Abstract
Purpose:
To examine associations between pregnancy timing relative to the COVID-19 pandemic, maternal SARS-CoV-2 infection, and perinatal outcomes.
Methods:
We conducted a retrospective cohort study of 189,097 singleton births in South Carolina (2018–2021). Pregnancy timing relative to the pandemic was classified as pre-pandemic (delivered before March 1, 2020), partial pandemic overlap (conceived before and delivered during the pandemic), or pandemic (conceived and delivered during the pandemic). We examined COVID-19 testing, severity, and timing. Modified Poisson regression models with robust variance were used.
Results:
Compared to the pre-pandemic group, the partial overlap group had lower risks of low birthweight (LBW) (aRR=0.93, 95 % CI 0.89–0.97) and preterm birth (PTB) (aRR=0.91, 95 % CI 0.88–0.95). The pandemic group had increased risks of LBW (aRR=1.10, 95 % CI 1.06–1.14), PTB (aRR=1.10, 95 % CI 1.07–1.14), and NICU admissions (aRR=1.13, 95 % CI 1.09–1.17) but a decreased risk of breastfeeding initiation (aRR=0.98, 95 % CI 0.97–0.98). Moderate-to-severe COVID-19 symptoms increased PTB (aRR=1.34, 95 % CI 1.13–1.58). Third-trimester COVID-19 infection increased LBW (aRR=1.23, 95 % CI 1.10–1.37), PTB (aRR=1.18, 95 % CI 1.07–1.30), and NICU admissions (aRR=1.17, 95 % CI 1.05–1.30).
Conclusions:
Our findings highlight the importance of considering both maternal COVID-19 infection and pandemic-related factors in optimizing perinatal outcomes.
Keywords: Breastfeeding initiation, Coronavirus, low birthweight, NICU admission, perinatal outcomes, preterm birth
Introduction
The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1] and associated prevention measures, significantly impacted health and society [2], with pregnant women being vulnerable due to their altered immune system [3]. By 2022, over 225,000 pregnant women in the United States (US) had contracted the virus [4], raising concerns about its possible influence on perinatal outcomes.
Emerging literature suggests that the COVID-19 pandemic and pandemic-related mitigation measures affected perinatal risks, including an unexpected decrease in preterm birth (PTB) early in the pandemic [5–7]. However, systematic reviews consistently report that SARS-CoV-2 infection during pregnancy is associated with increased risks of PTB [8–11], low birthweight (LBW) [9], and neonatal intensive care unit (NICU) admissions [8–11], with severe COVID-19 infection exacerbating these risks [11,12]. Yet, evidence regarding other perinatal outcomes, such as small-for-gestational-age (SGA) and breastfeeding initiation, is still exploratory.
Many studies focus on the negative outcomes of maternal SARS-CoV-2 infection, but often fail to distinguish the direct effect of SARS-CoV-2 infection from broader pandemic-related factors [7]. Previous studies often had limitations such as small sample sizes, few COVID-19 cases, limited generalizability, selection bias, or short durations [13]. Fewer studies have explored pregnancy timing relative to the pandemic and its association with adverse perinatal outcomes, while accounting for COVID-19 severity and timing using US population-level data [12]. To address these gaps, our study aimed to examine the associations between SARS-CoV-2 infection, including its severity and timing, pregnancy timing relative to the pandemic, and adverse perinatal outcomes using statewide linked data.
Methods
Data source and study population
We conducted a statewide retrospective cohort study linking South Carolina (SC) birth certificates with all-payer hospital utilization data (also known as Uniform Billing (UB) Public Use data, hereinafter, referred to as hospital data) and SC COVID-19 testing registry data from January 2018 to December 2021 (Fig. 1). Considering that at-home testing was not widespread in the US before January 2022, we studied COVID testing data up to December 2021 to ensure reliable COVID-19 test reporting.
Fig. 1.
Flow chart of the included singleton births in South Carolina, January 2018 – December 2021 SC, South Carolina; COVID, coronavirus disease 2019.
The unique maternal identifier was generated by the SC Office of Revenue and Fiscal Affairs using the mother’s name, date of birth, and social security number. Our team received de-identified datasets with unique maternal identifiers [14]. Initially, we identified obstetric deliveries from all hospitals in SC using all-payer hospital utilization data and a published algorithm based on ICD-10-CM diagnoses and procedure codes pertaining to obstetric delivery and Diagnosis-Related Group delivery codes [15,16] (Supplemental Table 1). The UB data cover inpatient admissions and discharges, emergency visits, outpatient surgeries, and other outpatient services, as well as associated demographics, diagnoses, procedures, and discharge statuses. Multiple deliveries per woman were included if the interval between the date of delivery and the conception date of the next delivery was greater than six months [17]. Identified childbirth encounters were linked with SC birth certificates using the unique maternal identifier and year of childbirth. Around 1.6 % (n = 3146) births from birth certificates were not matched to the all-payer file, likely due to out-of-hospital births. All births from birth certificates were included regardless of whether they were in hospital data or COVID-19 registry data. Details about the cohort creation are also available in previous publications [16,18]. COVID-19 testing results were obtained from the SC Case Report Form (CRF) for SARS-CoV-2 infection, a standard form issued by the SC Department of Health and Environmental Control (DHEC). According to SC Law (44–29–10) and Regulations (61–20), all testing facilities were required to report COVID-19 testing results to DHEC during the pandemic [19]. The CRF collected data on the results of COVID-19 diagnostic tests, the date of symptoms onset, and the progression of symptoms [20].
Records with multiple gestations, birthweight < 500 g, gestational age > 44 weeks, deliveries beyond December 31, 2021, or records with missing values for birthweight, gestational age, maternal age at birth, race, smoking during pregnancy, prenatal care initiation, maternal education, residence, SGA, or parity were excluded (Fig. 1).
