Caring for Pregnant Patients With Asthma During the COVID-19 Pandemic

Updated July, 2022

There is increasing information about COVID-19 and pregnancy. We hope the following information will be useful to practicing allergists and their patients.

Does pregnancy increase the need for critical care in the setting of COVID-19 infection?

Historically, pregnant individuals have been thought to be at increased risk of severe morbidity and mortality from specific respiratory infections, such as flu and SARS. As of March 2021, more than 73,600 infections and 80 maternal deaths have occurred in pregnant women in the United States (CDC).

A recent prospective cohort study from Italy found that the cumulative incidence of COVID-19 infection during the first trimester was 10.1% with a high prevalence of asymptomatic patients (Cosma). In another prospective cohort study of 137 pregnant women infected with SARS-CoV2 on admission for delivery, 75% were asymptomatic on admission and 63.5% of these women remained asymptomatic throughout hospitalization. Only 3.6% developed a severe infection (Hcini).

In an analysis of approximately 400,000 women aged 15–44 years with symptomatic COVID-19, intensive care unit (ICU) admission, invasive ventilation, extracorporeal membrane oxygenation, and death were more likely in pregnant women than in nonpregnant women.

Risk of receiving invasive ventilation in pregnant women aged 35-44 was 3.6 times that of non-pregnant women (Zambrano). However, the data did not distinguish hospitalizations for COVID-19 from hospital admissions for pregnancy-related conditions or for delivery. A recent meta-analysis of 77 studies from China, Europe and the United States reported that high body mass index, chronic hypertension, and pre-existing diabetes were associated with severe COVID-19 in pregnancy. Pre-existing comorbidity was a risk factor for admission to the ICU [odds ratio (OR) 4.21, 95% confidence interval (CI) 1.06-16.72] and invasive ventilation (OR 4.48, 95% CI 1.40-14.37) (Allotey). Pregnant women should be counseled about the potential risk for severe illness from COVID-19 and conscientiously take the same precautions as the general public to prevent infection, particularly if they have comorbid conditions mentioned above. If they do become sick, prompt management of symptoms is important. 

In a large nationwide registry study of over 100,000 pregnant women, pregnant women were not at higher risk of SARS-CoV-2 infection, but pregnancy increased the risk of receiving specialist care and hospitalization for COVID-19 compared with non-pregnant women (Magnus).

Is timing of delivery affected by COVID-19?

Having severe symptoms or complications from any illness might affect timing of delivery. Reports of women hospitalized with symptoms of COVID-19 during the second and third trimesters of pregnancy have included preterm deliveries, but it is not clear if these were due to the mother’s infection or other reasons (Rasmussen). For women with suspected or confirmed COVID-19 in the third trimester who recover, it is reasonable to attempt to postpone elective delivery until a negative test result is obtained in an attempt to avoid transmission to the neonate. 

Does COVID-19 present an increased risk of adverse perinatal and fetal outcomes?

Maternal SARS-CoV-2 infection may lead to perinatal complications directly or indirectly through placental dysfunction. Placental abnormalities such as malperfusion and functional impairment have been reported in pregnant women with COVID-19, potentially leading to outcomes such as preterm birth, intrauterine growth restriction, low birth weight and possibly early pregnancy loss (Cavalcante). As noted above, some pregnant women with COVID-19 have had preterm births, and early reports showed a higher rate of delivery by caesarean sections. This was supported by a prospective cohort study of 675 pregnant patients from three New York City hospitals. Caesarean delivery rates were 46.7% in symptomatic COVID-19 and 45.5% in asymptomatic COVID-19 versus 30.9% in patients without COVID-19 (Prabhu).

A U.K. study compared rates of stillbirth and preterm delivery in pre-pandemic and pandemic cohorts. The incidence of stillbirth was significantly higher during the pandemic period (9.31 per 1,000 births) versus the pre-pandemic period (2.38 per 1,000 births). There was no increase in the incidence of preterm births. Interestingly, none of the women who experienced stillbirths had symptoms suggestive of SARS-CoV-2 infection, so the reasons for this increase remain unclear (Khalil).

