Supplemental Digital Content is Available in the Text.
Key Words: SARS-CoV-2, HIV, pregnancy, pregnancy outcomes, low birth weight, small for gestational age
Abstract
Background:
COVID-19 and HIV infection are independently associated with increased risk of adverse pregnancy outcomes. However, there is limited evidence on the effect of SARS-CoV-2 infection during pregnancy in sub-Saharan Africa, particularly among women living with HIV (WLWH).
Setting:
Two antenatal clinics in southern Malawi (2018–2022).
Methods:
We conducted a prospective cohort study of singleton pregnancies enrolled at 20–36 weeks gestation. SARS-CoV-2 infection was determined through serologic testing at enrollment and delivery. Participants were enrolled based on HIV status and viral suppression: (1) WLWH with detectable viral load (VL), (2) WLWH with undetectable VL, and (3) HIV-negative women. We used a multivariable logistic regression with adjustment for confounding to evaluate the effect of SARS-CoV-2 alone or in combination with HIV infection on the following adverse birth outcomes: low birth weight (LBW), preterm birth, small-for-gestational-age (SGA), and stillbirth or early neonatal death.
Results:
Among 905 pregnant women, 29% tested positive for SARS-CoV-2, 87% of infections were mild or asymptomatic. Overall, SARS-CoV-2 infection was significantly associated with SGA births (adjusted OR [aOR]: 1.49, 95% CI: 1.03 to 2.13) but not associated with other adverse outcomes. Among WLWH, SARS-CoV-2 was significantly associated with increased odds of LBW (aOR: 2.07, 1.10 to 3.91) and SGA births (aOR: 1.73, 1.01 to 2.91). The effect of SARS-CoV-2 infection among WLWH did not differ based on VL.
Conclusions:
SARS-CoV-2 infection during pregnancy was associated with adverse birth outcomes, particularly among WLWH. These findings underscore the need for integrated antenatal care and targeted infection prevention strategies for pregnant women with HIV in high-burden settings.
INTRODUCTION
The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to pose a significant global public health challenge, especially among vulnerable groups. Although people of all ages are susceptible to infection, pregnant women and people living with human immune-deficiency virus (HIV) infection are at increased risk of severe illness and mortality due to COVID-19.1–4 Pregnant women are particularly at increased risk of complications from SARS-CoV-2 because of physiological changes which occur during pregnancy.5 SARS-CoV-2 infection in pregnancy has been associated with severe adverse maternal and perinatal outcomes such as increased maternal hospitalization, preterm births, small-for-gestational-age, and low birth weight.6–10 Similarly, HIV infection significantly increases the risk of adverse maternal and perinatal outcomes among pregnant women living with HIV (WLWH),11–14 particularly among individuals with high HIV viral load.15,16
Sub-Saharan Africa (SSA) remains the epicenter of the global HIV/AIDS epidemic, with most infections found in women.17 In Malawi, HIV prevalence is estimated at 8.9% among adults aged 15–64 years, and 10.5% among women.18 Estimates of SARS-CoV-2 seroprevalence in Malawi throughout the pandemic ranged from 8% in late 2020,19 to 89% in rural areas, and 94% in urban settings by April 2022,20 with all studies reporting largely asymptomatic transmission. The high prevalence of HIV in Malawi, as in other SSA countries, may exacerbate the risk of morbidity and mortality related to SARS-CoV-2, particularly among pregnant women.6,21 WLWH may also experience an increased disease burden with SARS-CoV-2 compared with those without HIV infection. This is of particular concern among individuals with high viral loads and low CD4 counts, which show delayed antibody responses against SARS-CoV-2.10,21–26 This situation raises concerns about the combined effects of HIV and SARS-CoV-2 infections on pregnancy outcomes.
There is extremely limited data on the effect of SARS-CoV-2 infections among pregnant women in SSA or among WLWH. One previous study in Botswana found that HIV and SARS-CoV-2 coinfections interacted to elevate the risk of adverse pregnancy outcomes.21 However, there is a critical need for more research focused on understanding the combined effects of HIV and SARS-CoV-2 coinfection on pregnant women, particularly because no studies have examined how the effect of SARS-CoV-2 infection varies by HIV viral load or ART exposure. The burden of the COVID-19 pandemic is likely underestimated owing to lack of data in these high-risk groups, but understanding the effect of SARS-CoV-2 on pregnant WLWH can both help to inform current SARS-CoV-2 response and future pandemic preparedness. This study aims to evaluate the effect of SARS-CoV-2 exposure on adverse pregnancy outcomes by HIV status and will further investigate the role of HIV viral load in modifying the effect of SARS-CoV-2 infection on these outcomes. We hypothesize that SARS-CoV-2 infection will significantly worsen the risk of adverse pregnancy outcomes, with more severe effects anticipated among pregnant WLWH, particularly in those with high viral loads, compared with their virally suppressed or HIV-negative counterparts. This research seeks to fill critical gaps in our understanding of the combined effects of HIV and SARS-CoV-2 infections on pregnancy outcomes in SSA.
METHODS
Study Design and Population
We conducted a prospective cohort study among pregnant women in 3 cohorts based on their HIV and viral load status in 2 research clinics near Blantyre, Malawi. Cohort recruitment has been described previously.27 The study enrolled pregnant women at antenatal care (ANC) clinics in their second trimester and followed them through delivery, with their newborn infants monitored postnatally. Pregnant women were recruited into 3 cohorts according to their HIV status and viral load: (1) Pregnant WLWH with high viral loads (>10,000 copies/mL), with no previous reported ART use; (2) Pregnant WLWH with undetectable viral loads (<400 copies/mL), reporting ongoing ART use; and (3) Pregnant women uninfected with HIV. Pregnant women were enrolled between 2018 and 2022, spanning both the prepandemic and COVID-19 pandemic period. Malawi reported its first confirmed COVID-19 case in April 2020 and subsequently experienced multiple epidemic waves associated with Beta, Delta, and Omicron variants despite limited testing and genomic surveillance capacity throughout Malawi.28,29
Study Setting and Eligibility
Participants were recruited from 2 ANC clinics—Ndirande and Bvumbwe. Ndirande Health Facility is located in the urban area of Ndirande, Blantyre, Malawi. It serves a densely populated community, providing a wide range of health services including maternal and child health, outpatient care, and HIV testing and treatment. Bvumbwe Health Facility is situated in the rural area of Bvumbwe, Thyolo District, Malawi. It serves a largely agrarian community, offering essential health services such as antenatal and postnatal care, HIV testing and treatment, immunizations, and treatment for common illnesses. SARS-CoV-2 vaccination and testing was not widely available in Malawi at the time of the study with only 4% of eligible adults vaccinated at the time recruitment ended,30 making it unlikely that any participants were vaccinated.
