COVID-19 vaccination during pregnancy safe for infant neurodevelopment through 18 months.
HealthDay News — COVID-19 vaccination during pregnancy seems safe in terms of neurodevelopment through 18 months of age, according to a study published online January 22 in JAMA Pediatrics.
Eleni G. Jaswa, MD, from the University of California in San Francisco, and colleagues conducted a prospective cohort study, Assessing the Safety of Pregnancy During the Coronavirus Pandemic (ASPIRE), to examine whether in utero exposure to maternal COVID-19 vaccination is associated with differences in scores on the Ages and Stages Questionnaire, third edition (ASQ-3), at ages 12 and 18 months. A total of 2487 pregnant participants were enrolled at less than 10 weeks of gestation. Neurodevelopmental assessments were included for 2261 and 1940 infants aged 12 and 18 months, respectively.
The researchers found that 30.6% of 1541 exposed infants and 28.2% of 720 unexposed infants screened abnormally for developmental delay at 12 months; the corresponding prevalences were 20.1% and 23.2% of 1301 and 639 infants at 18 months, respectively. After adjustment for confounding variables, including maternal age, race, ethnicity, education, income, maternal depression, and anxiety, there was no difference seen in risk for abnormal ASQ-3 screened at 12 or 18 months. The results were not affected after further adjustment for preterm birth and infant sex.
“These data suggest that maternal vaccination against COVID-19 during pregnancy was safe from the perspective of offspring neurodevelopment through 18 months of age,” the authors write.
Syringes with COVID-19 vaccines in Berlin, Germany, on Feb. 28, 2022.
A serious side effect linked to COVID-19 vaccines can lead to death, according to a new study.
Post-vaccination myocarditis, a form of heart inflammation, was identified in a subset of people who died “unexpectedly” at home within 20 days of receiving a COVID-19 vaccine. Researchers analyzed autopsies that had been performed on the people and conducted additional research, including studying tissue samples.
Researchers started with a group of 35, but excluded 10 from further analysis because other causes of death were identified. Of the remaining 25, researchers identified evidence of myocarditis in five.
All of the five people received a Moderna or Pfizer vaccine within seven days of their death, with a mean of 2.5 days. The median age was 58 years. None of the people had COVID-19 infection prior to being vaccinated and nasal swabs returned negative.
Autopsy findings combined with the lack of evidence of other causes of death and how the vaccination happened shortly before the deaths enabled researchers to say that for three of the cases, vaccination was the “likely cause” of the myocarditis and that the cardiac condition “was the cause of sudden death.”
In one of the other cases, myocarditis was believed to be the cause of death but researchers detected a herpes virus, an alternative explanation for the incidence of heart inflammation. The remaining case did not include an alternative explanation for the myocarditis but the researchers said the impact of the inflammation was “discrete and mainly observed in the pericardial fat.” They classified the two cases as possibly caused by vaccination.
“In general, a causal link between myocarditis and anti-SARS-CoV-2 vaccination is supported by several considerations,” the researchers said, including the “close temporal relation to vaccination”; the “absence of any other significant pre-existing heart disease”; and the negative testing for any “myocarditis-causing infectious agents.”
Limitations included the small cohort size.
The study (pdf) was published by Clinical Research in Cardiology on Nov. 27. The researchers all work for Heidelberg University Hospital. They were funded by German authorities.
Moderna and Pfizer did not respond to requests for comment.
The meticulous ruling out of possible causes apart from vaccination signals that the cases are “the tip of the iceberg,” Dr. Andrew Bostom, a heart expert based in Rhode Island, told The Epoch Times.
“If there’s a seemingly healthy person that dies suddenly in their sleep, essentially, these are typically the cases that are autopsied, and clearly the most common finding is some form of atherosclerotic coronary heart disease. But they basically ruled that out in these cases. And then they came up with the most plausible proximate cause being vaccination,” he said. “And so it suggests that the phenomenon could actually be broader than it’s been suspected to be.”
Myocarditis
Myocarditis is a serious heart condition that can manifest as chest pain and typically leads the sufferer to seek hospital care.
Doctors usually advise against all or most physical activity for a period of time.
Causes include bacteria, viruses, and fever.
Acute myocarditis resolves in about half of cases in the first two to four weeks, researchers have found, but another quarter feature longer-term problems and many of the rest lead to death or heart transplantation.
The incidence of myocarditis among COVID-19 vaccine recipients was higher than expected, researchers in the United States, Israel, and other countries have found. The highest rates have been detected in young people, particularly young males.
Estimates of the typical myocarditis incidence rates are 0.2 to 2.2 per million persons within seven days. Reports to the Vaccine Adverse Event Reporting System show higher rates for males aged 5 to 49 and females aged 12 to 29. The highest rate was 75.9 per million second doses administered. Reports to the system don’t prove causality but the system suffers from severe underreporting, according to studies, indicating the rates are even higher.
The U.S. Centers for Disease Control and Prevention (CDC) continues to recommend vaccination for virtually all people aged 6 months and older, asserting that the benefits of the vaccines outweigh the risks. Some experts disagree, saying side effects like myocarditis tilt the calculus to the risks being higher in some age groups.
Government officials have repeatedly said that most of the myocarditis cases resolve within weeks, but CDC researchers found in September that many youths who experienced post-vaccination myocarditis still had abnormal MRI results months later.
The incidence has been much lower among older people, according to U.S. authorities, which have refused to make public the autopsy results of people who die after vaccination, and various studies.
The new study “suggests we’ve been missing some severe myo[carditis] cases in our studies,” Dr. Tracy Høeg, an epidemiologist who advises the Florida Department of Health, said on Twitter.
Causality
Several vaccines have been linked to myocarditis and a related condition, pericarditis. They are made by Moderna and Pfizer and are the two most widely administered in the United States and Germany.
Both vaccines utilize messenger RNA (mRNA) technology.
Causality means that a vaccine causes a condition.
Top CDC researchers have said (pdf) the current evidence shows a causal link between the mRNA shots and heart inflammation. Other researchers have also reachedthat conclusion.
The U.S. Food and Drug Administration warns potential vaccine recipients that “postmarketing data demonstrate increased risks of myocarditis and pericarditis, particularly within 7 days following the second dose.”
Bostom said the evidence he’s reviewed shows a causal link.
“It’s as certain as most associations that we say are confirmed in medicine,” he said.
Some studies haveidentified COVID-19 as another cause of myocarditis and pericarditis, but othershave indicated it might not be associated.
Other Autopsy Findings
Before the German study, other researchers around the world had reported findings from autopsies of people who died suddenly after vaccination.
In 2021, U.S. researchers reported two adults developed myocarditis within two weeks of COVID-19 vaccination, and they were unable to find causes other than vaccination.
In 2021, South Korea researchers reported that after examining the death of a 22-year-old man who died five days after receiving the Pfizer vaccine, they determined the primary cause was “myocarditis, causally-associated” with the vaccine.
In January, New Zealand researchers reported that the Pfizer vaccine was probably responsible for sudden myocarditis that led to the death of a 57-year-old woman, writing that “other causes have been discounted with reasonable certainty.”