In a prospective study of over 20,000 pregnant women in Nepal, there was a significant increase in neonatal mortality during the pandemic (40 per 1,000 births) versus the pre-pandemic period (13 per 1,000 births), and stillbirths during the pandemic (21 per 1,000 births) versus pre-pandemic (14 per 1,000 births), highlighting the need for access to care for those in fragile healthcare systems (Ashish).

Using the Premier Healthcare Database Special COVID-19 release, a large U.S. hospital-based administrative database, the authors found that COIVD-19 was associated with an increased risk for still birth with a stronger association during the period of Delta variant predominance (DeSisto).

A recent multinational cohort study from 73 centers in 22 different countries found that earlier gestational age at infection (first trimester), maternal ventilator support and low birth weight are risk factors associated with adverse perinatal outcomes (DiMascio). A cross-sectional study of pregnant women with severe COVID-19 in Brazil found that the main risk factors for maternal death by COVID-19 were obesity, diabetes, cardiovascular disease, and presence of ARDS (Takemoto). This was supported by data from INTERCOVID, a multinational study. The authors reported that pregnant women with diabetes mellitus, gestational diabetes or who are overweight or obese have a high risk for COVID-19 (Eskenazi).

A U.S. matched case control study of 61 cases of pregnant women with COVID-19 infection found that odds of adverse outcomes such as preeclampsia, venous thromboembolism, maternal ICU admission, and maternal death, were 3.4 times more likely in the case group compared to uninfected matched comparison pregnancies. In addition, neonatal outcomes such as respiratory distress syndrome, intraventricular hemorrhage and neonatal death were 1.7 times more likely in the case group. This was largely driven by those patients with severe disease. In fact, those patients with mild COVID-19 had outcomes similar to matched controls (Brandt).

PRIORITY, a prospective U.S. cohort study, recently reported early findings in 263 infants born to mothers with confirmed SARS-CoV-2 during pregnancy. NICU admission, preterm birth and pneumonia or respiratory tract infection through 6-8 weeks of age did not differ between those born to mothers testing positive to SARS-CoV-2 and those born to mothers testing negative. However, infants born to mothers who first tested positive 0–14 days prior to delivery were also born earlier (Flaherman).

Among 3,912 infants with known gestational age born to women with SARS-CoV-2 infection in another study, 12.9% were preterm (<37 weeks), which was higher than a national estimate of 10.2% (Woodworth).

In a large population based study in the United States, COVID-19 diagnosis in pregnancy was associated with a 40% increased risk of preterm birth (Karasek).

A recent meta-analysis reported that pregnant women with COVID-19 are at increased risk of delivering a preterm birth (OR 3.01, 95% CI 1.16-7.85). However, this was based on a small number of studies with significant heterogeneity (Allotey).

In a recent study where all women presenting in labor underwent COVID-19 testing, 65% of women with positive tests were asymptomatic, and those who tested positive were more likely to have preeclampsia (7.7% versus 4.3%; prevalence ratio, 1.84; 95% CI, 1.004-3.36). COVID-19 illness severity may also affect pregnancy outcome (Ahlberg). In a cohort study of 252 SARS-CoV-2 positive pregnant women, severe or critical illness prior to 37 weeks gestation was associated with pregnancy loss and preterm birth (Adhikari).

In a U.S. retrospective cohort study of 1,856 births, there was a two-fold increased risk of hypertensive disorders of pregnancy in women with COVID-19 infection. In addition, early infection seemed to be more associated with hypertensive disorders developing (Rosenbloom). Similarly, in a prospective, observational study of 42 pregnancies, 75% of those women with severe COVID-19 presented with signs and symptoms of preeclampsia (Mendoza). A multi-center study including over 18,000 pregnancies across 3 years found no change in the rates of third trimester stillbirth during the first five months of the COVID-19 pandemic (Bunnell).

Another study looked at the association of early gestational infection with adverse fetal and perinatal outcomes. They found that infection during first or second trimesters was not associated with adverse perinatal outcomes such as growth restriction or placental dysfunction (Rosen).