Eligible participants were any pregnant women aged 18 years and older, who attended their first ANC visit between 20 and 36 weeks gestation (confirmed by ultrasound) at either of the study clinics, intended to breastfeed, were willing to deliver at the clinic, and planning to remain in the study area for at least 1 year. HIV-negative women were required to test negative by rapid HIV test at both enrollment and delivery. We excluded women with multiple gestations. All WLWH were on ART and monitored for ART adherence for the duration of the study and no opportunistic infections were detected during the study. All women with samples at enrollment and delivery for retrospective SARS-CoV-2 antibody assessment were included in this analysis, so some women were enrolled and delivered before the pandemic began and did not have opportunity to become infected with SARS-CoV-2. There were decreased health services available from April to June 2020, and women who delivered during this time did not provide samples and could not be included in retrospective SARS-CoV-2 serological assessment or this analysis.
Data Collection
Eligible participants underwent initial screening including HIV testing, documentation of ART exposure, gestational age assessment by ultrasound, and baseline viral load measurements for participants with HIV. Serum samples were collected at enrollment and at delivery from all participants and assessed for anti–SARS-CoV-2 antibodies retrospectively. Samples were assessed for anti–SARS-CoV-2 IgM and IgG using the RayBiotech COVID-19 S1 RBD Protein Human IgG ELISA Kit, which provides quantitative measurements of IgG antibodies and the Inbios SCoV-2 Detect IgM ELISA Kit, a qualitative test which detects the presence or absence of IgM antibodies. The selection of the S1 RBD is based on its high specificity for SARS-CoV-2, as prepandemic studies show minimal cross-reactivity with this protein, thereby minimizing false positives and enhancing the accuracy of infection identification.31
Variables and Definitions
Exposure
Exposure in this study is SARS-CoV-2 infection during pregnancy determined through serological testing for IgM and IgG antibodies. Participants were classified as infected during pregnancy if their serological testing met 1 of 3 criteria; (1) positive for anti–SARS-CoV-2 IgM antibodies at either the screening or delivery visit because IgM antibodies against SARS-CoV-2 typically appear within the first few weeks of infection and persist for several weeks31,32 or (2) if participants seroconverted by IgG from negative at screening to positive at delivery or (3) if the concentration of IgG antibodies at delivery was at least 3.5-fold higher than the concentration at screening. We did not consider IgG positive samples at screening as evidence of recent infection as IgG persists for up to 9 to 12 months after exposure.33 The precise timing of infection during pregnancy and whether it represented a first infection could not be determined.
Primary Outcome
The primary outcome of this study is any adverse birth outcome, which covers the occurrence of any of the following; maternal hospitalization, early neonatal death (ENND),34 stillbirth,35 low birth weight (LBW),36 small-for-gestational-age (SGA),37 and preterm birth.38 Additional other outcomes include: (1) LBW, (2) Preterm birth, (3) SGA birth, and (4) the combined outcome of ENND or stillbirth. According to the World Health organization (WHO) ENND is defined as a newborn death of a live-born baby within 7 days of life, and stillbirth as the death of a fetus before birth, which includes both antenatal and intrapartum deaths.34,35 Preterm birth is defined as birth that occurs before 37 weeks of gestation. LBW is defined as birth weight less than 2500 grams (up to and including 2499 grams), and SGA is defined as newborns with birth weight which is less than the 10th percentile for their gestational age.36–38 Outcomes are not mutually exclusive and pregnancies may have qualified for more than 1 adverse outcome, that is, LBW births are often either preterm or SGA. Adverse outcomes in this cohort have previously been described at length.27
Covariates
We selected covariates for final adjusted models using a Directed Acyclic Graph (Supplemental Figure 1, http://links.lww.com/QAI/C715). We categorized variables into (1) minimally sufficient confounders, identified a priori including: gravidity (primigravida/multigravida), maternal age (continuous variable in years), and residential location of each clinic (rural Bvumbwe/urban Ndirande); (2) Effect modifiers, assessed for interaction including: HIV status (positive/negative) and viral load status among WLWH (detectable/undetectable at screening and delivery), and CD4 count, (<350 cells/mL/≥350 cells/mL); and (3) Descriptive covariates, used in preliminary analysis to describe the study population but were not adjusted for in the final regression models including: Education level, ART regimen type (non-nucleoside reverse transcriptase inhibitor-based [NNRTI-based]/Dolutegravir-based [DTG-based]), and marital status (married or unmarried). Preselected confounders were removed from final adjusted models if they did not improve the model fit or alter the estimate of the main effect.
Data Analysis
We used univariate analyses to compute frequencies and proportions of participant characteristics at baseline, describing continuous variables with means and standard deviations and categorical variables with proportions. Bivariate relationships between participants' sociodemographic and clinical characteristics at baseline and SARS-CoV-2 status were examined using χ2 tests for categorical variables and Student t tests for continuous variables, with a significance level set at α = 0.05 to determine differences in SARS-CoV-2 seroconversion. We also assessed the bivariate relationship between baseline demographic characteristics and each outcome variable to identify significant predictors.
We used logistic regression to explore the association between SARS-CoV-2 seropositivity and 4 pregnancy outcomes: low birthweight, preterm birth, small-for-gestational-age, and the composite “any adverse outcome.” Owing to small numbers of stillbirths and ENND included in this study, we were unable to assess them as an outcome in regression models. Crude odds ratios (OR) and 95% CIs were calculated to test these associations. To examine the combined risk of SARS-CoV-2 seropositivity and HIV on pregnancy outcomes, we evaluated an interaction term (SARS-CoV-2*HIV) in the models. In addition, we conducted stratified analyses for SARS-CoV-2 infection by HIV and viral load status to explore effect modification by viral load on each adverse pregnancy outcome. Although CD4 levels were initially considered as an effect modifier, low power in subanalysis (owing to small cell counts) prevented meaningful interpretation. In the final adjusted multivariable logistic regression model, we adjusted for facility location (site) and gravidity.
