the time of recruitment. PARTICIPANTS/MATERIALS, SETTING, METHODS: The COVID-19 Contraception and Pregnancy Study (CAP-COVID) was an on-line survey study collecting longitudinal data from pregnant women in the UK aged 18 years or older. Women who were pregnant during the pandemic were asked to complete on-line surveys at the end of each trimester. We collected data on current and past pregnancy complications, their medical history and whether they or anyone in their household had symptoms or been diagnosed with SARS-CoV-2 infection during each trimester of their pregnancy. RT-PCR-based SARS-CoV-2 RNA detection from respiratory samples (e.g. nasopharynx) is the standard practice for diagnosis of SARS-CoV-2 in the UK. We compared rate of self-reported miscarriage in three groups: 'presumed infected', i.e. those who reported a diagnosis with SARS-CoV-2 infection in the first trimester; 'uncertain', i.e. those who did not report a diagnosis but had symptoms/household contacts with symptoms/diagnosis; and 'presumed uninfected', i.e. those who did not report any symptoms/diagnosis and had no household contacts with symptoms/diagnosis of SARS-CoV-2. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 3545 women registered for the CAP-COVID study at <13 weeks gestation and were eligible for this analysis. Data for the primary outcome were available from 3041 women (86%). In the overall sample, the rate of self-reported miscarriage was 7.8% (238/3041 [95% CI, 7-9]). The median gestational age (GA) at miscarriage was 9 weeks (interquartile range 8-11). Seventy-seven women were in the 'presumed infected' group (77/3041, 2.5% [95% CI 2-3]), 295/3041 were in the uncertain group (9.7% [95% CI 9-11]) and the rest in the 'presumed uninfected' (87.8%, 2669/3041 [95% CI 87-89]). The rate of early miscarriage was 14% in the 'presumed infected' group, 5% in the 'uncertain' and 8% in the 'presumed uninfected' (11/77 [95% CI 6-22] versus 15/295 [95% CI 3-8] versus 212/2669 [95% CI 7-9], P = 0.02). After adjusting for age, BMI, ethnicity, smoking status, GA at registration and the number of previous miscarriages, the risk of early miscarriage appears to be higher in the 'presumed infected' group (relative rate 1.7, 95% CI 1.0-3.0, P = 0.06). LIMITATIONS, REASONS FOR CAUTION: We relied on self-reported data on early pregnancy loss and SARS-CoV-2 infection without any means of checking validity. Some women in the 'presumed uninfected' and 'uncertain' groups may have had asymptomatic infections. The number of 'presumed infected' in our study was low and therefore the study was relatively underpowered. WIDER IMPLICATIONS OF THE FINDINGS: This was a national study from the UK, where infection rates were one of the highest in the world. Based on the evidence presented here, women who are infected with SARS-CoV-2 in their first trimester may be at an increased risk of a miscarriage. However, the overall rate of miscarriage in our study population was 8%. This is reassuring and suggests that if there is an effect of SARS-CoV-2 on the risk of miscarriage, this may be limited to those with symptoms substantial enough to lead to a diagnostic test. Further studies are warranted to evaluate a causal association between SARS-CoV-2 infection in early pregnancy and miscarriage risk. Although we did not see an overall increase in the risk of miscarriage, the observed comparative increase in the presumed infected group reinforces the message that pregnant women should continue to exercise social distancing measures and good hygiene throughout their pregnancy to limit their risk of infection. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by a grant from the Elizabeth Garrett Anderson Hospital Charity (G13-559194). The funders of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. J.A.H. is supported by an NIHR Advanced Fellowship. A.L.D. is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support to J.A.H. and A.L.D. as above; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER: N/A.

A Multidisciplinary, Family-Oriented Approach to Caring for Parents After Miscarriage: The Integrated Behavioral Health Model of Care.