A multinational cohort study of over 700 pregnant women with COVID-19 infection, reported a higher risk for preeclampsia (RR 1.76,95% CI, 1.27-2.43), ICU admission (RR 5.04, 95% CI, 3.13-8.10), maternal mortality (RR 22.3, 95%CI, 2.88-172), preterm birth (RR 1.59, 95%CI, 1.30-1.94), and neonatal morbidity (RR 2.66, 95% CI, 1.69-4.18) (Villar).

A retrospective analysis of a French national cohort of all hospitalizations for birth from January to June 2020 found that, compared to the non-COVID-19 group, women in the COVID-19 group had a higher frequency of admission to the ICU, mortality, preeclampsia, gestational hypertension, postpartum hemorrhage, preterm birth and caesarean section (Epelboin).

Similarly, in a retrospective cohort study of pregnant patients with COVID-19 infection, the rates of caesarean delivery, preterm birth, and neonatal ICU admission were increased in the Delta variant cohort compared to the cohort with pre-Delta COVID-19 infection (Seasely).

In utero exposure to maternal SARS-CoV-2 infection was not associated with significant neurodevelopment effects, regardless of infection timing or severity. (Shuffrey)

Can maternal SARS-CoV-2 infection be transmitted to the fetus?

In reports of a limited number of infants born to women with COVID-19 around the time of delivery, most newborns have not had evidence of infection. However, a small number of newborns have tested positive for the virus soon after delivery. This suggests the possibility that the virus could pass from a mother to a baby during pregnancy. A recent study measured viral load in COVID-19 positive pregnant mothers and found that it was not associated with COVID-19 positivity in neonates (Anand). In fact, risk of transmission to neonate by rooming-in and breastfeeding was low. In a meta-analysis including 230 women with COVID-19 and 156 newborns, the vertical transmission rate calculated by SARS-CoV-2 nucleic acid tests was 3.91% (Chi). In the PRIORITY study described above of 263 infants born to mothers with confirmed SARS-CoV-2 during pregnancy, the estimated incidence of a positive infant SARS- CoV-2 test was low at 1.1%. In another study, among 610 (21.3%) infants with testing results, 2.6% had positive SARS-CoV-2 results, primarily those born to women with infection at delivery (Woodworth). A retrospective cohort analysis of 100 neonates born to 100 mothers with SARS-CoV-2 infection in New York hospitals found that there was no evidence of vertical transmission (Dumitriu).

Are there special considerations for pregnant women with asthma?

Few data exist to indicate that having asthma is associated with an increased risk of becoming infected with COVID-19 or a more severe course in the non-pregnant infected patient. Recent reassuring data show that having asthma was not associated with an increased risk of hospitalization or even mortality in COVID-19 hospitalized patients (Chhiba). There are even fewer data for pregnant asthmatic women with COVID-19. However, the CDC does indicate that those with moderate to severe asthma might be at a higher risk for severe illness from COVID-19. In one study of 46 pregnant women with COVID-19 infection, four had asthma. Of the six women with severe disease in that study, two had asthma, but one was overweight and the other was obese with hypertension (Lokken).

A large prospective population-based cohort study in Denmark of over 80,000 pregnancies, found that asthma was a significant risk factor for infection with severe acute respiratory syndrome with COVID-19 (OR 2.12, 95%CI 1.41-3.41) (Aabakke). Current recommendations emphasize the need to maintain asthma control during pregnancy. Reducing controller therapy could put pregnant women with asthma at increased risk of an asthma exacerbation necessitating medical care, which could then put them at an increased risk of being exposed to COVID-19. 

Is breastfeeding safe during COVID-19 infection?