Independent variables
We examined two independent variables: pregnancy timing relative to the pandemic and COVID-19 infection during pregnancy. Pregnancy timing relative to the pandemic was classified into three groups: (1) pre-pandemic group (pregnancies delivered before the onset of the pandemic on March 1, 2020); (2) partially overlapping pandemic group (pregnancies conceived before March 1, 2020, but delivered on or after March 1, 2020); and (3) pandemic group (pregnancies conceived after March 1, 2020). COVID-19 infection was assessed using three variables: SARS-CoV-2 infection testing, COVID-19 severity, and the timing of the first COVID-19 infection during pregnancy. SARS-CoV-2 infection testing was categorized into three groups: (1) no COVID-19 testing, (2) COVID-19-negative, or (3) COVID-19-positive. COVID-19-positive cases included lab-confirmed cases, determined by SARS-CoV-2 RNA molecular amplification testing, as well as probable cases. Probable COVID-19 cases were those meeting specific clinical, epidemiological, or lab criteria (presence of specific antigens or antibodies even without a confirmed positive SARS-CoV-2 RNA molecular amplification test) [20]. “No COVID-19 testing” included women in the pre-pandemic group and those not tested during the pandemic. Severity and timing variables were created only among COVID-19-positive cases. COVID-19 severity was classified into three groups based on self-reported symptoms collected by the CRF for SARS-CoV-2 infection: (1) asymptomatic (no symptoms); (2) mild symptoms (fever, chills, muscle aches, runny nose, sore throat, loss of taste and smell, headache, fatigue, cough, abdominal pain, nausea, vomiting, diarrhea); (3) moderate-to-severe symptoms (difficulty breathing, pneumonia or acute respiratory distress syndrome, hospitalization, or intensive-care unit admission) [21]. For multiple positive COVID-19 tests during the same pregnancy, the highest severity was used. We classified the timing of the first infection as being diagnosed during the first/second trimester (91–280 days to birth) or the third trimester (0–90 days to birth).
For both the COVID-19 severity and COVID-19 timing variables, “No COVID-19” included women who were either not tested or tested negative during the pandemic. Early pandemic testing focused on symptomatic individuals, close contacts, or those needing tests for medical, travel, or employment reasons [22], suggesting that untested individuals likely did not have COVID-19.
Outcomes
We studied six perinatal outcomes, including LBW (birthweight <2500 g), SGA (birthweight <10th percentile of national birthweight centiles for sex and gestational age) [23], large-for-gestational-age (LGA, birthweight >90th percentile of national birthweight centiles for sex and gestational age) [23], PTB (delivery at <37 completed weeks of gestation), NICU admission, and breastfeeding initiation at birth. Outcomes were derived from the birth certificate data. These outcomes were selected for their clinical significance and the gaps identified in the literature.
Covariates
Covariates were selected based on the definition of confounding, relevant literature [7,8], and data availability. Maternal sociodemographic variables included maternal age at birth, race/ethnicity, education, pre-pregnancy body mass index (BMI), primary payer, smoking during pregnancy, substance use, parity, trimester of prenatal care initiation, previous PTB, pre-pregnancy diabetes, pre-pregnancy hypertension, and maternal residence (Table 1). Hospital characteristics included the level of inpatient perinatal care services as specified in the SC Code of Regulations (S.C. Code Regs. §61–16.1306). Race/ethnicity, primary payer, substance use, and inpatient perinatal care services were extracted from the hospital data. All other covariates were derived from birth certificate data. Unknown race from the hospital data (n = 3181, 1.6 %) was supplemented using the race variable from the birth certificate data. The records with missing information on inpatient perinatal care services, pre-pregnancy BMI, primary payer, and substance use were grouped into a separate “Unknown” category for each variable. The variance inflation factor values ranged from 1.01 to 2.49, indicating no evidence of high multicollinearity.
Table 1.
Characteristics of Singleton Childbirths Delivered in South Carolina by Pregnancy Timing Relative to COVID-19 Pandemic, January 2018-December 2021 (n = 189,097).
| Characteristic | Total | Pregnancy timing relative to COVID-19 pandemic | ||
|---|---|---|---|---|
| Pre-pandemic | Partial pandemic overlap | Pandemic | ||
| Total, N (Row %) | 189,097 (100.0) | 102,938 (54.4) | 34,989 (18.5) | 51,170 (27.1) |
| n (Col %) | ||||
| Maternal Race and Ethnicity | ||||
| Hispanic | 9084 (4.8) | 4800 (4.7) | 1734 (5.0) | 2550 (5.0) |
| Non-Hispanic Black | 57,830 (30.6) | 31,914 (31.0) | 10,669 (30.5) | 15,247 (29.8) |
| Non-Hispanic White | 108,721 (57.5) | 58,996 (57.3) | 19,969 (57.1) | 29,756 (58.2) |
| Non-Hispanic Other* | 13,462 (7.1) | 7228 (7.0) | 2617 (7.5) | 3617 (7.1) |
| Mother’s Age at Birth, Years | ||||
| <20 | 11,550 (6.1) | 6681 (6.5) | 2093 (6.0) | 2776 (5.4) |
| 20–24 | 42,468 (22.5) | 23,662 (23.0) | 7700 (22.0) | 11,106 (21.7) |
| 25–29 | 57,601 (30.5) | 31,748 (30.8) | 10,696 (30.6) | 15,157 (29.6) |
| 30–34 | 49,593 (26.2) | 26,194 (25.5) | 9378 (26.8) | 14,021 (27.4) |
| 35 + | 27,885 (14.8) | 14,653 (14.2) | 5122 (14.6) | 8110 (15.9) |
| Highest Maternal Education Attainment | ||||