Miscarriage is increasingly gaining recognition, both in scientific literature and media outlets, as a loss that has significant and lasting effects on parents, though often disenfranchised and overlooked by both personal support networks and healthcare providers. For both men and women, miscarriage can usher in intense grief, despair, and difficulty coping, and for women in particular, there is evidence of increased prevalence of depression, anxiety, and post-traumatic stress. Additionally, miscarriage can contribute to decreased relationship satisfaction and increased risk of separation, all while stigma and disenfranchisement create a sense of isolation. Despite this increased need for support, research indicates that many parents experience their healthcare providers as dismissive of the significance of the loss and as primarily focusing only on the physical elements of care. Research exploring the barriers to providers engaging in more biopsychosocial-oriented care has identified time constraints, lack of resources, lack of training in addressing loss, and compassion fatigue as key areas for intervention. This paper will review the biopsychosocial elements of miscarriage and discuss a multidisciplinary, family-oriented approach that can be implemented in healthcare settings to ensure a high quality and holistic level of care for individuals, couples, and families experiencing pregnancy loss.

Preliminary Results for Personalized Therapy in Pregnant Women with Polycystic Ovary Syndrome During the COVID-19 Pandemic.

Increased androgen level, hyperinsulinemia, diabetes, impaired fibrinolysis, obesity, hypertension, chronic inflammation, abnormal immune response to infections and hyperhomocysteinemia are the most common abnormalities related to polycystic ovary syndrome (PCOS) women and are the factors predisposing to the severe course of COVID-19. The SARS-Cov-2 infection during pregnancy is associated with an increased risk of complications (spontaneous abortion), similar to those in PCOS. The treatment of PCOS pregnant women with a history of fertility failures raises many doubts, especially during the COVID pandemic. However, due to the increasing incidence of infections among reproductive people and the potentially more serious course in pregnant women, numerous questions about the safety and effectiveness of the treatment are still very current. In our study we presented a series of cases of recurrent miscarriages or recurrent implantation failure PCOS pregnant women with confirmed COVID-19. The diagnosis of infertility confirmed the presence of plasminogen activator inhibitor type 1 and/or 5,10-methylenetetrahydrofolate reductase polymorphisms in each of them. Moreover, some of the women presented immune dysfunction associated with infertility. We have described the personalized treatments of each pregnant patient included: metformin, enoxaparin and tacrolimus. The treatment applied had the expected effect, supporting the implantation processes. Furthermore, despite the ambiguous data according to immunological therapy of infertile women during the COVID pandemic, we observed a mild or asymptomatic COVID-19 course and we noticed no pregnancy complications.

Preliminary findings on the experiences of care for parents who suffered perinatal bereavement during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic poses an unprecedented risk to the global population. Maternity care in the UK was subject to many iterations of guidance on how best to reconfigure services to keep women, their families and babies, and healthcare professionals safe. Parents who experience a pregnancy loss or perinatal death require particular care and support. PUDDLES is an international collaboration investigating the experiences of recently bereaved parents who suffered a late miscarriage, stillbirth, or neonatal death during the global COVID-19 pandemic, in seven countries. In this study, we aim to present early findings from qualitative work undertaken with recently bereaved parents in the United Kingdom about how access to healthcare and support services was negotiated during the pandemic. METHODS: In-depth semi-structured interviews were undertaken with parents (N = 24) who had suffered a late miscarriage (n = 5; all mothers), stillbirth (n = 16; 13 mothers, 1 father, 1 joint interview involving both parents), or neonatal death (n = 3; all mothers). Data were analysed using a template analysis with the aim of investigating bereaved parents' access to services, care, and networks of support, during the pandemic after their bereavement. RESULTS: All parents had experience of utilising reconfigured maternity and/or neonatal, and bereavement care services during the pandemic. The themes utilised in the template analysis were: 1) The Shock & Confusion Associated with Necessary Restrictions to Daily Life; 2) Fragmented Care and Far Away Families; 3) Keeping Safe by Staying Away; and 4) Impersonal Care and Support Through a Screen. Results suggest access to maternity, neonatal, and bereavement care services were all significantly reduced, and parents' experiences were notably affected by service reconfigurations. CONCLUSIONS: Our findings, whilst preliminary, are important to document now, to help inform care and service provision as the pandemic continues and to provide learning for ongoing and future health system shocks. We draw conclusions on how to enable development of safe and appropriate services during this pandemic and any future health crises, to best support parents who experience a pregnancy loss or whose babies die.