In February, researchers in several U.S. states reported that two teenage boys who died shortly after receiving Pfizer’s vaccine experienced heart inflammation and that the inflammation was the primary cause of death.
In May, CDC researchers reported that a young boy died after experiencing post-vaccination heart inflammation, with myocarditis being pegged as the cause of death.
In September, a German researcher reported that a 55-year-old who died four months after receiving the Pfizer vaccine died of myocarditis and said “these findings indicate that myocarditis, as well as thrombo-embolic events following injection of spike-inducing gene-based vaccines, are causally associated with a[n] injurious immunological response to the encoded agent.”
And just recently, Japanese researchers reported on results from a 27-year-old man who died 28 days after admission following vaccination.
Objective To assess the risk of preterm birth, small for gestational age at birth, and stillbirth after covid-19 vaccination during pregnancy.
Design Population based retrospective cohort study.
Setting Ontario, Canada, 1 May to 31 December 2021.
Participants All liveborn and stillborn infants from pregnancies conceived at least 42 weeks before the end of the study period and with gestational age ≥20 weeks or birth weight ≥500 g.
Main outcome measures Using Cox regression, hazard ratios and 95% confidence intervals were estimated for preterm birth before 37 weeks (overall and spontaneous preterm birth), very preterm birth (<32 weeks), small for gestational age at birth (<10th centile), and stillbirth. Vaccination against covid-19 was treated as a time varying exposure in the outcome specific risk window, and propensity score weighting was used to adjust hazard ratios for potential confounding.
Results Among 85 162 births, 43 099 (50.6%) occurred in individuals who received one dose or more of a covid-19 vaccine during pregnancy—42 979 (99.7%) received an mRNA vaccine. Vaccination during pregnancy was not associated with any increased risk of overall preterm birth (6.5% among vaccinated v 6.9% among unvaccinated; adjusted hazard ratio 1.02, 95% confidence interval 0.96 to 1.08), spontaneous preterm birth (3.7% v 4.4%; 0.96, 0.90 to 1.03), or very preterm birth (0.59% v 0.89%; 0.80, 0.67 to 0.95). No increase was found in risk of small for gestational age at birth (9.1% v 9.2%; 0.98, 0.93 to 1.03) or stillbirth (0.25% v 0.44%; 0.65, 0.51 to 0.84). Findings were similar by trimester of vaccination, mRNA vaccine product, and number of doses received during pregnancy.
Conclusion The findings suggest that vaccination against covid-19 during pregnancy is not associated with a higher risk of preterm birth, small for gestational age at birth, or stillbirth.
Introduction
Infection with SARS-CoV-2 during pregnancy has been associated with higher risks of admission to hospital, admission to an intensive care unit, and death for pregnant individuals.123 Furthermore, SARS-CoV-2 infection has been associated with a higher risk of preterm birth,345 fetal growth restriction,4 postpartum haemorrhage,4 and stillbirth.6 Many countries recommend covid-19 vaccination during pregnancy,7 which has been shown to be effective against covid-19 in pregnant individuals8 as well as their newborns910; however, vaccine coverage among pregnant individuals remains lower than among women of reproductive age.1112
Safety concerns about covid-19 vaccination during pregnancy remains a potential obstacle to improving coverage. As of July 2022, results published from epidemiological studies are reassuring—two case-control studies of covid-19 vaccination in early pregnancy found no association with spontaneous abortion.1314 Our recent study of pregnancies to 30 September 2021, including 22 660 individuals vaccinated during the second or third trimester, did not show any association with adverse peripartum outcomes such as postpartum haemorrhage or low Apgar scores.15 However, fewer studies have examined risk of adverse birth outcomes associated with prenatal covid-19 vaccination. A population based birth registry study from Sweden and Norway found no increased risks of preterm birth or small for gestational age at birth; importantly, stillbirth also was not associated with covid-19 vaccination in the study.16 Two cohort studies including pregnant individuals insured through large health maintenance organisations observed no associations with preterm birth or small for gestational age at birth.1718 In a large, province-wide population, we evaluated whether covid-19 vaccination during pregnancy was associated with risk of preterm birth (including spontaneous preterm birth and very preterm birth), small for gestational age at birth, or stillbirth.
Methods
We followed guidance for conducting studies of covid-19 vaccination during pregnancy19 and reporting observational studies.20
Study design, population, and data sources
We conducted a population based retrospective cohort study in Ontario, Canada, which provides publicly funded healthcare to all residents, including services relating to prenatal and obstetrical care. The provincial birth registry (Better Outcomes Registry and Network (BORN Ontario))21 was used to identify the study population—after extracting records for completed pregnancies between 1 May and 31 December 2021, we extracted the corresponding births to create distinct records for each live birth and stillbirth, including multi-fetal pregnancies. We excluded births to non-Ontario residents and births from pregnancies conceived less than 42 weeks before the end of the study (ie, last menstrual period date after 10 March 2021) to avoid cohort truncation bias caused by overrepresentation of preterm births close to the end of the study period.22 We also excluded any records with gestational age <20 weeks and birth weight <500 g, or following pregnancy termination, as these events are not systematically collected in the registry (see supplementary table 1 for additional details of data sources).21
The birth registry receives records for all liveborn infants and stillborn infants ≥20 weeks’ gestation or with birth weight ≥500 g from hospitals, birth centres, and midwifery practice groups (home births) across Ontario.21 Maternal personal characteristics, health behaviours, pre-existing health conditions, pregnancy history, obstetric complications, interventions, and birth outcomes are collected from medical records, clinical forms, and patient interview and were shown to be of high quality in a validation study.23 Unique health card numbers (available for 96.9% of the study population) were used to deterministically link birth records to the COVaxON database, which captures all covid-19 immunisations in the province. Since 1 March 2020, information on individuals with confirmed covid-19 during pregnancy has been captured from two sources: a voluntary hospital based or midwifery practice group based case report form submitted directly to the birth registry, and through deterministic linkage with Ontario’s database containing all individuals with polymerase chain reaction (PCR) confirmed covid-19 reported to public health (Public Health Case and Contact Management Solution).24 During the study period, free PCR testing was widely available and recommended for anyone with symptoms of covid-19 or those in close contact with an individual with confirmed covid-19, or both. Finally, maternal residential postal code was used to link to area based socioeconomic data from Statistics Canada’s 2016 census and the Ontario Marginalization Index.25
Outcome measures
Exposure variables
Ontario’s covid-19 vaccination programme began on 14 December 2020,26 and pregnant individuals were designated as a priority population for vaccination on 23 April 2021.27 Owing to a limited supply of covid-19 vaccines in Canada at that time, eligibility had not yet expanded to the general adult population; moreover, for several months during the spring of 2021, Canada used an extended dose interval of up to four months between the first and second vaccine dose.28 On 18 May 2021, all people older than 18 years became eligible to receive a covid-19 vaccine, and on 15 December 2021, all people older than 18 years, including pregnant people, became eligible to receive a covid-19 booster dose.29 From COVaxON, we identified vaccinations received between the estimated date of conception up to one day before birth. We treated vaccination as a time varying exposure within outcome specific risk windows—in the main analyses of preterm birth outcomes and stillbirth, ongoing pregnancies changed status from unvaccinated to vaccinated on the day that dose 1 was received in the risk window (see supplementary fig 1). For the assessment of small for gestational age at birth, we lagged the date of dose 1 by 14 days, since any potential effect of vaccination on fetal growth would not happen acutely.16 In subgroup analyses assessing the number of doses, an additional change in exposure status occurred if dose 2 was received in the risk window. Gestational timing of all doses received during pregnancy was classified as first trimester (pregnancy day 14 to 13 weeks+6 days), second trimester (14 weeks+0 days to 27 weeks+6 days), or third trimester (28 weeks+0 days to end of follow-up). Gestational age is recorded in the birth registry, and most pregnancy dating in Ontario is based on early ultrasound assessment.