We conducted a sensitivity analysis, repeating all analysis in a restricted analytic cohort of women enrolled on or after April 1, 2020, to address differences in SARS-CoV-2 exposure opportunity because of differential recruitment timing between WLWH and HIV-negative women.
Sample Size and Power
With a sample size of 905 pregnant women, including 258 exposed to SARS-CoV-2, assuming 23% prevalence of adverse pregnancy outcomes, our study has an 86.2% power to detect a 10% difference in adverse birth outcomes between SARS-CoV-2–positive and SARS-CoV-2–negative groups, using a two-sided hypothesis with a 0.05 significance level.
RESULTS
Characteristics of the Study Population
The initial study recruited 1781 pregnant women in their second trimester of pregnancy, of whom 905 were followed through to delivery, had samples tested for SARS-CoV-2 and were included in this analysis (Fig. 1). Among these participants, 29% tested positive for SARS-CoV-2 (n = 258). The study participants were evenly distributed between the 2 sites with a mean maternal age of 28 years. Among women who tested positive for SARS-CoV-2, 60% were HIV-negative and 40% were WLWH (P < 0.001; Table 1). A greater proportion of WLWH than those without HIV were recruited into the cohort before the onset of the COVID-19 pandemic. Among the 184 women enrolled before 2020 who were tested for SARS-CoV-2, 147 (80%) were WLWH. This differential timing of recruitment likely contributed to the observed difference in SARS-CoV-2 positivity between the 2 groups.
FIGURE 1.
Study flow diagram. HIV, human immunodeficiency virus; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2.
TABLE 1.
Characteristics of Study participants by SARS-CoV-2 Exposure
| Characteristic | Overall1 N = 905 |
SARS-CoV-2 Negative* N = 647 |
SARS-CoV-2 Positive* N = 258 |
P † |
| Site | ||||
| Bvumbwe | 412 (46%) | 293 (45%) | 119 (46%) | 0.8 |
| Ndirande | 493 (54%) | 354 (55%) | 139 (54%) | |
| Maternal age | ||||
| Mean (SD) | 28 (6) | 28 (6) | 28 (7) | 0.1 |
| Marital status | ||||
| Married | 819 (91%) | 587 (91%) | 232 (90%) | 0.8 |
| Not married | 85 (9%) | 60 (9%) | 25 (10%) | |
| Educational level | ||||
| Below secondary | 461 (51%) | 336 (52%) | 125 (49%) | 0.4 |
| Secondary and above | 443 (49%) | 311 (48%) | 132 (51%) | |
| Gravidity | ||||
| Multigravida | 785 (87%) | 564 (87%) | 221 (86%) | 0.5 |
| Primigravida | 120 (13%) | 83 (13%) | 37 (14%) | |
| Delivery method | ||||
| Others | 61 (7%) | 46 (7%) | 15 (6%) | 0.5 |
| Vaginal | 844 (93%) | 601 (93%) | 243 (94%) | |
| Infant sex | ||||
| Female | 444 (49%) | 318 (49%) | 126 (49%) | >0.9 |
| Male | 461 (51%) | 329 (51%) | 132 (51%) | |
| HIV status | ||||
| Negative | 457 (50%) | 303 (47%) | 154 (60%) | <0.001 |
| Positive | 448 (50%) | 344 (53%) | 104 (40%) | |
| CD4 counts | ||||
| Mean (SD) | 589 (242) | 577 (237) | 630 (255) | 0.07 |
| Viral load | ||||
| Detectable | 72 (16%) | 55 (16%) | 17 (16%) | >0.9 |
| Undetectable | 376 (84%) | 289 (84%) | 87 (84%) |
n (%).
Pearson χ2 tests for categorical variables and Wilcoxon rank-sum test for continuous variables.
Bolded values indicate significant results
SARS-CoV-2 Symptoms and Severity
Among the 905 women tested for SARS-CoV-2, 401 (44%) sought treatment during follow-up for illness or injury. Among women with SARS-CoV-2 infections, only 34/258 (13%) sought treatment for respiratory symptoms during pregnancy. Those who sought treatment with respiratory symptoms additionally reported muscle aches (n = 11, 32%), headache (n = 10, 29%), and fever (n = 7, 20%), with 4 (12%) women reporting chest pain or shortness of breath. Two SARS-CoV-2–positive women were diagnosed with pneumonia.
Pregnancy Outcomes
Among 905 women, 297 (33%) experienced any adverse pregnancy outcome. The most frequent outcome was SGA birth (168 cases, 19%), followed by LBW (80 cases, 9.1%) and preterm birth (79 cases, 8.7%). Among LBW births, 95% were classified as either preterm or SGA as well. A total of 13 stillbirths and 3 early neonatal deaths were recorded, with only 2 stillbirths occurring among women with SARS-CoV-2–positive pregnancies. SARS-CoV-2 infection was significantly associated with SGA in preliminary analysis with 59 (24%) of SARS-CoV-2 infected women having SGA births, compared with 109 (17%) of women without SARS-CoV-2 infections. However, SARS-CoV-2 was not significantly associated with LBW, preterm birth, or early neonatal death in the total population (Table 2).
TABLE 2.
