Medically Attended Acute Adverse Events in Pregnant People After Coronavirus Disease 2019 (COVID-19) Booster Vaccination

Abstract

In this multisite, observational, matched cohort study of more than 80,000 pregnant people, receipt of an mRNA monovalent coronavirus disease 2019 (COVID-19) booster vaccination in pregnancy was not associated with increased risk for thrombocytopenia, myocarditis, venous thromboembolism, ischemic stroke, or other serious adverse events within 21 or 42 days after booster vaccination. The mRNA monovalent COVID-19 booster in pregnancy was associated with an increased risk for medically attended malaise or fatigue within 7 days of vaccination (adjusted rate ratio [aRR] 3.64, 95% CI 2.42–5.48) and lymphadenopathy or lymphadenitis within 21 days (aRR 3.25, 95% CI 1.67–6.30) or 42 days (aRR 2.18, 95% CI 1.33–3.58) of vaccination. Our findings are consistent with prior evaluations of the primary COVID-19 vaccine series and are reassuring with respect to COVID-19 booster vaccination in pregnancy.

In Brief

Receipt of an mRNA monovalent coronavirus disease 2019 (COVID-19) booster vaccination in pregnancy was not associated with increased risk for serious acute adverse events.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy is associated with maternal morbidity and adverse perinatal outcomes.¹ Maternal vaccination can prevent severe coronavirus disease 2019 (COVID-19) and reduce risks for adverse birth outcomes^1,2 and may confer protection for newborns.^3,4 Prior studies have demonstrated primary COVID-19 vaccine series safety during pregnancy.^5–8 Despite preliminary data that booster doses are safe in pregnancy,^9,10 only half of pregnant people who had completed a primary COVID-19 vaccine series had received a COVID-19 booster 6 months after booster dose authorization.¹¹ We evaluated acute safety outcomes after mRNA monovalent COVID-19 booster vaccination in pregnancy.

METHODS

This multisite, observational, matched cohort study included eight Vaccine Safety Datalink sites (HealthPartners, Marshfield Clinic, Denver Health, and Kaiser Permanente: Northern California, Southern California, Northwest, Washington, and Colorado). This study was approved by the IRBs of all participating health care organization sites, with a waiver of informed consent, and was conducted consistent with federal law and Centers for Disease Control and Prevention policy (see, for example, 45 C.F.R. part 46.102(l) (2), 21 C.F.R. part 56; 42 U.S.C. §241(d); 5 U.S.C. §552a; 44 U.S.C. §3,501 et seq).

Pregnant people were identified with a validated algorithm, using automated electronic health data.¹² Eligible pregnant people included those aged 16–49 years with at least two prenatal care visits (including one before the third trimester) and without ectopic pregnancy, molar pregnancy, or elective termination.

COVID-19 vaccines administered from December 14, 2020, through June 30, 2022, were identified from electronic health records, claims, and regional or state immunization information systems.¹³Booster dose was defined as an mRNA monovalent COVID-19 vaccine received between September 23, 2021, and June 30, 2022, and at least 2 months after completion of the two-dose mRNA primary series. Bivalent COVID-19 vaccines were not available during this period.

Pregnant people receiving a booster dose during pregnancy or within 28 days of their last menstrual period (LMP) were matched 1:1 to pregnant people who did not receive a COVID-19 vaccine during pregnancy or within 28 days of LMP (“unexposed”) using a greedy matching algorithm.¹⁴ Unexposed pregnant people either received no COVID-19 vaccines or may have received COVID-19 vaccines before or after pregnancy or the study period. Matching variables included site and LMP (±14 days). Unexposed pregnant people were assigned an index date equivalent to their match's gestational age at booster dose.

Acute safety outcomes within 42 days after booster vaccination were identified consistent with our prior evaluation of the primary COVID-19 vaccine series in pregnancy.^7,15 Briefly, outcomes were identified using diagnostic codes at inpatient, outpatient, or emergency department clinical encounters (ie, medically attended), with outcome-specific exclusions applied (Appendix 1, available online at https://links.lww.com/AOG/D177). Selected outcomes (anaphylaxis, venous thromboembolism, pulmonary embolism, cerebral venous sinus thrombosis, and myocarditis or pericarditis) were confirmed with medical record review.

Anaphylaxis within 1 day of vaccination was evaluated only in the COVID-19 booster group. The remaining acute vaccine safety outcomes were evaluated during specific risk windows after booster vaccination or index date: 1–7 days, 1–21 days, or 1–42 days.

Poisson regression with robust standard errors was used to estimate adjusted rate ratios (aRRs) and 95% CIs after applying stabilized inverse probability of vaccination weights to quantify the association between outcomes and receipt of COVID-19 booster vaccination. We used an offset to account for follow-up time, censoring at 7 days after the pregnancy ended. For acute safety outcomes observed in only one group, we used exact Poisson regression to estimate a median unbiased rate ratio and one-tailed 95% CI.