Outcome variables
We defined preterm birth and very preterm birth as a live birth before 37 and 32 completed weeks of gestation, respectively. Preterm birth subtype was considered spontaneous if it occurred after spontaneous onset of labour or preterm premature rupture of membranes.30 Small for gestational age at birth was defined as a singleton live born infant below the 10th centile of the sex specific birth weight for gestational age distribution, based on a Canadian reference standard.31 Stillbirth was defined as an antepartum or intrapartum fetal death at ≥20 weeks, with the gestational timing of the event based on the date of birth (information on the exact timing of fetal death was not available). The end of the outcome specific risk windows were 36 weeks+6 days of gestation for preterm birth (pregnancy day 258), 31 weeks+6 days for very preterm birth (pregnancy day 223), and end of pregnancy for small for gestational age infants and stillbirths.
Covariates
We adjusted for a range of covariates potentially associated with study outcomes or covid-19 vaccination, or both, using propensity score methods: maternal age at delivery (years), prepregnancy body mass index ≥30 (v <30), self-reported smoking status (yes or no) or substance use during pregnancy (yes or no), public health unit region (seven regions), pre-existing maternal health conditions (composite of asthma, chronic hypertension, diabetes, heart disease, thyroid disease; yes or no), parity (number of previous live births and stillbirths), multi-fetal pregnancy (yes or no), rural or urban residence, neighbourhood income fifths, neighbourhood marginalisation fifths (four dimensions: residential instability, material deprivation, dependency, ethnic concentration), calendar week of conception (categorical), and first visit for prenatal care in the first trimester (yes or no). Supplementary table 2 provides additional details on outcomes and covariates.
Statistical analysis
We used discrete time survival analysis to account for the time dependent nature of vaccination status and study outcomes. Each pregnancy contributed gestational time in days starting on the estimated date of conception (pregnancy day 14); ongoing pregnancies on 1 May (start of the study) started contributing time from that point (see supplementary fig 1), and follow-up continued until either the event or censoring at the end of the outcome specific risk window.
We used extended Cox proportional hazards regression models with gestational age in days as the time scale, and robust sandwich variance estimation to account for statistical dependence across repeated observations as a result of changes in vaccination status, which was treated as time varying. We estimated hazard ratios with 95% confidence intervals and used inverse probability of treatment weights to generate adjusted hazard ratios.32 The weights were derived from a propensity score representing the predicted probability of having received one dose or more of a covid-19 vaccine during pregnancy—for vaccine exposed births, the weight was computed as the inverse of the propensity score, and for unexposed births, the inverse of 1 minus the propensity score. To account for any extreme weights, we stabilised the weights to the entire population and trimmed the values to the 0.01st to 99.99th centiles.32 Missing covariate values were assumed to be missing at random, and we imputed missing values before generating propensity scores using a fully conditional specification (MI procedure in SAS Version 9.4, SAS Institute, Cary, NC).33 The percentage of missing data for any individual covariate included in propensity scores was low (range 0-3.5%), with the exception of body mass index, which had 10.2% missing. Across all the covariates included in the propensity scores, 15.4% of records had missing information for one or more covariates. Weighted Cox regression models from which we derived adjusted results were fitted on each of the five imputed datasets, and the results were combined using the MIANALYZE procedure (SAS Institute). As the distribution of maternal age after weighting the study population with the stabilised inverse probability of treatment weights remained imbalanced across the two exposure groups (as indicated by a standardised difference >0.134), all weighted models additionally included continuous maternal age.
In primary analyses, we evaluated vaccination status as receipt of one dose or more of a covid-19 vaccine in the outcome specific risk window. We performed subgroup analyses for preterm birth and small for gestational age at birth to evaluate trimester specific associations according to the number of doses (treating each dose as time varying), mRNA vaccine product for dose 1, and vaccine product combinations for those who received two mRNA doses; the number of events for the other outcomes was insufficient to conduct these subgroup analyses. In sensitivity analyses, we added covid-19 during pregnancy as a time varying covariate to the model and, separately, excluded individuals with a history of covid-19 during pregnancy. To assess for potential residual confounding, we stratified the original models by neighbourhood income (two highest and three lowest fifths) and limited the unvaccinated group to those who received their first vaccine dose after pregnancy, because in an earlier study of this population their baseline characteristics were shown to be more similar to individuals vaccinated during pregnancy than to those never vaccinated at any time.15 We also repeated the original analyses limited to singleton births.
Patient and public involvement
Owing to covid-19 related resource and time constraints, it was not feasible to directly involve patients in the design, conduct, reporting, or writing of our study. Although no patients were directly involved, the study team included several obstetrical care providers who were involved from the outset of planning the study and brought forward their experiences from patient interactions related to covid-19 vaccination during pregnancy. These were taken into consideration in planning this research and its dissemination to ensure relevancy for a broad group of knowledge users, including pregnant people.
Results
After exclusions, 85 162 live births and stillbirths occurred during the study period (fig 1); of these, 43 099 (50.6%) were related to individuals who received one dose or more of a covid-19 vaccine during pregnancy. Those vaccinated during pregnancy were more likely to be ≥30 years of age, nulliparous, and live in the highest income neighbourhoods; they were less likely to be smokers, report substance use during pregnancy, or live in a rural setting (table 1 and table 2). A total of 3328 births (3.9%) were to individuals who had covid-19 during pregnancy. The proportion with covid-19 during pregnancy was lower in the vaccinated group than unvaccinated group (2.9% v 4.9%; table 2). However, most of the covid-19 episodes in the vaccinated group (1056/1247; 84.6%) preceded dose 1 by a median of 10.1 weeks (interquartile range 5.3-17.6 weeks).