| No High School | 24,028 (12.7) | 13,801 (13.4) | 4356 (12.5) | 5871 (11.5) |
| High School | 48,626 (25.7) | 26,067 (25.3) | 9207 (26.3) | 13,352 (26.1) |
| Some College | 62,114 (32.9) | 34,400 (33.4) | 11,254 (32.2) | 16,460 (32.2) |
| Bachelor’s Degree | 34,808 (18.4) | 18,461 (17.9) | 6505 (18.6) | 9842 (19.2) |
| Graduate School | 19,521 (10.3) | 10,209 (9.9) | 3667 (10.5) | 5645 (11.0) |
| Pre-pregnancy BMI | ||||
| Underweight: <18.5 kg/m2 | 6017 (3.2) | 3338 (3.2) | 979 (2.8) | 1700 (3.3) |
| Normal weight: 18.5–24.9 kg/m2 | 68,677 (36.3) | 38,203 (37.1) | 12,519 (35.8) | 17,955 (35.1) |
| Overweight: 25.0–29.9 kg/m2 | 47,853 (25.3) | 25,744 (25.0) | 8993 (25.7) | 13,116 (25.6) |
| Obese: ≥ 30.0 kg/m2 | 64,836 (34.3) | 34,431 (33.5) | 12,068 (34.5) | 18,337 (35.8) |
| Unknown | 1714 (0.9) | 1222 (1.2) | 430 (1.2) | 62 (0.1) |
| Smoking during pregnancy | 13,446 (7.1) | 8273 (8.0) | 2321 (6.6) | 2852 (5.6) |
| Substance use | ||||
| No | 174,042 (92.0) | 94,744 (92.0) | 32,197 (92.0) | 47,101 (92.1) |
| Yes | 12,288 (6.5) | 6834 (6.6) | 2240 (6.4) | 3214 (6.3) |
| Unknown | 2767 (1.5) | 1360 (1.3) | 552 (1.6) | 855 (1.7) |
| Primary Payer | ||||
| Private | 75,024 (39.7) | 39,861 (38.7) | 14,115 (40.3) | 21,048 (41.1) |
| Medicaid | 82,300 (43.5) | 45,558 (44.3) | 14,754 (42.2) | 21,988 (43.0) |
| Other Public | 25,321 (13.4) | 14,127 (13.7) | 4857 (13.9) | 6337 (12.4) |
| Uninsured | 3635 (1.9) | 1996 (1.9) | 710 (2.0) | 929 (1.8) |
| Unknown | 2817 (1.5) | 1396 (1.4) | 553 (1.6) | 868 (1.7) |
| Nulliparous | 74,311 (39.3) | 40,312 (39.2) | 13,738 (39.3) | 20,261 (39.6) |
| Prenatal care initiated in the 1st trimester | 143,384 (75.8) | 77,832 (75.6) | 26,963 (77.1) | 38,589 (75.4) |
| Previous Preterm birth | 9697 (5.1) | 5232 (5.1) | 1736 (5.0) | 2729 (5.3) |
| Pre-pregnancy Diabetes Mellitus | 2332 (1.2) | 1171 (1.1) | 455 (1.3) | 706 (1.4) |
| Pre-pregnancy Hypertension | 7278 (3.9) | 3677 (3.6) | 1420 (4.1) | 2181 (4.3) |
| Infant’s sex, females | 92,528 (48.9) | 50,332 (48.9) | 17,099 (48.9) | 25,097 (49.1) |
| Rural residence † | 39,749 (21.0) | 21,805 (21.2) | 7281 (20.8) | 10,663 (20.8) |
| Level of Hospital’s Prenatal Service ‡ | ||||
| Level 1 | 25,344 (13.4) | 13,121 (12.8) | 4940 (14.1) | 7283 (14.2) |
| Level 2 | 72,165 (38.2) | 38,332 (37.2) | 13,647 (39.0) | 20,186 (39.5) |
| Level 3 | 71,041 (37.6) | 39,439 (38.3) | 12,802 (36.6) | 18,800 (36.7) |
| Unknown | 20,547 (10.9) | 12,046 (11.7) | 3600 (10.3) | 4901 (9.6) |
COVID, coronavirus disease 2019; BMI, Body Mass Index
Pregnancy timing relative to the COVID-19 pandemic was classified into 3 groups: (1) pre-pandemic (delivered before the onset of the pandemic on March 1, 2020), (2) partial overlap group (conceived before the pandemic’s onset and delivered after), and (3) pandemic (conceived after the pandemic’s onset).
“Non-Hispanic Other” includes Asian, American Indian and other races.
Rural-urban commuting area codes were used to classify maternal residence.
Level of inpatient perinatal care services as specified in the SC Code of Regulations (S.C. Code Regs. § 61–16.1306): Level 1 (base care), Level 2 (specialty care), Level 3 (subspecialty care).
Statistical analyses
We examined perinatal outcome prevalence differences by pregnancy timing relative to pandemic and SARS-CoV-2 testing groups using Chi-square tests of independence. Modified Poisson regression with robust variance was used to examine the associations between COVID-19 infection, pregnancy timing relative to pandemic, and outcomes [24]. To examine the associations between pandemic pregnancy timing, COVID-19 infection, and perinatal outcomes, we analyzed the entire sample (n = 189,097) using two models. Model 1 estimated the association with pregnancy timing relative to the pandemic, adjusting for all covariates. Model 2 additionally adjusted for COVID-19 testing. Models 3 and 4 assessed associations between COVID-19 severity, timing of infection, and perinatal outcomes among women who delivered during the pandemic period (n = 86,159). We accounted for correlations from multiple pregnancies per woman (n = 24,172 women) by nesting observations within maternal ID and clustering them by maternal residential counties. Adjusted relative risks (aRR) and 95 % confidence intervals (95 % CI) were estimated from the models. Analyses were conducted using SAS® 9.4 (SAS Institute Inc., Cary, NC, USA).
We performed a complete case analysis. Because the proportions of missing data were small (ranging from 0.002 % for race to 0.95 % for prenatal care initiation), the application of missing data methods was unnecessary. To ensure the robustness of our findings, we conducted an additional analysis on the overall sample to examine the associations between pandemic pregnancy timing, COVID-19 severity, and timing of infection with perinatal outcomes. This study protocol received clearance for exempt status from the institutional review board.
Results
Characteristics of study population
The sample included 189,097 singleton births to pregnant women in SC (Fig. 1). Among these infants, 57.5 % were born to non-Hispanic White women, 30.6 % to non-Hispanic Black, 4.8 % to Hispanic, and 7.1 % to women of other non-Hispanic races. Approximately 59.6 % of the women were overweight or obese before pregnancy. Nulliparous women comprised 39.3 % of the total sample, and 85.2 % were younger than 35 years old. Public insurance covered 56.9 % of the sample (43.5 % had Medicaid), and 21.0 % of the women resided in rural counties (Table 1).
