Abstract
Objective:
To evaluate whether there is an association between a maternal classification of Long COVID and adverse pregnancy outcomes.
Methods:
Researching COVID to Enhance Recovery (RECOVER)-Adult is a multicenter prospective longitudinal cohort study of adults, with and without prior SARS-CoV-2 infection enrolled from October 2021 through January 2024. This analysis included participants with a SARS-CoV-2 infection and at least one symptom survey for classification of Long COVID status recorded before or during pregnancy. Participants were classified as either likely Long COVID [Long COVID Research Index (LCRI) score of ≥ 11] or as Long COVID-indeterminate (LCRI score 0–10) with comparisons made between groups. The primary outcome was preterm birth <37 weeks’ gestation. Secondary outcomes included hypertensive disorders of pregnancy, cesarean delivery, neonatal ICU admission, and small for gestational age (<10th percentile). Propensity score methods with full matching were used to balance differences in baseline characteristics in estimating an ‘average treatment effect’ (ATE), with a sensitivity analysis estimating the ‘average treatment effect among the treated’ (ATT).
Results:
Among 603 participants, 118 (19.6%) were classified as likely Long COVID prior to or during pregnancy. Participants classified as likely Long COVID were more likely to have specific adverse social determinants of health (difficulty covering expenses and paying bills, food insecurity, missed care due to cost, to have experienced medical discrimination), and had higher pre-pregnancy body mass index than those who were Long COVID-indeterminate. In the primary ATE analysis, there was no association between likely Long COVID and preterm delivery (adjusted outcome rate 8.1% exposed vs 9.6% unexposed, aRR 0.82, 95% CI: 0.36–1.90) or secondary outcomes. In ATT sensitivity analyses, likely Long COVID was similarly not associated with preterm delivery (aRR 1.11, 95% CI 0.60 – 2.06), but was associated with an increased risk of hypertensive disorders of pregnancy (adjusted outcome rate 39.0% exposed vs 25.9% unexposed, aRR 1.51, 95% CI: 1.12–2.03), but not with other secondary outcomes.
Conclusion:
A classification of likely Long COVID was not significantly associated with preterm birth or several other adverse pregnancy outcomes. However, the association with hypertensive disorders of pregnancy in the ATT analysis highlights the need for further research.
Precis:
Maternal Long COVID existing before or during pregnancy was not associated with preterm birth, but may be associated with hypertensive disorders of pregnancy.
INTRODUCTION
Long COVID has been defined as an infection-associated chronic condition that occurs after SARS-CoV-2 infection and is present for at least 3 months as a continuous, relapsing and remitting, or progressive disease state that affects one or more organ systems.1 Centers for Disease Control and Prevention estimates suggest between 5–10% of adults in the U.S. currently have Long COVID.2
While acute SARS-CoV-2 infection during pregnancy has been strongly associated with adverse pregnancy outcomes including preterm birth and maternal morbidity and mortality3–6, pregnancy outcomes among those with a diagnosis of Long COVID remain unknown. Approximately 10% of reproductive age females are estimated to develop Long COVID after an initial SARS-CoV-2 infection7,8, with many of them subsequently experiencing pregnancy. It is biologically plausible that Long COVID could adversely affect pregnancy outcomes via viral persistence, ongoing changes in inflammatory markers and immune system response, or underlying damage to the affected organs from the SARS-CoV-2 virus, which could all result in preterm delivery (either spontaneous or medically indicated).
Some of the primary symptoms of Long COVID that could affect pregnancy physiology include brain fog, post-exertional malaise, chronic cough, and shortness of breath.8 There are also changes in the vascular system, with some patients developing chronic hypertension, endothelial dysfunction, thromboses and postural orthostatic hypotension after SARS-CoV-2 infection.9, 10 Given the importance of the vascular system during pregnancy and at the maternal-fetal interface, it is important to investigate whether these or other changes are associated with adverse short-term outcomes including preterm delivery, so that patients can receive anticipatory counseling prior to pregnancy, and optimize their care.
The primary aim of our study was to evaluate whether being classified as likely Long COVID based on a validated research instrument was associated with preterm delivery at less than 37 weeks’ gestation. Our secondary objective was to evaluate whether a classification of likely Long COVID was associated with other adverse pregnancy and perinatal outcomes.
