By Katherine Rivlin, MD, MSc
Associate Professor, Obstetrics and Gynecology, The Ohio State University Medical Center, Columbus
Pregnancy is independently associated with severe COVID-19 disease. Yet, with pregnant and lactating women excluded from participation in vaccine trials, the remaining information gap too often is filled with misinformation. With the increasing circulation of the delta variant, it has become critically important for clinicians to discuss COVID-19 vaccination with patients, and, specifically, to address concerns related to pregnancy, lactation, and fertility. The following is a review of the most recent guidance from the American College of Obstetricians and Gynecologists (ACOG), the Society of Maternal-Fetal Medicine (SMFM), and the American Society for Reproductive Medicine (ASRM) on vaccination in reproductive-age individuals.
VACCINE DEVELOPMENT, MECHANISMS OF ACTION, EFFICACY, AND SIDE EFFECTS
Considering the magnitude of the pandemic, the effort to develop vaccines has been rapid. Yet, no safety standards have been relaxed in this process. Instead, additional safety monitoring systems are in place to monitor and track vaccines, including real-time assessments. The FDA has issued an emergency use authorization (EUA) for three vaccines.
The Pfizer-BioNTech (Pfizer) mRNA vaccine, for use in individuals age 12 years and older, is a two-dose regimen, given three weeks (or 21 days) apart. The Moderna mRNA vaccine, for use in individuals age 18 years and older, is a two-dose regimen given one month (or 28 days) apart. The Johnson & Johnson) vaccine, for use in individuals age 18 years and older, is a single-dose regimen.
mRNA VACCINES (PFIZER AND MODERNA)
mRNA vaccines are a novel vaccine technology. They consist of mRNA encapsulated in lipid nanoparticles for transportation into host cells. The host cells create coronavirus spike proteins, causing immune cells to make COVID-19 antibodies. These vaccines are not live and do not enter the host cell’s nucleus or alter DNA. Their mechanism of action, the safety and efficacy data from Phase I and II trials, and the observational data collected since vaccine distribution all indicate mRNA vaccines are safe in pregnancy. The Pfizer vaccine is 95% effective and the Moderna vaccine is 94.1% effective in clinical trials at preventing laboratory-confirmed COVID-19 illness.1
ADENOVIRUS-VECTOR VACCINES (J&J)
Adenovirus-vector vaccines are monovalent shots made of a recombinant human adenovirus. They encode a stabilized form of a coronavirus spike protein. The vaccine cannot replicate, is not live, and does not contain preservatives. Other adenovirus-vector vaccines studied in pregnancy, such as HIV and Ebola vaccines, have no known pregnancy-related safety concerns. Clinical trials indicate the J&J vaccine is 66.9% effective at preventing moderate COVID-19 illness, 76.7% effective at preventing severe/critical COVID-19 illness, and 93.1% effective at preventing hospitalization related to COVID-19.
Side effects from all three vaccines are common, expected, and indicate development of COVID-19 antibodies. Most people will experience mild flu-like symptoms, and clinicians should discuss this as part of anticipatory guidance. Allergic reactions, such as anaphylaxis, are rare. Clinicians should manage such reactions similarly in both pregnant and nonpregnant patients by notifying emergency medical services, placing the patient in the supine position, giving epinephrine, and monitoring for reoccurrence.1
THROMBOSIS AND THROMBOCYTOPENIA SYNDROME
The FDA has added a warning and fact sheet to the J&J vaccine about the possibility of thrombosis and thrombocytopenia syndrome (TTS) following vaccination. TTS is rare, occurring in only 8.9 per 1 million doses of the J&J vaccine. Most incidences occurred in women of reproductive age, none of whom were pregnant. The risk of thrombosis increases in pregnancy, postpartum, and in patients using estrogen-containing contraceptives. However, these factors likely do not increase the risk of TTS after using the J&J vaccine. Therefore, ACOG does not recommend stopping estrogen-containing contraceptives after the J&J vaccine. Considering the high risk of serious illness from COVID-19 and the low incidence of TTS, women of reproductive age and pregnant patients still can receive the J&J vaccine.1
SAFETY OF THE COVID-19 VACCINE IN PREGNANCY
Despite advocacy efforts by ACOG, SMFM, and the National Academy of Medicine to include pregnant and lactating individuals in vaccine trials, none of the COVID-19 vaccines approved under an EUA were tested in pregnant women. Unfortunately, the concept of “protection by exclusion” leads to experimentation on pregnant and lactating women outside of clinical trials, without the protections that clinical trials provide.2 Although studies are underway, most of the current data come from post-marketing surveillance. One prospective cohort study showed vaccinated pregnant and lactating patients produced comparable immune responses to nonpregnant controls.3
In Phase II and Phase III trials, some inadvertent pregnancies occurred. Researchers are following these patients for safety outcomes. The CDC is monitoring more than 100,000 pregnancies through the v-safe post-vaccination health checker. Although self-reported, these data do not indicate pregnancy-related safety concerns. To date, the CDC’s v-safe pregnancy registry includes more than 6,000 pregnancies. Vaccine-related adverse events and side effects appear similar in pregnant and nonpregnant women. The post-vaccination miscarriage rate also appears consistent with the background rate, although a risk estimate is unavailable.4
