Pregnancy and COVID-19: prevention, vaccination, therapy, and beyond

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has alarmed the world since its first emergence. As pregnancy is characterized by significant changes in cardiovascular, respiratory, endocrine, and immunological systems, there are concerns on issues like the course of disease in pregnant women, safety of medications, route of delivery and risk of obstetric complications. The aim of this review is to summarize the current literature in the management of pregnant women during the COVID-19 pandemic. Although more than 90% of pregnant women with COVID-19 recover without serious morbidity, rapid deterioration of disease and higher rates of obstetric complications may be observed. The risk of vertical transmission has not been clearly revealed yet. Decreasing the number of prenatal visits, shortening the time allocated for the examinations, active use of telemedicine services, limiting the number of persons in healthcare settings, combining prenatal tests in the same visit, restricting visitors during the visits, providing a safe environment in healthcare facilities, strict hygiene control, and providing personal protective equipment during the visits are the main strategies to control the spread of disease according to current guidelines. Although new medication alternatives are being proposed every day for the treatment of COVID-19, our knowledge about the use of most of these drugs in pregnancy is limited. Preliminary results are promising for the administration of SARS-CoV-2 vaccines in the pregnant population. Timing of delivery should be decided based on maternal health condition, accompanying obstetric complications and gestational age. Cesarean delivery should be performed for obstetric indications. Breast feeding should be encouraged as long as necessary precautions for viral transmission are taken. In conclusion, an individualized approach should be provided by a multidisciplinary team for the management of pregnant women with COVID-19 to achieve favorable outcomes.

SARS-CoV2 Infection During Pregnancy Causes Persistent Immune Abnormalities in Women Without Affecting the Newborns.

SARS-CoV2 infection in pregnancy and exposed newborns is poorly known. We performed a longitudinal analysis of immune system and determined soluble cytokine levels in pregnant women infected with SARS-CoV2 and in their newborns. Women with confirmed SARS-CoV2 infection and their exposed uninfected newborns were recruited from Hospital General Universitario Gregorio Marañón. Peripheral blood mononuclear cells (PBMCs), cord cells and plasma were collected at birth and 6 months later. Immunophenotyping of natural killer (NK), monocytes and CD4/CD8 T-cells were studied in cryopreserved PBMCs and cord cells by multiparametric flow cytometry. Up to 4 soluble pro/anti-inflammatory cytokines were assessed in plasma/cord plasma by ELISA assay. SARS-CoV2-infected mothers and their newborns were compared to matched healthy non-SARS-CoV2-infected mothers and their newborns. The TNFα and IL-10 levels of infected mothers were higher at baseline than those of healthy controls. Infected mothers showed increased NK cells activation and reduced expression of maturation markers that reverted after 6 months. They also had high levels of Central Memory and low Effector Memory CD4-T cell subsets. Additionally, the increased CD4- and CD8-T cell activation (CD154 and CD38) and exhaustion (TIM3/TIGIT) levels at baseline compared to controls remained elevated after 6 months. Regarding Treg cells, the levels were lower at infected mothers at baseline but reverted after 6 months. No newborn was infected at birth. The lower levels of monocytes, NK and CD4-T cells observed at SARS-CoV2-exposed newborns compared to unexposed controls significantly increased 6 months later. In conclusion, SARS-CoV2 infection during pregnancy shows differences in immunological components that could lead newborns to future clinical implications after birth. However, SARS-CoV2 exposed 6-months-old newborns showed no immune misbalance, whereas the infected mothers maintain increased activation and exhaustion levels in T-cells after 6 months.

Drug development research in pregnant and lactating women.

Pregnant and lactating women are considered "therapeutic orphans" because they generally have been excluded from clinical drug research and the drug development process owing to legal, ethical, and safety concerns. Most medications prescribed for pregnant and lactating women are used "off-label" because most of the clinical approved medications do not have appropriate drug labeling information for pregnant and lactating women. Medications that lack human safety data on use during pregnancy and lactation may pose potential risks for adverse effects in pregnant and lactating women as well as risks of teratogenic effects to their unborn and newborn babies. Federal policy requiring the inclusion of women in clinical research and trials led to considerable changes in research design and practice. Despite more women being included in clinical research and trials, the inclusion of pregnant and lactating women in drug research and clinical trials remains limited. A recent revision to the "Common Rule" that removed pregnant women from the classification as a "vulnerable" population may change the culture of drug research and drug development in pregnant and lactating women. This review article provides an overview of medications studied by the Obstetric-Fetal Pharmacology Research Units Network and Centers and describes the challenges in current obstetrical pharmacology research and alternative strategies for future research in precision therapeutics in pregnant and lactating women. Implementation of the recommendations of the Task Force on Research Specific to Pregnant Women and Lactating Women can provide legislative requirements and opportunities for research focused on pregnant and lactating women.