METHODS
Researching COVID to Enhance Recovery (RECOVER)-Adult is a multicenter prospective longitudinal cohort study of adults age 18 years or older, with and without prior SARS-CoV-2 infection, enrolled from October 2021 through January 2024. The design of this study has been described previously.11,12 Briefly, demographics and health history (including pregnancy history) were self-reported at enrollment. A comprehensive set of surveys was completed in 3-month intervals including assessments of social determinants of health, SARS-CoV-2 vaccination status, and the presence and severity of 44 health symptoms that could be indicative of Long COVID.
Participants in RECOVER-Adult meeting eligibility criteria for this analysis included reproductive-age individuals aged 18–45 years whose sex was assigned female at birth, and who had a SARS-CoV-2 infection prior to or during a pregnancy, and had symptom survey data available 45 days after the index SARS-CoV-2 infection to calculate a Long COVID Research Index score. Pregnancies were excluded if self-reported pregnancy outcome data were unavailable, if the pregnancy involved multiple gestations, or if gestational age at delivery was less than 20 weeks as this would be considered a miscarriage. For enrolled individuals with more than one eligible pregnancy, only the first eligible pregnancy was included in the analysis.
The index date was defined as the date of first SARS-CoV-2 infection (suspected, probable, or confirmed as defined by World Health Organization criteria13). Participants who were uninfected at enrollment but had a positive nucleocapsid antibody result at enrollment were considered as infected, with an index date set to 90 days before the positive test consistent with RECOVER protocol.11 Additionally, participants in RECOVER who were uninfected at enrollment but had an on-study first infection were considered as infected with index date based on this infection. Those without evidence of ever having a SARS-CoV-2 infection (by self-report or nucleocapsid antibody testing) were excluded.
The primary exposure was the presence of likely Long COVID prior to or during pregnancy. Long COVID status was classified using the modified RECOVER-Adult Long COVID Research Index (LCRI) system-based algorithm.14 This scoring system was created based on data from 13,647 participants in the NIH RECOVER cohort based on serial symptom surveys among those with and without a history of SARS-CoV-2 infection. Symptoms included in the score are postexertional malaise, fatigue, brain fog, dizziness, palpitations, change in smell or taste, thirst, chronic cough, chest pain, shortness of breath and sleep apnea. These symptoms were selected from a symptom survey of 44 symptoms using a LASSO regression approach. Scores were then calculated as a sum of the points for each symptom. An LCRI value (ranging from 0 through 30) was computed, and participants with an LCRI at least 11 were considered likely Long COVID as their reported symptoms were consistent with having highly symptomatic Long COVID.14 The remaining participants were considered Long COVID-indeterminate (did not meet research classification criteria for Long COVID but not necessarily asymptomatic).
Those with an LRCI score of zero and those with an LCRI score of 1–10 (possible Long COVID) were all grouped into a COVID-indeterminate group for the purposes of this analysis. The grouping was to ensure that patients with likely Long COVID were compared with all other participants to mostly closely approximate a comparison to the general population. The term COVID-indeterminate is preferred by patients affected by Long COVID as some patients who would be clinically diagnosed with Long COVID do not reach an LCRI score ≥11.
The primary outcome was preterm delivery less than 37 weeks’ gestation (either spontaneous or medically indicated). Gestational age at delivery was calculated as the difference between participant-reported due date and participant-reported delivery date. Secondary outcomes included hypertensive disorders of pregnancy (gestational hypertension, preeclampsia with and without severe features, eclampsia, HELLP syndrome), cesarean delivery, neonatal ICU admission, and small for gestational age (birth weight less than the 10th percentile for gestational age and sex)15.
Demographic characteristics were summarized by Long COVID status. Medians with interquartile ranges were used for continuous variables and counts and percentages were used for categorical variables. Covariates considered clinically relevant or previously shown to be associated with Long COVID7,16 included maternal age, difficulty paying bills (based on social determinants of health survey responses that covering expenses and paying bills was “somewhat difficult” or “very difficult”), food insecurity, experienced medical discrimination, missed care due to cost, SARS-CoV-2 infection during the Omicron variant period, pregestational diabetes, self-reported history of high blood pressure, pre-pregnancy body mass index, prior cesarean delivery, prior preterm birth, parity, tobacco use within 12 months before index date (including e-cigarettes, smokeless tobacco, or cigarettes), acute SARS-CoV-2 infection during the pregnancy of interest, and vaccination status. All covariates were dichotomous with the exception of maternal age and BMI, which were continuous.
