key: cord-0858683-wn0ig1v9
authors: Rasmussen, Sonja A.; Jamieson, Denise J.
title: COVID-19 and Pregnancy
date: 2022-01-31
journal: Infect Dis Clin North Am
DOI: 10.1016/j.idc.2022.01.002
sha: 629ee26dd12c44e9e9180c5fa27230030bcc25e7
doc_id: 858683
cord_uid: wn0ig1v9

Pregnancy appears to be a risk factor for severe disease with COVID-19. Although SARS-CoV-2 intrauterine transmission appears to be rare, most studies show COVID-19 during pregnancy increases the risk for pregnancy complications, with higher risk among those with severe disease compared with those mildly affected. Studies suggest that COVID-19 vaccination during pregnancy is safe and effective. Antibodies to SARS-CoV-2 have been found in umbilical cord blood and breast milk following maternal vaccination, which might provide protection to the infant. However, vaccination rates during pregnancy remain low. Studies are needed to understand ways to address SARS-CoV-2 vaccine hesitancy among pregnant persons.

Since the emergence of SARS-CoV-2 in late 2019, the virus and the response to it have had catastrophic effects on the world's health, societies, and economies. Early on, data on the effects of SARS-CoV-2 on the pregnant person and fetus were limited. Data on the effects during pregnancy of previous coronaviruses (severe acute respiratory syndrome [SARS] and Middle East respiratory syndrome [MERS] ) are sparse, but those data along with information on other respiratory infections such as influenza raised concerns about the potential effects of COVID-19 during pregnancy. 1 Here we review available information on the effects of SARS-CoV-2 infection during pregnancy and on the effectiveness and safety of the SARS-CoV-2 vaccines in protecting pregnant persons and their newborns from COVID-19.

An initial question after emergence of a novel pathogen is whether pregnancy is a risk factor for infection or severe disease. Successful pregnancy requires changes in the pregnant person's immune system to tolerate a genetically foreign fetus. These changes in the immune system as well as alterations in the cardiac, pulmonary and other systems can result in increased susceptibility to or increased morbidity and mortality with infection during pregnancy. 2 Understanding the susceptibility to infection during pregnancy is challenging, given that the number of infections observed depends not only on susceptibility, but also to the level of exposure to the pathogen. Pregnant persons might be more cautious about risk, resulting in a lower level of exposure, which could appear as decreased susceptibility. To adequately address this question, a comparison of incident rates between pregnant persons and women of the same age with similar levels of SARS-CoV-2 exposure would be needed. A prospective cohort J o u r n a l P r e -p r o o f analysis of incident disease among pregnant persons identified through weekly self-collected testing showed an incidence during pregnancy that was similar to the modelled estimates for US adults of reproductive age during the same time period. 3 Thus, currently available data do not support increased susceptibility to SARS-CoV-2 infection during pregnancy, 4 but conclusions are difficult, given issues with potential differences in exposure levels between pregnant and nonpregnant persons.

Studies to determine whether pregnancy increases the risk for severe disease are also challenging, given the increased surveillance and enhanced clinical response to illness that occur during pregnancy, as well as potential confounding factors (e.g., pregnancy being a marker of better health). 5 Several early studies did not include appropriate comparison groups; however, later studies that have compared pregnant persons to nonpregnant women of reproductive age have suggested that pregnancy is a risk factor for severe disease. 4 Studies of COVID-19 suggest that the postpartum period is also one of increased risk, similar to what was seen with 2009 H1N1 influenza. 9 For example, analysis of a prospective cohort from New York City showed a high risk of severe disease during the postpartum period; among patients with an asymptomatic presentation during pregnancy, clinical worsening or new symptoms occurred during the first 7 days after birth in 13% of women. 10 The risk for postpartum complications (e.g., fever, hypoxia, or need for readmission) was higher among patients with COVID-19 (12.9%) compared to those without COVID-19 (4.5%, p<0.001). 10 In a multivariate analysis in Brazil that compared non-pregnant SARS-CoV-2-infected women to those who were pregnant or postpartum (defined as up to 42 days after childbirth), the postpartum period was associated with the highest odds for death (OR=1.90, 95% CI 1.53-2.35).