Preeclampsia and COVID-19: results from the INTERCOVID prospective longitudinal study.

BACKGROUND: It is unclear whether the suggested link between COVID-19 during pregnancy and preeclampsia is an independent association or if these are caused by common risk factors. OBJECTIVE: This study aimed to quantify any independent association between COVID-19 during pregnancy and preeclampsia and to determine the effect of these variables on maternal and neonatal morbidity and mortality. STUDY DESIGN: This was a large, longitudinal, prospective, unmatched diagnosed and not-diagnosed observational study assessing the effect of COVID-19 during pregnancy on mothers and neonates. Two consecutive not-diagnosed women were concomitantly enrolled immediately after each diagnosed woman was identified, at any stage during pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed until hospital discharge using the standardized INTERGROWTH-21st protocols and electronic data management system. A total of 43 institutions in 18 countries contributed to the study sample. The independent association between the 2 entities was quantified with the risk factors known to be associated with preeclampsia analyzed in each group. The outcomes were compared among women with COVID-19 alone, preeclampsia alone, both conditions, and those without either of the 2 conditions. RESULTS: We enrolled 2184 pregnant women; of these, 725 (33.2%) were enrolled in the COVID-19 diagnosed and 1459 (66.8%) in the COVID-19 not-diagnosed groups. Of these women, 123 had preeclampsia of which 59 of 725 (8.1%) were in the COVID-19 diagnosed group and 64 of 1459 (4.4%) were in the not-diagnosed group (risk ratio, 1.86; 95% confidence interval, 1.32-2.61). After adjustment for sociodemographic factors and conditions associated with both COVID-19 and preeclampsia, the risk ratio for preeclampsia remained significant among all women (risk ratio, 1.77; 95% confidence interval, 1.25-2.52) and nulliparous women specifically (risk ratio, 1.89; 95% confidence interval, 1.17-3.05). There was a trend but no statistical significance among parous women (risk ratio, 1.64; 95% confidence interval, 0.99-2.73). The risk ratio for preterm birth for all women diagnosed with COVID-19 and preeclampsia was 4.05 (95% confidence interval, 2.99-5.49) and 6.26 (95% confidence interval, 4.35-9.00) for nulliparous women. Compared with women with neither condition diagnosed, the composite adverse perinatal outcome showed a stepwise increase in the risk ratio for COVID-19 without preeclampsia, preeclampsia without COVID-19, and COVID-19 with preeclampsia (risk ratio, 2.16; 95% confidence interval, 1.63-2.86; risk ratio, 2.53; 95% confidence interval, 1.44-4.45; and risk ratio, 2.84; 95% confidence interval, 1.67-4.82, respectively). Similar findings were found for the composite adverse maternal outcome with risk ratios of 1.76 (95% confidence interval, 1.32-2.35), 2.07 (95% confidence interval, 1.20-3.57), and 2.77 (95% confidence interval, 1.66-4.63). The association between COVID-19 and gestational hypertension and the direction of the effects on preterm birth and adverse perinatal and maternal outcomes, were similar to preeclampsia, but confined to nulliparous women with lower risk ratios. CONCLUSION: COVID-19 during pregnancy is strongly associated with preeclampsia, especially among nulliparous women. This association is independent of any risk factors and preexisting conditions. COVID-19 severity does not seem to be a factor in this association. Both conditions are associated independently of and in an additive fashion with preterm birth, severe perinatal morbidity and mortality, and adverse maternal outcomes. Women with preeclampsia should be considered a particularly vulnerable group with regard to the risks posed by COVID-19.