Breast milk provides protection against serious childhood infections. Women are often encouraged to continue breastfeeding or provide breast milk even when they are sick with a virus, such as the flu. Information about COVID-19 in breastfeeding women is limited at this time. Most case reports have not detected virus in the breast milk of infected mothers. In a study of 18 women with confirmed SARS-CoV-2 infection, one breast milk sample had detectable SARS-CoV-2 RNA, but the viral culture for that sample was negative (Chambers). No other breast milk samples from the 18 women had an evidence of infectious virus. In another study that included 24 mothers confirmed with COVID-19 and 19 with suspected infection, no breast milk samples tested positive for the SARS-Co-V-2 nucleic acid (Peng). In a review of 46 COVID-19 positive mothers whose breast milk samples were tested for SARS-CoV-2, 43 samples tested negative and only three tested positive. Of the three mothers whose breast milk samples tested positive, only one infant tested positive for the virus (Centeno-Tablante). This suggests that breast milk may not be a potential source of infection for the infant. In fact, one group found that there was no clinical evidence of infections in infants who were breastfed with mothers wearing masks, appropriate hand and breast hygiene, and with newborns kept six feet away from mothers (Kyle).

Are there any data on the safety of remdesivir in the management of critically ill pregnant COVID-19 patients?

Remdesivir was recently given emergency use authorization (EUA) by the Food and Drug Administration (FDA). Data on the use in pregnancy is limited. Manufacturer safety data indicate no reproductive developmental toxicity in animals at clinically relevant doses. Embryonic toxicity was only noted when systemically toxic doses were administered to female animals before conception. A recent case report describes one pregnant patient who received compassionate use of remdesivir and developed transaminitis, which is a noted side effect of remdesivir (Malderelli).

Should pregnant and lactating women receive the COVID-19 vaccine?

On December 11, 2020, the FDA issued the first EUA for a vaccine for the prevention of COVID-19 in individuals 16 years of age and older. The EUA allows the Pfizer-BioNTech COVID-19 vaccine to be distributed in the United States. However, the vaccine was not specifically tested in pregnant women or in those who were breastfeeding. Developmental and reproductive studies in animals to assess the potential effects on the fetus are underway. However, the FDA encourages vaccine companies to collect long-term data on how the vaccine performs in pregnant and lactating women. Without data, having a shared decision making dialogue with the pregnant patient regarding receiving the vaccine that considers exposure risk and underlying conditions will be essential. This is supported by the American College of Obstetricians and Gynecologists (ACOG) who recommends that COVID-19 vaccines should not be withheld from pregnant individuals who meet criteria for vaccination based on Advisory Committee on Immunization Practices (ACIP)-recommended priority groups and that pregnant individuals should be free to make their own decision in conjunction with their clinical care team.

More recently, the CDC recommended urgent action to increase COVID-19 vaccination among pregnant women, recently pregnant and lactating, those women trying to become pregnant and those who might be pregnant in the future (CDC -HAN).

In 2021, 97% of pregnant women who were hospitalized with COVID-19 infection were unvaccinated (COVID-NET).

As of September 2021, 31% of pregnant people were fully vaccinated before or during their pregnancy (CDC).

Assuming that the vaccination is at least 95% effective, one maternal death could be prevented by approximately 700 immunizations in the United States (Kalafat).

A study from Israel reported an estimated BNT162b2 mRNA vaccine effectiveness during pregnancy from 7-56 days after the second dose of 96% for any documented infection and 89% for COVID-19 hospitalizations (Dagan).

Global vaccine acceptance by pregnant women is largely unknown. A recent study using Pregristry, surveyed pregnant women from 16 countries and found that 52.0% of pregnant women (n = 2,747/5,282) and 73.4% of non-pregnant women (n = 9,214/12,562) indicated an intention to receive the vaccine. Vaccine acceptance was lowest in Russia, the United States and Australia (Skiefte).

A U.S. survey of 662 pregnant women found that 77.9% reported having already been vaccinated against influenza during the 2020-2021 season, and 58.3% said they would accept the COVID-19 vaccine while pregnant. Concern for the fetus and vaccine side effects were most common reasons for those declining vaccination (Levy).

Reported reasons for vaccine rejection include the concern for not enough safety information and belief in lack of effectiveness of the vaccine against COVID-19 (Oluklu).

In a retrospective study of 15,000 pregnant women in Israel, vaccination versus non-vaccination was associated with an adjusted hazard ratio for SARS-COV-2 infection of 0.22 (p<0.001) (Goldshtein).

Is there safety data on the use of COVID-19 vaccines in pregnancy?

