key: cord-1050861-8ndmi5ew
authors: Joseph, Naima T.; Rasmussen, Sonja A.; Jamieson, Denise J.
title: The Effects of COVID-19 on Pregnancy and Implications for Reproductive Medicine
date: 2021-01-01
journal: Fertil Steril
DOI: 10.1016/j.fertnstert.2020.12.032
sha: 87cffe3ccc9981f6fc0034ccdd31b5a711b45665
doc_id: 1050861
cord_uid: 8ndmi5ew

COVID-19 was officially declared a pandemic in March 2020. Since then, our understanding of its effects on pregnancy have evolved rapidly. Emerging surveillance data and large cohort studies suggest pregnancy is associated with an increased risk of ICU hospitalization, invasive ventilation, and death. Pregnancies complicated by SARS-CoV-2 infection are associated with increased likelihood of cesarean delivery and preterm birth. Intrauterine transmission occurs, but seems to be rare. Critical gaps remain, and rigorous, high-quality data are needed to better ascertain pregnancy risks and to inform antenatal and obstetric management.

Since the first reported cases of Coronavirus Disease 2019 in December of 2019 and the official declaration of the outbreak as a pandemic by the World Health Organization in March 2020 (1), there has been an explosion of cases and exponential growth in our understanding of the virulence, epidemiology, and clinical characteristics of this disease.

In this review, we summarize and synthesize rapidly evolving knowledge regarding COVID-19 in pregnancy and reproductive medicine, as well as discuss critical gaps in the literature.

Studies of pregnant women presenting for delivery have shown rates of SARS-CoV-2 infection in the United States to range from about 2 -20%, depending on the level of disease in the community studied (2) (3) (4) (5) . Although pregnant women have been shown to be at higher risk for severe complications from other respiratory pathogens (e.g., SARS-CoV-1, MERS-CoV, and influenza viruses) (6) (7) (8) , initial data did not consistently show pregnant women to be at heightened risk for severe disease from COVID-19. In February 2020, the WHO-China Joint Mission issued a 40-page report that briefly (3 lines) mentioned an investigation of 147 pregnant women whose risk of severe disease (8%) was not higher than that of the general population (World Health Organization, 2020).

There were inconsistent findings from several other initial reports from China comparing small numbers of pregnant women to nonpregnant controls; some reports found an increased risk of severe disease while others did not (10) (11) (12) (13) (14) Wei et al. compared 17 pregnant to 26 reproductive-aged nonpregnant controls with COVID-19 and found no adverse outcomes (ICU admission, mechanical ventilation, cardiac, pulmonary, or renal complications) in either group (10) . Cheng (14) . These studies were limited by their retrospective design and small sample size. In addition, there may have been some overlap in cases.

Although early reports from the United States reported severe outcomes in pregnant women with COVID-19, many did not include an appropriate comparison group of non-pregnant women matched by age and underlying medical conditions (15) (16) (17) . Later studies that included appropriate non-pregnant comparison groups suggested an emerging pattern of increased risk of disease severity in pregnancy. A national analysis of confirmed SARS-COV-2 infection among in all intensive care units in Sweden was one of the first studies to report increased morbidity in pregnancy. The authors compared pregnant to nonpregnant women aged 20 -44 years and found an increased incidence of ICU admission in pregnant women (14.4 per 100,000 population (95% CI 7.3-23.4) compared to non-pregnant reproductive-aged women (2.5 per 100,000 (95% CI 1.8-3.5); however, the authors could not differentiate between obstetric-related or disease-related indication for admission, nor were the data adjusted for underlying conditions (18) . In a retrospective-case control study across four large hospitals in France and Belgium, Badr et al. compared 83 pregnant (>20 weeks' gestation) to 107 propensity score-matched nonpregnant controls and found that pregnant women were at increased risk of disease-related J o u r n a l P r e -p r o o f hospitalization (58.2% vs 17.4%; p<.001), ICU admission (11.1% vs 2.4%; p=.02), and invasive ventilation (10.2% vs 1.7%; p=.02) (19) .

The largest report suggesting heightened risk of disease severity in pregnancy was based on a review of laboratory-confirmed SARS-CoV-2 infections reported to the US Centers for Disease Control and Prevention (CDC) from January-June 2020; the initial report found an increased risk of hospitalization, ICU admission, and mechanical ventilation, but not an increased risk for death (20) . These data were recently updated through October 3, 2020 to include data from 23 including missing pregnancy status in 65% of cases and potential reporting bias, with less severe cases likely underreported, these data suggest that pregnant women are at increased risk of severe disease, compared to nonpregnant women of reproductive age (21) . Several questions remain, including how the risk is modified by timing of the infection during pregnancy.