Fig 1
Study flow diagram. *Includes 366 who received a dose between the last menstrual period and estimated date of conception
Personal characteristics of study population overall and by covid-19 vaccination status during pregnancy. Values are numbers (percentages) unless stated otherwise
Pregnancy characteristics of study population overall and by covid-19 vaccination status during pregnancy. Values are numbers (percentages) unless stated otherwise
Among 43 099 individuals who were vaccinated during pregnancy, 13 416 (31.1%) received one vaccine dose, 29 650 (68.8%) received two doses, and 33 (0.1%) received three doses (table 3). Overall, 12.1% (n=5213) received dose 1 during the first trimester, 48.1% (n=20 715) during the second trimester, and 39.8% (n=17 171) during the third trimester. The median gestational age at dose 1 was 25 (interquartile range 18-32) weeks—later, when only one dose was received during pregnancy (median 34 (interquartile range 31-36) weeks; n=13 416) and earlier when two doses were received during pregnancy (median 21 (interquartile range 16-26) weeks; n=29 650) (fig 2). Overall, 80.1% (n=34 526) of dose 1 administrations during pregnancy were BNT162b2 (Comirnaty; Pfizer-BioNTech) and 19.6% (n=8453) were mRNA-1273 (Spikevax; Moderna); <1% (0.3%; n=120) were another vaccine product (Vaxzevria; Oxford-AstraZeneca: n=101; other: n=19).
Table 3
Vaccination characteristics among 43 099 pregnant individuals who received one dose or more of a covid-19 vaccine during pregnancy. Values are numbers (percentages) unless stated otherwise
Gestational timing of covid-19 vaccine doses received during pregnancy among 43 099 pregnant individuals in Ontario, Canada. (Top panel) Gestational age in days when dose 1 was received, among births to individuals who received only one vaccine dose during pregnancy (n=13 416). (Bottom panel) Gestational age in days when dose 1 and dose 2 were received, among births to individuals who received only two doses during pregnancy (n=29 650). Data for individuals who received three doses during pregnancy (n=33) are not shown. Vertical dotted line represents the end of the risk window for preterm birth (pregnancy day 258)
Overall, 5719 (6.7%) preterm births occurred; 3450 (4.1%) were spontaneous preterm births (table 4). The cumulative incidence of overall preterm birth was 6.5% among those who were vaccinated during pregnancy and 6.9% among those who were unvaccinated during pregnancy. Vaccination was not associated with an increased risk of overall preterm birth (adjusted hazard ratio 1.02, 95% confidence interval 0.96 to 1.08), spontaneous preterm birth (0.96, 0.90 to 1.03), or very preterm birth (0.80, 0.67 to 0.95). In subgroup analyses, results for overall preterm birth were similar by trimester (adjusted hazard ratios: first trimester, 0.98, 95% confidence interval 0.87 to 1.10; second trimester 0.98, 0.91 to 1.04; third trimester 1.00, 0.92 to 1.08) and vaccine product for dose 1, as well as by number of doses received during pregnancy, and vaccine product combination for those who received both doses during pregnancy (see supplementary table 3). Subgroup analyses could not be conducted for spontaneous preterm birth or very preterm birth owing to the small number of events.
Table 4
Association between covid-19 vaccination during pregnancy and study outcomes
The cumulative incidence of small for gestational age at birth was 9.1% (n=3743) among births to individuals who received one dose or more of a covid-19 vaccine during pregnancy, and 9.2% (n=3722) among births to unvaccinated individuals. No association was observed between vaccination during pregnancy and small for gestational age at birth overall (adjusted hazard ratio 0.98, 0.93 to 1.03; table 4), or in subgroup analyses by trimester and vaccine product for dose 1 (see supplementary table 3). A small increased association was observed for only dose 1 administered during pregnancy (1.09, 1.01 to 1.16), which was not observed among individuals who received two doses during pregnancy (0.92, 0.87 to 0.97; see supplementary table 3). The cumulative incidence of stillbirth was 0.25% (n=107) among births to individuals who received one dose or more of a covid-19 vaccine during pregnancy, and 0.44% (n=184) among births to unvaccinated individuals. Vaccination was not associated with any increase in the risk of stillbirth (0.65, 0.51 to 0.84; table 4). The number of stillbirths was not large enough for subgroup analyses.
Sensitivity analyses
When covid-19 during pregnancy was added to the model as a time varying exposure and when births to individuals with covid-19 during pregnancy were excluded, the results remained unchanged for all outcomes (see supplementary table 4). Estimates for most outcomes were similar across strata of neighbourhood income; although stratum specific estimates for individuals of higher income (fourth and fifth fifths) and lower income (first to third fifths) were different in magnitude for very preterm birth and for stillbirth, the direction of the stratum specific point estimates was consistent with that of the main analyses, and confidence intervals overlapped. When the comparison group was restricted to unvaccinated individuals who initiated their covid-19 vaccine series after pregnancy, the results for all outcomes remained unchanged. Analyses restricted to singleton births were similar for preterm birth outcomes; however, the estimate for stillbirth moved closer to the null value (adjusted hazard ratio 0.74, 0.57 to 0.96).
Discussion
In this large population of more than 85 000 live births and stillbirths up to 31 December 2021, we found no evidence that vaccination during pregnancy with an mRNA covid-19 vaccine was associated with a higher risk of preterm birth, spontaneous preterm birth, very preterm birth, small for gestational age at birth, or stillbirth. These results—based on more than 43 000 fetuses exposed to at least one dose of mRNA covid-19 vaccine—did not differ by trimester of vaccination, number of doses received during pregnancy, or mRNA vaccine product.
Comparison with other studies
Our findings for preterm birth and small for gestational age at birth are consistent with a recent Scandinavian birth registry based study of 157 521 births (103 409 from Sweden and 54 112 from Norway) to 12 January 2022, in which 18% of the births (n=28 506) were to individuals who were vaccinated during pregnancy.16 The adjusted estimates pooled across Sweden and Norway were consistent in magnitude and direction with our results for preterm birth (adjusted hazard ratio 0.98, 95% confidence interval 0.91 to 1.05) and small for gestational age at birth (0.97, 0.90 to 1.04).16 A US Vaccine Safety Datalink study of 46 079 singleton live births to 22 July 2021 (21.8% (n=10 064) of individuals received a covid-19 vaccine during pregnancy) reported adjusted hazard ratios for preterm birth (0.91, 95% confidence interval 0.82 to 1.01) and small for gestational age at birth (0.95, 0.87 to 1.03) that were similar to our estimates.17 An Israeli cohort study of 24 288 singleton live births to 30 September 2021 (68.7% (n=16 697) individuals received BNT162b2 during pregnancy)18 reported no increased risk of preterm birth (adjusted risk ratio 0.95, 95% confidence interval 0.83 to 1.10) or small for gestational age at birth (0.97, 0.87 to 1.08), and no differences in risk of infants being admitted to hospital or mortality up to 7 months of age.18 The Scandinavian study16 and the Vaccine Safety Datalink study17 both used a similar methodology as our study—treating vaccination during pregnancy as a time varying exposure—as has been recommended.19 Similar to our results, neither of these two studies1617 observed any patterns of concern when outcomes were assessed by number of vaccine doses, mRNA vaccine product, or trimester of vaccination.
