The data on the risk of preterm labor in pregnant patients with COVID-19 as opposed to those without is very mixed. A systematic review of over 350 pregnant patients showed that preterm labor rates in patients >30 weeks' gestation were 15%. This rate is increased from the national average of 10% preterm birth rate in the United States. Another observational study of 55 pregnant patients with infection yielded a rate of 43% preterm labor in that specific cohort. These patients ranged in age from 23 to 40 years old, and all were infected with COVID-19 in the third trimester. There is thought that the infection and fever may increase the likelihood of preterm labor. There is also a sense of bias in the data, as many providers are more inclined to induce labor in infected patients for fear of unknown or unforeseen complications. There is insufficient data to determine the exact etiology of the cause of preterm labor and whether there is a causal relationship between COVID-19 infection and preterm labor. However, there appears to be an association of third trimester COVID-19 infections and the rate of preterm labor.
Similar to the rates of preterm labor, the rates of cesarean delivery in patients afflicted with COVID-19 are elevated due to provider preference not to deliver vaginally. An extensive systematic review of over 500 COVID-19 infected pregnant patients reported rates for delivery in 435 patients. The cesarean delivery rate in these patients was at 84.7%; only a reported 8 cases required ICU level of care. This indicates that the cesarean delivery rate was correlated to physician practice and erring on the side of caution rather than required cesarean for maternal and neonatal complications. There were no maternal deaths in this study and only one neonatal death.
Similarly, another cohort study between March and April showed increased cesarean rates from normal in COVID-19-infected patients. These patients were stratified from asymptomatic to severe disease based on WHO classification. In the severely infected patients, 52.4% were delivered via C-section instead of 92% of the critical patients delivered via C-section. There were decreased rates in asymptomatic and mild cases. This cohort study made an association between the severity of the COVID-19 infected and the mode of delivery with higher rates of cesarean in patients with more severe disease. Lastly, another systematic review in pregnant patients with greater than 90% hospitalization rates for COVID-19 pneumonia showed an increased C-section rate of 91%. This study shows the increased rate in severe COVID-19 pneumonia requiring oxygen support and hospitalization and is not representative of most of the population infected with COVID-19.
There is little data regarding the differing rates between post-partum hemorrhage (PPH) in those vaginally delivered with and without COVID-19 serologically identified infection. Due to the hypercoagulable changes associated with pregnancy and COVID-19, there is reason to believe there would be altering PPH rates in patients afflicted. However, early Chinese studies showed there was no increased risk of PPH in patients delivering with COVID-19, although in the study, there was increased usage of oxytocin during and after delivery. In the event of PPH, there has been a suggestion against the use of antifibrinolytic agents, such as tranexamic acid, due to the increased risk of thrombosis involved in severe and critical COVID-19-infected patients. Thus, practitioners may choose against this and other treatments that can cause pulmonary arterial vasoconstriction, such as methylergotamine, due to hypoxia's theoretical risk. There is limited data to support these suggestions or findings.
There was seemingly no increased rate of maternal mortality in multiple systematic reviews and cohort studies in those hospitalized with COVID-19. The mortality rate in pregnant and non-pregnant patients is relatively equal. In two systematic reviews in New York and of selected widespread databases, the mortality rate of over 250 and 350 patients, respectively, was 0.0%. In contrast to other coronavirus outbreaks such as SARS and MERS, COVD-19 shows no increased maternal mortality risk. SARS had reported 25% and MERS a 28% risk of maternal mortality. There is an increased hospitalization and ICU admissions rate with mechanical ventilation compared to a matched non-pregnant cohort. However, this is not associated with any increased rate of mortality in pregnant patients. There is no known correct number of maternal mortalities currently, but it is believed to be similar to the rate of COVID-19 infection mortality of the general population. In Florida, pregnancy mortality is assessed quarterly by the Pregnancy Associated Mortality Review (PAMR), a statewide maternal mortality review process tasked to better understand why women are dying during pregnancy, childbirth, and the year post-partum. Approximately half the states in the U.S. have a comprehensive maternal mortality review process.
As important as the effects of COVID-19 infection are on the mother, the infection may also impact the developing fetus. Due to the unknown nature of the coronavirus, infected pregnant patients will often have questions and concerns regarding the effects of coronavirus on their fetus. Most importantly, they will have concern for risk of transmission to the fetus, risk of fetal mutations and malformations, and, ultimately, risk for fetal demise. As per the currently available literature, there seems to be no clear vertical transmission of the virus to the fetus. A small observation study conducted in the U.S. of 43 newborns from infected mothers showed 0 positive results upon testing during the first day of life. In opposition, there is data showing a small positive rate in newborns. In a relatively larger systematic review of 936 positive mothers, there was a 3.2% COVID-19 PCR positive rate via nasopharyngeal swab (27/936) in neonates. This rate mirrored other studies done in China in 2020 during the outbreak. These rates were for third-trimester maternal COVID-19 infection. These rates were deemed to be similar to pathogens that cause congenital infections. Due to the limited data of first-trimester infections, it is difficult to conclude any early antepartum vertical transmission to the neonate. A lancet observational cohort study done in New York City of over 1400 deliveries, including 116 to COVID-19 positive mothers, showed that no neonates at 24 hours tested positive for coronavirus. Of the 82 neonates who followed up within 5 to 7 days, 68 roomed with their mothers, and 64 were breastfed for the 5 to 7 days of rooming. The repeat COVID-19 PCR was negative in all neonates who were breastfed and who followed up. This suggests that breastfeeding is safe, and there is limited vertical transmission of COVID-19 to neonates. There may be components of inappropriate measures taken in those with positive COVID-19 serologies at 24 hours. This conflicting data makes it difficult for physicians to educate their patients regarding vertical COVID-19 transmission.