The clinical presentation and risk factors for severe disease in pregnant women are similar to that seen in nonpregnant, reproductive-aged females. Although the prevalence of various symptoms in pregnant compared to non-pregnant women varies in different reports (10, 14, 19, 22) , a recent meta-analysis found pregnant women were less likely to have fever and myalgia compared with nonpregnant women of reproductive age (23) . However, large differences in clinical presentation have not been found. In one study, pregnant patients experienced a longer duration of symptoms with 25% of women reporting persistent symptoms 8 weeks after symptom onset (22) . Diagnostic findings are also similar, with pregnant patients with severe COVID as likely to demonstrate abnormalities in laboratory values and radiographic J o u r n a l P r e -p r o o f findings (11, 14) . Risk factors for severe disease in pregnant women appear similar to those seen in the general population, and include obesity, hypertension, diabetes, and asthma (20, 24, 25) . It is notable that approximately two-thirds of pregnant women with severe COVID-19 did not have an identified risk factor (23) . A disproportionate percentage of COVID-19 hospitalizations occurs in minority populations. (20, 24, 25) Obstetric Complications Adverse maternal and obstetric outcomes appear to occur more often among pregnancies complicated by COVID-19 than among unaffected pregnancies. Reports of SARS-CoV-2 infection in early gestation are scant and obstetric outcomes have not been systematically reported. A few case reports have detailed outcomes in women with first-or second-trimester infection; pregnancy loss has been the primary reported outcome, although whether SARS-CoV-2 infection caused the pregnancy loss unknown (26) (27) (28) . In a case-control study that compared 100 cases of spontaneous abortion to 125 controls with ongoing pregnancies, no difference in the cumulative incidence of SARS-CoV-2 infection was seen (29) .

Data from late second-and third-trimester pregnancies suggest an increased risk of adverse obstetric outcomes associated with SARS-CoV-2 infection. Among Swedish women presenting in labor, SARS-CoV-2-positive women were matched using propensity scores to those testing negative; SARS-CoV-2-positive women were more likely than those testing negative to have preeclampsia (7.7% vs 4.3%; prevalence ratio, 1.84; 95% CI, 1.0-3.4), although the finding was of borderline statistical significance. SARS-CoV-2-infected women were less likely to undergo labor induction (18.7% vs. 29.6%; prevalence ratio 0.64; 95% CI, 0.45-0.90). Other maternal outcomes, such as postpartum hemorrhage and mode of delivery did not differ, nor was there any difference in neonatal outcomes including birth weight for gestational age, 5-minute Apgar scores, or rate of preterm birth (30) .

Pregnant women with COVID-19 are more likely to be delivered by cesarean delivery, but it is unclear whether the indication for the cesarean delivery was for worsening maternal status, other obstetric indications, or concern for perinatal transmission. US cohort data suggest that cesarean rates are higher in pregnancies with SARS-CoV-2 infection compared to noninfected pregnancies, with rates higher with more severe disease. Among pregnant women who were universally tested at hospital admission for labor, Prabhu et al. found that SARS-CoV-2positive women were more likely to undergo cesarean delivery than women testing negative Eighty percent were considered to be iatrogenic; 48% were due to maternal COVID-19, 14% to fetal compromise, and 18% to other obstetric conditions (25) .

Conversely, studies incorporating SARS-CoV-2-negative pregnant controls were equivocal or failed to find increased risk of preterm birth, but were limited by small sample size (30, 34) . Although the study by Flaherman et al. did not find a difference in preterm birth rates between pregnant women with SARS-CoV-2 infection and uninfected pregnant controls, the mean gestational age at delivery decreased from 39 weeks in women with COVID-19 diagnosed >14 days before delivery compared to 37.5 weeks for those diagnosed <14 days before delivery (p=0.0009). No difference in neonatal complications in infants born to infected mothers (low birth weight, difficulty breathing, apnea, or respiratory infection through 8 weeks of age) was observed (34) .

An increased risk of stillbirth has been reported in one study. Panagiotakopoulos et al found stillbirth prevalence (3.2%) to be more than four times higher among SARS-CoV-2infected women than their baseline rate (0.6%) (32).

Perinatal transmission of SARS-CoV-2 may occur during pregnancy (intrauterine) or during labor and delivery (intrapartum). The high proportion of cesarean deliveries among SARS-CoV-2-infected mothers has limited our understanding of intrapartum transmission.

Intrauterine transmission occurs when SARS-CoV-2 crosses the placenta to infect the fetus. 

The COVID-19 pandemic has emphasized the contribution of structural racism and social determinants to health inequities. Similar to data from the general population, SARS-CoV-2 infection and disease severity have been higher in pregnant women who were racialethnic minorities, uninsured, low income, or from neighborhoods with low income, high crowding, or increased density. These findings have been seen in different US locations (42, 43) and internationally (25, 44) . COVID-19 has the potential to worsen existing disparities in maternal and infant mortality (45, 46) .

In addition to direct effects of SARS-CoV-2 on infected pregnant women, the effects of pandemic mitigation efforts on uninfected pregnant women also need to be considered.

