In late January, 2021, just a month after the Pfizer and Moderna COVID-19 vaccines were granted Emergency Use Authorization (EUA) by the Food and Drug Administration (FDA) in December 2020, a dramatic change in Google trend searches for “decidual cast” was evident.
Another surge in interest occurred in mid-June 2021, a month after the Pfizer vaccine was granted an expanded EUA for adolescents ages 12–15 years.
A decidual cast is defined as: “a large, intact piece of tissue that is passed through the vagina in one solid piece. It happens when the thick mucus lining of the uterus, called the decidua, sheds in the near exact shape of a uterine cavity, creating a triangular cast.”
Women began reporting unusual menstrual conditions on social media, including decidual cast shedding (DCS). This prompted several internet-based surveys, one of which was conducted by MyCycleStory.com.
While the literature contains only case reports of DCS, making the true prevalence difficult to measure, the condition is thought to be quite rare. Fewer than 40 cases have been published over the course of 100 years, usually related to ectopic pregnancy, miscarriage, or prolonged progesterone use.
However, 292 women reported experiencing DCS during a 7.5 month MyCycleStory study period in 2021.
Even though the absolute number of cases is not that high, this unusually increased incidence over the background rate requires further study to ascertain the cause, and any other potential contributors related to the pandemic.
Studies Observe an Impact on Women’s Menstrual Cycle
In the United States Vaccine Adverse Event Reporting System (VAERS), over 11,000 people self-reported a menstrual-related issue to the system following COVID-19 vaccination by April 2022. Events included heavy bleeding, irregular or delayed menstruation, oligomenorrhea, and amenorrhea.
Likewise, the United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA) yellow card surveillance scheme received 51,695 reports of menstrual disorders, including heavier or delayed periods, and unexpected bleeding, after the COVID-19 vaccine.
Findings from these databases suggested the possibility of negative impacts in menstrual cycles following COVID-19 vaccination. The relationship between COVID-19 vaccination and menstrual cycle has been evaluated in several peer-reviewed studies.
In a large prospective cohort study conducted by Harvard, the Apple Women’s Health study, cycle length was manually tracked by 9,682 vaccinated and unvaccinated women who contributed 128,094 menstrual cycles, most of whom were vaccinated (88 percent) with Pfizer (55 percent) or Moderna (37 percent). Both cycle length and menses length were tracked prospectively to capture baseline, vaccination, and follow-up measures.
This study found that mean cycle length did increase following vaccination, particularly for women who received their vaccine during the first two weeks of the cycle, during the follicular phase.
Following the first dose in the follicular phase, the cycle length increased by 0.97 days, and following the second dose by 1.43 days. The cycle remained longer for one to two months after vaccination then returned to baseline.
Women who were vaccinated during the luteal phase tended to have a shorter cycle (-0.97 days).
Another prospective United States cohort study of nearly 4,000 women ages 18 to 45 years evaluated those with normal cycle lengths for three consecutive cycles before the first vaccine dose and three post-vaccine cycles (cycles 4, 5, and 6). Those who were unvaccinated were evaluated over six cycles during a similar time period.
The investigators computed within-individual changes in cycle length and menses length for cycles 1–3 and 4–6 then used mixed-effects models to compare differences in cycle and menses length between the vaccinated and unvaccinated cohorts.
The investigators found a mean 0.91 day increase in mean cycle length for women receiving the mRNA vaccine during their second vaccine cycle.
More vaccine recipients had a cycle length change of at least 8 days than unvaccinated (6.5 percent vs 4.6 percent, p=0.017). The longer vaccine cycles seemed to be concentrated among the 358 individuals who received both doses within a single cycle.
In this subgroup of vaccinated women, the unadjusted mean cycle length increase was 2.38 days and a substantially larger proportion (10.6 percent) had an increased cycle length of at least 8 days compared with the unvaccinated cohort (4.3 percent, P<.001).
The authors found no difference in menses length between cohorts.
