The Society for Obstetric Anesthesia and Perinatology Coronavirus Disease 2019 Registry: An Analysis of Outcomes Among Pregnant Women Delivering During the Initial Severe Acute Respiratory Syndrome Coronavirus-2 Outbreak in the United States : Anesthesia & Analgesia

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Original Research Articles: Original Clinical Research Report

The Society for Obstetric Anesthesia and Perinatology Coronavirus Disease 2019 Registry: An Analysis of Outcomes Among Pregnant Women Delivering During the Initial Severe Acute Respiratory Syndrome Coronavirus-2 Outbreak in the United States

Katz, Daniel MD*; Bateman, Brian T. MD, MSc; Kjaer, Klaus MD; Turner, Dana P. PhD§; Spence, Nicole Z. MD; Habib, Ashraf S. MBBCh; George, Ronald B. MD#; Toledano, Roulhac D. MD, PhD**; Grant, Gilbert MD**; Madden, Hannah E. BS§; Butwick, Alex J. MBBS, MS††; Lynde, Grant MD‡‡; Minehart, Rebecca D. MD, MSHPEd§; Beilin, Yaakov MD§§; Houle, Timothy T. PhD§; Sharpe, Emily E. MD‖‖; Kodali, Bhavani MD¶¶; Bharadwaj, Shobana MBBS¶¶; Farber, Michaela K. MD, MS; Palanisamy, Arvind MD##; Prabhu, Malavika MD***; Gonzales, Nikolai Y. MD†††; Landau, Ruth MD‡‡‡; Leffert, Lisa MD§

Author Information
doi: 10.1213/ANE.0000000000005592

Abstract

KEY POINTS

  • Question: Is severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection associated with adverse peripartum outcomes?
  • Findings: Maternal and neonatal outcomes were less favorable in symptomatic pregnant women delivering with SARS-CoV-2 infection compared to controls but not in asymptomatic women, and women with SARS-CoV-2 in this cohort had lower utilization of neuraxial labor analgesia.
  • Meaning: The presence or absence of maternal SARS-CoV-2 symptoms at the time of delivery might help stratify risk and management, and provision of labor analgesia and potential barriers during a pandemic warrant further investigation.

As of January 17, 2021, there were >93 million confirmed cases of coronavirus disease 2019 (COVID-19) and >2 million deaths globally.1 In the obstetric population, initial reports from China seemed encouraging, documenting less morbidity with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy than with SARS or Middle East respiratory syndrome (MERS) infections.2 However, as the virus spread, it was difficult to formulate a consistent picture of the clinically relevant maternal and neonatal peripartum risks of SARS-CoV-2 infection. Initial reports cautioned that severe thrombocytopenia might be associated with COVID-19 infection3–5 and that “excessive” hypotension might be induced by neuraxial anesthesia during cesarean delivery.6 Despite the growing body of literature on pregnancy and SARS-CoV-2 infection,7–9 there has been little data comparing asymptomatic and symptomatic patients, and infected versus noninfected patients, with respect to obstetrical outcomes and anesthetic management.

Thrombotic complications and coagulopathy emerged along with the evidence that SARS-CoV-2 induced a hypercoagulable state.10,11 Pathological changes, such as intervillous thrombi, found in the placentas of patients infected with SARS-CoV-2, have been similar to those found in patients with hypertensive disorders of pregnancy, intrauterine growth restriction, and preterm delivery12,13, suggesting that pregnant patients with SARS-CoV-2 might be at risk for adverse pregnancy outcomes.12 Although these associations are clinically plausible, our understanding of this disease has been limited by small cohorts, a lack of contemporary control groups, outcomes that are confounded by a focus on women with symptomatic and/or severe disease, and the aggregation of cases at different stages of pregnancy.14–17 Over time, an increasing number of reports have suggested that a subset of obstetric patients become critically ill,18–20 rendering case identification, risk stratification, and subsequent management crucial.