Pregnancy alters interleukin-1 beta expression and antiviral antibody responses during severe acute respiratory syndrome coronavirus 2 infection.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2, the disease-causing pathogen of the coronavirus disease 2019 pandemic, has resulted in morbidity and mortality worldwide. Pregnant women are more susceptible to severe coronavirus disease 2019 and are at higher risk of preterm birth than uninfected pregnant women. Despite this evidence, the immunologic effects of severe acute respiratory syndrome coronavirus 2 infection during pregnancy remain understudied. OBJECTIVE: This study aimed to assess the impact of severe acute respiratory syndrome coronavirus 2 infection during pregnancy on inflammatory and humoral responses in maternal and fetal samples and compare antibody responses to severe acute respiratory syndrome coronavirus 2 among pregnant and nonpregnant women. STUDY DESIGN: Immune responses to severe acute respiratory syndrome coronavirus 2 were analyzed using samples from pregnant (n=33) and nonpregnant (n=17) women who tested either positive (pregnant, 22; nonpregnant, 17) or negative for severe acute respiratory syndrome coronavirus 2 (pregnant, 11) at Johns Hopkins Hospital. We measured proinflammatory and placental cytokine messenger RNAs, neonatal Fc receptor expression, and tetanus antibody transfer in maternal and cord blood samples. In addition, we evaluated antispike immunoglobulin G, antispike receptor-binding domain immunoglobulin G, and neutralizing antibody responses to severe acute respiratory syndrome coronavirus 2 in serum or plasma collected from nonpregnant women, pregnant women, and cord blood. RESULTS: Pregnant women with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection expressed more interleukin-1 beta, but not interleukin 6, in blood samples collected within 14 days vs >14 days after performing severe acute respiratory syndrome coronavirus 2 test. Pregnant women with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection also had reduced antispike receptor-binding domain immunoglobulin G titers and were less likely to have detectable neutralizing antibody than nonpregnant women. Although severe acute respiratory syndrome coronavirus 2 infection did not disrupt neonatal Fc receptor expression in the placenta, maternal transfer of severe acute respiratory syndrome coronavirus 2 neutralizing antibody was inhibited by infection during pregnancy. CONCLUSION: Severe acute respiratory syndrome coronavirus 2 infection during pregnancy was characterized by placental inflammation and reduced antiviral antibody responses, which may impact the efficacy of coronavirus disease 2019 treatment in pregnancy. In addition, the long-term implications of placental inflammation for neonatal health require greater consideration.

Pregnancy Outcomes and SARS-CoV-2 Infection: The Spanish Obstetric Emergency Group Study.

Pregnant women who are infected with SARS-CoV-2 are at an increased risk of adverse perinatal outcomes. With this study, we aimed to better understand the relationship between maternal infection and perinatal outcomes, especially preterm births, and the underlying medical and interventionist factors. This was a prospective observational study carried out in 78 centers (Spanish Obstetric Emergency Group) with a cohort of 1347 SARS-CoV-2 PCR-positive pregnant women registered consecutively between 26 February and 5 November 2020, and a concurrent sample of PCR-negative mothers. The patients' information was collected from their medical records, and the association of SARS-CoV-2 and perinatal outcomes was evaluated by univariable and multivariate analyses. The data from 1347 SARS-CoV-2-positive pregnancies were compared with those from 1607 SARS-CoV-2-negative pregnancies. Differences were observed between both groups in premature rupture of membranes (15.5% vs. 11.1%, p < 0.001); venous thrombotic events (1.5% vs. 0.2%, p < 0.001); and severe pre-eclampsia incidence (40.6 vs. 15.6%, p = 0.001), which could have been overestimated in the infected cohort due to the shared analytical signs between this hypertensive disorder and COVID-19. In addition, more preterm deliveries were observed in infected patients (11.1% vs. 5.8%, p < 0.001) mainly due to an increase in iatrogenic preterm births. The prematurity in SARS-CoV-2-affected pregnancies results from a predisposition to end the pregnancy because of maternal disease (pneumonia and pre-eclampsia, with or without COVID-19 symptoms).

Does having a high-risk pregnancy influence anxiety level during the COVID-19 pandemic?