Characteristics of pregnant women across the three pandemic groups were similar, with a few exceptions. Pregnant women in the partial overlap and pandemic groups had higher proportions of maternal risk factors, such as pre-pregnancy obesity, pre-pregnancy diabetes mellitus, and pre-pregnancy hypertension. Smoking during pregnancy showed a gradual decline from the pre-pandemic group (8.0 %) to the partial overlap (6.6 %) group and the pandemic group (5.6 %) (Table 1).
COVID-19 testing and SARS-CoV-2 infection
Among pregnant women in the partial overlap and pandemic groups, 62.9 % (54,218/86,159) were never tested for COVID-19, while 30.1 % tested negative. Only 6.9 % of women in our sample tested positive for COVID-19 (Supplemental Table 2). Among COVID-19-positive cases, 55.9 % were asymptomatic, 30.5 % had mild symptoms, and 13.6 % had moderate-to-severe symptoms. Half of the SARS-CoV-2 infections were first diagnosed during the third trimester, and the other half during the first or second trimester (Table 2). There were no major differences in the distribution of most characteristics across the COVID-19 testing groups. Pregnant women residing in rural areas, those with pre-pregnancy obesity, and those with pre-pregnancy hypertension had higher proportions testing positive than negative for COVID-19. Smoking during pregnancy was more prevalent among the untested group (6.3 %) and lower among those who tested positive (4.2 %) (Supplemental Table 2).
Table 2.
Prevalence of Perinatal Outcomes by Pregnancy Timing Relative to COVID-19 Pandemic, COVID Infection, Severity and Timing During Pregnancy among Singleton Births in South Carolina, January 2018 – December 2021.
| Exposure | Total | Low birthweight | Small-for-gestational age | Large-for-gestational age | Preterm birth | NICU admission | Breastfeeding initiation at birth* |
|---|---|---|---|---|---|---|---|
| n (%) | |||||||
| Overall sample (n = 189,097) | |||||||
| All | 189,097 | 14,898 (7.9) | 19,181 (10.1) | 17,229 (9.1) | 17,973 (9.5) | 14,520 (7.7) | 147,091 (78.0) |
| Pandemic Pregnancy Timing † | |||||||
| Chi-square test P-values | <.0001 | 0.083 | 0.0441 | <.0001 | <.0001 | 0.0013 | |
| Pre-pandemic | 102,938 | 8074 (7.8) | 10,587 (10.3) | 9238 (9.0) | 9684 (9.4) | 7687 (7.5) | 80,136 (78.1) |
| Partial pandemic overlap | 34,989 | 2491 (7.1) | 3497 (10.0) | 3201 (9.2) | 2988 (8.5) | 2594 (7.4) | 27,397 (78.5) |
| Pandemic | 51,170 | 4333 (8.5) | 5097 (10.0) | 4790 (9.4) | 5301 (10.4) | 4239 (8.3) | 39,558 (77.4) |
| COVID—19 testing | |||||||
| Chi-square test P-values | <.0001 | 0.0042 | 0.3782 | <.0001 | <.0001 | 0.3082 | |
| Not tested‡ | 157,156 | 12,074 (7.7) | 15,902 (10.1) | 14,262 (9.1) | 14,668 (9.3) | 11,637 (7.4) | 122,219 (78.0) |
| Tested, COVID − | 25,954 | 2323 (9.0) | 2732 (10.5) | 2397 (9.2) | 2676 (10.3) | 2366 (9.1) | 20,253 (78.2) |
| Tested, COVID + | 5987 | 501 (8.4) | 547 (9.1) | 570 (9.5) | 629 (10.5) | 517 (8.6) | 4619 (77.3) |
| Restricted to pandemic period, March 2020 – December 2021, (n = 86,159) | |||||||
| COVID—19 severity | |||||||
| Chi-square test P-values | 0.559 | 0.1325 | 0.5775 | 0.0002 | 0.0334 | 0.0386 | |
| No COVID§ | 80,172 | 6323 (7.9) | 8047 (10.0) | 7421 (9.3) | 7660 (9.6) | 6316 (7.9) | 62,336 (77.9) |
| COVID +, Asymptomatic | 3344 | 277 (8.3) | 303 (9.1) | 321 (9.6) | 326 (9.8) | 276 (8.3) | 2549 (76.4) |
| COVID +, Mild | 1829 | 152 (8.3) | 174 (9.5) | 164 (9.0) | 189 (10.3) | 156 (8.5) | 1451 (79.4) |
| COVID +, Moderate-to-severe | 814 | 72 (8.9) | 70 (8.6) | 85 (10.4) | 114 (14.0) | 85 (10.4) | 619 (76.0) |
| COVID timing | |||||||
| Chi-square test P-values | <.0001 | 0.0064 | 0.0501 | 0.0003 | 0.005 | 0.0117 | |
| No COVID§ | 80,172 | 6323 (7.9) | 8047 (10.0) | 7421 (9.3) | 7660 (9.6) | 6316 (7.9) | 66,337 (77.9) |
| 1st/2nd trimester | 2987 | 207 (6.9) | 248 (8.3) | 312 (10.4) | 278 (9.3) | 233 (7.8) | 2360 (78.8) |
| 3rd trimester | 3000 | 294 (9.8) | 299 (10.0) | 258 (8.6) | 351 (11.8) | 284 (9.5) | 2259 (75.8) |
COVID, coronavirus disease 2019; NICU, neonatal intensive care unit.
We examined the differences in the prevalence of perinatal outcomes by pregnancy timing relative to the pandemic, SARS-CoV-2 infection testing groups, COVID-19 severity and timing using Chi-square test of independence.
n = 188,664 for breast feeding initiation at birth outcome
Pregnancy timing relative to the COVID-19 pandemic was classified into 3 groups: (1) pre-pandemic (delivered before the onset of the pandemic on March 1, 2020), (2) partial overlap group (conceived before the pandemic’s onset and delivered after), and (3) pandemic (conceived after the pandemic’s onset).
