Abstract
This cohort study examines the association of COVID-19 vaccination status and in vitro fertilization (IVF)-fresh embryo transfer cycle stimulation characteristics and outcomes.
Introduction
Women of reproductive age have been at the forefront of COVID-19 vaccine hesitancy, citing concerns about the vaccine’s effect on future fertility, current pregnancy, and breastfeeding (among others).1 As of February 2022, only 57% of pregnant patients were fully vaccinated against COVID-19 prior to becoming pregnant, a rate that lags that of the general population.2 To date, current literature surrounding COVID-19 vaccination and potential associations with infertility have been performed mainly in frozen embryo transfer cycles or in vitro fertilization cycles (IVF) using intracytoplasmic sperm injection (ICSI), both of which do not occur in in vivo conception.3,4 The aim of this study was to investigate the association of COVID-19 vaccination status with IVF-fresh embryo transfer cycle stimulation characteristics and clinical outcomes.
Methods
The University of Iowa institutional review board approved this retrospective cohort study. Patients undergoing IVF-fresh embryo transfer cycles at a single academic institution from December 14, 2020, to September 30, 2021, were included. All patients gave written informed consent to be included in our IVF institutional research database. Cycle characteristics and clinical outcomes were compared between COVID-19 vaccinated and unvaccinated patients. Vaccination status was determined by accessing immunization records in the electronic medical record for each patient. Bivariate analysis was performed using t tests, Mann-Whitney U tests, and χ2 tests. Generalized estimating equations were used to control for multiple cycles per patient and odds ratios were calculated adjusting for age and body mass index (BMI). In addition, subanalysis was performed for (1) exclusion of day 5 morula transfers and (2) standard insemination–only cycles. Additional methods are described in the eAppendix of the Supplement. Statistical analysis was performed using SPSS version 27 (IBM Corp), and a 2-sided P < .05 was considered statistically significant.
Results
Study demographics and clinical characteristics are shown in Table 1; 142 patients were vaccinated against COVID-19 and 138 patients were unvaccinated. The majority of patients were young, nulliparous, and overweight. As seen in Table 1, the 2 groups were similar at baseline. In the vaccinated group, 127 patients (89.7%) were fully vaccinated and 15 patients (10.6%) were partially vaccinated. The mean (SD) time from last vaccination to oocyte retrieval was 93 (65) days. There was no difference in ovarian reserve (mean [SD] antral follicle count for vaccinated group: 23 [13] vs unvaccinated group: 24 [15]; P = .42) or ovarian response (mean [SD] days of gonadotropin stimulation for vaccinated group: 9.8 [1.6] vs unvaccinated group: 9.6 [1.4]) (Table 1). The mean (SD) number of oocytes retrieved (vaccinated group: 14 [8] vs unvaccinated group: 15 [9]) and mean (SD) number of useable embryos produced (vaccinated group: 4 [3] vs unvaccinated group: 4 [3]) were also similar between groups (Table 2). Vaccinated patients had higher mean (SD) fertilization rates than unvaccinated patients (77.45% [41.45%] vs 68.66% [20.51%]; P = .03). In addition, after controlling for factors that can influence IVF success (age and BMI), there were no significant differences in ongoing clinical pregnancy rate (adjusted odds ratio [aOR], 0.79; 95% CI, 0.48-1.29) and miscarriage rate (aOR, 2.15; 95% CI, 0.62-7.47) in vaccinated vs unvaccinated patients. A subanalysis excluding day 5 morula transfers found no difference in ongoing clinical pregnancy rate (aOR, 0.82; 95% CI, 0.49-1.36) and miscarriage rate (aOR, 1.28; 95% CI, 0.32-5.07). Lastly, when comparing standard insemination-only cycles, there was also no difference in ongoing clinical pregnancy (aOR, 0.94; 95% CI, 0.47-1.87) or miscarriage rate (aOR, 4.09; 95% CI, 0.35-47.74).