OBJECTIVE: We aimed to analyze the changing level of anxiety during COVID-19 pandemic in pregnant women, with and without high-risk indicators separately, in a tertiary care center serving also for COVID-19 patients, in the capital of Turkey. STUDY DESIGN: We designed a case-control and cross-sectional study using surveys. The Spielberger State-Trait Anxiety Scale questionnaire (STAI-T) and Beck Anxiety Inventory (BAI) which were validated in Turkish were given to outpatient women with high-risk pregnancies as study group and normal pregnancies as control group. A total of 446 women were recruited. RESULTS: There was a statistically significant difference between those with and without high-risk pregnancy in terms of Trait-State Anxiety scores with COVID-19 pandemic (p < 0.05). We found an increased prevalence of anxiety during COVID-19 pandemic in high-risk pregnant women comparing to pregnancies with no risk factors (p < 0.05). There was a statistically significant difference between the education level in high-risk pregnant women in terms of anxiety scores (p < 0.05), Beck Anxiety score was highest in high school graduates (42.75). While the level of Trait Anxiety was the highest with pandemic in those with high-risk pregnancy with threatened preterm labor and preterm ruptures of membranes (58.0), those with thrombophilia were the lowest (50.88). The State Anxiety level and Beck Anxiety Score of those with maternal systemic disease were the highest (53.32 and 45.53), while those with thrombophilia were the lowest (46.96 and 40.08). The scores of Trait Anxiety (56.38), State Anxiety (52.14), Beck Anxiety (43.94) were statistically higher during the pandemic in those hospitalized at least once (p < 0.05). CONCLUSION: High-risk pregnant women require routine anxiety and depression screening and psychosocial support during the COVID-19 pandemic. High-risk pregnancy patients have comorbid conditions most of the time, hence they not only at more risk for getting infected, but also have higher anxiety scores because of the stress caused by COVID-19 pandemic.

The impact of the Covid-19 pandemic on maternity services: A review of maternal and neonatal outcomes before, during and after the pandemic.

OBJECTIVE: To explore any apparent trends in maternal or neonatal outcomes during the Covid-19 pandemic by comparing the maternity outcomes before, during and after the pandemic. STUDY DESIGN: A retrospective review was performed of maternity statistics recorded on the hospital database of a large tertiary referral centre in Dublin with over 8000 deliveries per annum from 1st January to 31st July 2020. This time period represented the months prior to, during the peak and following the pandemic in Ireland. RESULTS: There was no correlation between the monthly number of Covid deaths and the monthly number of perinatal deaths (r = 0.465, NS), preterm births (r = 0.339, NS) or hypertensive pregnancies (r = 0.48, NS). Compared to the combined numbers for the same month in 2018 and 2019, there were no significant changes in perinatal deaths or preterm births in the months when Covid deaths were at their height. The rate of preterm birth was significantly less common in January-July 2020 compared to January-July in 2018/2019 (7.4 % v 8.6 %, chi-sq 4.53, P = 0.03). CONCLUSION: The was no evidence of a negative impact of the Covid-19 pandemic on maternity services, as demonstrated by maternal and neonatal outcomes.

Maternal and infant outcomes of full-term pregnancy combined with COVID-2019 in Wuhan, China: retrospective case series.

OBJECTIVE: To investigate the maternal and infant outcomes of full-term pregnant patients in Wuhan, China, who were infected with 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is responsible for coronavirus disease 2019 (COVID-2019). DESIGN: Retrospective case series. SETTING: The Central Hospitals of Wuhan, Tongji Medical College, Huazhong University of Science and Technology in Wuhan, China. PARTICIPANTS: Twenty one full-term pregnant patients who were admitted to the Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, confirmed SARS-CoV-2 infection and COVID-2019 with laboratorial and clinical methods, were reviewed by our medical team, and the data were collected from January 20, 2020 to February 29, 2020. MAIN CLINICAL DATA COLLECTION: Clinical data had been collecting using a standard case report form, such as epidemiological history, clinical manifestations, auxiliary examination of major laboratory and clinic, etc. All the information was collected and confirmed by our medical team. RESULTS: Twenty one full-term pregnant patients were reviewed (median age 29 years), and no patients were admitted to intensive care unit (ICU), and died during the treating progress. According to our review, all the cases were infected by human to human transmission, and the most common symptoms at onset of illness were cough in 17 (80.95%), fatigue in 10 (47.62%), fever in 7 (33.33%), expectoration in 1 (4.76%), and only one patient (4.76%) developed shortness of breath on admission. The median time from exposure to onset of illness was 10 days (interquartile range 7 -2 days), and from onset of symptoms to first hospital admission was 1 day (interquartile range 1-2 days). CONCLUSIONS: As of February 29, 2020, all the patients who were full-term pregnancy combined with COVID-2019 were cured and delivered successfully, and all the newborns were not infected with SARS-CoV-2, and there were no evidence of mother-to-child transmission.