Among those who were postpartum, age over 35 years and diabetes were independently associated with increased risk of death. Postpartum status was also associated with an increased rate of ICU admission and of invasive ventilation. 11 Because SARS-CoV-2 testing is often performed as part of screening for hospital admission at delivery, pregnant and recently pregnant persons who test positive for SARS-CoV-2 infection are less likely to report symptoms (OR 0.28, 95% CI 0.13-0.62). 6 In a prospective cohort of individuals tested weekly for SARS-CoV-2, 99 participants tested positive, with 20 (20%) reporting no symptoms throughout their infections. Among those with detailed symptom J o u r n a l P r e -p r o o f data, nasal congestion (72%), cough (64%), headache (59%), and changes in taste or smell (54%) were most commonly reported; a measured or subjective fever was reported in 28%. 3 

The National Institutes of Health has developed treatment guidelines for care of patients with COVID-19, which are updated regularly. https://www.covid19treatmentguidelines.nih.gov/ Many clinical trials evaluating novel treatments for COVID-19 have excluded pregnant persons; however, treatment recommended for the non-pregnant population should not be withheld from pregnant persons. This includes treatment with remdesivir, dexamethasone, and monoclonal antibodies. Given that pregnancy is a risk factor for progression to serious disease, pregnant persons are eligible to receive outpatient treatment or post-exposure prophylaxis with anti-SARS-CoV-2 monoclonal antibodies under the Emergency Use Authorization. 4, 12 Clinical algorithms for care of pregnant and nonpregnant patients with COVID-19 are generally similar; however, use of algorithms specific to pregnancy can account for some important differences. For example, peripheral oxygen saturation during pregnancy should be maintained at 95% or greater to ensure a favorable oxygen diffusion gradient across the placenta. 13 Timing of delivery for pregnant patients needs to be individualized, weighing the benefits and the risks to the patient and fetus. 13 In the setting of a patient with refractory hypoxemia at or after 32 weeks gestation or in the setting of worsening or persistent critical illness, it is reasonable to consider delivery. In a recent study of pregnant patients with COVID-19 related acute respiratory distress syndrome (ARDS), delivery resulted in a small improvement of pO2/FiO2 ratio, an indicator of ARDS severity. 14 However, the authors emphasized that this J o u r n a l P r e -p r o o f study was not generalizable to patients without ARDS who are at significantly lower morbidity and mortality risk.

Several studies have shown that SARS-CoV-2 infection during pregnancy increases the risk of pregnancy complications. In a systematic review and meta-analysis that included 42 studies of 438,548 pregnant persons, COVID-19 was associated with an increased risk for preeclampsia, preterm birth, and stillbirth, compared to no SARS-CoV-2 infection during pregnancy. Severe COVID-19 disease (defined as presence of dyspnea, respiratory rate of >=30 breaths per minute and an oxygen saturation of 93% or less on room air, or findings consistent with pneumonia) was strongly associated with preeclampsia, gestational diabetes, cesarean delivery, preterm birth, low birth weight, and admission to the neonatal intensive care unit (NICU), compared to mild disease (defined as a positive test for SARS-CoV-2 without severe symptoms). 15 In a large study using data from 499 US academic health centers or community affiliates published after the systematic review, COVID-19 diagnosis was not associated with an increased risk of cesarean delivery (p=0.57); however, the association between diagnosis of COVID-19 and preterm birth remained (p<0.001). 16 A systematic review and meta-analysis focusing on the effects of SARS-CoV-2 infection during pregnancy and preeclampsia showed increased odds for preeclampsia; preeclampsia with severe features; eclampsia; and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome among pregnant persons with SARS-CoV-2 infection compared to those without SARS-CoV-2 infection. Increased odds of preeclampsia were seen in patients with both asymptomatic and symptomatic SARS-CoV-2 infection; however, the odds were higher among symptomatic patients. 17 In a recent study of J o u r n a l P r e -p r o o f nearly 500,000 hospitalizations in 703 US hospitals, pregnant persons with a documented COVID-19 diagnosis were only slightly more likely to have a cesarean delivery (33.5 vs. 32.0%, p=0.0093) and preterm labor with a preterm delivery (adjusted risk ratio [aRR] 1.2, 95% CI 1.1-1.3) than those without a COVID-19 diagnosis. The authors noted that differences in the risks of cesarean delivery and of preterm birth might be related to different obstetric intervention practices across populations and geographic areas. 18