A smaller Israel study among 219 women regularly tracking cycles also found changes in menstruation reported by almost 40 percent of vaccinated women. Parity (number of pregnancies) and medication use seemed to be risk factors for menstrual irregularities.
Half of those suffering from irregular bleeding were multiparous versus 31.5 percent multiparity among women with no irregular bleeding. Presence of comorbidities was also higher among women reporting irregular bleeding.
Interestingly, women reporting regular medication use were less likely to report irregular bleeding.
Another study included both a prospective cohort of 79 women and a retrospective cohort of 1273 women.
The study did also find a cycle length increase (delay to the next period) in women cycling spontaneously, suggesting that COVID-19 vaccination can lengthen the menstrual cycle.
However, no such change was observed among those using contraception, suggesting that this effect of COVID-19 vaccination may be mediated by ovarian hormones.
While several studies (references 9–14) have suggested that COVID-19 infection can cause changes in cycle length, the Nurses’ Health Study did not detect such an association following COVID-19 infection.
In this study, COVID-19 vaccination was associated with cycle length in the short term (within 6 months of vaccination), particularly among women with short, long, or irregular cycles prior to vaccination. Changes in cycle length were detected for both mRNA and adenovirus-vectored vaccines.
A plausible connection between COVID-19 vaccination–both mRNA and adenovirus-vectored vaccines–and increased cycle length appears reasonable. The effect seems most pronounced among women who have already had a child and who receive both doses within a single cycle, which is consistent with the survey study from Israel.
VAERS Data Suggests Increased Risks of Menstruation and Pregnancy Irregularities
A preprint study of adverse events (AE) reported to the Vaccine Adverse Events Reporting System (VAERS) compared the ratio of AEs due to COVID-19 vaccines to influenza vaccines. Thorp and colleagues gathered data on pregnancy and menstruation irregularities reported to VAERS between Jan. 1, 1998 to June 30, 2022.
The reporting ratio for AEs related to COVID-19 vaccines compared to influenza vaccines were at least double (and statistically significant at p<0>
It should be noted that for any VAERS study, this is a passive reporting system which relies on physician reporting and may not reflect the true rate for the AE. Detection of AEs may vary significantly depending on public awareness of the AE, thus sensitivity may be as low as 1% percent of all AEs or 67 percent. Self-reports by patients are not necessarily confirmed by a physician diagnosis. The VAERS database is appropriate for hypothesis-generation, but population-based studies are needed to understand true incidence and causation.
Canadian Study Observed Increased Risks of Severe Adverse Events During Pregnancy
A Canadian prospective observational cohort study of COVID-19 vaccines, published in Lancet Infectious Disease pregnancy, evaluated the frequency of significant health events among 5625 pregnant / vaccinated, compared with 339 pregnant / unvaccinated and 185 735 nonpregnant / vaccinated controls, resulting a total of 191,360 women ages 15–49 years included.
The data were collected by survey with follow-up phone calls to those reporting any medically attended event.
The pregnant vaccinated females had a 4.4-fold (95 percent CI 2.4-8.3) increased risk of a severe health event after dose two of Moderna compared to pregnant unvaccinated females; this association was not seen for those vaccinated with Pfizer.
The dose of Moderna vaccine (100mcg) is more than 3 fold that of Pfizer (30mcg) in adults, which may well explain the different results among vaccine brands.
Miscarriage or stillbirth was the most frequently reported adverse pregnancy outcome. Both miscarriage and stillbirth describe pregnancy loss, but they differ according to when the loss occurs. In the United States, a miscarriage is usually defined as loss of a baby before the 20th week of pregnancy, and a stillbirth is loss of a baby at or after 20 weeks of pregnancy.
It was reported at similar rates between control (2.1 percent of 339) and vaccinated groups within seven days after dose one of any mRNA vaccine (1.5 percent of 5,597).
Other rare adverse pregnancy outcomes such as vaginal bleeding, abnormal fetal heart rate, and reduced fetal movement were increased slightly within seven days following any mRNA vaccination compared to control.