We observed a reduction in stillbirth risk among vaccinated individuals (adjusted hazard ratio 0.65, 95% confidence interval 0.51 to 0.84), even after adjustment for a range of potential confounders through propensity score weighting. A reduced risk of stillbirth was also observed in the Scandinavian study, although the estimate was smaller in magnitude (pooled adjusted hazard ratio 0.86, 95% confidence interval 0.63 to 1.17).16 Collectively, the findings from these two studies are reassuring and are consistent with no increased risk of stillbirth after covid-19 vaccination during pregnancy. In contrast, covid-19 disease during pregnancy has been associated with an increased risk of stillbirth.6 Although fetal viraemia from SARS-CoV-2 transmission across the placenta is considered uncommon, it is biologically plausible that vaccination could protect against stillbirth through preventing SARS-CoV-2-associated placental damage35 or other immunological responses to clinical or subclinical infection. Nevertheless, we did not observe any difference in our findings in sensitivity analyses adjusting for confirmed covid-19 during pregnancy or after excluding individuals with covid-19 during pregnancy, suggesting it is unlikely to fully account for the suggested protective benefit of vaccination during pregnancy. Residual confounding by unmeasured characteristics or temporal issues could also have biased the estimate away from the null value.1922 Interestingly, a reduced stillbirth risk after influenza vaccination during pregnancy was also reported in some large cohort studies of 2009 pandemic A/H1N1 monovalent influenza vaccines and seasonal trivalent influenza vaccines—adjusted risk estimates for stillbirth ranged from 0.44 to 0.88 and several were statistically significant.36 Similar to influenza vaccination,37 vaccine derived maternal antibodies are known to cross the placenta after covid-19 vaccination during pregnancy,38 and emerging evidence supports protective benefits to newborns from covid-19 in the early months of life.910
Strengths and limitations of this study
Strengths of this study include the large birth population and number of individuals vaccinated during pregnancy. We used deterministically linked population based data sources within a publicly funded healthcare system; thus, identification of births and vaccinations was highly complete and minimised potential selection or exposure misclassification bias. As gestational age at birth is mostly based on early ultrasound assessment in Ontario, the accuracy of classifying gestational timing of vaccination was probably high. Although we adjusted for many potential confounders using a propensity score based approach, we cannot dismiss the possibility of residual confounding, particularly given the potential for healthy vaccinee bias in observational studies of vaccination.19 Moreover, despite using recommended methodological approaches for handling time dependent exposures and pregnancy outcomes,1922 we cannot rule out residual temporal confounding, particularly given the complex temporal dynamics of the pandemic and vaccination programme. We used a comprehensive strategy to identify cases of covid-19 during pregnancy, including the province-wide public health database for polymerase chain reaction confirmed covid-19; however, individuals who did not seek testing could be misclassified as not having had covid-19 during pregnancy. Pregnancies ending before 20 weeks’ gestation are not systematically captured in the birth registry and could not be evaluated; however, previous high quality case-control studies did not find any evidence of an increased risk of miscarriage associated with covid-19 vaccination during early pregnancy.1314 Despite the large sample size, our study might have been underpowered to rule out small associations for some rarer outcomes. During the study period, the proportion of vaccines administered in the first trimester was relatively low (12.1%). Moreover, we were unable to assess covid-19 vaccination before pregnancy or around the time of conception, as the time period covered by our study did not include sufficient numbers of these early vaccinations; evaluation of outcomes after vaccination in these time windows is planned for in future studies. We were unable to evaluate booster doses because pregnant Ontario residents were not eligible until December 2021, and most of these pregnancies are ongoing. Finally, we were limited to assessment of mRNA vaccine products, as use of other covid-19 vaccine types in the pregnant population in Canada has been limited.
Conclusions
We did not find evidence of an increased risk of preterm birth, small for gestational age at birth, or stillbirth after covid-19 vaccination during any trimester of pregnancy in this large population based study including more than 43 000 births to individuals vaccinated during pregnancy. Our findings—along with extant evidence that vaccination during pregnancy is effective against covid-19 for pregnant individuals and their newborns, and that covid-19 during pregnancy is associated with increased risks of adverse maternal, fetal, and neonatal outcomes—can inform evidence based decision making about covid-19 vaccination during pregnancy. Future studies to assess similar outcomes after immunisation with non-mRNA covid-19 vaccine types during pregnancy should be a research priority.
What is already known on this topic
SARS-CoV-2 infection during pregnancy is associated with adverse maternal and birth outcomes
Pregnancy specific safety information about covid-19 vaccination is important for pregnant individuals, healthcare providers, and policy makers to guide decision making
Evidence from large comparative studies about pregnancy outcomes after covid-19 vaccination during pregnancy is limited
What this study adds
No association was found between immunisation with an mRNA covid-19 vaccine during pregnancy and increased risk of preterm birth, spontaneous preterm birth, very preterm birth, small for gestational age at birth, or stillbirth
These findings can help inform evidence based decision making about the risks and benefits of covid-19 vaccination during pregnancy.
The risk of acute liver injury (ALI) after COVID-19 vaccination (either the mRNA vaccine BNT162b2 or inactivated vaccine CoronaVac) was assessed in a case series analysis in Hong Kong of >2.3 million recipients of a COVID-19 vaccine who were at risk. The incidence of ALI after COVID-19 vaccination was very low and not increased compared with the non-exposure period; the majority of post-vaccination ALI was mild and self-limiting. The authors concluded that the potential benefits of mass vaccination for COVID-19 outweigh the risks of ALI from vaccination and SARS-CoV-2 infection.
Susan Weiner, MS, RDN, CDCES, FADCES, talks with Stephen W. Ponder, MD, FAAP, CDCES, about the effects of COVID-19 infection and vaccination for people with diabetes.
Weiner: We know people with diabetes are at higher risk for severe illness with COVID-19. Can they lower their diabetes-related risk?
Health care professionals can lead by example and share their experience for people with diabetes who are reluctant to get a COVID-19 vaccine.
Ponder: The same steps used by others to reduce the risk of COVID infection applies to persons with diabetes — even more so. The basics: Masking, social distancing, avoiding large crowds and frequent hand-washing are vital to lowering risk for infection. A medical mask or N95 quality mask is more useful than a cloth mask if someone must go into risky areas. But keep in mind that friends and family members can also transmit the infection. Around our inner circle, there is always a greater tendency to let our guard down.
Isolation and hygiene measures, while essential, are not enough. Immunization with either the Moderna or the Pfizer vaccine, plus a later booster, provides the best proven method to lower risks for serious illness or death from COVID-19. Getting boosted with the non-original vaccine brand is a clever idea.
Working to get the best achievable blood glucose profile is associated with greater resiliency against any infection, COVID included. That means lowering HbA1c toward the goal set by the person with diabetes and the diabetes provider or team. If someone is overweight or obese, their risk is higher for serious effects from a COVID infection. If someone smokes or vapes, their risk is also higher. This is a good reason to resolve to make lifestyle changes that would help in all those areas.
Persons with diabetes are at elevated risk for death and serious illness from COVID-19. The need to take protective measures listed above is still important. Although spared from the worst outcomes, someone taking precautions can still get infected and spread the infection — even unknowingly — to others.
Persons with diabetes share many of the same risk factors as persons without diabetes: overweight or obesity, other chronic illnesses, poor health habits, etc. While many of these behaviors cannot be changed overnight, they will add to the risk one carries with a COVID infection, vaccinated or not.