Fetal Complications in COVID-19 Infected Pregnant Woman: A Systematic Review and Meta-Analysis.

Background Pregnancy is an immunocompromised state and, for this reason, a pregnant woman is at a higher risk of getting infected as compared with a healthy individual. There is limited data available regarding the impact of COVD-19 on pregnancy; however, the case of miscarriage due to placental infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in second trimester has already been reported. Methods We searched for all published articles in PubMed, Science Direct, Cochrane, Scopus, and Embase. The literature search produced 167 relevant publications; 67 manuscripts were further excluded because they did not satisfy our inclusion criteria. Out of the remaining 100 articles, 78 were excluded after full text screening. Therefore, a total of 22 articles were eligible for review in our study. Results Overall, these 22 studies included a total of 7,034 participants: 2,689 (38.23%) SARS-CoV-2 positive pregnant women, of which 2,578 (95.87%) were laboratory confirmed and 111 (4.13%) were clinically diagnosed. Among the positive patients, there were 174 (6.47%) cases of abortion, of them 168 (96.55%) were spontaneous abortions and 6 (3.45%) were missed. Most patients either reported mild symptoms of fever, cough, fatigue, and anosmia or they presented asymptomatic. Conclusion Additional investigation and rigorous research are warranted to confirm placental pathology mechanisms concerning COVID-19 to protect maternal and fetal health.

The Impact of the Coronavirus Disease 19 Pandemic on Early Pregnancy Outcomes Among Patients Undergoing In Vitro Fertilization Treatment.

Objective: To determine if pregnancy rates (PRs) or pregnancy loss rates (PLRs) were altered in patients undergoing single, euploid frozen-thawed embryo transfer (FET) during the initial peak of the Coronavirus Disease 19 (COVID-19) pandemic. Materials and Methods: This was a retrospective cohort study performed in a single academic center. Patients undergoing single, euploid FET cycles from January to May 2017-2020 were included. Cycles with FET performed in January-May of 2020 ("COVID-surge cohort") were compared to cycles with FET performed in January-May of 2017-2019 ("pre-COVID cohort"). Pregnancy rate (PR), clinical pregnancy rate (CPR), pregnancy loss rate (PLR), and clinical pregnancy loss rate (CLR) were compared between the cohorts. Results: A total of 2629 single, euploid FET cycles were included: 2070 from January to May, 2017-2019 and 559 from January to May 2020. PR was similar when comparing FET performed from January to May 2020 (COVID-surge) to those performed from January to May, 2017-2019 (pre-COVID) (77.6% vs. 73.7%, p = 0.06), while CPR was higher among the COVID-surge compared to the pre-COVID cohort (65.5% vs. 60.0%, p = 0.02). No differences were seen in PLR and CLR among the COVID-surge and pre-COVID cohorts (28.3% vs. 32.0%, p = 0.08; 15.0% vs. 16.5%, p = 0.50). PR, CPR, PLR, and CLR were similar when comparing individual months between the cohorts. Adjusted analysis showed no differences in PR, CPR, PLR, or CLR when comparing the cohorts overall or when comparing corresponding individual months in the two time periods. Conclusion: PRs and PLRs were not decreased when SARS-CoV-2 transmission was widespread in our geographic area, suggesting that high COVID-19 transmission does not compromise early pregnancy outcomes.

Effect of paternal health on pregnancy loss-A review of current evidence.

Pregnancy loss has multifactorial causes, and the maternal risk factors are the most investigated. Therefore, this review investigates the current literature regarding the effect of paternal health on pregnancy loss. This review is conducted according to the PRISMA guidelines. The electronic databases PubMed and Medline were the primary sources of information. The online tool covidence.org was used for the screening process. The Newcastle-Ottawa Scale was used for assessment of risk of bias across the non-RCT (Randomized Controlled Trials) included studies. Six cohort studies and one randomised clinical trial were included for assessment in this review. Especially three large retrospective studies reported that circulatory paternal health issue, increasing metabolic syndrome diagnoses and paternal age was significantly associated with a higher risk of pregnancy loss. Lower pregnancy loss was also found in couples with diabetes in the man compared to couples without diabetes. One study suggests a connection between varicocelectomy and improved sperm DNA fragmentation and lower abortion rate. This review confirms that paternal age, somatic health and particularly health regarding cardiovascular and metabolic disease are associated positively with risks of pregnancy loss. However, further research may lead to evidence, which are more conclusive.