Pregnancy Outcomes by SARS-CoV-2 Exposure
| Characteristic | Overall, N = 905* | SARS-CoV-2 Negative, N = 647* | SARS-CoV-2 Positive, N = 258* | P † |
| Any adverse outcome | ||||
| Present | 297 (33%) | 204 (32%) | 93 (36%) | 0.2 |
| Absent | 608 (67%) | 440 (68%) | 164 (64%) | |
| Low birth weight | ||||
| Present | 80 (9%) | 54 (8%) | 26 (10%) | 0.4 |
| Absent | 798 (91%) | 575 (91%) | 223 (90%) | |
| Small-for-gestational-age | ||||
| Absent | 709 (81%) | 519 (83%) | 190 (76%) | 0.03 |
| Present | 168 (19%) | 109 (17%) | 59 (24%) | |
| Hospitalization | ||||
| Present | 75 (8%) | 56 (9%) | 19 (7%) | 0.5 |
| Absent | 829 (92%) | 590 (91%) | 239 (93%) | |
| Preterm birth | ||||
| Present | 79 (9%) | 57 (9%) | 22 (9%) | 0.9 |
| Absent | 826 (91%) | 590 (91%) | 236 (91%) | |
| Early neonatal death/stillbirth | ||||
| Present | 16 (2%) | 14 (2%) | 2 (1%) | 0.4 |
| Absent | 889 (98%) | 633 (98%) | 256 (99%) |
n (%).
Pearson χ2 test.
Bolded values indicate significant results
Association Between Adverse Pregnancy Outcomes and Covariates
In bivariate analysis (Supplemental Digital Content, Tables, http://links.lww.com/QAI/C715), we assessed the relationship between baseline sociodemographic characteristics and each of the 5 adverse pregnancy outcomes. We found that LBW was significantly associated with HIV status, site, gravidity, and parity, whereas other adverse pregnancy outcomes, including the composite outcome of any adverse events, preterm, SGA birth, and stillbirth/early neonatal death showed associations with sociodemographic factors such as gravidity, parity, maternal age, site, delivery method, and HIV status.
Regression Models for Effect of SARS-CoV-2 Infection on Pregnancy Outcomes
Among all women in the study, regardless of HIV status, we assessed the unadjusted association between SARS-CoV-2 and each of the adverse pregnancy outcomes. Only SGA showed a statistically significant association with SARS-CoV-2 positivity in the total population (OR: 1.48, 95% CI: 1.03 to 2.11, P = 0.03) (Table 3, Fig. 2). Stratified analysis by HIV status found no evidence of association between SARS-CoV-2 and adverse pregnancy outcomes among HIV-negative pregnant women (Fig. 2). However, among WLWH, SARS-CoV-2 positivity was significantly associated with an increased odds of LBW (aOR of 2.04 [95% CI: 1.09 to 3.82, P = 0.023]) and SGA birth (aOR = 1.73. 95% CI: 1.01 to 2.91, P = 0.04) (Fig. 2). SARS-CoV-2 positivity was not associated with preterm birth or stillbirth/early neonatal death in either group. There was significant interaction between HIV status and SARS-CoV-2 infection in models for LBW, but not for any of the other outcomes, and final adjusted models are presented in Table 3. Final multivariable regression models (Table 3) were adjusted for site and gravidity, because these were identified as key confounders from our directed acyclic graph and preliminary analysis.
TABLE 3.
Association Between SARS-CoV-2 Exposure and Pregnancy Outcomes From Logistic Regression Models
| Outcomes | Overall | SARS-CoV-2 | Unadjusted | Adjusted | |||||
| Negative | Positive | OR | 95% CI | P | aOR | 95% CI | P | ||
| Total population | |||||||||
| Any adverse event | |||||||||
| Present | 297 (33%) | 204 (32%) | 93 (36%) | 1.22 | 0.90 to 1.66 | 0.2 | 1.23 | 0.91 to 1.67 | 0.2 |
| Absent | 608 (67%) | 440 (68%) | 164 (64%) | ||||||
| Low birth weight | |||||||||
| Present | 80 (9.1%) | 54 (8.6%) | 26 (10%) | 1.24 | 0.75,2.01 | 0.4 | 1.24 | 0.75 to 2.02 | 0.4 |
| Absent | 798 (91%) | 575 (91%) | 223 (90%) | ||||||
| Preterm birth | |||||||||
| Present | 79 (8.7%) | 57 (8.8%) | 22 (8.5%) | 0.96 | 0.57,1.59 | 0.9 | 0.97 | 0.57 to 1.60 | 0.9 |
| Absent | 826 (91%) | 590 (91%) | 236 (91%) | ||||||
| Small-for-gestational-age | |||||||||
| Present | 168 (19%) | 109 (17%) | 59 (24%) | 1.48 | 1.03 to 2.11 | 0.03 | 1.49 | 1.03 to 2.13 | 0.03 |
| Absent | 709 (81%) | 519 (83%) | 190 (76%) | ||||||
| Women without HIV | |||||||||
| Any adverse event | |||||||||
| Present | 137 (30%) | 87 (29%) | 50 (32%) | 1.27 | 0.94 to 1.73 | 0.12 | 1.2 | 0.78 to 1.82 | 0.4 |
| Absent | 320 (70%) | 216 (71%) | 104 (68%) | ||||||
| Low birth weight | |||||||||
| Present | 29 (6.4%) | 21 (7.0%) | 8 (5.3%) | 0.74 | 0.32 to 1.71 | 0.5 | 0.76 | 0.31 to 1,70 | 0.5 |
| Absent | 423 (94%) | 279 (93%) | 144 (95%) | ||||||
| Preterm birth | |||||||||
| Present | 31 (6.8%) | 21 (6.9%) | 10 (6.5%) | 0.93 | 0.43 to 2.03 | 0.86 | 0.94 | 0.41 to 2.00 | 0.9 |
| Absent | 426 (93%) | 282 (93%) | 144 (94%) | ||||||
| Small-for-gestational-age | |||||||||
| Present | 81 (18%) | 49 (16%) | 32 (21%) | 1.37 | 0.83 to 2.24 | 0.2 | 1.39 | 0.83 to 2.29 | 0.2 |
| Absent | 371 (82%) | 251 (84%) | 120 (79%) | ||||||
| Women living with HIV | |||||||||
| Any adverse event | |||||||||
| Present | 284 (63%) | 224 (65%) | 60 (58%) | 1.37 | 0.87 to 2.15 | 0.2 | 1.37 | 0.87 to 2.15 | 0.2 |
| Absent | 164 (37%) | 120 (35%) | 44 (42%) | ||||||
| Low birth weight | |||||||||
| Present | 51 (12%) | 33 (10%) | 18 (19%) | 2.04 | 1.09 to 3.82 | 0.03 | 2.07 | 1.10 to 3.91 | 0.03 |
| Absent | 375 (88%) | 296 (90%) | 79 (81%) | ||||||
| Preterm birth | |||||||||
| Present | 48 (11%) | 36 (10%) | 12 (12%) | 1.13 | 0.56 to 2.23 | 5 | 1.13 | 0.54 to 2.21 | 0.7 |
| Absent | 400 (89%) | 308 (90%) | 92 (88%) | ||||||
| Small-for-gestational-age | |||||||||
| Present | 87 (20%) | 60 (18%) | 27 (28%) | 1.72 | 1.02 to 2.91 | 0.04 | 1.73 | 1.01 to 2.91 | 0.04 |
| Absent | 338 (80%) | 268 (82%) | 70 (72%) | ||||||
aOR, adjusted odds ratio, adjusted models adjusted for site and gravidity; OR, odds ratio.