The Society for Obstetric Anesthesia and Perinatology (SOAP) COVID-19 registry was created with the primary goal of investigating peripartum outcomes and anesthetic management in women with and without SARS-CoV-2 infection during delivery hospitalizations in institutions with widespread testing, thus better representing the full spectrum of disease. Our hypothesis was that women with SARS-CoV-2 infection would have worse outcomes that those without SARS-CoV-2 infection.

METHODS

Sites and Case Ascertainment

The SOAP registry was created in March 2020. A registry Executive Committee was formed (6 members) and the SOAP President (L. Leffert) made initial contact with SOAP leaders at 29 affiliated hospitals across the United States via e-mail. The 14 medical centers (including 17 hospitals) that agreed to participate included hospitals from the Northeast, South, Midwest, and Western regions of the United States. Each site obtained individual site institutional review board (IRB) approval and written informed consent waivers and screened their own patients for inclusion. The sites had the option to either host a local research electronic data capture (REDCap) database and then share data with the Massachusetts General Hospital (MGH) central database (after signing the data transfer and use agreement [DTUA]) or enter data directly into the central MGH database maintained in the Partners REDCap server after the DTUA was signed.

Consecutive sampling was used to identify all delivery hospitalizations occurring in participating centers between March 19 and May 31. Women were defined as infected in the peripartum period if they had a positive polymerase chain reaction (PCR) test for SARS-CoV-2 within 14 days of their delivery date. Over the course of the study period, testing evolved from symptoms based in the early study period to universal screening at most participating institutions in the later study period. For each patient added to the registry, it was documented whether the patient was admitted and tested under universal screening.

Initially, a single control patient without SARS-CoV-2 infection was identified using a convenience sampling method defined by investigators at each hospital for each day that an infected patient delivered and linked with all of the infected patients who delivered on that day (ie, all selected deliveries on that day were considered as belonging to a cluster). This method resulted in a paucity of controls (215) that were considered to be limited by an unacceptable risk of selection bias given the lack of a standardized approach for their identification. As such, a new control group was created. Because data extraction involved manual record review, it was not feasible to include all delivering patients during the observation period. Therefore, for each identified patient with SARS-CoV-2 infection, 2 controls without a positive SARS-CoV-2 test were identified for inclusion. To best approximate a random sample, all potential controls who delivered on the same day and center as the case parturient were given case identification (ID) numbers in sequential order according to the timing of their deliveries. Using a random number generator from a uniform distribution (“runif” in R 3.6, The R Foundation for Statistical Computing), 2 control IDs were randomly selected without replacement for each case by a statistician at the coordinating institution for each patient with infection. If insufficient control numbers existed, all available controls for that day were selected. A ratio of 1:2 was targeted to provide improved precision of our proposed exposure-outcome association. Assuming an event rate of 10%, an odds ratio (OR) of 1.5 was expected to have approximately 30% relative precision for a 95% confidence interval (CI) if a 1-to-1.75 sampling ratio was achieved.

Data Elements

Prespecified primary obstetric outcomes included cesarean delivery, hypertensive disorders of pregnancy (gestational hypertension, chronic hypertension with superimposed preeclampsia, preeclampsia with and without severe features, hemolysis, elevated liver enzymes, and low platelets [HELLP] syndrome), preterm delivery, placental abruption, length of stay, estimated blood loss, and a composite adverse neonatal composite outcome measure, defined as experiencing any (ie, one or more) of the following: positive by an APGAR score <7 at 1 or 5 minutes, escalation of care in the delivery room with either usual or prolonged hospital stay or transfer to the neonatal intensive care unit (NICU), or the need for respiratory support in the delivery room (eg, transient mask ventilation, continuous positive airway support [CPAP], or intubation at delivery). Prespecified (secondary) anesthetic outcomes included the following: for laboring patients, receipt of labor analgesia (neuraxial or other), and for cesarean delivery, anesthetic technique (ie, neuraxial anesthesia or general anesthesia). Other secondary outcomes included maternal signs and symptoms of infection (eg, fever or dyspnea), maternal vital signs and laboratory values on admission, and additional medical outcomes (eg, supplemental oxygen or intensive care unit [ICU] status).