Propensity score matching methods were used to balance baseline characteristics between those who were classified as likely Long COVID and those who were classified as Long COVID-indeterminate. Propensity score weights were generated based on the probability of having likely Long COVID prior to or during pregnancy, estimated using logistic regression. Weights for each participant were matched using constrained full matching which uses all eligible participants and yields weighted exposure groups that are balanced on all covariates. The constrained match limits the number of Long COVID-indeterminate controls who could be matched with an individual classified as likely Long COVID; this method has been shown to reduce bias.17 The resulting weights applied to the analysis cohort estimates an overall ‘average treatment effect’ (ATE) or effect of being exposed to Long COVID (“the treatment”) for the whole population. To assess covariate balance, the distribution of propensity scores for both exposed and unexposed participants were assessed using histograms and standardized mean differences of each covariate before and after propensity score weighting. An absolute value of the standardized mean difference less than 0.1 was considered balanced. Missing data in covariates were assumed to be missing at random. Covariates with missing data were imputed using multiple imputation via chained equations (M=100 imputed datasets), where analyses using propensity scores were performed in each imputed dataset and the results pooled according to Rubin’s rules.18
Two pre-specified subgroup analyses were conducted: among pregnant individuals that had SARS-CoV-2 infection during the Omicron variant period and among those without acute infection during the pregnancy of interest. Subgroup analyses were not performed for secondary outcomes with low frequencies. Sensitivity analyses considered alternative propensity score weights targeting an ‘average treatment effect among the treated’ (ATT), by weighting the Long COVID-indeterminate group to have a distribution of covariates that matches the group classified as likely Long COVID. Given the outcome of preterm delivery is defined as delivery <37 weeks’ gestation, additional sensitivity analyses were performed: (1) excluded participants classified as likely Long COVID during pregnancy based on symptom assessment after 37 weeks’ gestation, (2) reclassified individuals who were classified as likely Long COVID during pregnancy based on symptom assessment after 37 weeks’ gestation as Long COVID-indeterminate.
Statistical analyses were performed using R software (version 4.4.0) via the National Heart, Lung, and Blood Institute’s BioData Catalyst. The ‘mice’ (version 3.18.0)19 and ‘MatchThem’ (version 1.2.1)20 packages were used for multiple imputation and propensity score estimation and weighting. All statistical tests were two-sided and significance level less than 0.05 was considered statistically significant. The current study was approved by the NYU Langone Health Institutional Review Board (IRB), which served as a single IRB for most sites, while others required local IRB approval. All participants provided written informed consent prior to enrollment. STROBE guidelines for cohort studies were followed.
RESULTS
Among 603 included participants, 118 were classified as likely Long COVID during pregnancy, and 485 participants were classified as Long COVID-indeterminate (Figure 1). Characteristics by Long COVID classification during pregnancy are presented in Table 1. Maternal age, race-ethnicity, SARS-CoV-2 infection during Omicron variant, pre-gestational diabetes, self-reported history of high blood pressure, tobacco use, vaccination status, and prior pregnancy history were similar between groups. Participants classified as likely Long COVID during pregnancy were more likely to have difficulty covering expenses and paying bills, to have experienced food insecurity and medical discrimination, to have missed care due to costs, and had higher pre-pregnancy body mass index. The majority of participants only had missing data for one of the covariates considered in this analysis. One percent of participants had missing data on more than two covariates.
Figure 1.
Study participant flowchart. RECOVER, Researching COVID to Enhance Recovery.
TABLE 1.
Demographic characteristics
| Characteristic | Likely Long COVID (n=118) |
Long COVID Indeterminate (n=485) |
Overall (N=603) |
|---|---|---|---|
| Maternal age at delivery (years) | 32 (29 – 35) | 32 (29 – 35) | 32 (29 – 35) |
| Not otherwise classified or mixed race | 40 (33.9) | 133 (27.4) | 173 (28.7) |
| Difficulty covering expenses | 62 (54.4) | 175 (37.5) | 237 (40.8) |
| Food insecurity | 29 (24.6) | 55 (11.3) | 84 (13.9) |
| Experienced medical discrimination | 38 (32.2) | 83 (17.1) | 121 (20.1) |
| Missed care due to cost | 9 (7.6) | 13 (2.7) | 22 (3.6) |
| Pre-Omicron variant | 32 (27.1) | 100 (20.6) | 132 (21.9) |
| Pregestational diabetes | 11 (9.3) | 29 (6.0) | 40 (6.6) |
| Self-reported history of high blood pressure | 11 (9.3) | 47 (9.7) | 58 (9.6) |
| Pre-pregnancy BMI (kg/m2) | 28.5 (23.5 – 35.4) | 25.5 (22.0 – 31.0) | 25.9 (22.6 – 31.7) |
| Prior cesarean delivery | 20 (27.0) | 70 (22.1) | 90 (23.0) |
| Prior preterm delivery | 11 (9.3) | 26 (5.4) | 37 (6.1) |
| Tobacco use | 16 (13.8) | 55 (11.5) | 71 (12.0) |
| Acute SARS-CoV-2 infection during pregnancy | 40 (33.9) | 136 (28.0) | 176 (29.2) |
| Vaccinated prior to delivery | 67 (57.8) | 320 (66.9) | 387 (65.2) |
Abbreviations: BMI, body mass index
Values reported as median (interquartile range) or count (percentage), unless otherwise specified.