When a newborn infant tests positive for SARS-CoV-2, it can be difficult to determine whether transmission was intrauterine (during pregnancy and before labor onset), intrapartum (during labor and delivery), or postnatal, either through contact with the mother or others or through breastfeeding. Criteria to evaluate whether intrauterine transmission has occurred have been developed and include documentation of maternal infection, identification of SARS-CoV-2 in the first 24 hours of life, and evidence of persistence of infection in the neonate. [19] [20] [21] While intrauterine transmission of SARS-CoV-2 has been documented, 22 it appears to be rare. In a systematic review that included 1141 neonates born to infected pregnant persons, 58 newborns had documented SARS-CoV-2 infection; four of these were believed to be congenital (2 confirmed, 1 probable, and 1 "not sure"), 41 were acquired postpartum, and 13 were unclassified because of missing information. 23 A recent study has suggested that the placental immune response to SARS-CoV-2 infection differs depending on the sex of the fetus. When the fetus was male, maternal SARS-CoV-2 antibody titers were lower, and antibody transfer across the placenta was impaired. 28 Whether these differences result in increased vulnerability of male infants to early life SARS-CoV-2 infection is unknown. 

With regard to effectiveness, antibody responses during pregnancy were found to have similar immunogenicity and reactogenicity to those in nonpregnant women. 31, 32 The second dose of the vaccine was essential for pregnant persons to achieve adequate immune responses similar to those of nonpregnant women. 33 An analysis of responses against the B.1.1.7 (Alpha) and B.1.351 (Beta) variants of concern showed reduced antibody titers, but preserved T-cell responses. 34 In addition, vaccine-generated antibodies during pregnancy were found to be significantly higher than those induced by SARS-CoV-2 infection during pregnancy. 31 In a large retrospective cohort study from Israel, the likelihood of infection in vaccinated vs. unvaccinated pregnant persons suggested significant protection from the vaccine (adjusted hazard ratio of 0.22 (95% CI 0.11-0.43)). 35 Vaccine effectiveness after the second dose of vaccine during pregnancy was found to be similar to that seen in the general population: 96% (95% CI 89-100%) for any documented infection, 97% (95% CI 91-100%) for symptomatic infection, and 89% (95% CI 43-100%) for COVID-19-associated hospitalization against alpha and ancestral variants. 36 

Safety data on mRNA vaccine-exposed pregnancies from three vaccine safety systems in the United States have been reassuring. Pregnant persons were less likely to report headache, J o u r n a l P r e -p r o o f myalgia, chills and fever, and more likely to report pain at the injection site. The frequencies of adverse pregnancy and neonatal outcomes were similar to those seen in studies before the COVID-19 pandemic, suggesting no increase in adverse outcomes related to vaccination. 37 Similar findings were seen in studies from Israel. A study of over 500 pregnant persons who were vaccinated throughout pregnancy showed no increase in the rate of obstetric complications. 38 In a study of over 700 pregnant persons vaccinated in the third trimester of pregnancy, adverse maternal outcomes were not increased; however, those who were vaccinated had a higher rate of elective cesarean delivery and a lower rate of vacuum-assisted vaginal delivery. A composite score for adverse neonatal outcomes showed a lower risk among those vaccinated compared to unvaccinated. 39 Three studies have specifically addressed the risk of pregnancy loss after receiving the SARS-CoV-2 vaccine. These included data from a CDC COVID-19 vaccine pregnancy registry, 40 a case-control analysis from eight health systems in the United States, 41 and a case-control study using several Norwegian national health registries. 42 These studies primarily focused on the use of mRNA vaccines, although a small proportion of pregnancies in the study from Norway were exposed to the ChAdOx1-S/nCoV- 19 [recombinant] vaccine.