Weiner: Do COVID vaccines affect blood glucose levels?
Ponder: The metabolic response a person has to any vaccine is an individual one. This is the same with COVID vaccines. Aside from a sore arm, the signs and symptoms are the same as with other vaccines and can range from nothing at all to fatigue, malaise, headache, gastrointestinal upset, low-grade fever and body aches. As with any other vaccine, the impact on blood glucose levels may be none to minimal to large. In most instances, it is more likely to be minimal.
In my case, there were no measurable effects on my blood glucose profiles after any of the COVID vaccines I received. I have also received influenza, shingles, pneumonia, hepatitis and tetanus vaccines as an adult and experienced no issues with my blood sugar after any of them either. Nevertheless, it is possible the immune response to any vaccine could influence one’s blood glucose. Therefore, I recommend careful attention to blood glucose levels after any vaccine, COVID or otherwise. Someone who experiences unexpected blood glucose changes should remember to employ their basic diabetes skills — correction doses of carbs or insulin — to manage them effectively.
Weiner: How do you discuss COVID vaccines with someone who may be reluctant to get one?
Ponder: Leading by example is one way to passively encourage others. If asked, I am happy to share that I was early to get my vaccine series, plus my later booster. As mentioned above: I experienced no serious adverse effects at all. I also have many patients and their parents who share their experiences with me that they did not have adverse reactions. For those who did have reactions, they were mild and quickly passed.
Unfortunately, leading by example does not directly address the widespread misinformation regarding COVID vaccines. The internet is the best place to find answers to questions that best suit our biases. Combined with some fancy talk and big technical words, health disinformation sites are ideally suited to confuse and sow doubt in the minds of good people. Such sites also aim to drive a wedge of distrust and suspicion regarding advice from reputable sources. COVID has highlighted this dark side of social media and the internet regarding its impact on our unity as a people.
In these cases, I realize there is little more I can do than provide support should it be necessary later. People must choose for themselves. Parents must also choose for their children. Frankly, there are no patients in my practice who follow every piece of preventive advice or recommendation given by me — or any other health care professional for that matter. Recommendations about COVID vaccines are no different in that regard, and I must live with that. It saddens me when I hear of serious illness or even death befalling someone who chose not to receive vaccines they were eligible for.
Weiner: What other advice do you give people with diabetes regarding COVID-19 infection or vaccination?
Ponder: The greatest medical advancements of the 20th century were the creation of antibiotics and vaccines. This saved countless lives globally for more than a century and continues to do so each day. Sadly, this is taken for granted in many areas of the world, especially in the U.S. Infectious diseases, regardless of their origins, are part of our collective past, present and future.
Most people with diabetes are dominating or living productive lives with a disease that was uniformly fatal before the 20th century. Success over diabetes is possible due to science and good sense to leverage every available tool with prudent and proactive decisions made each day. If you fall ill to COVID, the science behind its management improves daily. Vaccines unequivocally blunt COVID’s impact on us. Oral FDA-approved medications are now available to keep early COVID from overwhelming the body. As a person with diabetes, take these facts into account as you make your own choices regarding COVID-19 prevention and management.
COVID-19 vaccination is not associated with changes in thyroid function or an increased risk for adverse outcomes for people with hypothyroidism, according to data presented at ENDO 2022.
“Our current study represents the first to evaluate the safety of COVID-19 vaccination specifically among patients treated for hypothyroidism in a population-based cohort,” David T. W. Lui, MBBS, clinical assistant professor in the department of medicine at The University of Hong Kong, told Healio. “Although there were reports of thyroid dysfunction — such as thyroiditis and Graves’ disease — after COVID-19 vaccination, we showed that both inactivated and mRNA COVID-19 vaccines are not causing disturbances to thyroid function among patients treated for hypothyroidism.”
Lui is a clinical assistant professor in the department of medicine at The University of Hong Kong.
Lui and colleagues conducted a population-based cohort study using electronic health records from the Hong Kong Hospital Authority. Adults using levothyroxine were categorized as unvaccinated (n = 23,423) or having received one of two vaccines available in Hong Kong during the study period: BNT162b2 (Pfizer-BioNTech) mRNA vaccine (n = 12,310) and CoronaVac (Sinovac Life Sciences) inactivated vaccine (n = 11,353). Data was obtained between Feb. 23, 2021, and Sept. 9, 2021. Outcomes included dose reduction or escalation of levothyroxine, emergency department visits, unscheduled hospitalization, adverse events of special interest according to the WHO global advisory committee on vaccine safety, and all-cause mortality.
“The thyroid gland is a potential target of attack by SARS-CoV-2,” Lui said during a press conference. “Studies have found the expression of angiotensin-converting enzyme 2, the entry receptor for SARS-CoV-2, expressed in the thyroid cells. There were also cases of subacute thyroiditis and Graves’ disease among COVID-19 patients. Therefore, there were also similar concerns raised regarding the potential of COVID-19 vaccination in inducing thyroid dysfunction.”
Both COVID-19 vaccines were not associated with increased risks for levothyroxine dose changes, emergency department visits or unscheduled hospitalization. Sensitivity analyses according to age, gender and pre-vaccination thyroid status was consistent with the main analysis.
Of the study cohort, two who received the BNT162b2 vaccine died during the follow-up period and six had adverse events of special interests. Of those who received CoronaVac, one died and three had adverse events of special interest.
“These reassuring data should encourage patients treated for hypothyroidism to get vaccinated against COVID-19 for protection from potentially worse COVID-19-related outcomes,” Lui told Healio.
Findings have shown that COVID-19 mRNA vaccines are safe and effective during pregnancy, and evidence also suggests that the benefits of maternal vaccination extend to newborns.
Key takeaways of COVID-19 vaccination during pregnancy: Safe for mothers and newborns; Mothers pass anti-spike IgG antibodies to infants; Infants retain antibodies at 6 months
A recent analysis showed that pregnant women are motivated to get vaccinated if health care workers explain how immunization benefits their baby. We spoke with experts about the safety of COVID-19 vaccines during pregnancy and the studies showing how maternal vaccination can protect infants.
‘Primum non nocere’
In a study published this year, Goldshtein and colleagues found that rates of preterm birth, all-cause neonatal hospitalization, post-neonatal hospitalization, congenital anomalies and infant mortality were similar between newborns who were and were not exposed to the Pfizer-BioNTech vaccine in utero.
Mary Jane Minkin
“The two important tenets of medicine are ‘primum non nocere’ and ‘secundum bene facere’ — first do no harm; second, do good,” Mary Jane Minkin, MD, clinical professor in the department of obstetrics, gynecology and reproductive sciences at the Yale School of Medicine, told Healio. “[This study] clearly outlines no harm … and there are also other studies out there confirming this.”
One such study found that babies exposed to the vaccine during their mothers’ pregnancy did not hinder fetal brain development.
‘Secundum bene facere’
Multiple studies have shown that newborns may benefit from maternal vaccination, fulfilling the “do good” principle to which Minkin alluded.