Number of missing values: sociodemographic survey (difficulty covering expenses, n=22), pregestational diabetes (n=1), self-reported history of high blood pressure (n=1), body mass index (n=333), prior cesarean delivery (n=212), tobacco use (n=10), vaccination status (n=9).
Among participants included in this analysis, 13 (11%) participants who were considered likely Long COVID and 46 (9%) Long COVID-indeterminant participants had a preterm delivery. The propensity score distributions by exposure classification had reasonable overlap, and the resulting propensity score weighted groups were well balanced on the covariates (see Appendix 2, available online at http://links.lww.com/xxx). In the primary propensity score weighted analysis, there was no statistically significant difference in preterm delivery between those classified as likely Long COVID and those classified as Long COVID-indeterminate (aRR 0.82, 95% CI: 0.36–1.90) (Table 2 and 3). For secondary outcomes, there were no differences in hypertensive disorders or pregnancy, cesarean delivery, NICU admission, or small for gestational age (Table 2 and 3).
TABLE 2:
Pregnancy and neonatal outcomes
| Outcome | Likely Long COVID (n=118) |
Long COVID Indeterminate (n=485) |
Crude RR (95% CI) |
|---|---|---|---|
| Preterm delivery less than 37 weeks | 13 (11.0) | 46 (9.5) | 1.16 (0.62 – 2.01) |
| Gestational age at delivery (weeks) | 39.0 (38.0 – 39.6) | 39.1 (38.3 – 39.9) | - |
| Eclampsia | 0 | 1 (0.2) | |
| Cesarean delivery | 39 (33.1) | 136 (28.0) | 1.18 (0.86 – 1.56) |
| Live birth | 118 | 485 | |
| NICU | 29 (24.6) | 76 (15.7) | 1.57 (1.06 – 2.26) |
| Small for gestational age less than 10th percentile | 6 / 115 (5.2) | 43 / 477 (9.0) | 0.58 (0.23 – 1.22) |
| Birthweight (grams) | 3345 (2977 – 3643) | 3317 (3033 – 3629) | - |
Values reported as median (interquartile range) or count (percentage), unless otherwise specified.
Number of missing values: size for gestational age (n=11).
TABLE 3:
Pregnancy and neonatal outcomes comparison using propensity score weighting
| Outcome | Adjusted Relative Risk (95% CI) |
Adjusted Percent Difference (95% CI) |
Adjusted Outcome Rate (95% CI) | |
|---|---|---|---|---|
| Likely Long COVID | Long COVID Indeterminate | |||
| Preterm delivery less than 37 weeks | 0.82 (0.36 – 1.90) | −1.6 (−8.6 – 5.4) | 8.1 (1.7 – 14.4) | 9.6 (6.7 – 12.5) |
| Hypertensive disorder of pregnancy | 1.30 (0.87 – 1.95) | 7.7 (−5.1 – 20.5) | 32.8 (20.9 – 44.7) | 25.1 (20.9 – 29.3) |
| Cesarean delivery | 1.12 (0.74 – 1.70) | 3.5 (−9.6 – 16.6) | 31.9 (19.6 – 44.1) | 28.4 (23.8 – 33.0) |
| NICU | 1.31 (0.75 – 2.28) | 5.0 (−6.2 – 16.3) | 20.8 (10.3 – 31.4) | 15.8 (12.2 – 19.4) |
| Small for gestational age less than 10th percentile | 0.40 (0.12 – 1.30) | −5.4 (−10.7 – 0.0) | 3.8 (0.0 – 8.2) | 9.1 (6.3 – 12.0) |
| Subgroup Analysis: Omicron variant (Likely Long COVID, n=86; Long COVID Indeterminate, n=385) | ||||
| Preterm delivery less than 37 weeks | 0.93 (0.39 – 2.22) | −0.6 (−9.2 – 8.1) | 9.8 (1.7 – 17.9) | 10.3 (7.0 – 13.7) |
| Hypertensive disorder of pregnancy | 1.33 (0.83 – 2.13) | 8.2 (−6.4 – 22.8) | 32.4 (18.6 – 46.2) | 24.2 (19.7 – 28.8) |
| Cesarean delivery | 1.17 (0.74 – 1.86) | 5.1 (−9.8 – 19.9) | 33.0 (18.6 – 47.4) | 27.9 (22.9 – 32.9) |
| Subgroup Analysis: No acute infection during pregnancy (Likely Long COVID, n=78; Long COVID Indeterminate, n=349) | ||||