Data from several studies suggest declines in preterm birth during the lockdown period (47) (48) (49) . In Denmark, the prevalence of extreme prematurity (≤27w6d) was significantly lower during the lockdown period than during the same time period in previous years (odds ratio 0.09 J o u r n a l P r e -p r o o f (95%CI 0.01-0.40)) (47) . Using quasi-expermental methods in the Netherlands, Been et al. demonstrated reduction in preterm birth across gestational age strata, but were statistically significant only for gestational age of 32 weeks to 36 weeks and 6 days (48) . Similarly, Philip and colleagues found a 73% reduction (p=0.022) in the rate of very low birth weight (<1500g) infants during the lockdown period in Ireland, compared to data from the preceding two decades (49) . The authors did not determine whether the reductions were due to differences in spontaneous vs indicated preterm birth. The mechanism responsible for the reduction in preterm births is unknown; further study of these findings could lead to identification of measures to reduce preterm birth.

Data on rates of stillbirth during the pandemic from the United Kingdom and from Nepal tell a different story (50, 51) . The study from the United Kingdom showed a significantly higher incidence of stillbirth during the pandemic period (9.3/1000 births) than during the pre-pandemic period (2.4/1000 births) (difference, 6.9/1000 births [95% CI, 1.8-12.0]; P=.01) (50) . Similarly, data from Nepal showed an increased risk of stillbirth during the lockdown (21/1000 births), compared to before the lockdown (14/1000 total births) (p=0.0002) (51) . Whether these findings were due to direct effects of COVID-19, or an indirect effect associated with changes in health care attendance or delivery is unknown.

Reports have demonstrated worsening of maternal mental health status and increased isolation during pregnancy and the postpartum period related to the pandemic. A cross-sectional study of postpartum depression in a setting with universal prenatal depression screening demonstrated increased rates of depressive symptoms after the pandemic delaration (29.6%) compared with before (26.0%, P=.02) (52) . Higher levels of pandemic-related stress in pregnant women were associated with abuse history, chronic illness, income loss due to the pandemic, perceived risk of having had COVID-19, alterations to prenatal appointments, high-risk J o u r n a l P r e -p r o o f pregnancy, and being a woman of color (53) . The pandemic's effects on maternal mental health and wellbeing, partner bonding given restrictions in visitor policies and labor personnel, and long-term familial well-being will need to be explored (52, 54) .

The COVID-19 pandemic and associated mitigation efforts have had significant effects on health care systems. Shifts in healthcare delivery toward emergency preparedness and response might have led to reduction in other health services, which could have deleterious downstream effects in reproductive health (e.g., increase in unplanned pregnancies, increased sexually transmitted infections, decreased prenatal care attendance, increased maternal and infant mortality) (55) . Several reports have documented potentially deleterious effects related to reduced health care seeking behaviors, including reduced prenatal care utilization and hospitalizations (56) (57) (58) (59) .

However, the respose to COVID-19 has also brought about innovations around health system delivery including the widespread, rapid implementation of telehealth.A randomized controlled trial conducted in the U.S. before the pandemic demonstrated that a model of prenatal care that reduced the number of in-person prenatal visits and incorporated home monitoring and virtual care was associated with high acceptability, reduced pregnancy-related stress, and similar perceived quality compared to usual care (60) . However, telehealth services had not been commonly used in obstetrics before the pandemic. During the pandemic, CDC recommended optimizing use of telehealth services and the federal government improved access to telehealth services. In addition, American College of Obstetricians and Gynecologists published recommendations for telehealth use in February of 2020. Models of prenatal care which reduce in-person visits and telehealth visits were rapidly integrated into many health care systems. In addition to potentially reducing the risk of exposure in the healthcare setting, models such as this found high patient satisfaction (61). Additionally, this has the capacity to improve access, attendance, and utilization of pregnancy-services to those previously unable to access care. In this way, health systems are capitalizing on health information technologies and mobile health platforms to improve access, especially to those in remote or resource-limited settings.

Critical gaps and priority research areas Although pregnancy should not be an exclusion for patients otherwise eligible for therapeutic and preventive interventions, better data are needed to inform pregnancy-specific effectiveness, risks, and benefits. For instance, prone positioning has been demonstrated to reduce severity of lung injury and mortality in patients with moderate-severe disease (64, 65) .

Modified prone positioning is feasible in late gestation (66) but its effectiveness has not be J o u r n a l P r e -p r o o f established and whether this is an acceptable alternative that mitigates poor outcomes is not known. Similarly, remdesivir and tocilizumab have safely been administered in pregnancy outside of clinical trials (67, 68) but these data are difficult to assess given lack of clear criteria for administration, difficulty to establish therapeutic efficacy, and inability to provide pregnancyspecific guidance for administration and monitoring. J o u r n a l P r e -p r o o f Conclusion Our understanding of COVID-19 has evolved rapidly. Pregnancy appears to be an independent risk factor for severe COVID-19-associated complications. Severe COVID-19 in pregnancy is associated with increased rates of cesarean delivery and preterm birth. Efforts to make evidence-based recommendations regarding care of pregnant women and their newborns are hampered by the paucity of rigorous, high-quality data. Improved reporting systems are needed to inform new standards in maternal care. Until such data are available, we must harness lessons learned from other infectious outbreaks, such as the importance of fostering research, public health surveillance, synthesizing and intergrating rapidly evolving research into clinical practice, and mitigating disease transmission whenever possible.

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