Since the EUA for the Pfizer and Moderna vaccines, over 128,306 pregnant patients have received the vaccine and registered with the CDC V-safe program (Pham).

Using data from the V-safe program, the CDC reviewed preliminary data on over 35,000 women who identified as pregnant after their vaccine. Data on almost 4,000 who participated in the pregnancy registry did not show any safety signals of concern, and outcomes were similar to studies on pregnant women before the pandemic. The CDC now recommends that all pregnant women be vaccinated (Shimabukuro).

Reports of thrombosis with thrombocytopenia (TTS) have been associated with the Johnson & Johnson-Janssen vaccine. Although the overall risk of thrombosis is increased during pregnancy and postpartum, the mechanism is distinct from pregnancy-associated thrombosis and therefore there are no specific concerns for pregnant women (ACOG).

Using data from 131 reproductive age vaccine recipients, the authors found that pregnant and lactating women elicited comparable vaccine-induced humoral immune responses to non-pregnant controls and generated higher antibody titers than those observed following SARS-CoV-2 infection in pregnancy. Vaccine-generated antibodies were present in umbilical cord blood and breast milk after maternal vaccination (Gray).

Similarly, in 103 pregnant women who received COVID-19 mRNA vaccine, binding, neutralizing, and functional non-neutralizing antibody responses were present in pregnant, lactating, and nonpregnant women following vaccination. Binding and neutralizing antibodies were also found in infant cord blood and breast milk (Collier).

Recently it was found that COVID vaccination led to maternal antibody production as early as 5 days after the first vaccination dose and transplacental transfer of passive immunity to the neonate as early as 16 days after the first vaccination dose (Prabhu).

Recent reports from the V-safe surveillance system found that there was no increased risk of spontaneous abortion (among 2,456 pregnant women who received the mRNA COVID-19 vaccine preconception or prior to 20 weeks gestation (Zauche).

This was supported by data from Vaccine Safety Datalink, which showed that in over 10,000 cases of spontaneous abortion, there was no increased odds of exposure to COVID-19 vaccine in the prior 28 days (OR, 1.02; 95% CI, 0.96-1.08) (Kharbanda).

A large case control study from Norway found no evidence of an increased risk for first trimester miscarriages in pregnant women receiving COVID-19 vaccination (Magnus).

In a retrospective cohort study of live births from eight Vaccine Safety Datalink (VSD) healthcare organizations, COVID-19 vaccination was not associated with small for gestational age at birth (aHR=0.95;95%CI 0.87-1.03) or preterm birth (aHR=0.91;95%CI 0.82-1.01). There was also no association with increased risk for preterm birth or SGA at birth when evaluating vaccination by trimester (Lipkind).

A recent large population-based study from Israel reported that 16,000 exposed newborns to maternal vaccination in utero, manifested no differences in preterm birth rates, SGA, or congenital anomalies when compared to unexposed newborns (Goldshtein).

A Danish registry-based retrospective cohort study of over 150,000 births, found that vaccination was not significantly associated with preterm birth (aHR=0.98;95%CI 0.91-1.05), still birth (aHR=0.86;95%CI 0.63-1.17) or small for gestational age (sHR=0.97;95%CI 0.90-1.04) (Magnus).

Which trimester of pregnancy is ideal for receiving the COVID-19 vaccine?

In an ideal scenario, vaccinating a pregnant patient should result in a maximum coverage period during pregnancy while providing protection through delivery. Another issue is the protection that maternal vaccination during pregnancy provides for the infant.

One multicenter study found that mRNA COVID-19 vaccination during the third trimester was associated with a strong maternal humoral IgG response that crossed the placental barrier and approached maternal titers in the fetus within 15 days after the first dose (Beharer). Another study found that early compared with late third-trimester maternal SARS-CoV-2 immunization enhanced transplacental antibody transfer and increased neonatal neutralizing antibody levels (Rottenstreich).

In a prospective cohort study of women who received mRNA vaccination during the second trimester of pregnancy, neonatal IgG titers were higher than maternal titers, representing 100% placental antibody transfer (Kugelman).