There were an additional individuals who reported experiencing miscarriage or stillbirth between the first COVID-19 vaccine dose and completion of the second (dose two) survey (up to 10 days after dose two), however the precise timing of these events relative to vaccination was not known.
Impact on Fertility
The impact of vaccination and infection on ovarian function and fertility is a heavy topic. The key findings from a number of peer-reviewed publications and preprints has been summarized here.
Reduced Total Fertility Rate (TFR)
There is a population-wide change in fertility after vaccination campaigns. In a new preprint, the total fertility rate (TFR) in Sweden and Germany was trended over time, from early in the pandemic through 2022.
Many countries noticed a fertility decline early in the pandemic, but Germany and Sweden were largely unaffected. These countries, however, recently experienced a reduction in the TFR.
The seasonally-adjusted TFR in Germany declined 14 percent from 1.5-1.6 in 2021 to 1.3-1.4 in early 2022. A similar trend was seen in Sweden, with a 10 percent decline from 1.7 to 1.5-1.6.
The authors note that the sharp declines in TFR align with the onset of vaccination campaigns precisely nine months prior. The authors speculate that concerns about vaccine safety during conception and pregnancy might have caused women to hold off on starting their family until after vaccination.
Further population-based longitudinal research is necessary to detect any slight but significant effects of vaccination on fertility.
A systematic review and meta-analysis has evaluated the impact of COVID-19 vaccines on fertility
In the systematic review, 29 studies conducted in Israel, United States, Russia, China, Italy, North America, and Turkey were included.
The pregnancy rates were observed to decline in the vaccinated group by 15 percent for biochemical pregnancy rate and by 4.3 percent for clinical pregnancy rate, in a comparison to the unvaccinated group.
It is reported that both declines did not reach a statistical difference among vaccinated and not vaccinated groups. However, a clinical meaningful decline is not necessarily to be statistically significant. And whether to achieve a statistical difference or not may be confounded by the power of studies.
Furthermore, meta-analyses were performed for pre- and post-vaccination sperm progressive motility (44 percent versus 43 percent, p = 0.07).
Anti-Müllerian Hormone (AMH)
Anti-Müllerian hormone (AMH) has been used as a marker to assess ovarian function in women and it impacts fertility. It gives an estimate of ovarian reserve–how many eggs are remaining in the ovaries. Older women normally have lower levels than younger women.
In a prospective study conducted in Israel among 129 women who received two mRNA vaccines, the change in AMH was assessed via baseline and 90-day measurements, pre- and post-vaccination.
In this study, no change was detected in AMH levels pre- vs post-vaccination (5.3 vs 5.3 µg/l, respectively).
The authors concluded that while this study was limited to a three-month followup after the first vaccination, there did not appear to be any effect of mRNA vaccination on ovarian function.
Another similar but smaller Israeli prospective study among 31 women undergoing in vitro fertilization (IVF) treatment found that AMH remained stable pre- and post-mRNA vaccination.
There are limitations of the AMH studies. First, there is no control group and only self control was used.
Second, serum AMF levels are known to be affected by multiple factors including obesity, vitamin D levels, oral contraceptive therapies, genes (BRCA mutations contributing to breast and ovarian cancers), chemotherapy, common ovulatory disorders (polycystic ovary syndrome, PCOS), and history of ovarian surgery. Any potential changes in common confounding factors for serum AMF levels (body weight, contraceptives, vitamin D levels) in these subjects should be analyzed and reported.
In a retrospective study including 200 women undergoing IVF, no difference in fertility outcomes was detected, including oocyte retrieval, fertilization and pregnancy rates, and embryo quality.
Although this study found similar pregnancy rates between vaccinated and unvaccinated (32.8 percent and 33.1 percent, respectively), it would have required a much larger sample size to detect a small but meaningful difference.
A sample of at least 985 participants would be needed to detect a smaller 5 percent difference in pregnancy rates. In other words, this study was underpowered to detect a meaningful difference of reduction in pregnancy rates.