Bolded values indicate significant results
FIGURE 2.
Adjusted odds ratios from logistic regression for effect of SARS-CoV-2 infection compared with pregnant women without SARS-CoV-2 infections. Models adjusted for site and gravidity. LBW= low birth weight; SGA, small-for-gestational-age.
Effect of Viral Load on SARS-CoV-2 and Pregnancy Outcomes
To assess whether HIV viral load modifies the effect of SARS-CoV-2 on pregnancy outcomes, we conducted a stratified analysis among WLWH with detectable and undetectable viral load (Table 4). There was no statistically significant association between SARS-CoV-2 and any adverse outcome across viral load status because of lower power in the HIV subgroups. However, the magnitude and direction of effect for all outcomes was similar by viral load detection status.
TABLE 4.
Unadjusted Association Between SARS-CoV-2 Infection and Pregnancy Outcomes Among Women Living With HIV by Viral Load Status
| All HIV Positive | Overall* | SARS-CoV-2 Negative* | SARS-CoV-2 Positive* | OR | 95% CI | P |
| Any adverse event | ||||||
| Present | 164 (37%) | 120 (35%) | 44 (42%) | 1.37 | 0.87 to 2.14 | 0.2 |
| Absent | 284 (63%) | 224 (65%) | 60 (58%) | |||
| Low birth weight | ||||||
| Present | 51 (12%) | 33 (10%) | 18 (19%) | 2.04 | 1.08 to 3.78 | 0.02 |
| Absent | 375 (88%) | 296 (90%) | 79 (81%) | |||
| Preterm birth | ||||||
| Present | 48 (11%) | 36 (10%) | 12 (12%) | 1.12 | 0.54 to 2.18 | 0.8 |
| Absent | 400 (89%) | 308 (90%) | 92 (88%) | |||
| SGA | ||||||
| Present | 87 (20%) | 60 (18%) | 27 (28%) | 1.72 | 1.01 to 2.89 | 0.04 |
| Absent | 338 (80%) | 268 (82%) | 70 (72%) | |||
| Detectable viral load | ||||||
| Any adverse event | ||||||
| Present | 31 (36%) | 24 (35%) | 7 (41%) | 1.5 | 0.90 to 2.49 | 0.6 |
| Absent | 55 (64%) | 45 (65%) | 10 (59%) | |||
| Low birth weight | ||||||
| Present | 7 (8.6%) | 5 (7.5%) | 2 (14%) | 2.07 | 0.36 to 11.92 | 0.4 |
| Absent | 74 (91%) | 62 (93%) | 12 (86%) | |||
| Preterm birth | ||||||
| Present | 8 (9.3%) | 6 (8.7%) | 2 (12%) | 1.3 | 0.55 to 2.84 | 0.7 |
| Absent | 78 (91%) | 63 (91%) | 15 (88%) | |||
| SGA | ||||||
| Present | 16 (20%) | 12 (18%) | 4 (29%) | 1.6 | 0.87 to 2.86 | 0.5 |
| Absent | 65 (80%) | 55 (82%) | 10 (71%) | |||
| Undetectable viral load | ||||||
| Any adverse event | ||||||
| Present | 119 (34%) | 85 (32%) | 34 (41%) | 1.23 | 0.40 to 3.62 | 0.1 |
| Absent | 228 (66%) | 180 (68%) | 48 (59%) | |||
| Low birth weight | ||||||
| Present | 40 (12%) | 26 (10%) | 14 (18%) | 1.94 | 0.95 to 3.92 | 0.06 |
| Absent | 294 (88%) | 230 (90%) | 64 (82%) | |||
| Preterm birth | ||||||
| Present | 32 (9.2%) | 23 (8.7%) | 9 (11%) | 1.4 | 0.19 to 6.81 | 0.5 |
| Absent | 315 (91%) | 242 (91%) | 73 (89%) | |||
| SGA | ||||||
| SGA | 69 (21%) | 48 (19%) | 21 (27%) | 1.59 | 0.88 to 2.88 | 0.1 |
| Not SGA | 265 (79%) | 208 (81%) | 57 (73%) |
SGA, small-for-gestational-age. * n (%).
Bolded values indicate significant results
In a sensitivity analysis restricted to women enrolled on or after April 1, 2020 (N = 709), the direction and magnitude of effect estimates were consistent with the primary analysis across all outcomes and subgroups. The association between SARS-CoV-2 infection and SGA in the total population (aOR:1.38, 95% CI:0.93–2.05) and LBW among WLWH (aOR: 1.53, 95% CI: 0.73–3.13) were attenuated and no longer statistically significant. Full sensitivity analysis results are presented in Supplemental Digital Content, Tables, http://links.lww.com/QAI/C715.
DISCUSSION
In this cohort of Malawian pregnant women, serological evidence of SARS-CoV-2 infection during pregnancy was significantly associated with an increased risk of SGA birth in all included pregnant women, regardless of HIV status. Notably, among WLWH, SARS-CoV-2 infection was significantly associated with an increased risk of both LBW and SGA. These associations did not differ significantly regardless of whether or not the woman had fully controlled HIV (undetectable viral load) throughout pregnancy, although power was limited for these subanalyses. These findings indicate that SARS-CoV-2 seropositivity during pregnancy, even in the absence of severe COVID-19 disease, is associated with increased risk of adverse pregnancy outcomes, and WLWH are particularly vulnerable to the adverse effects of SARS-CoV-2 infection.