In one study, Yang and colleagues evaluated levels of anti-spike immunoglobin G (IgG) antibodies in pregnant women who had received at least one dose of either the Moderna, Pfizer-BioNTech or Johnson & Johnson vaccines. Their data showed that being fully vaccinated at any time during pregnancy was associated with the presence of maternal antibodies.
Conti and colleagues studied a contrasting cohort — mothers with COVID-19 — and found that infants had antibodies in their saliva, “which may partly explain why newborns are resistant to SARS-CoV-2 infection,” they said. They also found that antibodies can be transferred via breast milk to newborns.
Despite this seeming benefit of infection, Yang and colleagues discovered that vaccination during the third trimester yielded maternal and umbilical antibody titers comparable to those observed in women with previous SARS-CoV-2 infection. Additionally, they found that receiving a booster shot during the third trimester was associated with an even greater concentration of antibodies than natural infection.
Another study conducted by Kugelman and colleagues supported these findings, specifically regarding the Pfizer-BioNTech vaccine administered during the second trimester. Though both mothers and their babies in this study had humoral responses, newborns had a 2.6-times higher level of antibodies compared with their mothers.
This transfer of antibodies is crucial for protecting the youngest children, Minkin emphasized.
“Newborns are basically immunocompromised; they cannot make antibodies when they are born,” said Minkin, who is also a Healio Women’s Health & OB/GYN Peer Perspective Board Member. “No trials on immunization to kids are going to look at newborns under 6 months old, so getting this vulnerable group antibodies is key.”
Looking past the newborn stage, Shook and colleagues found that 57% of infants aged 6 months whose mothers had been vaccinated during pregnancy had retained antibodies, compared with 8% of those whose mothers were infected with SARS-CoV-2 during pregnancy. Though this study was small, “these findings provide further incentive for pregnant individuals to pursue COVID-19 vaccination,” the researchers wrote.
Importance of vaccination
As data continue to support the benefits of maternal COVID-19 vaccination for newborns, doctors must continue to advocate for vaccination of pregnant women, according to experts.
Sarah Stock
“There is now good evidence that vaccination is the safest and most effective way for pregnant women to protect themselves and their babies against COVID-19 infection,” Sarah Stock, MD, PhD, a reader in maternal and fetal health and an honorary consultant and subspecialist in maternal and fetal medicine at the University of Edinburgh Usher Institute, told Healio. “If you are at any stage in pregnancy or hoping to become pregnant, I would strongly encourage you to get vaccinated.”
“All these [studies] demonstrate that maternal vaccination is safer for the mother, but also safer for her newborn, so why not get the vaccination?” she said. “We often don’t get the opportunity to take a win-win situation.”
Vaccination against covid-19 provides protection against the potentially serious consequences of SARS-CoV2 infection, but as the vaccines were rolled out into younger age groups, clinicians were increasingly approached by patients worried that the vaccine had caused a change to their periods.
More than 36 000 reports of menstrual changes or unexpected vaginal bleeding following covid-19 vaccination have so far been made to the yellow card surveillance scheme run by the UK Medicine and Healthcare Products Regulatory Agency (MHRA).1 But as cycles vary naturally and the MHRA does not collect comparison data from unvaccinated people, these data cannot be used to establish whether menstrual changes increase after vaccination. A similar signal appeared in the US vaccine adverse event reporting system (VAERS), and as a result the National Institutes of Health allocated $1.67m (£1.2m; €1.4m) for research into a possible connection.2
The first of these studies has now reported.3 The authors took advantage of an existing dataset from a menstrual cycle tracking app: 3959 Americans logged at least six consecutive cycles; 2403 of them were vaccinated and the remainder acted as a control group. In adjusted models, the first dose of vaccine had no effect on timing of the subsequent period, while the second dose was associated with a delay of 0.45 days (98.75% confidence interval 0.06 to 0.84).
Most affected were the 358 individuals who received both doses of the vaccine in the same cycle, experiencing a 2.32 day (98.75% CI 1.59 to 3.04) delay to their next period. Among this group, 10.6% experienced a change in cycle length of more than 8 days, which is considered clinically significant,4 compared with 4.3% in the unvaccinated cohort (P<0.001). In all groups, cycle lengths returned to normal by two cycles after vaccination.
A study from the Norwegian Institute of Public Health asked a pre-existing cohort of 5688 Norwegians whether they had experienced specific menstrual changes (such as unexpected breakthrough bleeding or worse than normal period pain) in the cycles before and after each vaccine dose.5 The high level of variation in normal cycles is underlined by the finding that 37.8% of participants reported at least one change from normal even in pre-vaccination cycles. The study identified heavier than normal bleeding as the change most associated with vaccination (first dose: relative risk 1.9, 95% confidence interval 1.69 to 2.13; second dose:1.84, 1.66 to 2.03).
The findings from both these studies are reassuring: changes to the menstrual cycle do occur following vaccination, but they are small compared with natural variation and quickly reverse. But how applicable are these results to the UK? Unlike the US and Norway, where the interval between the first two vaccine doses is 3-4 weeks, the interval in the UK is 8 weeks. Under the UK vaccination schedule, it is therefore impossible to receive both doses of the vaccine in the same cycle, and this may mean that the changes observed in the US and Norway do not occur here. A study using data from UK users of the same menstrual cycle tracking app as in the US study is expected to clarify this point soon. In the interim, the MHRA says that current evidence does not support a link between changes to menstrual periods and covid vaccination in the UK, and it continues to advise that anyone noticing a change to their periods that persists over several of cycles, or who has any new vaginal bleeding after the menopause, be treated according to the usual clinical pathways.1
Unanswered questions
Taking advantage of pre-existing datasets and cohorts means we have been able to make progress on these questions in a short time, but there is still much to learn. Scientifically, it will be important to characterise the mechanism by which post-vaccination menstrual changes occur. Medically, we must also determine whether any group is particularly vulnerable—for example, those with pre-existing gynaecological conditions—so they can be counselled appropriately. There is already evidence that covid infection can alter periods,67 but better defining the extent and persistence of these changes will also be important in counselling women on the risks and benefits of vaccination.
Much of the public concern around this issue arises from misinformation that covid-19 vaccines cause female infertility.8 Although we already have evidence that this is not the case, it comes from the clinical trials, in which pregnancy rates were extremely low because participants were using contraception,910 and fertility clinics, where users do not necessarily reflect the broader population.11121314 Studies of pregnancy rates in couples trying to conceive through intercourse are needed, and they should also include analyses of the effects of having covid-19, because evidence suggests that infection may reduce sperm count and quality.15 A deeper understanding of the effects of both infection and vaccination on fertility will enable better counselling of patients for whom this is of particular concern.
The work that has been done represents a step in the right direction, but the fact that it has taken us so long to get here reflects the low priority with which menstrual and reproductive health is often treated in medical research. The widespread interest in this topic highlights how pressing a concern this is for the public. It’s time we started listening to them.
Two recent studies have found small but reversible changes in menstruation following COVID-19 vaccination, according to a review of recent data published in the BMJ.