Table 1. Study Demographics and Clinical Characteristics.
| Characteristic | Vaccinated (n = 142) | Unvaccinated (n = 138) |
|---|---|---|
| Demographics | ||
| Age, mean (SD), y | 34 (4) | 33 (4) |
| BMI, mean (SD) | 28.08 (7.43) | 29.28 (7.25) |
| Weight, mean (SD), kg | 80.42 (21.36) | 79.58 (21.31) |
| Gravida, median (IQR) | 0 (0-1) | 1 (0-2) |
| Para, median (IQR) | 0 (0-1) | 0 (0-1) |
| Vaccination characteristics, No. (%) | ||
| Doses of vaccine | ||
| Partially vaccinated | 15 (10.6) | NA |
| Fully vaccinated | 127 (89.7) | NA |
| Vaccine name, No. (%) | ||
| mRNA-1273 (Moderna) | 70 (49.3) | NA |
| BNT162b2 (Pfizer-BioNTech) | 65 (45.8) | NA |
| Ad26.COV2.S (Janssen) | 7 (4.9) | NA |
| Time between last vaccine dose and retrieval, mean (SD), d | 93 (65) | NA |
| Cycle characteristics | ||
| Cycle No., median (IQR) | 1 (1-2) | 1 (1-1) |
| Protocol, No (%) | ||
| Antagonist | 13 (9.2) | 7 (5.1) |
| Dual trigger | 67 (47.2) | 64 (46.4) |
| Long agonist | 32 (22.5) | 33 (23.9) |
| Microdose flare | 17 (12.0) | 15 (10.9) |
| Estrogen prime | 13 (9.2) | 19 (13.8) |
| Diagnosis, No. (%) | ||
| AMA | 19 (13.4) | 12 (8.7) |
| DOR | 20 (14.1) | 20 (14.5) |
| Anovulation | 13 (9.2) | 16 (11.6) |
| Male Factor | 42 (29.6) | 45 (32.6) |
| Endometriosis | 13 (9.2) | 13 (9.4) |
| Tubal factor | 17 (12.0) | 20 (14.5) |
| RPL | 6 (4.2) | 1 (0.7) |
| Uterine/cervical | 1 (0.7) | 1 (0.7) |
| Unexplained | 34 (23.9) | 33 (23.9) |
| Antral follicle count, mean (SD) | 23 (13) | 24 (15) |
| Insemination method, No. (%) | ||
| Regular | 66 (46.5) | 74 (53.6) |
| ICSI | 76 (53.5) | 64 (46.4) |
| Duration of stimulation, mean (SD) | 9.8 (1.6) | 9.6 (1.4) |
| No. transferred, No. (%) | ||
| SET | 20 (14.1) | 20 (14.5) |
| eSET | 93 (65.5) | 91 (65.9) |
| DET | 29 (20.4) | 27 (19.6) |
Abbreviations: AMA, advanced maternal age; BMI, body mass index, calculated as weight in kilograms divided by height in meters squared; DET, double embryo transfer; DOR, diminished ovarian reserve; eSET, elective single embryo transfer (at least 1 additional embryo available to cryopreserve); ICSI, intracytoplasmic sperm injection; RPL, recurrent pregnancy loss; SET, single embryo transfer (no embryos available to cryopreserve).
Table 2. Cycle Characteristics and Clinical Outcomes in COVID-19 Vaccinated and Unvaccinated Patients.