In another retrospective cohort study of 222 vaccinated and 983 unvaccinated women who underwent ovarian hyperstimulation, no effect of vaccination was found for the primary outcome, fertilization rate, nor any of the secondary outcomes, including eggs retrieved, mature oocytes retrieved, mature oocyte ratio, blastulation rate, or euploid rate.
For 214 vaccinated and 733 unvaccinated women undergoing frozen-thawed euploid transfer, the adjusted analysis found no significant association for vaccination and the primary outcome, clinical pregnancy (adjusted odds ratio [aOR] 0.79, 95 percent CI 0.54-1.16), nor any of the secondary outcomes: pregnancy (aOR 0.88, 95 percent CI 0.58-1.33), ongoing pregnancy (aOR 0.90, 95 percent CI 0.61-1.31), biochemical pregnancy loss (aOR 1.21, 95 percent CI 0.69-2.14), or clinical pregnancy loss (aOR 1.02, 95 percent CI 0.51-2.06).
However, these confidence intervals are large and the sample size insufficient to rule out a small but clinically meaningful difference in outcomes.
A small cohort study of 32 individuals (9 recovered SARS-CoV-2 positive, 9 vaccinated, 14 uninfected/unvaccinated) found no differences in follicular function and oocyte quality.
Together, these studies suggest that any effect of either infection or vaccination on fertility will be difficult to detect unless studies are designed with sufficient statistical power geared to expected changes in primary and secondary endpoints.
A decrease of 0.3 percent in the vaccinated group is 30 fewer pregnancies per 10,000 women, thus any study designed to detect a difference this slight would need to enroll 770,000 women.
Some might suggest powering phase III clinical trials to detect fertility impact is impractical, but certainly intentional post-marketing surveillance when vaccine uptake is in the millions is possible.
Mechanism of Action of AEs in Reproductive Health
A number of molecular mechanism of actions have been discussed which may contribute to the AEs observed in women.
First, immune activation following exposure to spike protein after vaccination might trigger an abnormal innate immune response, activate inflammatory cytokines and inflammatory genes.
Second, the spike protein induced local and systemic inflammation might impact the signaling between the brain and ovaries (the hypothalamus-pituitary-adrenal or HPA axis), resulting in hormone imbalances, prolongation of follicular recruitment during the early part of the cycle, and lengthening the cycle.
On the other hand, vaccination during the luteal phase may suppress growth of the endometrial lining and affect endometrial stability, thus shortening the cycle.
Third, ovarian inflammation may also be caused by lipid nanoparticles (LNP) effects on hormones, an autoimmune reaction with anti-syncytin antibodies at the endometrium, or inflammatory processes triggered by the spike protein either from the vaccine or infection.
Fourth, abnormal bleeding can be caused by abnormal local clotting in the endometrium during the period.
A large body of evidence has shown that the spike protein can trigger the clotting cascade via inducing endothelial disruption, inflammation of endothelial cells, massively released activated vWF, overactivating platelet, fibrous network from neutrophil extracellular traps (NETs), as well as increasing angiotensin II level, activating Toll-like receptor 4, all adding up to initiate blood clotting cascades.
Based on the evidences of spike protein’s domino-like activities related to abnormal blood clotting, the potential role of spike protein originating from SARS-CoV-2 or COVID-19 vaccine in the abnormal bleeding of vaccinated women is likely to contribute to the surge of increased DCS and menstrual disorders during COVID pandemic, amongst other dysregulated immune and hormone mediated pathologies.
Impact on Lactation: Antibodies Detected in Milk and Symptoms Reported
A prospective cohort study included 50 lactating women who received mRNA vaccines with both blood and milk samples prior to their first vaccination dose, immediately prior to dose two, and four to ten weeks after their second dose.
Anti-SARS-CoV-2 receptor binding domain (RBD) antibodies were measured in each sample, and blood samples were collected from a subset of infants whose mothers were vaccinated while lactating.