COVID-19 and miscarriage: From immunopathological mechanisms to actual clinical evidence.

The association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the first half of pregnancy and pregnancy loss is still unknown. Infections by other coronaviruses, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV), appear to increase the risk of miscarriage. The purpose of this study is to assess whether SARS-CoV-2 infection increases the risk of miscarriage. Firstly, a narrative review of the literature on animal and human studies was performed to analyze the immunopathological mechanisms of SARS-CoV-2 infection during preconception and early pregnancy, by which it may increase the risk of miscarriage. Secondly, a systematic review/meta-analysis of studies was conducted to assess the prevalence of miscarriage in COVID-19 patients diagnosed during pregnancy. Meta-analysis of proportions was used to combine data, and pooled proportions were reported. Seventeen case series and observational studies and 10 prevalence meta-analyses were selected for the review. The estimate of the overall miscarriage rate in pregnant women with COVID-19 was 15.3 % (95 % CI 10.94-20.59) and 23.1 (95 % CI 13.17-34.95) using fixed and random effect models, respectively. Based on the data in the current literature, the miscarriage rate (<22 weeks gestation) in women with SARS-CoV-2 infection is in the range of normal population. Well-designed studies are urgently needed to determine whether SARS-CoV-2 infection increases the risk of miscarriage during periconception and early pregnancy.

Incidence of first trimester pregnancy loss in the infertile population during the first wave of the coronavirus disease 2019 pandemic in New York City.

OBJECTIVE: To describe the incidence of first trimester clinical pregnancy loss in the infertile population during the first wave of the COVID-19 pandemic in New York City. DESIGN: Web-based cross-sectional survey. SETTING: New York City-based academic reproductive medicine practice. PATIENTS: A total of 305 infertile patients with a confirmed intrauterine pregnancy in their first trimester between December 1, 2019, and April 1, 2020, were matched by age and treatment type to pregnant patients from the year prior. INTERVENTIONS: None. MAIN OUTCOME MEASURES: First trimester clinical pregnancy loss rate. RESULTS: In total, the first trimester pregnancy loss rate was lower in the COVID-19 era cohort compared with that in the pre-COVID-19 era cohort (11.9% vs. 20.1%). There was no difference between cohorts in the pregnancy loss rate of women conceiving via fresh embryo transfer (19.6% vs. 24.4%) or via frozen embryo transfer with preimplantation genetic testing (5.4% vs. 9.5%,). In women conceiving via frozen embryo transfer without preimplantation genetic testing, the pregnancy loss rate was statistically lower in the COVID-19 group (12.5% vs. 24.5%). There was no difference in the pregnancy loss rate by treatment type when stratifying by COVID-19 testing or symptom status. Of the 40 (13.1%) patients with a pregnancy loss, there was no difference in self-reported COVID-19 symptoms or symptom type compared with results in those who did not experience a pregnancy loss. CONCLUSION: Despite patients expressing significant worry about COVID-19 and pregnancy, our data provides reassuring information that the first trimester pregnancy loss rate is not elevated for women conceiving via assisted reproductive technology during the global COVID-19 pandemic.

A three-arm, multicenter, open-label randomized controlled trial of hydroxychloroquine and low-dose prednisone to treat recurrent pregnancy loss in women with undifferentiated connective tissue diseases: protocol for the Immunosuppressant regimens for LIving FEtuses (ILIFE) trial.