“No COVID-19 testing” included women in pre-pandemic group and those not tested during the pandemic period
“No COVID-19” included those not tested or tested negative during the pandemic period
Associations between pandemic pregnancy timing and perinatal outcomes
In the partial overlap group, compared to the pre-pandemic group, the prevalence of LBW (7.1 % vs. 7.8 %) and PTB (8.5 % vs. 9.4 %) was lower, while no differences were observed in the prevalence of other perinatal outcomes. In the pandemic group compared to the pre-pandemic group, the prevalence of most outcomes increased, including LBW (8.5 % vs. 7.8 %), LGA (9.4 % vs. 9.0 %), PTB (10.4 % vs. 9.4 %), and NICU admission (8.3 % vs. 7.5 %). In contrast, the prevalence of SGA (10.0 % vs 10.3 %) and breastfeeding initiation (77.4 % vs 78.1 %) were lower in the pandemic compared to the pre-pandemic group (Table 2).
The risk of delivering an LBW infant and PTB was correspondingly 7 % (adjusted RR [aRR] 0.93, 95 % CI 0.89–0.97) and 9 % (aRR 0.91, 95 % CI 0.88–0.95) lower when comparing the partial overlap group to the pre-pandemic group. However, when comparing the pandemic group to the pre-pandemic group, pregnant women had a 10 % higher risk of LBW (aRR 1.10, 95 % CI 1.06–1.14), and PTB (aRR 1.10, 95 % CI 1.07–1.14), and a 13 % higher risk of having neonates admitted to the NICU (aRR 1.13, 95 % CI 1.09–1.17). Among the pandemic group, pregnant women were less likely to initiate breastfeeding compared to the pre-pandemic group (aRR 0.98, 95 % CI 0.97–0.98) (Model 1, Table 3). Pregnancy timing relative to the pandemic appeared to affect the prevalence of LBW, PTB, NICU admissions, and breastfeeding initiation independently of SARS-CoV-2 infection, its severity, or timing during pregnancy (Model 2, Table 3; Models 3A and 4A, Supplemental Table 3).
Table 3.
Adjusted Relative Risks (aRR) and 95 % Confidence Intervals (CI) for Associations Between Pregnancy Timing relative to the COVID-19 Pandemic and COVID-19 Infection During Pregnancy and Infant Outcomes among Singleton Births in South Carolina, January 2018 – December 2021 (n = 189,097).
| Exposure | Low birthweight | Small-for-gestational age | Large-for-gestational age | Preterm birth | NICU admission | Breastfeeding initiation at birth* |
|---|---|---|---|---|---|---|
| aRR (95 % CI)† | ||||||
| Model 1: Pregnancy timing relative to pandemic | ||||||
| Partial pandemic overlap vs Pre-pandemic‡ | 0.93 (0.89–0.97) b | 0.99 (0.96–1.03) | 0.99 (0.96–1.03) | 0.91 (0.88–0.95) c | 1.02 (0.97–1.06) | 1.00 (0.99–1.00) |
| Pandemic vs Pre-pandemic | 1.10 (1.06–1.14) c | 1.00 (0.96–1.03) | 1.00 (0.96–1.03) | 1.10 (1.07–1.14) c | 1.13 (1.09–1.17) c | 0.98 (0.97–0.98) c |
| Model 2: Pregnancy timing relative to pandemic and COVID—19 testing | ||||||
| Pregnancy timing relative to pandemic | ||||||
| Partial pandemic overlap vs Pre-pandemic | 0.91 (0.87–0.95) c | 0.98 (0.95–1.02) | 0.99 (0.96, 1.03) | 0.91 (0.87–0.95) c | 0.98 (0.94–1.02) | 1.00 (0.99–1.00) |
| Pandemic vs Pre-pandemic | 1.04 (0.99–1.08) | 0.97 (0.94–1.01) | 1.00 (0.96, 1.04) | 1.08 (1.04, 1.12) c | 1.02 (0.97–1.06) | 0.97 (0.97–0.98) c |
| COVID—19 testing | ||||||
| Tested, COVID− vs Not tested§ | 1.13 (1.08–1.19) c | 1.06 (1.01–1.11) a | 1.00 (0.95–1.04) | 1.03 (0.99–1.08) | 1.23 (1.17–1.29) c | 1.01 (1.00–1.02) |
| Tested, COVID+ vs Not tested | 1.09 (1.00–1.19) | 0.98 (0.90–1.06) | 0.97 (0.89–1.05) | 1.04 (0.96–1.13) | 1.15 (1.06–1.26) b | 1.00 (0.98–1.01) |
aRR, adjusted Relative Risk; CI, Confidence Interval; COVID, coronavirus disease 2019; NICU, neonatal intensive care unit Bold indicates statistical significance marked as a p < 0.05; b p < 0.01; c p < 0.001.
n = 188,664 for breast feeding initiation at birth
Model 1 focused only on estimating the association with the pregnancy timing relative to the COVID-19 pandemic, adjusting for all covariates. Model 2 additionally adjusted for COVID-19 testing. Both models were adjusted for race, age group at birth, education, pre-pregnancy BMI, smoking during pregnancy, substance use, primary payer, parity, urban/rural residence, prenatal care initiation, pre-pregnancy diabetes, pre-pregnancy hypertension, previous preterm birth, and the hospital’s level of prenatal services.
Pregnancy timing relative to the COVID-19 pandemic was classified into 3 groups: (1) pre-pandemic (delivered before the onset of the pandemic on March 1, 2020), (2) partial overlap group (conceived before the pandemic’s onset and delivered after), and (3) pandemic (conceived after the pandemic’s onset).
“No COVID-19 testing” included women in pre-pandemic group and those not tested during the pandemic period
Associations between COVID-19 infection and perinatal outcomes
COVID-19-positive mothers had a higher prevalence of PTB and delivery of infants requiring NICU admission, compared to untested mothers (10.5 % vs. 9.3 % for PTB and 8.6 % vs. 7.4 % for NICU admissions). Infants born to mothers who tested negative for COVID-19, compared to those born to untested mothers, also had higher rates of LBW, PTB, SGA, and NICU admissions (Table 2). After adjusting for covariates, COVID-19 infection during pregnancy was associated with an increased risk of NICU admissions (aRR 1.15, 95 % CI 1.06–1.26). Infants born to mothers who tested negative for COVID-19 had a 23 % increased risk of NICU admissions (aRR 1.23, 95 % CI 1.17–1.29) compared to those born to untested mothers (Model 2, Table 3).