After vaccination, levels of anti-SARS-CoV-2 IgG and IgM significantly increased in maternal plasma and there was significant transfer of IgA and IgG antibodies to milk.
Self-reported symptoms (fever, chills, headache, joint pain, muscle aches or body aches, and fatigue or tiredness) were reported by significantly more participants after the 2nd dose than after the 1st dose.
Two mothers reported slightly less milk production in the first 24-72 hours after vaccine doses.
Twelve percent of infants were reported with at least one symptom after the 1st maternal vaccine dose, which are primarily gastrointestinal symptoms and sleep changes.
The study lacked an unvaccinated control and these changes in infant behaviors are common; future studies should evaluate these reports.
The study also collected symptoms following vaccination and noted that more vaccine-related side effects may be experienced by those receiving Moderna compared to Pfizer, which should be again attributed to the higher dose of Moderna.
Natural Immunity Impact on Lactation
Finally, a study of mothers recently recovered from SARS-CoV-2 infection evaluated both antibodies and T cells in breastmilk. Because only about one in four women elect to be vaccinated during pregnancy, the ability of the mother to confer passive immunity to her infant through breast milk is an important question to assess.
In this small study of 30 lactating women, both antibody and T cell parameters were evaluated in milk samples collected at 12 timepoints over the course of a month.
A second set of samples were donated four months after a positive SARS-CoV-2 test to test durability of the immune markers.
The study confirms that women recently infected with SARS-CoV-2 have antibodies in their milk which can neutralize the spike complex. The milk is also enriched with mucosal memory T cells.
This study may be the first to demonstrate that breast milk from mothers who have recovered from SARS-CoV-2 infection contains long-lasting IgA and IgG antibody responses and that breastmilk can provide passive protection to the infant via mucosal-homing, effector-memory T cells which can seed the infant gastrointestinal tract.
Summary of Key Observations
Based on the available data collected from clinical studies, vaccine safety databases or surveys, a summary of key observations include:
- Concerns about the negative impacts of COVID-19 vaccination on the menstrual cycle have been validated by peer-reviewed research.
- The cycle length appears to increase following both mRNA and adenovirus-vectored vaccination, particularly for those women who received both doses within a single cycle (21-28 day interval), and those who were vaccinated during the follicular phase.
- VAERS data suggests increased risks of menstruation and pregnancy irregularities. A Canadian study also observed increased risks of severe adverse events during pregnancy associated with the Moderna vaccine.
- Sharp decline of total fertility rates were reported in Germany and Sweden in 2022. A 15 percent decline in the biochemical pregnancy rate and a 4.3 percent decline in the clinical pregnancy rate were reported, though AMU studies did not detect any meaningful change.
- Spike protein induced inflammation, immune disorders, and hormone mediated mechanisms of action as well as abnormal clotting cascades and overactivation have been correlated to these clinical adverse events.
- COVID vaccine induced antibodies have been detected in milk, as well as symptoms among mothers and infants post vaccination are reported.
- The effect has been observed across spike protein-based COVID-19 vaccines regardless of vaccine type. The higher dose mRNA vaccine (Moderna) is associated with a higher likelihood of these events than the lower dose mRNA vaccine (Pfizer).
These findings strongly suggest that more rapid and intentional post-marketing surveillance is necessary to detect impacts of vaccination on menstrual, pregnancy, and lactation events.
The CDC continues to recommend vaccination and boosters for all individuals over 5 years of age despite a lack of evidence regarding an incremental reduction in serious COVID-19 illness among those younger than 40 years of age.
To address vaccine hesitancy, public health officials and regulatory agencies must demonstrate that individual concerns are addressed and that clinical trials are designed to detect rare adverse events in otherwise healthy, young individuals prior to issuing broad recommendations.
A phased trial rollout which prioritizes enrollment of higher risk individuals and follows them for clinically important endpoints, such as hospitalization and death, would allow rapid deployment of lifesaving vaccines while minimizing harm to those at low risk of serious illness.
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