BACKGROUND: Undifferentiated connective tissue disease (UCTD) is known to induce adverse pregnancy outcomes and even recurrent spontaneous abortion (RSA) by placental vascular damage and inflammation activation. Anticoagulation can prevent pregnancy morbidities. However, it is unknown whether the addition of immune suppressants to anticoagulation can prevent spontaneous pregnancy loss in UCTD patients. The purpose of this study is to evaluate the efficacy of hydroxychloroquine (HCQ) and low-dose prednisone on recurrent pregnancy loss for women with UCTD. METHODS: The Immunosuppressant for Living Fetuses (ILIFE) Trial is a three-arm, multicenter, open-label randomized controlled trial with the primary objective of comparing hydroxychloroquine combined with low-dose prednisone and anticoagulation with anticoagulation alone in treating UCTD women with recurrent spontaneous abortion. The third arm of using hydroxychloroquine combined with anticoagulant for secondary comparison. A total of 426 eligible patients will be randomly assigned to each of the three arms with a 1:1:1 allocation ratio. The primary outcome is the rate of live births. Secondary outcomes include adverse pregnancy outcomes and progression of UCTD. DISCUSSION: This is the first multi-center, open-label, randomized controlled trial which evaluates the efficacy of immunosuppressant regimens on pregnancy outcomes and UCTD progression. It will provide evidence on whether the immunosuppressant ameliorates the pregnancy prognosis in UCTD patients with RSA and the progression into defined connective tissue disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT03671174 . Registered on 14 September 2018.

SARS-CoV-2 in first trimester pregnancy: a cohort study.

STUDY QUESTION: Does maternal infection with severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) in first trimester pregnancy have an impact on the fetal development as measured by nuchal translucency thickness and pregnancy loss? SUMMARY ANSWER: Nuchal translucency thickness at the first trimester scan was not significantly different in pregnant women with versus without SARS-CoV-2 infection in early pregnancy and there was no significantly increased risk of pregnancy loss in women with SARS-CoV-2 infection in the first trimester. WHAT IS KNOWN ALREADY: Pregnant women are more vulnerable to viral infections. Previous coronavirus epidemics have been associated with increased maternal morbidity, mortality and adverse obstetric outcomes. Currently, no evidence exists regarding possible effects of SARS-CoV-2 in first trimester pregnancies. STUDY DESIGN, SIZE, DURATION: Cohort study of 1019 women with a double test taken between 17 February and 23 April 2020, as a part of the combined first trimester risk assessment, and 36 women with a first trimester pregnancy loss between 14 April and 21 May 2020, prior to the double test. The study period was during the first SARS-CoV-2 epidemic wave in Denmark. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cohort 1 included pregnant women with a double test taken within the study period. The excess serum from each double test was analyzed for SARS-CoV-2 antibodies. Results were correlated to the nuchal translucency thickness and the number of pregnancy losses before or at the time of the first trimester scan. Cohort 2 included women with a pregnancy loss before the gestational age for double test sample. Serum from a blood test taken the day the pregnancy loss was identified was analyzed for SARS-CoV-2 antibodies. The study was conducted at a public university hospital serving ∼12% of pregnant women and births in Denmark. All participants in the study provided written informed consent. MAIN RESULTS AND THE ROLE OF CHANCE: Eighteen (1.8%) women had SARS-CoV-2 antibodies in the serum from the double test suggestive of SARS-CoV-2 infection in early pregnancy. There was no significant difference in nuchal translucency thickness for women testing positive for previous SARS-CoV-2 infection (n = 16) versus negative (n = 966) (P = 0.62). There was no significantly increased risk of pregnancy loss for women with antibodies (n = 1) (OR 3.4, 0.08-24.3 95% CI, P = 0.27). None of the women had been hospitalized due to SARS-CoV-2 infection. None of the women with pregnancy loss prior to the double test (Cohort 2) had SARS-CoV-2 antibodies. LIMITATIONS, REASONS FOR CAUTION: These results may only apply to similar populations and to patients who do not require hospitalization due to SARS-CoV-2 infection. A limitation of the study is that only 1.8% of the study population had SARS-CoV-2 antibodies suggestive of previous infection. WIDER IMPLICATION OF THE FINDINGS: Maternal SARS-CoV-2 infection had no effect on the nuchal translucency thickness and there was no significantly increased risk of pregnancy loss for women with SARS-CoV-2 infection in first trimester pregnancy. Evidence concerning COVID-19 in pregnancy is still limited. These data indicate that infection with SARS-CoV-2 in not hospitalized women does not pose a significant threat in first trimester pregnancies. Follow-up studies are needed to establish any risk to a fetus exposed to maternal SARS-CoV-2 infection. STUDY FUNDING/COMPETING INTEREST(S): Prof. H.S.N. and colleagues received a grant from the Danish Ministry of Research and Education for research of COVID-19 among pregnant women. The Danish government was not involved in the study design, data collection, analysis, interpretation of data, writing of the report or decision to submit the paper for publication. A.I., J.O.-L., J.B.-R., D.M.S., J.E.-F. and E.R.H. received funding from a Novo Nordisk Foundation (NNF) Young Investigator Grant (NNF15OC0016662) and a Danish National Science Foundation Center Grant (6110-00344B). A.I. received a Novo Scholarship. J.O.-L. is funded by an NNF Pregraduate Fellowship (NNF19OC0058982). D.W. is funded by the NNF (NNF18SA0034956, NNF14CC0001, NNF17OC0027594). A.M.K. is funded by a grant from the Rigshospitalet's research fund. H.S.N. has received speaker's fees from Ferring Pharmaceuticals, Merck Denmark A/S and Ibsa Nordic (outside the submitted work). N.l.C.F. has received a grant from Gedeon Richter (outside the submitted work). A.M.K. has received speaker's fee from Merck (outside the submitted work). The other authors did not report any potential conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Coronavirus disease 2019 and first-trimester spontaneous abortion: a case-control study of 225 pregnant patients.