Pregnant women with moderate-to-severe COVID-19 had a 34 % higher risk of PTB (aRR 1.34, 95 % CI 1.13–1.58) compared to those with no COVID-19. Maternal COVID-19 confirmed during the third trimester was associated with an increased risk of delivering an LBW infant (aRR 1.23, 95 % CI 1.10–1.37), PTB (aRR 1.18, 95 % CI 1.07–1.30), and NICU admission (aRR 1.17, 95 % CI 1.05–1.31) (Models 3 and 4, Table 4).
Table 4.
Adjusted Relative Risks (aRR) and 95 % Confidence Intervals (CI) for Associations Between COVID-19 Severity, COVID-19 Timing During Pregnancy and Perinatal Outcomes among Singleton Births in South Carolina during COVID-19 Pandemic, March 2020 – December 2021 (n = 86,159).
| Exposure | Low birthweight | Small-for-gestational age | Large-for-gestational age | Preterm birth | NICU admission | Breastfeeding initiation at birth* |
|---|---|---|---|---|---|---|
| aRR (95 % CI) † | ||||||
| Model 3: COVID—19 severity | ||||||
| COVID +, Asymptomatic vs No COVID‡ | 1.07 (0.95–1.20) | 0.94 (0.84–1.04) | 1.01 (0.91–1.12) | 1.01 (0.91–1.12) | 1.04 (0.93–1.17) | 0.98 (0.96–1.00) |
| COVID +, Mild vs No COVID | 1.10 (0.95–1.28) | 1.01 (0.88–1.16) | 0.90 (0.78–1.05) | 1.08 (0.94–1.23) | 1.07 (0.93–1.24) | 1.00 (0.98–1.03) |
| COVID +, Moderate-to-severe vs No COVID | 1.09 (0.88–1.35) | 0.90 (0.72–1.12) | 1.03 (0.85–1.26) | 1.34 (1.13–1.58) c | 1.21 (0.99–1.47) | 0.98 (0.94–1.02) |
| Model 4: COVID—19 timing | ||||||
| 1st/2nd trimester vs No COVID‡ | 0.92 (0.81–1.05) | 0.89 (0.79–1.01) | 1.04 (0.94–1.16) | 0.97 (0.87–1.09) | 0.98 (0.87–1.11) | 0.99 (0.97–1.01) |
| 3rd trimester vs No COVID | 1.23 (1.10–1.37) c | 1.01 (0.91–1.12) | 0.91 (0.81–1.02) | 1.18 (1.07–1.30) c | 1.17 (1.05–1.30) b | 0.98 (0.96–1.00) |
aRR, adjusted Relative Risk; CI, Confidence Interval; COVID, coronavirus disease 2019; NICU, neonatal intensive care unit Bold indicates statistical significance marked as a p < 0.05; b p < 0.01; c p < 0.001.
n = 86,004 for breast feeding initiation at birth
Models 3 and 4 separately estimated the associations of COVID-19 severity and COVID-19 timing adjusted for covariates (race, age group at birth, education, pre-pregnancy BMI, smoking during pregnancy, substance use, primary payer, parity, urban/rural residence, prenatal care initiation, pre-pregnancy diabetes, pre-pregnancy hypertension, previous preterm birth, and the hospital’s level of prenatal services). NICU admission models were adjusted for the same set of covariates except substance use (due to small outcomes counts for the levels of substance use).
For both COVID-19 severity and COVID-19 timing variables, “No COVID-19” included those not tested or tested negative during the pandemic
Comment
Using SC birthing cohort data, we found that the influence of pregnancy timing relative to the pandemic on PTB and LBW varied over time. Compared to the pre-pandemic group, the partial overlap group, representing the early pandemic months, was associated with decreased risks of LBW and PTB. However, LBW and PTB prevalence increased in the pandemic group compared to the pre-pandemic group. The pandemic group also experienced increased NICU admissions and reduced breastfeeding initiation. SARS-CoV-2 infection during pregnancy increased NICU admission risk but did not affect other outcomes. Pregnant women with moderate-to-severe COVID-19 symptoms were more likely to have PTB than those without COVID-19. Maternal COVID-19 in the third trimester increased the risks of LBW, PTB, and NICU admissions.
Our finding aligns with the literature showing a PTB decrease during the early pandemic months [6,7]. Reduced air pollution [25], fewer infections due to limited social interactions and lockdown [5], improved work-life balance [5,26], and decreased smoking [5] may contribute to the PTB decrease. However, as the pandemic continued, PTB prevalence increased, possibly due to increasing stress (e.g., job losses), relaxed mitigation measures, and healthcare system disruptions (e.g., limited prenatal care access) [27,28]. Our finding of reduced breastfeeding initiation in the late pandemic might be the result of shorter hospital stays and reduced in-hospital lactation support during the pandemic [29].
Systematic reviews and studies from different countries consistently report the association between maternal SARS-CoV-2 infection and increased NICU admissions [8–11], PTB [8–11,30,31], and LBW risk [9]. Yet, we found that COVID-19 was associated only with NICU admission. The increase in NICU admission during the pandemic may result from hospital policies mandating quarantine for infants of COVID-19-positive mothers, regardless of the neonates’ health. Our data support this, showing higher NICU admissions for neonates born to women infected during the third trimester compared to the first and second trimesters. Differences in study populations, clinical settings, SARS-CoV-2 detection, and virus variants may explain discrepancies in results.
Limited literature shows that severe COVID-19 during pregnancy increases the risk of PTB, LBW, and NICU admission [11,12]. However, we found COVID-19 severity was associated only with PTB. Observed differences may result from different comparison groups or COVID-19 severity definitions. Our results align with findings that COVID-19 in the third trimester was associated with increased risk of PTB, LBW, and NICU admission [32]. Interestingly, COVID-19-negative pregnant women had increased risks of LBW and NICU admission, possibly due to false-negative test results from missing a specific time window after symptom onset [33].