| Preterm delivery less than 37 weeks | 0.87 (0.30 – 2.55) | −0.9 (−9.6 – 7.7) | 7.8 (0.0 – 15.9) | 8.7 (5.6 – 11.8) |
| Hypertensive disorder of pregnancy | 1.24 (0.74 – 2.07) | 5.6 (−8.7 – 20.0) | 28.8 (15.1 – 42.4) | 23.1 (18.5 – 27.7) |
| Cesarean delivery | 1.08 (0.67 – 1.74) | 2.7 (−13.1 – 18.5) | 33.7 (18.6 – 48.7) | 31.0 (25.3 – 36.6) |
| Sensitivity Analysis: Propensity score weights based on Average ‘Treatment’ Effect on the ‘Treated’ (ATT) | ||||
| Preterm delivery less than 37 weeks | 1.11 (0.60 – 2.06) | 1.1 (−5.5 – 7.7) | 11.0 (5.4 – 16.7) | 9.9 (6.5 – 13.3) |
| Hypertensive disorder of pregnancy | 1.51 (1.12 – 2.03) | 13.1 (2.9 – 23.3) | 39.0 (30.2 – 47.8) | 25.9 (20.8 – 30.9) |
| Cesarean delivery | 1.05 (0.76 – 1.45) | 1.6 (−8.8 – 12.1) | 33.1 (24.6 – 41.5) | 31.4 (25.3 – 37.5) |
| NICU | 1.47 (0.98 – 2.20) | 7.9 (−1.0 – 16.7) | 24.6 (16.8 – 32.4) | 16.7 (12.5 – 20.9) |
| Small for gestational age less than 10th percentile | 0.60 (0.25 – 1.42) | −3.6 (−8.9 – 1.8) | 5.3 (1.2 – 9.4) | 8.9 (5.5 – 12.3) |
In ATT analysis, propensity score weights are only applied to Long COVID indeterminate group to match covariate distribution of participants that were Long COVID likely.
In planned subgroup analyses, results were similar among those with SARS-CoV-2 infection during the Omicron variant period and among those without acute infection during pregnancy (data not shown). Results were also consistent in sensitivity analyses excluding those likely Long COVID during pregnancy after 37 weeks’ gestation and with reclassifying those with likely Long COVID after 37 weeks’ gestation as Long COVID-indeterminate (see Appendix 2, available online at http://links.lww.com/xxx). In sensitivity analyses where propensity score weighting was based on the likely Long COVID covariate distribution (i.e., Average ‘Treatment’ Effect on the ‘Treated’, ATT analysis), likely Long COVID during pregnancy was associated with an increased risk of hypertensive disorder of pregnancy (aRR 1.51, 95% CI: 1.12–2.03) (Table 3).
DISCUSSION
We found that being classified as someone who likely has Long COVID that was pre-existing or identified during pregnancy was not associated with preterm birth or adverse pregnancy outcomes in our primary analysis using propensity score ATE weighting. However, having likely Long COVID during pregnancy was associated with an increased risk of hypertensive disorders of pregnancy in ATT analyses. Propensity score methods address confounding by equalizing or ‘balancing’ the distributions of covariates between likely Long COVID and Long COVID-indeterminate groups, with the ATE setting both groups to resemble the cohort as a whole, and the ATT setting both groups to resemble the Long COVID group in particular, i.e., with lower vaccination rates, greater socioeconomic risk factors, higher rates of pre-existing health conditions, etc. As a result, differences between the ATE and ATT analyses may reflect variation in the association between Long COVID and hypertensive disorders in populations with different demographic, health history, or infection characteristics. Alternatively, there may have been other unknown covariates that were not adequately accounted for with propensity score weighting and were also risk factors for hypertensive disorders of pregnancy, or this was an observed association due to chance. Given the lack of data on pregnancy outcomes in this population, these findings warrant further investigation in other similar cohorts.