BACKGROUND: The disease caused by the severe acute respiratory syndrome coronavirus 2 was named coronavirus disease 2019 and classified as a global public health emergency. The evidence related to the impact of coronavirus disease 2019 on pregnancy is limited to the second and third trimester of pregnancy, whereas data on the first trimester are scant. Many viral infections can be harmful to the fetus during the first trimester of pregnancy, and whether severe acute respiratory syndrome coronavirus 2 is one of them is still unknown. OBJECTIVE: With this study, we evaluated severe acute respiratory syndrome coronavirus 2 infection as a risk factor for early pregnancy loss in the first trimester of pregnancy. Furthermore, coronavirus disease 2019 course in the first trimester was assessed. STUDY DESIGN: Between February 22 and May 21, 2020, we conducted a case-control study at S. Anna Hospital, Turin, among pregnant women in their first trimester, paired for last menstruation. The cumulative incidence of coronavirus disease 2019 was compared between women with spontaneous abortion (case group, n=100) and those with ongoing pregnancy (control group, n=125). Current or past infection was determined by the detection of severe acute respiratory syndrome coronavirus 2 from nasopharyngeal swab and severe acute respiratory syndrome coronavirus 2 immunoglobulin G and immunoglobulin M antibodies in a blood sample. Patient demographics, coronavirus disease 2019-related symptoms, and the main risk factors for abortion were collected. RESULTS: Of 225 women, 23 (10.2%) had a positive test result for coronavirus disease 2019. There was no difference in the cumulative incidence of coronavirus disease 2019 between the cases (11/100, 11%) and the controls (12/125, 9.6%) (P=.73). Logistic regression analysis confirmed that coronavirus disease 2019 was not an independent predictor of early pregnancy loss (odds ratio, 1.28; confidence interval, 0.53-3.08). Coronavirus disease 2019-related symptoms in the first trimester were fever, anosmia, ageusia, cough, arthralgia, and diarrhea; no cases of pneumonia or hospital admission owing to coronavirus disease 2019-related symptoms were recorded. No difference in the incidence of symptoms was noted between the 2 groups. CONCLUSION: Severe acute respiratory syndrome coronavirus 2 infection during the first trimester of pregnancy does not seem to predispose to early pregnancy loss; its cumulative incidence did not differ between women with spontaneous abortion and women with ongoing pregnancy. Coronavirus disease 2019 appears to have a favorable maternal course at the beginning of pregnancy, consistent with what has been observed during the second and third trimesters.