Data Analysis

The sampling plan allowed the comparison between locally and temporally similar deliveries but created clustering in the data structure. To account for the clustering within site-specific measurement occasions, the obstetric, neonatal, and anesthetic outcomes were analyzed using generalized estimating equations (GEEs; “geepack” using R 3.6) with appropriate distribution and link functions, with robust standard error estimation. A sampling unit ID was specified for patients and controls according to the site and day of delivery, and an exchangeable covariance matrix was used to accommodate the covariance. Two versions of each model were conducted that considered both unadjusted and exposure-outcome associations adjusted for the prespecified confounders. The specified confounders were age, race, ethnicity, body mass index (BMI), and maternal comorbidities including diabetes, preexisting hypertension, cardiac, pulmonary or autoimmune disease for the obstetric, neonatal composite outcomes, and the anesthetic management. For some outcomes, the low observed event frequency precluded the use of a multivariable model to control for potential confounders.

The primary obstetric and anesthetic outcome analyses were repeated with predefined sensitivity analyses that redefined the exposure group as asymptomatic SARS-CoV-2–infected patients (excluding symptomatic patients) and asymptomatic SARS-CoV-2–infected patients (excluding symptomatic patients). Crude differences between background health characteristics of SARS-CoV-2–infected patients and controls were reported using standardized mean differences (SMDs), and following the recommendations of Austin21 interpreted as meaningful if SMD >0.1

(1.96×1964+1490). Contrasts were estimated along with 95% CIs.

Results of all analyses are presented as contrasts with a reference group and are interpreted based on the magnitude of the point estimates, factoring the precision of each estimate as reflected in the width of its 95% CI. Specifically, the following considerations were used in interpretation: (1) the strength of the adjusted effect size estimate (irrespective of whether the 95% CI includes the null), (2) the degree to which the upper bound of the 95% CI excludes a large, clinically relevant increased risk of the adverse event, and (3) the degree to which the effect estimates were consistent across sensitivity analyses.22 Each analysis was conducted on the available data, with no attempts made to impute missing values. Missing data (%) are noted for all major primary and secondary data elements.

RESULTS

Table 1. - Baseline Characteristics of Obstetric Patients With and Without SARS-CoV-2 Infection in the Peripartum Period
Characteristic SARS-CoV-2 Control SMD % Missing
N = 490 N = 964
Age, mean (SD) 30.4 (6.2) 32.0 (5.6) 0.268 0.2
Parity, n (%)
 0 183 (37.5) 470 (48.8) 0.329 0.1
 1 138 (28.3) 300 (31.1)
 2+ 167 (34.2) 194 (20.1)
Singleton or multiple pregnancy, n (%)
 Singleton 478 (98.4) 933 (97.2) 0.079 0.6
 Multiple pregnancy 8 (1.6) 27 (2.8)
BMI (kg/m3), mean (SD) 31.4 (6.1) 30.2 (5.9) 0.199 5.6
Obese, n (%) 258 (56.6) 410 (44.8) 0.261 5.6
Race, n (%)
 Caucasian 171 (34.9) 432 (44.8) 0.365 0.0
 African American 80 (16.3) 133 (13.8)
 Asian 24 (4.9) 100 (10.4)
 Multiple or other 181 (36.9) 226 (23.4)
 Unknown 34 (6.9) 73 (7.6)
Ethnicity
 Hispanic 191 (39.0) 205 (21.3) 0.394 0.0
 Non-Hispanic 299 (61.0) 759 (78.7)
Comorbidities, n (%)
 Total number of patients with any comorbidities 111 (22.7) 244 (25.3) 0.058 0.1
Diabetes
 Preexisting 10 (2.0) 14 (1.5) 0.267 0.0
 Gestational 33 (6.7) 67 (7.0)
Hypertension—preexisting 26 (5.3) 48 (5.0) 0.026 0.0
Cardiac disease 4 (0.8) 15 (1.6) 0.220 0.0
Pulmonary disease
 Asthma 40 (8.2) 95 (9.9) 0.062 0.0
 Other 2 (0.4) 5 (0.5)
Autoimmune disease 17 (3.4) 47 (4.9) 0.424 0.1
Percentage of missing data are provided for all variable categories with expected values for all patients.
Note: Crude differences between SARS-CoV-2–infected patients and controls were reported using SMDs, and following the recommendations of Austin21 interpreted as meaningful if SMD > 0.1
(
1.96×1964+1490
).
Abbreviations: BMI, body mass index; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; SD, standard deviation; SMD, standardized mean difference.