Pregnancy outcomes among individuals diagnosed with Long COVID remain unknown. Long COVID shares some clinical symptoms such as post-exertional malaise, autonomic dysfunction and brain fog with other infection-associated chronic conditions, such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS).21 Pregnancy data for these chronic conditions are also very limited and focused primarily on how pregnancy affects the symptoms of these chronic conditions, rather than pregnancy outcomes for people living with these conditions.21, 22 One study surveyed patients with ME/CFS and reported on their pregnancy outcomes before and after diagnosis with ME/CFS.23 The authors found a higher rate of spontaneous abortion following diagnosis of ME/CFS but urged caution in the interpretation of this result, which may have been related to older maternal age at the time of the subsequent pregnancy. Other pregnancy outcomes were similar before and after ME/CFS diagnosis, consistent with our findings. Notably, 21% of the patients reported that they decided not to have children (or more children) because of their illness, reflecting uncertainty about outcomes both related to their pregnancy and potential progression of their condition.
The association between being classified as likely Long COVID and hypertensive disorders of pregnancy in the ATT analysis warrants further investigation in similar large cohorts. SARS-CoV-2 infection, especially infection requiring hospitalization, has been associated with new onset hypertension.24–26 Proposed mechanisms for the observed increase in hypertension include endothelial changes and changes in the renin-angiotensin-aldosterone system, predominantly an increase in renin and vasoconstriction.25 Others have also hypothesized that lifestyle modification among those affected by Long COVID may also contribute, as many individuals affected by Long COVID cannot sustain prior levels of physical activity.25
Limitations of our study include self-reported pregnancy outcomes, limited availability of pregnancy history variables due to nature of available survey responses, and possible residual confounding since we only accounted for known confounders that were deemed clinically relevant. While the LCRI measure14 is likely to appropriately identify those who have highly symptomatic Long COVID, it may not identify all people with Long COVID or who would be diagnosed with Long COVID in a clinical setting. There is no test available to definitively diagnose Long COVID; thus, the terminology of “diagnosed Long COVID” was intentionally avoided. For this analysis, we grouped those with an LCRI score of zero with those who had scores 1–10; those with scores in the range of 1–10 in other analyses have been separately classified as possible Long COVID to make the closest approximation to comparison to the general population. We excluded participants with no prior SARS-CoV-2 infection due to low numbers and because they could not have developed Long COVID regardless of calculated LCRI score without a prior infection. We did not evaluate early pregnancy outcomes such as miscarriage. We were limited by the available sample size; thus, there is the possibility of type II error. In addition, there was no adjustment made for multiple comparisons; thus, the finding of an association between likely Long COVID and hypertensive disorders may be a result of chance. Since this is a secondary analysis of an observational study, these results should be interpreted as exploratory.
Strengths include multicenter data collection from a diverse population, which enhances the generalizability of the results. We used a validated measure, the LCRI14, to identify those who were exposed to likely Long COVID. Participants were followed prospectively and completed detailed health symptom surveys to ascertain “real time” reports of their health status and the severity of their symptomatology. Propensity score weighting was utilized to rigorously adjust for differences between groups at baseline.
Overall, our results are reassuring in that being classified as likely having Long COVID was largely not associated with adverse pregnancy outcomes, which is in contrast to what has been observed for exposure to acute SARS-CoV-2 infection during pregnancy.3–6 However, further work is needed in this area so that patients with Long COVID can be adequately counseled about how their condition affects pregnancy outcomes, and whether pregnancy affects the symptoms of Long COVID, which remains unknown.
Supplementary Material
Acknowledgements:
This study is part of the NIH Researching COVID to Enhance Recovery (RECOVER) Initiative, which seeks to understand, treat, and prevent the post–acute sequelae of SARS-CoV-2 infection (PASC). For more information on RECOVER, visit https://recovercovid.org/. We would like to thank the National Community Engagement Group (NCEG), all patient, caregiver and community representatives, and all the participants enrolled in the RECOVER Initiative.