Other vaccines (i.e., inactivated influenza and the tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap)) vaccines are recommended during pregnancy because of their ability to protect infants from influenza and pertussis, respectively, during the first few months of life. Therefore, another important question is whether SARS-CoV-2 vaccine during pregnancy provides immune protection to the infant. SARS-CoV-2 antibodies were seen in umbilical cord blood and breast milk after vaccination with mRNA vaccines during pregnancy in J o u r n a l P r e -p r o o f several studies, suggesting that maternal vaccination might provide some protection to the infant. 31, 34, [43] [44] [45] In one study, infants whose mothers had a longer time period between vaccination and delivery and who had received both doses of the vaccine had higher levels of IgG antibodies. In three infants (one set of twins) who did not have IgG in umbilical cord blood, mothers were vaccinated less than 3 weeks before delivery. 43 In another study, IgG antibodies were detected in maternal and umbilical cord blood samples of all pregnancies by 4 weeks after the vaccine dose, except for one. IgG was detectable in 44% and 99% of cord blood samples in which the pregnant person had received only one vaccine dose and two doses of vaccine, respectively, 46 again emphasizing the importance of pregnant persons receiving the full vaccine series.

Despite the availability of reassuring data on effectiveness and safety of the SARS-CoV-2 vaccines, the uptake of SARS-CoV-2 vaccines has been lower than that of the general population. As of October 23, 2021, less than 35% of pregnant people in the US reported being fully vaccinated for COVID-19 before or during pregnancy. Rates varied by race and ethnicity, ranging from the highest rate in non-Hispanic Asians (49.8%) and the lowest rate in non-Hispanic Black persons (19.2%). 47 In a study of vaccine uptake among healthcare workers in a medical center in Israel during the first months after vaccine roll-out, the most common reason for declining the vaccine was concerns about risks during pregnancy. 48 Other studies have identified factors associated with the likelihood of receiving COVID-19 vaccination during pregnancy. In an analysis of pregnant patients in Israel, those who received both doses of the vaccine were likely to be older and to have had previous miscarriages, previous cesarean deliveries, or fertility treatments. 39 In a study of persons giving birth at a J o u r n a l P r e -p r o o f hospital in the United Kingdom, lower vaccine uptake was seen among younger persons, persons of lower socioeconomic background, and people not identifying as White. Higher vaccine uptake was seen in pregnant persons with pre-pregnancy diabetes. 49 In a survey of pregnant persons in Italy, 28.2% agreed to be vaccinated. Most noted that pregnancy influenced their decision, even though the majority (90.1%) reported being generally in favor of vaccines. The main reason for declining the vaccine was fear of the effects on their baby's health. 50 before onsite vaccine availability. No difference in vaccine uptake was noted during these time periods, suggesting that vaccine hesitancy, not convenience, was the critical issue causing low vaccination rates in their population. 52 Shook and colleagues recently proposed a framework to address vaccine hesitancy during pregnancy. Their framework included addressing the "four Cs": confidence, complacency, convenience, and compassion. 53 Increasing vaccine confidence by addressing concerns about J o u r n a l P r e -p r o o f safety, combatting complacency due to the perception that a pregnant person is at low-risk, increasing vaccine convenience by offering the vaccine at the time of a prenatal appointment, and the need for compassionate conversations between obstetric care providers and vaccinehesitant pregnant persons are all believed to be important to increase vaccination rates among this population.