F1
Figure.:
Distribution of patients included in the registry by geography, symptom status, and critical illness. BMC indicates Boston Medical Center; BWH, Brigham and Women's Hospital; MGH, Massachusetts General Hospital; NYU, New York University; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; UCSF, University of California at San Francisco.

During the study period (March 19 to May 31, 2020), 1454 peripartum women from 14 medical centers (17 hospitals) were included in the registry: 495 had SARS-CoV-2 infection and 964 were controls (Figure). Five identified SARS-CoV-2 were excluded: due to a duplicate entry (n = 1), presumed to be SARS-CoV-2 positive on admission but later found to be SARS-CoV-2 negative (n = 2), and missing neonatal information (n = 2), for a final total of N = 490 COVID-19 patients (176 [35.9%] were symptomatic). The majority of patients (80.0%) were ascertained in the context of universal screening. One hundred percent of the SARS-CoV-2–infected patients had a positive PCR test; 83.7% of controls had a negative PCR test, and the other negative controls were symptom-free and presumed negative. Baseline characteristics, demographic information, and comorbidities are reported in Table 1. Patients with SARS-CoV-2 infection were slightly younger (age 30.4 vs 32.0 years) and more likely to be nonnulliparous and nonwhite, and of Hispanic ethnicity than controls. They were also more likely to have comorbid diabetes, obesity, or cardiac disease and less likely to have autoimmune disease than controls.

Initial Clinical Presentation and Laboratory Tests

Most commonly, patients with SARS-CoV-2 infection were asymptomatic (314/490 [64.1%]) (Supplemental Digital Content, Table, https://links.lww.com/AA/D542). Symptomatic patients with SARS-CoV-2 infection most often presented with cough 110/176 (62.5%) and low-grade fever 84/176 (47.7%). In contrast, temperature >38 °C on admission was extremely rare in both groups of patients (0.3%–0.4%). Admission laboratory values were similar in patients with SARS-CoV-2 infection and in controls, except that lymphopenia was more common in infected patients. Thrombocytopenia, defined as a platelet count <100 × 106/L, was equally rare in infected and control patients (1%–2%). Only 1 woman with asymptomatic SARS-CoV-2 infection had a platelet count <70,000 × 106/L. Her platelet count of 49,000 × 106/L on admission increased to 63,000 × 106/L peripartum. She had immune thrombocytopenia (ITP), protein S deficiency, and delivered vaginally without neuraxial analgesia.

Obstetric and Neonatal Outcomes

Primary obstetric outcomes (adjusted and unadjusted) are displayed in Table 2. After adjustment for potential confounders, SARS-CoV-2 infection was associated with an increased risk for delivery at <37 weeks of gestation compared to controls, 73 (14.8%) vs 98 (10.2%) (adjusted odds ratio [aOR], 1.47 [95% CI, 1.03–2.09]). Risk estimates for cesarean delivery and obstetric outcomes including hypertensive disorders of pregnancy, postpartum hemorrhage, and the neonatal composite outcome measure were not meaningfully different between the groups, although CIs were wide and did not preclude clinically meaningful increases in risk. In a post hoc sensitivity analysis model that adjusted for gestational age, the association between SARS-CoV-2 infection and the composite neonatal outcome was changed little (OR, 1.29; 95% CI, 0.91–1.83).