“I wrote an editorial in the BMJ last September calling for more research to be done into reports that people were noticing changes to their menstrual cycles following vaccination,” Victoria Male, PhD, a lecturer of reproductive immunology at Imperial College London, told Healio. “That editorial got a lot of attention, so I felt a responsibility — now the research has been done — to come back and tell the readers of the BMJ what it found.”
In her review, Male discussed findings from a study by Alison Edelman, MD, MPH, and colleagues in Obstetrics & Gynecology, which showed that patients who received their first dose of a COVID-19 vaccine had no change in the start of their next cycle, whereas the second dose was associated with a half-day delay.
Victoria Male
“Among [patients who received two doses within one cycle], 10.6% experienced a change in cycle length of more than 8 days, which is considered clinically significant, compared with 4.3% in the unvaccinated cohort,” Male wrote of their findings. “In all groups, cycle lengths returned to normal by two cycles after vaccination.”
Male also mentioned a study from the Norwegian Institute of Public Health that “identified heavier than normal bleeding as the change most associated with vaccination.”
“Until I saw these results, I was completely on the fence as to whether there would be a real change associated with vaccination, or whether people were just noticing and discussing normal variation in their menstrual cycle in a way that they wouldn’t usually,” Male told Healio. “What I think is interesting, though, is that these two studies identified delays and heavier periods following vaccination, and these were precisely the changes that were most commonly reported anecdotally, and to post-marketing surveillance schemes like Yellow Card,” which is run by the Medicines and Healthcare products Regulatory Agency in the United Kingdom.
Moving forward, Male said more studies are needed to solidify these data, as well as to look more closely at certain subgroups of patients.
“These results are reassuring, but one thing I’m asked a lot is whether people with certain gynecological conditions, like endometriosis or [polycystic ovary syndrome], might be more vulnerable to these changes,” she said in the interview. “It would be good to see work that specifically addressed this issue, so that people with these conditions could feel more comfortable in making their decision about getting vaccinated. I think we also need to know more about how COVID infection affects menstrual cycles, as this will also play into the decision about vaccination for many people.”
COVID-19 vaccination did not impair fertility, early pregnancy outcomes or sperm quality, according to findings from three studies presented at the American Society for Reproductive Medicine Scientific Congress & Expo.
“We all know firsthand how the COVID-19 pandemic has changed the landscape of health care,” Devora Aharon, MD, a fellow in reproductive endocrinology and infertility at Icahn School of Medicine at Mount Sinai, said during a presentation. “Vaccination presents a path forward through the pandemic. However, there is still a high prevalence of vaccine hesitancy nationwide.”
Studies show COVID-19 vaccinations don’t hinder fertility.
IVF outcomes
Aharon and colleagues conducted a retrospective cohort study to assess possible effects of the Pfizer-BioNTech and Moderna COVID-19 vaccines on early pregnancy outcomes among women undergoing in-vitro fertilization. The study included 169 patients who underwent a single euploid frozen-thawed embryo transfer (FET) from February to July, 14 days or more following a second vaccine dose. Aharon and colleagues also included a control group of 657 unvaccinated patients who underwent an FET. Baseline age, oocyte age and BMI were similar between vaccinated and unvaccinated individuals.
Pregnancy rates were comparable between the groups: 74.6% among vaccinated individuals and 74.7% among unvaccinated individuals. In addition, clinical pregnancy rates, which the researchers defined as visualization of the gestational sac on an ultrasound, were identical at 63.8%.
The researchers observed no significant differences in pregnancy loss rates (20.3% vs. 22.4%) or clinical pregnancy loss (13.7% vs. 13.1%) between vaccinated vs. unvaccinated participants.
Aharon and colleagues concluded that there was no significant association between COVID-19 vaccination and pregnancy rates, clinical pregnancy rates or pregnancy loss. However, the researchers said they did not evaluate whether women were previously infected with SARS-CoV-2 and their antibody levels.
“The administration of COVID-19 mRNA vaccines does not interfere with implantation in patients who undergo single euploid FET,” Aharon said.
Data ‘refute the rumors’
In a similar study, Randy S. Morris, MD, medical director of IVF1 at the University of Chicago, and Alex J. Morris, an undergraduate student at IVF1, analyzed whether prior in-vivo ovarian exposure to an mRNA COVID-19 vaccine reduced fertility in women who underwent FET between Jan. 1 and Aug. 13.
In the ongoing observational study, patients had their serum analyzed for anti-SARS-CoV-2 antibodies prior to egg retrieval. They were then divided into groups based on their antibody status: vaccinated (n = 48), previously infected (n = 15) or neither (n = 116).
An interim analysis showed that embryos from oocytes exposed to mRNA COVID-19 vaccination were not less likely to produce pregnancy or more likely to miscarry. The implantation rate was 74.2% in unvaccinated and uninfected women, 78.6% in vaccinated women and 77.8% in previously infected women, and the sustained implantation rate was 50%, 57.1% and 44.4%, respectively, according to the researchers.
The findings “refute the rumors that COVID-19 vaccinations are ‘toxic’ to the ovaries,” the researchers wrote.
These rumors are “based on purposeful misinterpretation of biodistribution data,” R. Morris said during the presentation.
Sperm quality
In a third study, Daniel Gonzalez, a medical student at the University of Miami School of Medicine, and colleagues conducted a single-center prospective cohort study on the effect of mRNA COVID-19 vaccines on sperm quality.
“As COVID-19 vaccination in the U.S. opens to children and adolescents, evaluating any potential impact of the vaccine on male reproduction is imperative for public reassurance,” Gonzalez said during a presentation. “We hypothesized that since both vaccines only contain mRNA SARS-CoV-2 spike protein without the biologic ability to replicate the actual virus, the vaccines would not decrease semen parameters.”
The cohort included 45 men who provided semen samples after 2 to 7 days of abstinence prior to receiving the first COVID-19 vaccine dose and then again about 72 days following the second dose. The men ranged in age from 18 to 50 years and were considered healthy.
Sperm concentration and total motile sperm count did not significantly decline following COVID-19 vaccination, according to Gonzalez and colleagues. However, 12 men experienced a marginal, yet insignificant, decrease. The other 33 men demonstrated normal sperm parameters following COVID-19 vaccination. Also, eight men with oligospermia did not experience a decrease in spermatogenesis after they received the vaccine, Gonzalez said. Only one man demonstrated an abnormal total motile sperm count of less than nine after vaccination.
In this first evaluation of male fertility following mRNA COVID-19 vaccination, Gonzalez said that the “vaccines do not negatively impact male fertility potential.”
References:
Gonzalez D, et al. P-453. Presented at: American Society of Reproductive Medicine Scientific Congress & Expo; Oct. 17-20, 2021; Baltimore (hybrid meeting).
Lee JA, et al. O-177. Presented at: American Society of Reproductive Medicine Scientific Congress & Expo; Oct. 17-20, 2021; Baltimore (hybrid meeting).
Morris AJ, et al. O-190. Presented at: American Society of Reproductive Medicine Scientific Congress & Expo; Oct. 17-20, 2021; Baltimore (hybrid meeting).
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