One reason frequently cited for declining COVID-19 vaccination has been concerns about fertility. The issue regarding female fertility initially arose from a blog post that noted a similarity between the spike protein of SARS-CoV-2 and a protein on the placenta, syncytin-1, with a hypothesis that vaccine-induced antibodies could target the placental protein and result in infertility. While the similarity between the two proteins is minimal and no evidence for infertility had been seen among women following COVID-19 infection, who also would have exposure to antibodies to the spike protein, this false information spread quickly. Several pieces of information can be used to address this rumor. First, convalescent serum from patients with COVID-19 does not react with syncytin-1 protein. Second, no evidence of fertility issues was seen in the developmental and reproductive toxicology studies done on animals before vaccine authorization. Third, despite pregnant people being excluded from the clinical trials and participants being were asked to avoid pregnancy, 57 pregnancies occurred, with similar numbers of inadvertent pregnancies in the vaccinated and placebo groups. Finally, no increases in rates of miscarriage have been seen following vaccination in pregnancy, a finding that might be expected if antibodies were causing damage to the placenta. 54 More recently, concerns, again unfounded, have been raised about male infertility. Studies have shown no decreases in any sperm parameters after receipt of a COVID-19 mRNA vaccine. 55 Thus, based on available data, J o u r n a l P r e -p r o o f there is no evidence to support any negative effects on female or male fertility related to SARS-CoV-2 vaccines.

Pregnant persons appear to be at increased risk for severe disease during pregnancy, with increased risk of admission to an ICU, increased need for mechanical ventilation, need for ECMO, and likely increased risk of death. In general, treatment of COVID-19 during pregnancy is similar to non-pregnant persons, with a few modifications. Treatment should not be withheld based on pregnancy status, but rather pregnant persons should be prioritized for early treatments such as antivirals and monoclonal antibodies to prevent severe outcomes. Intrauterine transmission of SARS-CoV-2 occurs but is rare, possibly related to the low rate of SARS-CoV-2 viremia and an absence of co-expression of receptors on the placenta that facilitate SARS-CoV-2's entry into cells. However, even in the absence of intrauterine transmission, SARS-CoV-2 infection during pregnancy increases the risk of adverse pregnancy outcomes, especially among those severely affected. Available data on SARS-CoV-2 vaccines during pregnancy suggest that they are safe and effective. In addition, SARS-CoV-2 antibodies have been identified in umbilical cord blood and in breast milk following vaccination during pregnancy, suggesting that maternal vaccination provides some degree of protection to the infant. However, coverage rates among pregnant persons remain low as of late 2021; available data suggest that concerns regarding the safety of the vaccine on the fetus are key to vaccine hesitancy during pregnancy.

Additional studies are needed to better understand ways to address vaccine hesitancy among pregnant persons.

J o u r n a l P r e -p r o o f

 Effective COVID-19 treatments such as remdesivir, dexamethasone, and monoclonal antibodies should not be withheld from pregnant persons. Pregnancy is a high-risk condition, which is considered a priority indication for early treatment or prophylaxis with SARS-CoV-2 monoclonal antibodies and antivirals.

 Since COVID-19 is associated with an increased risk of poor pregnancy outcomes such as preeclampsia, preterm birth, and stillbirth, pregnant persons with COVID-19 infection should be closely monitored, particularly those with severe disease. 