Table 2. - Analysis of Obstetric Outcomes for Peripartum Patients With and Without SARS-CoV-2 Infection
Obstetrical outcome SARS-CoV-2 (N = 490), n (%) Controls (N = 964), n (%) Unadjusted effect estimate (95% CI); P value Adjusted effect estimate (95% CI); P value % missing
Mode of delivery—cesarean 171 (34.9) 331 (34.4) 1.07 (0.84–1.38); .587 1.02 (0.79–1.32); .866 5.9
Hypertensive disorders of pregnancy 75 (15.3) 123 (12.8) 1.31 (0.84–1.38); .587 1.12 (0.75–1.67); .584 6.1
Gestational age at delivery, wk 38.1 (2.6) 38.4 (2.4) −0.32a (0.90–1.92); .163 −0.28a (−0.56 to 0.00); .051 6.4
 Delivery <37 wk 72 (14.8) 98 (10.2) 1.56 (1.11–2.19); .011 1.47 (1.03–2.09); .035
 Delivery <34 wk 25 (5.1) 43 (4.5) 1.07 (0.63–1.82); .789 0.96 (0.57–1.61); .873
Placental abruption 6 (1.2) 10 (1.0) 1.42 (0.45–4.47); .552 NA 6.2
Postpartum length of stay, d 2.7 (3.5) 1.9 (1.2) 0.80a (0.45–1.16); <.001 0.77a (0.44–1.11); <.001 5.9
Estimated blood loss, mL 466.8 (359.6) 468.7 (473.7) −11.4a (−61.31 to 38.51); .654 −22.10a (−69.46 to 25.27); .361 7.6
 >500 mL for vaginal delivery 35 (11.4) 66 (10.5) 1.10 (0.70–1.73); .694 1.10 (0.70–1.75); .676
 >1 L for cesarean delivery 18 (10.8) 40 (12.2) 0.74 (0.38–1.42); .365 0.66 (0.33–1.30); .228
Neonatal composite outcome 97 (19.6) 164 (16.5) 1.24 (0.90–1.71); .193 1.21 (0.86–1.70); .266 3.7
Percentage of missing data are provided for all variable categories with expected values for all patients.
All effect estimates are odds ratios except where noted by a, which indicates effect estimates in the original units. Neonatal composite outcome includes 1- and 5-min APGAR scores as well as the need for respiratory support or an escalation of care in the delivery room.
Adjusted for confounding variables: age, race, ethnicity, BMI, and maternal morbidities (including diabetes, preexisting hypertension, and cardiac, pulmonary, or autoimmune disease).
Abbreviations: APGAR, appearance, pulse, grimace, activity, and respiration; BMI, body mass index; CI, confidence interval; NA, model was not conducted; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2.