SAFETY OF THE COVID-19 VACCINE DURING LACTATION
No biological plausibility exists to support a concern for lactating women and COVID-19 vaccination. ACOG and SMFM recommend vaccination for lactating patients. Although this population was not included in most clinical trials, the potential benefits far outweigh theoretical concerns. Patients can initiate and continue breastfeeding after COVID-19 vaccination. After natural COVID-19 infection, specific antibodies are present in human milk, which may offer protection to the newborn. In a prospective trial, vaccine-generated antibodies also were present in umbilical cord blood and breastmilk after maternal vaccination, which also may confer immunity.5
VACCINE SAFETY AMONG THOSE CONTEMPLATING PREGNANCY
Although fertility outcomes were not studied specifically in vaccine trials, ACOG, SMFM, and ASRM recommend COVID-19 vaccination for women actively trying to become pregnant or contemplating pregnancy. All COVID-19 vaccines available do not replicate and immediately clear from tissue following injection. Yet, misinformation around the COVID-19 vaccine and its effects on fertility is widespread on social media. The proposed mechanism of infertility relies on a presumed similarity between the SARS-CoV-2 spike protein and the syncytin-1, a protein necessary for the formation of the syncytiotrophoblast in a developing embryo. According to this theory, immune cross-reactivity could damage the trophoblast and prevent implantation. Such cross-reactivity not only would occur following vaccination, but also following natural illness. Yet, such cross-reactivity has never been demonstrated in laboratory analysis or in human clinical data, nor have effects on male fertility been shown.6,7 Anecdotal post-vaccine menstrual disturbances have been reported, but little evidence exists. Although environmental stresses can affect menses temporarily, no prior vaccines have been associated with changes to menses. The National Institutes of Health put out a special call for research on this issue.1
CLINICAL CONSIDERATIONS AND CONCLUSIONS
Clinicians should understand vaccine hesitancy exists in all populations, but that historical and current healthcare injustices play an important role. Communities of color have been affected disproportionately by COVID-19, with higher rates of severe illness and death. Yet, Black and Latinx populations generally receive vaccines at lower rates, in part as the result of differential access. Clinicians should listen to and validate patient fears and concerns, while providing accurate information and resources for accessing vaccination. Should patients decline vaccination, the clinician should continue to provide support and recommend protective measures, such as hand washing, social distancing, and masking. Providers should discuss vaccination with individuals in future visits if they are amenable.1 ACOG recommends discussing and documenting vaccination status with everyone. Patients need not undergo pregnancy testing or a conversation with clinicians before vaccination, although discussions can occur as needed. The COVID-19 vaccine can be administered simultaneously with other vaccines, including within 14 days of other shots. The CDC, ACOG, SMFM, and ASRM all recommend vaccination in pregnancy.8 Still, vaccination rates are notably low among pregnant women. Clinicians should underscore the safety of vaccination and the risks of natural infection, particularly in pregnancy and in patients with underlying comorbidities. Finally, the notable absence of pregnant and lactating women in vaccination trials and the lack of fertility outcomes all have left a notable gap in available evidence. Misinformation has filled this gap, even as we have relied on the public to accept vaccination to combat the pandemic.
REFERENCES
- American College of Obstetricians and Gynecologists. COVID-19 vaccination considerations for obstetric-gynecologic care. Updated Nov. 3, 2021.
- Costantine MM, Landon MB, Saade GR. Protection by exclusion: Another missed opportunity to include pregnant women in research during the coronavirus disease 2019 (COVID-19) pandemic. Obstet Gynecol 2020;136:26-28.
- Gray KJ, Bordt EA, Atyeo C, et al. Coronavirus disease 2019 vaccine response in pregnant and lactating women: A cohort study. Am J Obstet Gynecol 2021; Mar 26:S0002-9378(21)00187-3. doi: 10.1016/j.ajog.2021.03.023. [Online ahead of print].
- Centers for Disease Control and Prevention. V-safe COVID-19 Vaccine Pregnancy Registry. Updated Nov. 22, 2021.
- Juncker HG, Mulleners SJ, van Gils MJ, et al. The levels of SARS-CoV-2 specific antibodies in human milk following vaccination. J Hum Lact 2021;37:477-484.
- Morris RS. SARS-CoV-2 spike protein seropositivity from vaccination or infection does not cause sterility. F S Rep 2021;2:253-255.
- American Society for Reproductive Medicine. Patient management and clinical recommendations during the coronavirus (COVID-19) pandemic.
- Centers for Disease Control and Prevention. COVID-19 vaccines while pregnant or breastfeeding. Updated Nov. 19, 2021.
Vaccination rates are notably low among pregnant women. Clinicians should underscore the safety of vaccination and the risks of natural infection, particularly in pregnancy and in patients with underlying comorbidities.
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