We observed an increase in LBW, PTB, and NICU admission, with decreased breastfeeding initiation in the pandemic group. The influence of pregnancy timing relative to the pandemic on pregnancy outcomes indicates women’s vulnerability during the pandemic. During future pandemics, interventions to improve access to care and social support for this vulnerable population are needed. We observed varying associations between pregnancy timing relative to the pandemic and perinatal outcomes during the early and late pandemic periods. Understanding the underlying mechanisms that contributed to the decreased PTB and LBW rates in the early pandemic period is important for potential prevention efforts. COVID-19 severity and timing during pregnancy are important for planning prenatal care and interventions for COVID-19-positive pregnant women, especially in moderate-to-severe cases or during the third trimester. Future research can examine the association of pregnancy timing relative to the pandemic with elective, spontaneous, and medically indicated PTB, as well as the effects of COVID-19 vaccination or SARS-CoV-2 variants on perinatal outcomes.
Strengths and limitations
Strengths of this study include a large sample size with a long study period covering both pre-pandemic and 22-month pandemic periods, a statewide population-based cohort, and separating SARS-CoV-2 infection’s direct effect from the effect of pregnancy timing relative to the pandemic on perinatal outcomes. Detailed COVID-19 registry data allowed for examining the associations of COVID-19 severity and its timing with the outcomes. Additionally, we used a novel approach to classify pregnancy timing relative to the pandemic into three groups, enabling a more rigorous assessment of how individual pregnancy timing may affect perinatal outcomes.
Using data from one state with a low Hispanic and Asian representation may limit the generalizability of the results. Potential overestimation of COVID-19-positive cases, which includes both lab-confirmed and probable cases, could bias our results toward the null. Reliance on self-reported symptoms for COVID-19 severity is another limitation. Also, combining pre-pandemic and untested women during the pandemic might reduce the observed differences between the reference group and the COVID-19-positive group, potentially underestimating the true association of COVID-19 infection with perinatal outcomes. However, this approach allows us to separately assess the associations of pregnancy timing relative to the pandemic and COVID-19 infection. The high proportion of untested women reflects early pandemic symptom-based testing practices, leading to potential under-reporting of asymptomatic cases.
Misclassification of COVID-19 cases due to unreported home testing is a potential limitation, though home tests were not widely used until the end of 2021.
Some statistically significant differences may not be clinically meaningful; reported confidence intervals clarify the data distributions [34]. However, even small changes in relative risk can have significant public health implications. For example, even small, non-significant changes in breastfeeding initiation can set back the U.S. by several years, as seen in the CDC Breastfeeding Report Card data [35].
Conclusions
The timing of pregnancy relative to the pandemic independently influenced adverse perinatal outcomes, irrespective of COVID-19 infection, including its severity or timing during pregnancy. Moderate-to-severe SARS-CoV-2 and third-trimester infections were associated with an increased risk of adverse perinatal outcomes. Our findings highlight the importance of considering both maternal COVID-19 infection and pandemic-related factors in optimizing perinatal outcomes.
Supplementary Material
Funding sources
This study was supported by the National Institute of Allergy and Infectious Diseases and Office of the Director of the National Institutes of Health under Award Number 3R01AI127203-5S2. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Abbreviations:
- COVID-19
coronavirus disease 2019
- SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
- US
United States
- PTB
preterm birth
- LBW
low birth weight
- NICU
neonatal intensive care unit
- SC
South Carolina
- SGA
small-for-gestational-age
- LGA
large-for-gestational-age
- CRF
Case Report Form
- DHEC
Department of Health and Environmental Control
- BMI
Body Mass Index
- ARR
adjusted relative risk
- CI
confidence interval
- UB
Uniform Billing
Appendix A. Supporting information
Supplementary data associated with this article can be found in the online version at doi:10.1016/j.annepidem.2025.01.006.
Footnotes
CRediT authorship contribution statement
Liu Jihong: Writing – review & editing, Visualization, Supervision, Software, Resources, Project administration, Methodology, Investigation, Funding acquisition, Data curation, Conceptualization. Shih Yi-Wen: Writing – review & editing, Visualization, Software, Methodology, Investigation, Data curation, Conceptualization. Sevoyan Maria: Writing – review & editing, Writing – original draft, Visualization, Validation, Software, Methodology, Formal analysis, Data curation, Conceptualization. Li Xiaoming: Writing – review & editing, Supervision, Resources, Project administration, Investigation, Funding acquisition, Conceptualization. Hung Peiyin: Writing – review & editing, Validation, Software, Methodology, Data curation, Conceptualization. Zhang Jiajia: Writing – review & editing, Validation, Software, Methodology, Data curation, Conceptualization.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
References
- [1].Sohrabi C, Alsafi Z, O’Neill N, et al. World Health Organization declares global emergency: a review of the 2019 novel coronavirus (COVID-19). Int J Surg 2020;76:71–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [2].Nicola M, Alsafi Z, Sohrabi C, et al. The socio-economic implications of the coronavirus pandemic (COVID-19): a review. Int J Surg 2020;78:185–93. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [3].Silva C, Oliveira LV, Lopes LP, Santos W, Agra IKR. Immunological aspects of coronavirus disease during pregnancy: an integrative review. Rev da Assoc Med Bras 2020;66(5):696–700. [DOI] [PubMed] [Google Scholar]
- [4].Centers for Disease Control and Prevention (US). CDC COVID Data Tracker: data on COVID-19 during pregnancy: severity of maternal illness. 2022; 〈https://stacks.cdc.gov/view/cdc/119588〉. Accessed July 22, 2022. [Google Scholar]