Table 3. - Sensitivity Analysis of Primary Obstetrical Outcomes of Asymptomatic SARS-CoV-2 Patients Versus Controls and Symptomatic SARS-CoV-2 Patients Versus Controls
Obstetrical outcome Asymptomatic SARS-CoV-2+ Symptomatic SARS-CoV-2+ % missing
Unadjusted effect estimate (95% CI); P value Adjusted effect estimate (95% CI); P value Unadjusted effect estimate (95% CI); P value Adjusted effect estimate (95% CI); P value
Mode of delivery—cesarean 0.80 (0.60–1.07); .129 0.79 (0.58–1.07); .128 1.74 (1.24–2.45); .001 1.57 (1.09–2.27); .016 5.9
Hypertensive disorders of pregnancy 1.01 (0.67–1.53); .948 0.91 (0.59–1.40); .656 1.88 (1.11–3.19); .019 1.51 (0.86–2.64); .150 6.1
Gestational age at delivery, wk −0.15a (−0.47 to 0.17); .361 −0.13a (−0.44 to 0.18); .412 −0.65a (−1.13 to −0.18); .007 −0.56a (−1.03 to −0.10); .018 6.4
 Delivery <37 wk 1.20 (0.80–1.81); .382 1.16 (0.76–1.79); .49 2.30 (1.47–3.62); <.001 2.08 (1.29–3.36); .003
 Delivery <34 wk 0.75 (0.38–1.48); .400 0.68 (0.35–1.31); .248 1.70 (0.84–3.45); .138 1.50 (0.74–3.08); .262
Placental abruption 1.73 (0.50–5.94); .386 NA 0.83 (0.10–6.65); .859 NA 6.2
Postpartum length of stay, d 0.17a (−0.11 to 0.45); .232 0.18a (−0.10 to 0.46); .206 1.98a (1.24–2.72); <.001 1.89a (1.18–2.60); <.001 5.9
Estimated blood loss, mL −38.40a (−92.87 to 16.07); .167 −38.51a (−91.61 to 14.59); .155 38.08a (−33.04 to 109.21); .294 8.26a (−57.58 to 74.1); .806 7.6
 >500 mL for vaginal delivery 1.01 (0.59–1.73); .969 1.03 (0.6–1.78); .912 1.31 (0.66–2.62); .438 1.29 (0.64–2.61); .484
 >1 L for cesarean delivery 0.64 (0.27–1.50); .300 0.58 (0.24–1.42); .235 0.86 (0.38–1.96); .718 0.75 (0.32–1.74); .505
Neonatal composite outcome 0.82 (0.55–1.23); .345 0.82 (0.54–1.24); .339 2.17 (1.45–3.26); <.001 2.09 (1.35–3.25); .001 3.7
All effect estimates are odds ratios except where noted by a, which indicates effect estimates in the original units.
Adjusted for confounding variables: age, race, ethnicity, BMI, and maternal morbidities (including diabetes, preexisting hypertension, and cardiac, pulmonary, or autoimmune disease).
Percentage of missing data are provided for all variable categories with expected values for all patients.
Abbreviations: BMI, body mass index; CI, confidence interval; NA, model was not conducted; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2.

Table 3 displays the results of the subgroup (sensitivity) analysis comparing patients with asymptomatic or symptomatic SARS-CoV-2 infection with controls. In contrast to the analysis with SARS-CoV-2–infected patients in aggregate, there was an association between symptomatic SARS-CoV-2 infection and an increased risk for cesarean delivery compared to controls, 81/176 (46.0%) vs 331/964 (34.4%) (aOR, 1.57; 95% CI, 1.09–2.27), and increased postpartum length of stay compared to controls, 3.8 days vs 1.9 days (aOR, 1.89; 95% CI, 1.18–2.60). Symptomatic SARS-CoV-2 patients also had a greater risk of delivery before 37 weeks than controls, 35/176 (19.9%) vs 98/964 (10.2%) (aOR, 2.08; 95% CI, 1.29–3.36).

Anesthetic Management

Anesthetic modalities differed between infected patients and noninfected controls. Although the majority of laboring patients received neuraxial labor analgesia in both groups (297/374 [79.4%] of SARS-CoV-2 patients and 656/738 [88.9%] of controls), patients with SARS-CoV-2 were less likely to receive neuraxial labor analgesia in both the unadjusted and adjusted models (OR, 0.48; 95% CI, 0.34–0.70; aOR, 0.52; 95% CI, 0.35–0.75) (Table 4). No patients were recorded as having had nitrous oxide for labor analgesia during the study period. General anesthesia for cesarean delivery was utilized in 15/171 (8.7%) of patients with SARS-CoV-2 infection and 9/331 (2.6%) of controls (OR, 3.64; 95% CI, 1.45–9.12; aOR, 3.69; 95% CI, 1.40–9.74). Indications for general anesthesia in patients with SARS-CoV-2 infection were primarily related to maternal respiratory failure (12/15 [80.0%]) (Table 4). General anesthesia in patients without SARS-CoV-2 infection occurred more often in the setting of fetal indications (5/9 [55.6%]) or neuraxial failure (2/9 [22.2%]). All patients who received general anesthesia had either tracheal intubation via videolaryngoscopy or already had an endotracheal tube in place at the time of cesarean delivery.