This is 1 of the first reports of the effect of SARS-CoV-2 infection on adverse birth outcomes in SSA, and our findings are consistent with previous studies conducted in high-income settings.7,8,10,26,39 A systematic review of 42 studies found SARS-CoV-2 infection associated with increased risk of preterm birth (OR 1.82; 95% CI: 1.38 to 2.39), stillbirth (OR 2.11; 95% CI: 1.14 to 3.9), and low birth weight (OR 1.89; 95% CI: 1.14 to 3.12).6 Our study was designed before the COVID-19 pandemic began and did not include surveillance for clinical COVID-19 disease. Few participants sought care for respiratory symptoms during the study, and as such, many of the infections we identified were likely mild or asymptomatic. Previous studies have found increasing severity of COVID-19 symptoms in pregnant women is associated with higher risk of adverse outcomes.6 The mild nature of most infections in our study may have contributed to the less severe effect of SARS-CoV-2 in our overall study population, and particularly among healthy women without HIV, compared with previous studies. The absence of active disease surveillance limits our ability to fully characterize the potential effect of COVID-19 disease. However, our findings of increased risk of adverse pregnancy outcomes among a cohort with mostly mild infections are important, indicating that even mild or asymptomatic SARS-CoV-2 infections may influence pregnancy outcomes, particularly among vulnerable populations, highlighting the importance of infection prevention among WLWH and other high-risk populations.
Previous studies from sub-Saharan African nations examining the effect of SARS-CoV-2 infection on adverse birth outcomes in the presence of other comorbidities are few6 and frequently do not include controls without COVID-19, making them difficult to interpret. Our findings are in agreement with 1 previous study examining the combined effect of HIV and SARS-CoV-2 coinfection in Botswana, which reported increased risk of preterm birth and stillbirth among pregnant women with SARS-CoV-2 infection, with the greatest burden observed among WLWH.21 By contrast, recent data from Botswana during the Omicron era reported no significant association between SARS-CoV-2 infection and adverse birth outcomes, including among WLWH,40 suggesting any effect of SARS-CoV-2 on adverse pregnancy outcomes may be variant specific. Continuous monitoring and further research measuring coronavirus cases and other respiratory infections in pregnant women in Sub-Saharan Africa are necessary to fully understand the risks of SARS-CoV-2 infections and future pandemic respiratory infections on pregnant women in Sub-Saharan Africa.26
Despite the low overall risk of adverse outcomes related to SARS-CoV-2 in our study population, among WLWH, there was a two-fold significantly higher risk for LBW and 73% higher odds of SGA birth as a result of SARS-CoV-2 exposure. This finding did not differ by HIV viral load status; however, the power of this subanalysis was low as there were few women with detectable viral load. Although CD4 count data were available for a subset of participants, substantial missingness precluded a reliable assessment of the effect of CD4-defined immunosuppression. These findings may be driven by HIV-related immune dysregulation and chronic inflammation, rather than viral load differences. Studies have shown that HIV infection induces persistent immune activation, systemic inflammation, and placental insufficiency, all of which can impair fetal growth increasing the odds of LBW and SGA births.15,41–43 Similarly, SARS-CoV-2 infection has been reported to cause vascular dysfunction and placental inflammation.44,45 Thus, coinfection with HIV and SARS-CoV-2 infections may have a synergistic effect, exacerbating placental dysfunction. Alrubayyi et al23 reported that even with undetectable viral load immune dysfunction persists, affecting adaptive response to SARS-CoV-2. Our findings further emphasize the consequences of this immune dysfunction and the importance of prioritizing vaccination and other preventive services for WLWH.
Among the women included in our analysis, 29% tested positive for SARS-CoV-2, with 60% of these being HIV negative. The proportion of SARS-CoV-2 positivity was higher among HIV-negative pregnant women compared with WLWH (33.7% vs. 23.2%). This disparity likely reflects difference in timing of recruitment and biological response. Notably, 36% of the WLWH were recruited before Malawi's first confirmed COVID-19 case, compared with only 1% of HIV-negative women. As such, a larger proportion of the HIV-negative women were recruited during periods of high SARS-CoV-2 community transmission. To assess whether differential recruitment timing influenced our findings, we conducted a sensitivity analysis restricted to women enrolled after April 2020. The direction and magnitude of effects estimates were consistent across all outcomes and subgroups; however, power was limited to detect statistically significant differences in this restricted cohort. In addition, previous studies suggest that people living with HIV may mount a dampened serological response to SARS-CoV-223 potentially leading to misclassification of the exposure with a resultant underestimation of true effect among WLWH, biasing results toward the null. Furthermore, we did not perform PCR testing at the time of illness, which would have been necessary to confirm symptomatic COVID-19. As a result, many of the infections we detected in the cohort were likely asymptomatic or mild enough that participant did not seek care. Participant-level viral sequencing data were unavailable preventing assessment of differences by viral variants. Despite these limitations, we found a significant effect of SARS-CoV-2 infection on adverse pregnancy outcomes, indicating that the true effect of SARS-CoV-2 on pregnancy outcomes may be greater than estimated in this study, particularly among WLWH.
This study benefits from a prospective cohort study design, allowing for the observation of pregnancy outcomes over time and providing robust evidence for discerning the effects of SARS-CoV-2 infection on pregnancy outcomes. The design enabled subanalyses by HIV and viral load status, highlighting the differential effects of these factors within an underrepresented setting in current literature.
In conclusion, our study provides additional evidence of the increased risk pregnant women face as a result of SARS-CoV-2 infection, regardless of clinical symptoms, and in particular among WLWH. We additionally found evidence that viral suppression alone is insufficient to prevent the increased risk due to SARS-CoV-2 infection among WLWH. These findings may help inform public health policies and interventions aimed at improving maternal and child health outcomes, emphasizing the importance of integrated care models, ongoing surveillance, and tailored preventive services in the context of viral pandemics, particularly among WLWH. We recommend enhanced prenatal care including counseling on infection prevention measures and prioritized vaccination for pregnant WLWH.