Funding Source:
This research was funded by the National Institutes of Health (NIH) Agreements OTA OT2HL161847, OT2HL161841 and OT2HL156812 as part of the Researching COVID to Enhance Recovery (RECOVER) Research Initiative. No funding source had a role in study design, data collection, analysis, or interpretation; manuscript preparation; or the decision to submit the manuscript for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Financial Disclosure:
Torri D. Metz was the site PI for a Pfizer study of Paxlovid in pregnancy, is a site PI for a Moderna study of RSV vaccination in pregnancy, and is the site PI for a Pfizer study of RSV vaccination in pregnancy and GBS prevention in pregnancy. She has received UptoDate royalties for two topics on trial of labor after cesarean and as a section editor. Kelly S. Gibson disclosed that her institution received funding from Materna. Rachel Hess received payment from Astellas Pharmaceuticals. M. Camile Hoffman disclosed her institution received payment for her expert testimony for one medicolegal trial from Wheeler, Trigg, and Associates (a defense attorneys firm). Her institution also received payment for a disease state presentation on postpartum depression and zuranolone from SAGE/Biogen. Brenna L. Hughes disclosed receiving payments from UptoDate and Moderna. Grace A. McComsey served as an advisor for Gilead and ViiVGlaxoSmithKline. Patrick S. Ramsey disclosed receiving payments from UptoDate. Daniel W Skupski reports receiving payments from Organon, Inc. and Cooper Surgical. Hyagriv N. Simhan disclosed receiving payments from UptoDate.
Footnotes
Editors’ Disclaimer:
Torri D Metz, Associate Editor (Obstetrics) of Obstetrics & Gynecology, was not involved in the review or decision to publish this article. Grecio J Sandoval, Associate Editor (Statistics) of Obstetrics & Gynecology, was not involved in the review or decision to publish this article.
The other authors did not report any potential conflicts of interest.
Each author has confirmed compliance with the journal’s requirements for authorship.
Peer Review History
Received April 24, 2026. Received in revised form June 28, 2026. Accepted July 2, 2026. Peer reviews and author correspondence are available at http://links.lww.com/xxx.
REFERENCES
- 1.National Academies of Sciences, Engineering, and Medicine. 2024. A Long COVID Definition: A Chronic, Systemic Disease State with Profound Consequences. Washington, DC: The National Academies Press. [PubMed] [Google Scholar]
- 2.Centers for Disease Control and Prevention. Tracking Long COVID. https://www.cdc.gov/long-covid/php/surveillance/index.html#:~:text=Long%20COVID%20prevalence%20differs%20by,in%20a%20given%20time%20period. Accessed March 29, 2026.
- 3.Metz TD, Clifton RG, Hughes BL, et al. Disease Severity and Perinatal Outcomes of Pregnant Patients With Coronavirus Disease 2019 (COVID-19). Obstet Gynecol. 2021. Apr 1;137(4):571–580. doi: 10.1097/AOG.0000000000004339. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Gurol-Urganci I, Jardine JE, Carroll F, Draycott T, Dunn G, Fremeaux A, Harris T, Hawdon J, Morris E, Muller P, Waite L, Webster K, van der Meulen J, Khalil A. Maternal and perinatal outcomes of pregnant women with SARS-CoV-2 infection at the time of birth in England: national cohort study. Am J Obstet Gynecol. 2021. Nov;225(5):522.e1–522.e11. doi: 10.1016/j.ajog.2021.05.016. Epub 2021 May 20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Allotey J, Stallings E, Bonet M, et al. Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis. BMJ. 2020. Sep 1;370:m3320. doi: 10.1136/bmj.m3320. Update in: BMJ. 2022 May 30;377:o1205. doi: 10.1136/bmj.o1205. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Metz TD, Clifton RG, Hughes BL, et al. Association of SARS-CoV-2 Infection With Serious Maternal Morbidity and Mortality From Obstetric Complications. JAMA. 2022. Feb 22;327(8):748–759. doi: 10.1001/jama.2022.1190. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Metz TD, Reeder HT, Clifton RG, et al. Post-Acute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) After Infection During Pregnancy. Obstet Gynecol. 2024. Sep 1;144(3):411–420. doi: 10.1097/AOG.0000000000005670. Epub 2024 Jul 11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Metz TD, Reeder HT, Clifton RG, et al. Long COVID After Acquisition of the Omicron Variant of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) During Pregnancy Compared With Outside of Pregnancy. Obstet Gynecol. 2026. Mar 1;147(3):404–414. doi: 10.1097/AOG.0000000000006067. Epub 2025 Oct 2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Stojanovic M, Djuric M, Nenadic I, et al. Vascular Complications of Long COVID-From Endothelial Dysfunction to Systemic Thrombosis: A Systematic Review. Int J Mol Sci. 2025. Dec 31;27(1):433. doi: 10.3390/ijms27010433. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Tavee J. Current concepts in long COVID-19 brain fog and postural orthostatic tachycardia syndrome. Ann Allergy Asthma Immunol. 2024. Nov;133(5):522–530. doi: 10.1016/j.anai.2024.08.008. Epub 2024 Aug 21. [DOI] [PubMed] [Google Scholar]
- 11.Horwitz LI, Thaweethai T, Brosnahan SB, et al. Researching COVID to Enhance Recovery (RECOVER) adult study protocol: Rationale, objectives, and design. PLoS One. 2023. Jun 23;18(6):e0286297. doi: 10.1371/journal.pone.0286297. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Metz TD, Clifton RG, Gallagher R, et al. Researching COVID to enhance recovery (RECOVER) pregnancy study: Rationale, objectives and design. PLoS One. 2023. Dec 21;18(12):e0285351. doi: 10.1371/journal.pone.0285351. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.World Health Organization. WHO COVID-19: case definitions, updated in public health surveillance for COVID-19, 22 July 2022. https://www.who.int/publications/i/item/WHO-2019-nCoV-Surveillance_Case_Definition-2022.1. Accessed March 9, 2023.