A case report of a pregnant woman with full COVID-19 vaccination during the first trimester also provided similar passive fetal immunity (Cicalini).

Can COVID-19 vaccination during pregnancy provide protection to the unborn baby?

Vaccines such as influenza and TdaP have been recommended for use during pregnancy and have been shown to protect newborns via passage of antibodies through the placenta.

While it is unclear at this point whether COVID-19 vaccination could also protect the infant from the infection by passive transfer of antibodies, reports have shown the presence of SARS-CoV-2 IgG antibodies detectable in cord blood following maternal vaccination (Paul).

Another case report showed a persistence of anti-SARS-CoV2- antibodies in the infant at 2 weeks, 6 weeks, 3 months and 6 months of age after maternal vaccination during the second trimester (Mangat).

Data from the Overcoming COVID-19 network found that maternal completion of a two-dose primary mRNA COVID-19 vaccination series during pregnancy was associated with reduced risk for COVID-19 hospitalization among infants <6 months of age (Halasa).

Data from the Overcoming COVID-19 network found that maternal completion of a 2-dose primary mRNA COVID-19 vaccination series during pregnancy was associated with reduced risk for COVID-19 hospitalization among infants <6 months of age. (Halasa) Similarly, the results of a Norwegian population-based cohort study suggested a lower risk of a positive test for SARS-CoV-2 during the first 4 months of life among infants born to mothers who were vaccinated during pregnancy. (Carlsen)

In another study, COVID-19 mRNA vaccination during pregnancy elicited robust immune responses in mothers and efficient transplacental antibody transfer to the newborn. A booster dose during pregnancy significantly increased maternal and cord blood antibody levels, including against the Omicron variant. (Munoz)

Is COVID-19 vaccination safe while breastfeeding?

Although lactating people were excluded from vaccination trials, many received the vaccine after its release to the public. In a study of lactating people who received two-dose Pfizer/BioNTech vaccine, 61.8% of breast milk samples tested positive for anti-SARS-CoV-2 specific IgA at 2 weeks after the first dose and 86.1% 1 week after the booster dose (PERL). A recent meta-analysis of 30 studies addressed the effects of COVID-19 vaccination on lactating women. They found that vaccination during lactation was safe and posed no risk to mother or baby. Some women observe a temporary increase or decrease in milk supply without long-term effects (Muyldermans).

Are there ongoing studies to which pregnant women could be referred?

Researchers are still learning how COVID-19 affects pregnant women. As part of their pregnancy studies, the organization MotherToBaby is interested in examining the short and long-term effects of COVID-19 in pregnancy and breastfeeding, as well as COVID-19 vaccination in pregnancy or during breastfeeding. This study will consist of phone calls over the course of the pregnancy and post-delivery or while breastfeeding, release of medical records related to the pregnancy and infant’s development, and collection of breast milk samples. If you have a pregnant or breastfeeding patient with COVID-19, or who has been vaccinated please consider enrolling them at mothertobaby.org or by calling (877) 311-8972.

Women diagnosed with COVID-19 from all countries may enroll in the International Registry of Coronavirus Exposure in Pregnancy (IRCEP). Women can enroll and provide information to the IRCEP via its website and mobile app. The study will collect data on reproductive history, COVID-19 infection test and symptoms. Women will complete monthly modules until post-partum, and medical records from the mother and neonate will be requested. If you have a pregnant patient with COVID-19, consider enrolling them at ircep.preregistry.com

The Vaccines and Medications in Pregnancy Surveillance System (VAMPSS) also is continuing to study asthma medications during pregnancy. VAMPSS is a nationwide post-marketing surveillance system established to comprehensively monitor the use and safety of vaccines and medications during pregnancy, coordinated by the AAAAI. You can learn more about VAMPSS at the AAAAI website. If you have a pregnant patient with asthma, please consider enrolling them in the VAMPSS studies at mothertobaby.org or by calling (877) 311-8972.

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ACOG: https://www.acog.org/clinical-information/physician-faqs/covid-19-faqs-for-ob-gyns-obstetrics

MotherToBaby: https://mothertobaby.org//?s=covid

CDC: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html