Supplementary Material
Footnotes
Supported by National Institutes of Health R01HD100235 (to MKL, MG), R33HD103066 (to MKL, MG), and U01HD092308 (to MKL, CC), and K01MH134741 (PI Buchwald).
Preliminary analysis of this data was presented at the IAS Annual Meeting in Munich, Germany, in July 2024, abstract number: WEPEC324.
The authors have no conflicts of interest to disclose.
The study protocol and informed consent were reviewed and approved by the University of Maryland IRB and the Kamuzu University of Health Sciences (formerly University of Malawi College of Medicine) IRB. Written informed consent was obtained before conducting any study-related activities. The research was conducted in accordance with the ethical principles of the Declaration of Helsinki and relevant national and institutional guidelines.
I.A.E.I.—manuscript drafting, statistical analysis, figure making; A.R.K.—data production, conception, manuscript review; N.N.N.—data collection, manuscript review; F.M.—data collection, manuscript review; O.N.—data collection, manuscript review; R.M.—data collection, manuscript review; C.C.—funding acquisition, study design, manuscript review; M.G.—funding acquisition, study design, manuscript review; M.K.L.—funding acquisition, study design, conception, manuscript review; A.G.B.—conception, data analysis, funding acquisition, study design, manuscript review.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jaids.com).
Data is available on request from corresponding author.
Contributor Information
Ibrahim Ahmed El-Imam, Email: IAhmed@mgic.umaryland.edu.
Abra Rachida Koudjra, Email: akoudjra@som.umaryland.edu.
Nginache Nampota-Nkomba, Email: nnampota@som.umaryland.edu.
Felix Mkandawire, Email: fmkandawire@bmp.kuhes.ac.mw.
Osward Nyirenda, Email: onyirenda@bmp.kuhes.ac.mw.
Rhoda Masonga, Email: rmasonga@bmp.kuhes.ac.mw.
Cristiana Cairo, Email: ccairo@som.umaryland.edu.
Melissa Gladstone, Email: melglad@liverpool.ac.uk.
Miriam K. Laufer, Email: mlaufer@som.umaryland.edu.
Andrea G. Buchwald, Email: abuchwald@som.umaryland.edu.
REFERENCES
- 1.Wolff D, Nee S, Hickey NS, et al. Risk factors for Covid-19 severity and fatality: a structured literature review. Infection. 2021;49:15–28. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Mota M, Huerta-Álvarez C, Llorente A, et al. The risk of SARS-CoV-2 infection in pregnant women: an observational cohort study using the BIFAP database. Healthcare. 2022;10:2429. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Shoaib N, Noureen N, Munir R, et al. COVID-19 severity: studying the clinical and demographic risk factors for adverse outcomes. PLoS One. 2021;16:e0255999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Ssentongo P, Heilbrunn ES, Ssentongo AE, et al. Epidemiology and outcomes of COVID-19 in HIV-infected individuals: a systematic review and meta-analysis. Sci Rep. 2021;11:6283. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Richardson AN, Pollak EA, Williams D, et al. Intrauterine infection. In: Comprehensive Toxicology. 2nd ed. Elsevier Inc.; 2010:239–258. [Google Scholar]
- 6.Wei SQ, Bilodeau-Bertrand M, Liu S, et al. The impact of COVID-19 on pregnancy outcomes: a systematic review and meta-analysis. Can Med Assoc. 2021;193:E540–E548. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Smith V, Seo D, Warty R, et al. Maternal and neonatal outcomes associated with COVID-19 infection: a systematic review. PLoS One. 2020;15:e0234187. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.McClymont E, Albert AY, Alton GD, et al. Association of SARS-CoV-2 infection during pregnancy with maternal and perinatal outcomes. JAMA. 2022;327:1983–1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.de Waard L, Langenegger E, Erasmus K, et al. Maternal and neonatal outcomes of COVID-19 in a high-risk pregnant cohort with and without HIV. South Afr Med J. 2021;111:1174–1180. [DOI] [PubMed] [Google Scholar]
- 10.Piekos SN, Roper RT, Hwang YM, et al. The effect of maternal SARS-CoV-2 infection timing on birth outcomes: a retrospective multicentre cohort study. Lancet Digit Health. 2022;4:e95–e104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Brocklehurst P, French R. The association between maternal HIV infection and perinatal outcome: a systematic review of the literature and meta-analysis. Br J Obstet Gynaecol. 1998;105:836–848. [DOI] [PubMed] [Google Scholar]
- 12.Stringer EM, Kendall MA, Lockman S, et al. Pregnancy outcomes among HIV-infected women who conceived on antiretroviral therapy. PLoS One. 2018;13:e0199555. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Mazengia Alemu F, Worku Yalew A, Fantahun M, et al. SYSTEMATIC REVIEW antiretroviral therapy and pregnancy outcomes in developing countries: a systematic review. Int J MCH AIDS. 2015;3:31–43. [PMC free article] [PubMed] [Google Scholar]
- 14.Lokken EM Mathur A Bunge KE, et al. Pooled prevalence of adverse pregnancy and neonatal outcomes in Malawi, South Africa, Uganda, and Zimbabwe: results from a systematic review and meta-analyses to inform trials of novel HIV prevention interventions during pregnancy. Front Reprod Health. 2021;3. . [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Turner AN, Tabbah S, Mwapasa V, et al. Severity of maternal HIV-1 disease is associated with adverse birth outcomes in Malawian women: a cohort Study. EPIDEMIOLOGY AND PREVENTION [Internet]; 2013. Available at: http://links.lww.com/QAI/A445 [DOI] [PMC free article] [PubMed]
- 16.Thea D. M Steketee R. W Pliner V Bornschlegel K Brown T Orloff S, & Kalish M. L. The effect of maternal viral load on the risk of perinatal transmission of HIV-1. Aids. 1997;11(4):437–444. [DOI] [PubMed] [Google Scholar]
- 17.UNAIDS. 2022-global-aids-update_en. 2022. [Google Scholar]
- 18.Ministry of Health (MOH) M. Malawi population-based HIV impact assessment 2020-2021 Malawi Population-based HIV Impact Assessment MPHIA 2020-2021. Malawi population-based HIV impact assessment 2020- 2021 (MPHIA 2020-2021). 2021. Available at: http://phia.icap.columbia.edu