- 14.Geng LN, Erlandson KM, Hornig M, Letts R, Selvaggi C, Ashktorab H, Atieh O, Bartram L, Brim H, Brosnahan SB, Brown J. 2024 update of the RECOVER-adult long COVID research index. JAMA. 2025. Feb 25;333(8):694–700. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Duryea EL, Hawkins JS, McIntire DD, Casey BM, Leveno KJ. A revised birth weight reference for the United States. Obstet Gynecol. 2014. Jul;124(1):16–22. [DOI] [PubMed] [Google Scholar]
- 16.Feldman CH, Santacroce L, Bassett IV, Thaweethai T, Alicic R, Atchley-Challenner R, Chung A, Goldberg MP, Horowitz CR, Jacobson KB, Kelly JD. Social determinants of health and risk for long COVID in the US RECOVER-adult cohort. Annals of Internal Medicine. 2025. Sep;178(9):1287–97. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Austin PC, Stuart EA. The effect of a constraint on the maximum number of controls matched to each treated subject on the performance of full matching on the propensity score when estimating risk differences. Stat Med. 2021. Jan 15;40(1):101–118. doi: 10.1002/sim.8764. Epub 2020 Oct 7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Rubin DB (1987). Multiple Imputation for Nonresponse in Surveys. John Wiley & Sons, New York. [Google Scholar]
- 19.Van Buuren S, Groothuis-Oudshoorn K. mice: Multivariate imputation by chained equations in R. Journal of statistical software. 2011. Dec 12;45:1–67. [Google Scholar]
- 20.Pishgar Farhad, Greifer Noah, Leyrat Clémence and Stuart Elizabeth, The R Journal (2021) 13:2, pages 292–305. [Google Scholar]
- 21.Pollack B, von Saltza E, McCorkell L, Santos L, Hultman A, Cohen AK, Soares L. Female reproductive health impacts of Long COVID and associated illnesses including ME/CFS, POTS, and connective tissue disorders: a literature review. Front Rehabil Sci. 2023. Apr 28;4:1122673. doi: 10.3389/fresc.2023.1122673. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Slack E, Pears KA, Rankin J, Newton JL, Pearce M. Identifying, synthesising and appraising existing evidence relating to myalgic encephalomyelitis/chronic fatigue syndrome and pregnancy: a mixed-methods systematic review. BMJ Open. 2023. Oct 5;13(10):e070366. doi: 10.1136/bmjopen-2022-070366. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Schacterle RS, Komaroff AL. A comparison of pregnancies that occur before and after the onset of chronic fatigue syndrome. Arch Intern Med. 2004. Feb 23;164(4):401–4. doi: 10.1001/archinte.164.4.401. [DOI] [PubMed] [Google Scholar]
- 24.Zhang V, Fisher M, Hou W, Zhang L, Duong TQ. Incidence of New-Onset Hypertension Post-COVID-19: Comparison With Influenza. Hypertension. 2023. Oct;80(10):2135–2148. doi: 10.1161/HYPERTENSIONAHA.123.21174. Epub 2023 Aug 21. [DOI] [PubMed] [Google Scholar]
- 25.Bielecka E, Sielatycki P, Pietraszko P, Zapora-Kurel A, Zbroch E. Elevated Arterial Blood Pressure as a Delayed Complication Following COVID-19-A Narrative Review. Int J Mol Sci. 2024. Feb 2;25(3):1837. doi: 10.3390/ijms25031837. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Zuin M, Rigatelli G, Bilato C, Pasquetto G, Mazza A. Risk of Incident New-Onset Arterial Hypertension After COVID-19 Recovery: A Systematic Review and Meta-analysis. High Blood Press Cardiovasc Prev. 2023. May;30(3):227–233. doi: 10.1007/s40292-023-00574-5. Epub 2023 Apr 15. [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.