Table 4. - Analysis of Anesthetic Management for Peripartum Patients With and Without SARS-CoV-2 Infection
Anesthetic outcome SARS-CoV-2 (N = 490) Controls (N = 964) Unadjusted effect estimate (95% CI); P value Adjusted effect estimate (95% CI); P value % missing
Primary neuraxial labor analgesia 297 (79.4) 656 (88.9) 0.48 (0.34–0.70); <.001 0.52 (0.35–0.75); .001 6.1
 Epidural, n (%) 117 (31.3) 299 (40.5) NA NA
 CSE/DPE, n (%) 180 (48.1) 357 (48.4) NA NA
 Intravenous opioids, n (%) 2 (0.5) 2 (0.3) NA NA
 Nitrous oxide, n (%) 0 (0.0) 0 (0.0) NA NA
 None, n (%) 75 (20.1) 80 (10.8) NA NA
Primary anesthesia for cesarean delivery
 New neuraxial—spinal or CSE, n (%) 122 (74.4) 237 (68.5) 1.22 (0.83–1.81); .311 1.09 (0.70–1.68); .699 5.8
 General anesthesia, n (%) 15 (8.7) 9 (2.6) 3.64 (1.45–9.12); .006 3.69 (1.40–9.74); .008
  Indications for general anesthesia 12.5
   Maternal indications, n (%) 13 (86.7) 2 (22.2) 16.50 (1.67–162.92); .016 NA
    Maternal respiratory failure, n (%) 12 (80.0) 0 (0.0) NA NA
    Patient already intubated, n (%) 0 (0.0) 1 (11.1) NA NA
    Postpartum hemorrhage, n (%) 1 (6.7) 1 (11.1) NA NA
   Neuraxial failure, n (%) 0 (0.0) 2 (22.2) NA NA
   Fetal indications, n (%) 2 (13.3) 5 (55.6) 0.18 (0–26.90); .504 NA
Abbreviations: CI, confidence interval; CSE, combined spinal epidural; DPE, dural puncture epidural; NA, model was not conducted; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2.
All effect estimates are odds ratios. Adjusted for confounding variables: age, race, ethnicity, BMI, and maternal morbidities (including diabetes, preexisting hypertension, and cardiac, pulmonary, or autoimmune disease).
Percentage of missing data are provided for all variable categories with expected values for all patients.

Table 5. - Sensitivity Analysis of Primary Anesthetic Outcomes of Asymptomatic SARS-CoV-2 Patients Versus Controls and Symptomatic SARS-CoV-2 Patients Versus Controls
Anesthetic technique Asymptomatic SARS-CoV-2+ Symptomatic SARS-CoV-2+ % missing
Unadjusted effect estimate (95% CI); P value Adjusted effect estimate (95% CI); P value Unadjusted effect estimate (95% CI); P value Adjusted effect estimate (95% CI); P value
Primary neuraxial labor analgesia 0.52 (0.34–0.80); .003 0.56 (0.36–0.88); .011 0.43 (0.26–0.71); .001 0.44 (0.26–0.74); .002 6.1
Anesthesia for cesarean delivery
 New neuraxial 1.87 (1.15–3.06); .012 1.69 (0.99–2.88); .055 0.83 (0.49–1.42); .494 0.73 (0.41–1.29); .274 5.8
 General anesthesia 0.48 (0.06–3.95); .499 0.45 (0.06–3.47); .442 8.13 (3.26–20.26); <.001 9.68 (3.48–26.91); <.001
All effect estimates are odds ratios. Adjusted for confounding variables: age, race, ethnicity, BMI, and maternal morbidities (including diabetes, preexisting hypertension, and cardiac, pulmonary, or autoimmune disease).
Percentage of missing data are provided for all variable categories with expected values for all patients.
Abbreviations: BMI, body mass index; CI, confidence interval; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2.