Emerging infections and pregnancy

Clinical Characteristics, and Risk Factors of SARS-CoV-2 Infection among Pregnant Individuals in the United States

An update on COVID-19 and pregnancy

Pregnancy and the risk of severe coronavirus disease 2019 infection: methodological challenges and research recommendations

Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis

Update: Characteristics of Symptomatic Women of Reproductive Age with Laboratory-Confirmed SARS-CoV-2 Infection by Pregnancy Status -United States

Severity of illness by pregnancy status among laboratory-confirmed SARS-CoV-2 infections occurring in reproductive-aged women in Colombia

pandemic influenza A (H1N1) virus infection in postpartum women in California

Pregnancy and postpartum outcomes in a universally tested population for SARS-CoV-2 in New York City: a prospective cohort study

COVID-19-related deaths among women of reproductive age in Brazil: The burden of postpartum

Fact sheet for health care providers: Emergency Use Authorization (EUA) of REGEN-COV TM (casirivimab and imdevimab)

Society for Maternal-Fetal Medicine. Management considerations for pregnant patients with COVID-19

The relationship between delivery and the PaO2 /FiO2 ratio in COVID-19: a cohort study

SARS-CoV-2 infection during pregnancy and risk of preeclampsia: a systematic review and meta-analysis

Adverse Pregnancy Outcomes, Maternal Complications, and Severe Illness Among US Delivery Hospitalizations With and Without a Coronavirus Disease 2019 (COVID-19) Diagnosis

Vertical Transmission of SARS-CoV-2: What is the Optimal Definition?

Classification system and case definition for SARS-CoV-2 infection in pregnant women, fetuses, and neonates

World Health Organization. Definition andcategorization of the timing of mother-tochildtransmission of SARS-CoV-2 scientific brief

Transplacental transmission of SARS-CoV-2 infection

Clinical Features and Outcome of SARS-CoV-2 Infection in Neonates: A Systematic Review

ACE2 and the protease TMPRSS2 suggests susceptibility of the human embryo in the first trimester

Sexually dimorphic placental responses to maternal SARS-CoV-2 infection

Pregnancy, postpartum care, and COVID-19 vaccination in 2021

Healthy Advisory Network: COVID-19 Vaccination for Pregnant People to Prevent Serious Illness, Deaths, and Adverse Pregnancy Outcomes from COVID-19

Coronavirus disease 2019 vaccine response in pregnant and lactating women: a cohort study

COVID-19 vaccination in pregnant and lactating women: a systematic review

COVID-19 mRNA vaccines drive differential Fcfunctional profiles in pregnant, lactating, and non-pregnant women

Effectiveness of the BNT162b2 mRNA COVID-19 vaccine in pregnancy

Preliminary Findings of mRNA Covid-19

Vaccine Safety in Pregnant Persons

Short-term outcome of pregnant women vaccinated with BNT162b2 mRNA COVID-19 vaccine

Covid-19 vaccination during the third trimester of pregnancy: rate of vaccination and maternal and neonatal outcomes, a multicentre retrospective cohort study

Receipt of mRNA Covid-19 Vaccines and Risk of Spontaneous Abortion

Spontaneous Abortion Following

Vaccination During Pregnancy

Covid-19 Vaccination during Pregnancy and First-Trimester Miscarriage

Efficient maternal to neonatal transfer of antibodies against SARS-CoV-2 and BNT162b2 mRNA COVID-19 vaccine

High antibody levels in cord blood from pregnant women vaccinated against COVID-19

Antibody Response to Coronavirus Disease 2019 (COVID-19) Messenger RNA Vaccination in Pregnant Women and Transplacental Passage Into Cord Blood

COVID-19 vaccination among pregnant people aged 18-49 years overall, by race/ethnicity, and date reported to CDC -Vaccine Safety Datalink, United States

Coronavirus disease 2019 (COVID-19) vaccination uptake among healthcare workers

COVID-19 vaccination during pregnancy: coverage and safety

Pregnant women's perspectives on severe acute respiratory syndrome coronavirus 2 vaccine

Offering onsite COVID-19 vaccination to high-risk obstetrical patients: initial findings

Countering COVID-19 vaccine hesitancy in pregnancy: the "4 Cs

Are COVID-19 vaccines safe in pregnancy?

Effects of SARS CoV-2, COVID-19, and its vaccines on male sexual health and reproduction: where do we stand?