However, it is possible to educate patients regarding the potential risks of neonatal COVID-19 infection. The overwhelming majority of data regarding neonatal COVID-19 infections shows mild respiratory distress as the most common complication. A review in the Children's Hospital of Wuhan reported on 33 patients born from COVID-19 positive mothers, three of these patients had COVID-19 infection, and the symptoms included fever with neonatal sepsis and acute hypoxic respiratory failure without cyanosis.
Current data suggests that there is no risk of teratogenic effects in developing fetuses due to COVID-19 antepartum infection. Although the data is limited due to limited reviews and small observational studies, preliminary research shows no teratogenicity.
Treatment of infectious disease in pregnant patients often presents a unique challenge due to the many known and unknown adverse effects of antimicrobials on the developing fetus. This, coupled with the evolving treatment of COVID-19, makes this challenge even more difficult.
The current understanding and treatment of COVID-19 in non-pregnant patients is often influenced by the severity of the disease, individual comorbidities, degree of immunosuppression of the patient, and various other factors. Many patients are placed on an experimental treatment that shows promising preclinical or early phase clinical trial data. Many of the current pharmaceutical drugs used to treat COVID-19 are not well studied in pregnancy, adding even more reason for hesitancy in prescribing physicians. Thus, severity indexes must be used to stratify COVID-19 positive patients. Many stratification methods used in non-pregnant patients, such as D-dimer levels, Sequential organ failure assessment (SOFA) score, and O2 saturation, differ in pregnancy due to maternal physiologic changes. Pregnant patients have a hypercoagulable state coinciding with elevated D-dimer levels at baseline. Thus, D-dimer should not be used to stratify the severity of COVID-19 infection in pregnant patients. Oxygen saturation levels also differ in pregnant patients as, at baseline, this population has a higher resting PaO2 level to increase fetal oxygenation. Thus, there is a higher threshold for dropping oxygen saturation levels. Many physicians use the cutoff of <92% or even lower in non-pregnant patients with COVID to begin supplemental oxygen. However, the WHO recommends maintaining an O2 saturation between 92-95% and a PaO2 >70 in pregnant patients to decrease the risk of fetal hypoxemia and acidosis. The threshold for mechanical ventilation in pregnancy is also reduced for the reasons mentioned previously. With increasing oxygen supplementation without response and PaO2 <70, evidence suggests early intubation decreases the morbidity and mortality rates of pregnant patients with acute hypoxemic respiratory failure.
Pregnancy is a known state of hypercoagulability - predisposing patients to venous and arterial thromboembolism. There have been many preliminary reports and observational studies that support an increased risk of thrombosis in patients with COVID-19. Current evidence supports venous thromboembolism (VTE) prophylaxis with unfractionated or low-molecular-weight heparin (LMWH) for all pregnant patients admitted with COVID-19. Five thousand units of unfractionated heparin (UFH) every 12 hours are recommended over LMWH because it is more readily reversible. However, UFH is classified as a pregnancy category C drug while LMWH falls in category B, which may sway practitioners towards the use of LMWH for anticoagulation in the inpatient setting. LMWH may also be used in cases in which delivery is not expected within days to weeks. There are reports of many hospitals using full-dose anticoagulation in patients with worsening oxygen saturation <92% on >4L of supplemental oxygen. However, there is currently minimal data to support therapeutic dose anticoagulation without diagnosed deep vein thrombosis, pulmonary embolism or clinical signs, and symptoms of the clot.
Remdesivir is the most recent antiviral studied in the treatment of COVID-19. This antiviral is used in patients with severe COVID-19 under study protocol, initially given through compassionate use and more recently approved by the FDA for more widespread administration. This is less so done in pregnant patients as this drug was developed to treat Ebola and Marburg viruses. However, recently accepted manuscript data spanning from March 21 to June 16 described the use of remdesivir in hospitalized pregnant women with confirmed COVID-19 infection and O2 saturation <94% who met the criteria to be enrolled in the compassionate use program. Of the 86 patients enrolled in this study, 19 were delivered before their first course of remdesivir and were included in the immediate post-partum group. The remaining patients, whose median gestational age was 28 weeks, were started on remdesivir with follow-up after 28 days. After the 28-day follow-up, the oxygen requirement in 96% of the pregnant patients decreased.