- 19.Theu JA, Kabaghe AN, Bello G, et al. SARS-CoV-2 Prevalence in Malawi Based on Data from Survey of Communities and Health Workers in 5 High-Burden Districts, October 2020. Emerg Infect Dis. 2022;28:S76–S84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Banda L, Ho A, Kasenda S, et al. Characterizing the evolving SARS-CoV-2 seroprevalence in urban and rural Malawi between February 2021 and April 2022: a population-based cohort study. Int J Infect Dis. 2023;137:118–125. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Jackson-Gibson M, Diseko M, Caniglia EC, et al. Association of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection with maternal mortality and neonatal birth outcomes in Botswana by human immunodeficiency virus status. Obstet Gynecol. 2023;141:135–143. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Hoffmann C, Casado JL, Härter G, et al. Immune deficiency is a risk factor for severe COVID-19 in people living with HIV. HIV Med. 2021;22:372–378. [DOI] [PubMed] [Google Scholar]
- 23.Alrubayyi A, Gea-Mallorquí E, Touizer E, et al. Characterization of humoral and SARS-CoV-2 specific T cell responses in people living with HIV. Nat Commun. 2021;12:5839. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.González R, Nhampossa T, Figueroa-Romero A, et al. SARS-CoV-2 Seropositivity and HIV Viral Load Among Mozambican Pregnant Women [Internet]. JAIDS Journal of Acquired Immune Deficiency Syndromes 92.2:115-121. 2023; 2022. Available at: www.jaids.com [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Izzo I, Carriero C, Gardini G, et al. Impact of COVID-19 pandemic on HIV viremia: a single-center cohort study in northern Italy. AIDS Res Ther. 2021;18:31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Villar J, Ariff S, Gunier RB, et al. Maternal and neonatal morbidity and mortality among pregnant women with and without COVID-19 infection: the INTERCOVID multinational cohort Study. JAMA Pediatr. 2021;175:817–826. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Nampota-Nkomba N Buchwald A Nyirenda OMR, et al. Association between maternal HIV and adverse birth outcomes in the era of universal antiretroviral therapy in Malawi. JAIDS. 2025;10. . [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Anscombe C, Lissauer S, Thole H, et al. A comparison of four epidemic waves of COVID-19 in Malawi; an observational cohort study. BMC Infect Dis. 2023;23:79. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Mseka UL, Mandolo J, Nyoni K, et al. Omicron B.1.1.529 variant infections associated with severe disease are uncommon in a COVID-19 under-vaccinated, high SARS-CoV-2 seroprevalence population in Malawi. 2022. Available at: www.thelancet.com [DOI] [PMC free article] [PubMed]
- 30.Dashboards – Public Health Institute of Malawi. [cited 2026 Jun 11]. Available at: https://phim.health.gov.mw/dashboards/ [Google Scholar]
- 31.Premkumar L, Segovia-Chumbez B, Jadi R, et al. The receptor-binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients. Sci. Immunol. 2020. Available at: https://www.science.org [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Peghin M, De Martino M, Fabris M, et al. The fall in antibody response to SARS-CoV-2: a longitudinal study of asymptomatic to critically ill patients up to 10 months after recovery. J Clin Microbiol. 2021;59:e0113821. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Lugo-Trampe A, López-Cifuentes D, Mendoza-Pérez P, et al. Nine-month trend of IgG antibody persistence and associated symptoms Post-SARS-CoV-2 infection. Healthcare (Switzerland). 2024;12:948. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Pathirana J, Muñoz FM, Abbing-Karahagopian V, et al. Neonatal death: case definition & guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34:6027–6037. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Stillbirth. [cited 2024 Apr 7]. Available at: https://www.who.int/health-topics/stillbirth#tab=tab_1
- 36.Cutland CL, Lackritz EM, Mallett-Moore T, et al. Low birth weight: case definition & guidelines for data collection, analysis, and presentation of maternal immunization safety data. Vaccine. 2017;35:6492–6500. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Schlaudecker EP, Munoz FM, Bardají A, et al. Small for gestational age: case definition & guidelines for data collection, analysis, and presentation of maternal immunisation safety data. Vaccine. 2017;35:6518–6528. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Preterm birth [Internet]. [cited 2024 Apr 7]. Available at: https://www.who.int/news-room/fact-sheets/detail/preterm-birth
- 39.Smith ER, Oakley E, Grandner GW, et al. Adverse maternal, fetal, and newborn outcomes among pregnant women with SARS-CoV-2 infection: an individual participant data meta-analysis. BMJ Glob Health. 2023;8:e009495. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Banga J, Jackson-Gibson M, Diseko M, et al. No impact of COVID-19 at delivery on maternal mortality or infant adverse birth outcomes in Botswana during the Omicron era. PLoS One. 2024;19:e0310980. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Bruce-Brand C, Wright CA, Schubert PT. HIV, placental pathology, and birth outcomes: a brief overview. J Infect Dis. 2021;224:S683–S690. [DOI] [PubMed] [Google Scholar]
- 42.Ikumi NM, Matjila M, Gray CM, et al. Placental pathology in women with HIV. Placenta. 2021;115:27–36. [DOI] [PubMed] [Google Scholar]
- 43.Vyas P, Mathad JS, Leu CS, et al. Impact of HIV status on systemic inflammation during pregnancy. AIDS. 2021;35:2259–2268. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Wong YP, Tan GC, Omar SZ, et al. SARS-CoV-2 infection in pregnancy: placental histomorphological patterns, disease severity and perinatal outcomes. Int J Environ Res Public Health. 2022;19:9517. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Yao Y, Sun L, Luo J, et al. The effect of long-term COVID-19 infection on maternal and fetal complications: a retrospective cohort study conducted at a single center in China. Sci Rep. 2024;14:17273. [DOI] [PMC free article] [PubMed] [Google Scholar]