| Cycle characteristics | Mean (SD) | Mean difference (95% CI) | P value | |
|---|---|---|---|---|
| Vaccinated (n = 142) | Unvaccinated (n = 138) | |||
| No. of oocytes retrieved | 14 (8) | 15 (9) | –1 (–3 to 1) | .33 |
| No. of oocytes inseminated | 12 (7) | 13 (8) | –1 (–3 to 1) | .31 |
| No. of 2PN | 9 (8) | 8 (5) | 1 (–1 to 2) | .34 |
| Fertilization rate | ||||
| No. of 2PN/No. of oocytes inseminated | 77.45 (41.54) | 68.86 (20.51) | 8.78 (1.02 to 16.56) | .03 |
| Blastulation rate | ||||
| No. of blastocysts/No. of 2PN (%) | 44.37 (25.55) | 46.79 (26.54) | 2.42 (–3.71 to 8.55) | .44 |
| No. of blastocysts per retrieval | 4 (3) | 4 (3) | 0 (–1 to 1) | .83 |
| No. of embryos cryopreserved | 3 (3) | 3 (3) | 0 (–1 to 1) | .73 |
| Clinical outcomes | Vaccinated | Unvaccinated | OR (95% CI) a | aOR (95% CI) a |
| Full sample, No. | 142 | 138 | NA | NA |
| Ongoing clinical pregnancy, No. (%) | 65 (45.8) | 74 (53.6) | 0.73 (0.45 to 1.18) | 0.79 (0.48 to 1.29) |
| Miscarriage, No. (%) | 8/73 (11.0) | 4/78 (5.1) | 2.28 (0.66 to 7.87) | 2.15 (0.62 to 7.47) |
| Subsample excluding day 5 morula transfers, No. | 130 | 125 | NA | NA |
| Ongoing clinical pregnancy | 65 (50.0) | 71 (56.8) | 0.76 (0.46 to 1.25) | 0.82 (0.49 to 1.36) |
| Miscarriage | 5/70 (7.1) | 4/75 (5.3) | 1.37 (0.35 to 5.26) | 1.28 (0.32 to 5.07) |
| Subsample with only standard insemination cycles, No. | 66 | 74 | NA | NA |
| Ongoing clinical pregnancy | 34 (51.5) | 41 (55.4) | 0.86 (0.44 to 1.67) | 0.94 (0.47 to 1.87) |
| Miscarriage | 3/37 (8.1) | 1/42 (2.4) | 3.62 (0.36 to 36.39) | 4.09 (0.35 to 47.74) |
Abbreviations: aOR, odds ratios adjusted for age and body mass index; NA, not applicable; OR, unadjusted odds ratio; 2PN, 2 pronuclear.
Generalized estimating equations used to control for multiple cycles per patient.
Discussion
To our knowledge, this is one of the first studies to evaluate the association of COVID-19 vaccination status with IVF-fresh embryo transfer cycles (including a high proportion of standard insemination cycles). We found no evidence to suggest that COVID-19 vaccination negatively affects cycle stimulation characteristics, embryological variables, or clinical outcomes in IVF. Current and emerging scientific evidence continues to support that COVID-19 vaccination is safe and effective and has no impact on fertility. The results of this study can be used to provide reassuring data to patients planning on pregnancy considering COVID-19 vaccination.
eAppendix. Online Only Supplemental Material
eReferences
References:
- 1.Murewanhema G. Vaccination hesitancy among women of reproductive age in resource-challenged settings: a cause for public health concern. Pan Afr Med J. 2021;38:336. doi: 10.11604/pamj.2021.38.336.28953 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Centers for Disease Control and Prevention . COVID-19 vaccination among pregnant people aged 18-49 years overall, by race/ethnicity, and date reported to CDC- Vaccine Safety Datalink,*United States. Accessed February 18, 2022. https://covid.cdc.gov/covid-data-tracker/#vaccinations-pregnant-women
- 3.Aharon D, Lederman M, Ghofranian A, et al. In vitro fertilization and early pregnancy outcomes after coronavirus disease 2019 (COVID-19) vaccination. Obstet Gynecol. Published online January 25, 2022. doi: 10.1097/AOG.0000000000004713 [DOI] [PubMed] [Google Scholar]
- 4.Orvieto R, Noach-Hirsh M, Segev-Zahav A, Haas J, Nahum R, Aizer A. Does mRNA SARS-CoV-2 vaccine influence patients’ performance during IVF-ET cycle? Reprod Biol Endocrinol. 2021;19(1):69. doi: 10.1186/s12958-021-00757-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eAppendix. Online Only Supplemental Material
eReferences