- [5].Berghella V, Boelig R, Roman A, Burd J, Anderson K. Decreased incidence of preterm birth during coronavirus disease 2019 pandemic. Am J Obstet Gynecol MFM 2020;2(4):100258. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [6].Calvert C, Brockway MM, Zoega H, et al. Changes in preterm birth and stillbirth during COVID-19 lockdowns in 26 countries. Nat Hum Behav 2023;7(4):529–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [7].Chmielewska B, Barratt I, Townsend R, et al. Effects of the COVID-19 pandemic on maternal and perinatal outcomes: a systematic review and meta-analysis. Lancet Glob Health 2021;9(6):e759–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [8].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;370:m3320. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [9].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(1). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [10].Simbar M, Nazarpour S, Sheidaei A. Evaluation of pregnancy outcomes in mothers with COVID-19 infection: a systematic review and meta-analysis. J Obstet Gynaecol: J Inst Obstet Gynaecol 2023;43(1):2162867. [DOI] [PubMed] [Google Scholar]
- [11].Wei SQ, Bilodeau-Bertrand M, Liu S, Auger N. The impact of COVID-19 on pregnancy outcomes: a systematic review and meta-analysis. Medical Association journal = journal de l′Association medicale canadienne, 193. Canadian: CMAJ; 2021. p. E540–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [12].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;137(4):571–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [13].Vergara-Merino L, Meza N, Couve-Perez C, et al. Maternal and perinatal outcomes related to COVID-19 and pregnancy: an overview of systematic reviews. Acta Obstet Et Gynecol Scand 2021;100(7):1200–18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [14].Liu J, Hung P, Liang C, et al. Multilevel determinants of racial/ethnic disparities in severe maternal morbidity and mortality in the context of the COVID-19 pandemic in the USA: protocol for a concurrent triangulation, mixed-methods study. BMJ Open 2022;12(6):e062294. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [15].Kuklina EV, Whiteman MK, Hillis SD, et al. An enhanced method for identifying obstetric deliveries: implications for estimating maternal morbidity. Matern Child Health J 2008;12(4):469–77. [DOI] [PubMed] [Google Scholar]
- [16].Hung P, Liu J, Norregaard C, et al. Analysis of residential segregation and racial and ethnic disparities in severe maternal morbidity before and during the COVID-19 pandemic. JAMA Netw Open 2022;5(10):e2237711. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [17].DeSisto CL, Wallace B, Simeone RM, et al. Risk for stillbirth among women with and without COVID-19 at delivery hospitalization - United States, March 2020-September 2021. Mmwr-Morb Mortal W 2021;70(47):1640–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [18].Liu J, Hung P, Zhang J, et al. Severe maternal morbidity by race and ethnicity before vs. during the COVID-19 pandemic. Ann Epidemiol 2023;88:51–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [19].2019 South Carolina Department of Health and Environmental Control. South Carolina list of reportable conditions. https://scdhec.gov/health-professionals/south-carolina-list-reportable-conditions. Accessed June 15, 2023.
- [20].Council of State and Territorial Epidemiologists. Update to the Standardized Surveillance Case Definition and National Notification for 2019 Novel Coronavirus Disease (COVID-19). 2021; 〈https://cdn.ymaws.com/www.cste.org/resource/resmgr/21-ID-01_COVID-19_updated_Au.pdf〉. Accessed June 13, 2023.
- [21].Yang X, Zhang J, Chen S, et al. Demographic disparities in clinical outcomes of COVID-19: data from a statewide cohort in South Carolina. Open Forum Infect Dis 2021;8(9):ofab428. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [22].Kanyangarara M, Daguise V, Gual-Gonzalez L, et al. COVID-19 testing practices, preventive behaviors, and factors associated with test positivity: population-based statewide survey study. JMIR Public Health Surveill 2023;9:e34579. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [23].Talge NM, Mudd LM, Sikorskii A, Basso O. United States birth weight reference corrected for implausible gestational age estimates. Pediatrics 2014;133(5):844–53. [DOI] [PubMed] [Google Scholar]
- [24].Zou G A modified poisson regression approach to prospective studies with binary data. Am J Epidemiol 2004;159(7):702–6. [DOI] [PubMed] [Google Scholar]
- [25].Bauwens M, Compernolle S, Stavrakou T, et al. Impact of coronavirus outbreak on NO(2) pollution assessed using TROPOMI and OMI observations. Geophys Res Lett 2020;47(11):e2020GL087978. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [26].Hedermann G, Hedley PL, Baekvad-Hansen M, et al. Danish premature birth rates during the COVID-19 lockdown. Arch Dis Child Fetal Neonatal Ed 2021;106(1):93–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [27].Yang J, D’Souza R, Kharrat A, Fell DB, Snelgrove JW, Shah PS. COVID-19 pandemic and population-level pregnancy and neonatal outcomes in general population: a living systematic review and meta-analysis (Update#2: November 20, 2021). Acta Obstet Et Gynecol Scand 2022;101(3):273–92. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [28].Julceus EF, Olatosi B, Hung P, Zhang J, Li X, Liu J. Racial disparities in adequacy of prenatal care during the COVID-19 pandemic in South Carolina, 2018–2021. BMC Pregnancy Childbirth 2023;23(1):686. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [29].Turner S, McGann B, Brockway M. A review of the disruption of breastfeeding supports in response to the COVID-19 pandemic in five Western countries and applications for clinical practice. Int Breastfeed J 2022;17(1):38. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [30].Karasek D, Baer RJ, McLemore MR, et al. The association of COVID-19 infection in pregnancy with preterm birth: a retrospective cohort study in California. Lancet Reg Health Am 2021;2:100027. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [31].McClymont E, Albert AY, Alton GD, et al. Association of SARS-CoV-2 infection during pregnancy with maternal and perinatal outcomes. Jama 2022;327(20):1983–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [32].Neelam V, Reeves EL, Woodworth KR, et al. Pregnancy and infant outcomes by trimester of SARS-CoV-2 infection in pregnancy-SET-NET, 22 jurisdictions, January 25, 2020-December 31, 2020. Birth Defects Res 2023;115(2):145–59. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [33].Arevalo-Rodriguez I, Buitrago-Garcia D, Simancas-Racines D, et al. False-negative results of initial RT-PCR assays for COVID-19: a systematic review. PloS One 2020;15(12):e0242958. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [34].Kallogjeri D, Spitznagel EL Jr, Piccirillo JF. Importance of defining and interpreting a clinically meaningful difference in clinical research. JAMA Otolaryngol– Head Neck Surg 2020;146(2):101–2. [DOI] [PubMed] [Google Scholar]
- [35].Centers for Disease Control and Prevention (US). A Closer Look at the 2022 CDC Breastfeeding Report Card. United States: 2022. [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.