Furthermore, 93% of those requiring mechanical ventilation were extubated, 93% recovered, and 90% were discharged. Adverse events were experienced in 29% (22/67) of the cohort. These adverse events were described as anemia, constipation, dysphagia, worsening hypoxia, and deep vein thrombosis, among others. Other side effects shown included increasing liver function tests and serum creatinine levels with seven pregnant women discontinuing the study drug due to adverse events. Currently, remdesivir is classified as a pregnancy category B2 pharmaceutical drug - epitomizing the limited data of remdesivir in the pregnant cohort. There is little data regarding the fetal effects of remdesivir from its current usage in the treatment of COVID-19 infections or during prior clinical trials to treat Ebola. With consideration of the low molecular weight and avid protein binding, it is hypothesized that remdesivir may cross the placenta, although more clinical studies are needed to determine any adverse neonatal effects.
Corticosteroids, such as dexamethasone, are currently indicated in the treatment of severely ill non-pregnant patients who require oxygen or ventilatory support. Corticosteroids are often indicated in pregnant patients who are in or at high risk for preterm labor to promote fetal lung maturity. More recently, there has been data supporting the use of dexamethasone in patients with severe COVID-19 infection. This controlled trial demonstrated that in patients either requiring oxygen support or on mechanical ventilation, there was a decrease in 28-day mortality rates. Dexamethasone or betamethasone is the preferred agents used to induce fetal pulmonary maturation in patients between 24 and 34 weeks of gestation at increased risk for preterm labor. Other corticosteroids that have been used include methylprednisolone or hydrocortisone, as these steroids limit fetal steroid exposure. This theoretical usage has less published data for reducing maternal mortality. All corticosteroids, including dexamethasone, belong to the pregnancy category C due to the fact that these pharmaceutical drugs cross the placenta and are only partially metabolized by placental enzymes into inactive metabolites. These molecular properties, coupled with the potential teratogenicity of dexamethasone, have given physicians much trepidation. Potential side effects of dexamethasone on the developing fetus include theoretical distortions of osteogenesis in the fetus and fetal malformations such as oral clefts and intrauterine fetal growth restriction. Despite these possible adverse outcomes, the American College of Obstetricians and Gynecologists (ACOG) recommends that treatment with dexamethasone should not be withheld in pregnant patients when indicated. Thus, it is recommended to use dexamethasone in pregnant patients in the ICU or mechanically ventilated patients due to the benefits shown in the treatment of COVID-19 and for the maturing neonate.
With the recent release of the mRNA vaccines, Pfizer-BioNtech (BNT162b2) and Moderna (mRNA-1273), there is concern from pregnant patients regarding the vaccine's detrimental effects in utero. However, mRNA vaccines do not contain the live virus that causes COVID-19; therefore, COVID-19 cannot be contracted from the vaccine. Additionally, mRNA vaccines do not interact with one's DNA because the mRNA does not enter the nucleus of the cell. Cells break down the mRNA quickly after the mRNA is translated into the protein. Due to this fact, mRNA vaccines are unlikely to pose a specific risk in pregnancy. The actual risks of mRNA vaccines to the pregnant person and her fetus are unknown because these vaccines have not been adequately studied in this population. In a cohort study evaluating the immunogenicity and reactogenicity of COVID-19 mRNA vaccination (BNT162b2 and mRNA-1273) in pregnant and lactating women, the vaccines induced antibody titers equivalent in pregnant and lactating women to non-pregnant women. These mRNA COVID-19 vaccines generated robust humoral immunity in pregnant and lactating women, similar to that observed in non-pregnant women. Further, the vaccine-induced immune responses were significantly greater than the response to natural infection, and the immune transfer to neonates was also observed via placenta and breast milk.
COVID-19 vaccine (Ad26.COV2.S) functions differently:in that the vaccine is a viral vector vaccine. This uses a viral vector to deliver the COVID-19 spike protein from which immunity is developed. Viral vectors have been previously given to pregnant patients of all trimesters in large-scale Ebola vaccination trial and no adverse pregnancy-related outcomes that affect the infant, were associated with viral vector vaccination in these trials. Currently, an open-label, phase 2 study to evaluate the safety, reactogenicity, and immunogenicity of Ad26.COV2.S in healthy pregnant is ongoing. The purpose of this ongoing clinical trial is to assess the safety and reactogenicity of Ad26.COV2.S administered intramuscularly (IM) as a 2-dose schedule, in adult participants during the second and/or third trimester of pregnancy and (potentially) post-partum. This study is also going to assess the humoral immune response in peripheral blood of adult participants, to Ad26.COV2.S administered IM as a 2-dose schedule during the second and/or third trimester of pregnancy, 28 days after the first and second vaccination.
In animals, development and reproductive toxicity (DART) studies using the mRNA (BNT162b2 and mRNA-1273) and Ad26.COV2.S vaccines before or during pregnancy found no safety concerns. There were no direct or indirect harmful effects with respect to female reproduction, fetal/embryonal development, or postnatal development.
The American College of Obstetricians and Gynecologists (ACOG) recommends COVID-19 vaccines should not be withheld from pregnant individuals who meet the criteria for vaccination based on the Advisory Committee on Immunization Practices (ACIP)-recommended priority groups.