RESULTS

Among 40,208 people who received an mRNA COVID-19 booster dose in pregnancy, 15,782 (39.3%) received Moderna and 24,426 (60.7%) received Pfizer-BioNTech. Booster doses were administered in the first trimester for 12,596 (31.3%) people, in the second or third trimester for 23,213 (57.7%) people, and within 28 days of LMP for 4,399 (10.9%) people. Baseline characteristics of the cohort are shown in Table 1. The matched groups were well balanced after applying inverse probability of vaccination weights (Appendix 2, available online at https://links.lww.com/AOG/D177).

Table 1. - Baseline Characteristics (Unadjusted) of the Matched Pregnant Cohort From Eight Vaccine Safety Datalink Sites, by Receipt of Coronavirus Disease 2019 (COVID-19) mRNA Monovalent Booster in Pregnancy, September 23, 2021–June 30, 2022

Characteristic	Vaccinated with mRNA Monovalent COVID-19 Booster in Pregnancy*
	Yes (n=40,208)	No (n=40,208)
Maternal age (y)
16–24	2,097 (5.2)	6,841 (17.0)
25–29	7,964 (19.8)	11,867 (29.5)
30–34	17,169 (42.7)	13,090 (32.6)
35–39	10,812 (26.9)	6,795 (16.9)
40–49	2,166 (5.4)	1,615 (4.0)
Race and ethnicity†
Asian, non-Hispanic	9,963 (24.8)	4,656 (11.6)
Black, non-Hispanic	1,553 (3.9)	3,300 (8.2)
Hispanic	11,344 (28.2)	14,947 (37.2)
White, non-Hispanic	14,118 (35.1)	13,324 (33.1)
None of the above or unknown	3,230 (8.0)	3,981 (9.9)
Selected comorbidities‡
Obesity	5,199 (12.9)	5,337 (13.3)
Previous SARS-CoV2 infection	2,278 (5.7)	2,757 (6.9)
Hypertension	1,044 (2.6)	925 (2.3)
Pulmonary disease	2,068 (5.1)	2,117 (5.3)
Smoking ever	1,706 (4.2)	2,040 (5.1)

COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Data are n (%).

^*Vaccination during pregnancy includes period within 28 days of pregnancy start or last menstrual period; Unexposed did not receive a COVID-19 vaccine in the 28 days before pregnancy start date or during pregnancy and during the matched exposure window.

^†Race and ethnicity was included to characterize the study population and to provide information about the generalizability of the study results.

^‡Comorbidities based on having at least one diagnosis from October 1, 2015, up to 1 day before booster vaccination date or index date.

No confirmed cases of anaphylaxis occurred after a booster dose. Malaise or fatigue in a 1–7-day window (aRR 3.64 [95% CI 2.42–5.48]) and lymphadenitis or lymphadenopathy in a 1–21-day (aRR 3.25 [95% CI 1.67–6.30]) or 1–42-day window (aRR 2.18 [95% CI 1.33–3.58]) were increased in people who received a booster vaccination compared with those who were unexposed. The remaining acute safety outcomes did not differ significantly between patients who received a booster vaccination and those who were unexposed (Fig. 1) (Appendix 3, available online at https://links.lww.com/AOG/D177).

Fig. 1.: Number of events, incidence rates per 10,000, and adjusted rate ratios (aRR) with 95% CIs for medically attended acute adverse events occurring 1–7, 1–21, or 1–42 days after mRNA monovalent coronavirus disease 2019 (COVID-19) booster vaccination in pregnant people at eight Vaccine Safety Datalink sites, September 23, 2021–June 30, 2022. Rates of medically attended acute adverse events in pregnant people receiving a COVID-19 booster vaccine in the 28 days before pregnancy start date or during pregnancy were compared with those of an unexposed pregnant cohort who did not receive a COVID-19 vaccine in the 28 days before pregnancy start date or during the matched exposure window during pregnancy. Outcomes evaluated but for which there were no cases in the COVID-19 booster–vaccinated or unexposed groups include acute disseminated encephalomyelitis, cerebral venous sinus thrombosis, Guillain-Barré syndrome, Stevens-Johnson syndrome or toxic epidermal necrolysis, thrombosis with thrombocytopenia syndrome, transverse myelitis, and thrombotic thrombocytopenic purpura.

DISCUSSION

In this large observational cohort, receipt of an mRNA monovalent COVID-19 booster vaccination during pregnancy was associated with malaise or fatigue and lymphadenitis or lymphadenopathy, consistent with our prior primary vaccine series evaluation.⁷ In contrast with the primary series, booster vaccination was not associated with increased risk for medically attended fever or skin or soft tissue reactions, suggesting that booster vaccination may be less reactogenic than the primary series. No increased risks for other assessed adverse events after vaccination were detected, although, for many outcomes with low incidence, power was limited, resulting in wide CIs for the associated rate ratios. Safety monitoring of newer COVID-19 vaccine products and mRNA bivalent booster vaccines co-administered with other vaccines during pregnancy is important. This study offers further reassurance that COVID-19 vaccine boosters are safe in pregnant people.