The subgroup (sensitivity) analysis showed that patients with either asymptomatic SARS-CoV-2 infection or symptomatic patients were less likely to receive neuraxial analgesia for labor than were patients without SARS-CoV-2 infection (Table 5). In patients who had a cesarean delivery, symptomatic SARS-CoV-2 infection was associated with a marked increase in the utilization of general anesthesia 15/81 (18.5%) versus controls 9/331 (2.7%) (OR, 8.13; 95% CI, 3.26–20.26; aOR, 9.68; 95% CI, 3.48–26.91).

Medical Outcomes of the SARS-CoV-2 Cohort

Among the 490 SARS-CoV-2–infected cases, 41 (8.4 %) required supplemental oxygen during their delivery hospitalization and 18/490 (3.7%) required intubation. Admission to an ICU (general or obstetric ICU) was required in 28/490 cases, which represents 5.7% of the total SARS-CoV-2–infected cohort and 15.9% (28/176) of the symptomatic SARS-CoV-2–infected patients. Nineteen out of the 28 critically ill patients (67.9%) had acute respiratory distress syndrome (ARDS), 10/28 (35.7%) had (Cr > 0.8 mg/dL), the normal upper limit for pregnancy, and 1/28 (3.6%) had acute cardiac injury (high-sensitivity cardiac troponin = 75 ng/L). None of the patients required extracorporeal membrane oxygenation (ECMO) support. Most patients were discharged directly to home (487/490 [99.4%]), with 3 discharged to a rehabilitation facility. There were no maternal deaths, and 1 intrauterine fetal death occurred at 23 weeks of gestation in a SARS-CoV-2 patient.

DISCUSSION

In this large, multicenter US cohort of women with peripartum SARS-CoV-2 infection during widespread universal testing, we analyzed obstetric outcomes, neonatal outcomes, and anesthetic management among patients with and without infection after controlling for confounders. Studies examining the full spectrum and impact of asymptomatic and symptomatic SARS-CoV-2 infection on pregnancy outcomes have been scarce. Our registry included some of the highest volume hospitals for COVID-19 cases (eg, New York City and Boston) as well as those that were relatively spared during the study time period (eg, in the South and West of the country). Our findings suggest that asymptomatic peripartum SARS-CoV-2 infection might not markedly increase either the rate of adverse pregnancy outcomes or the relative odds for cesarean delivery for most patients. This is in contrast to some prior international studies that reported very high cesarean delivery rates among women with SARS-CoV-2 infection: 76.9% in 1 case series from China23 and 59%24 and 47%25 in cohort studies from the United Kingdom and Spain, respectively. These differences might reflect selection bias toward symptomatic pregnant patients with SARS-CoV-2 infection and those with severe illness, which would be consistent with our results, although we did not specifically compare symptomatic and asymptomatic women.

Smaller case series15 and studies26 reported rates of preterm delivery of up to 20%, including a large multinational meta-analysis of 10,996 cases in which the preterm birth was 21%.27 These findings are comparable to our results (14.8 %), which may have been primarily driven by symptomatic patients. Although our study did not allow us to separate spontaneous versus medically indicated preterm birth, the predominance of symptomatic patients delivering between 34 and 37 weeks may suggest that medically indicated deliveries are driving this finding.

Our study suggests that nonwhite race and minority ethnicity are overrepresented among pregnant SARS-CoV-2–infected cohorts. This result is corroborated by other studies in pregnant and nonpregnant patients with SARS-CoV-2 infection in the United States,27 including a recent Centers for Disease Control (CDC) report of over 460,000 SARS-CoV-2 cases in which 29.7% of pregnant patients versus 22.6% of nonpregnant were Hispanic.20 This finding is likely influenced by other factors such as population density, the inability to socially isolate, and other social determinants of health,28 which were not investigated in our or most others’ studies.

Among our symptomatic patients with SARS-CoV-2 infection, presenting signs and symptoms, primarily respiratory, were also consistent with other reports.24,27 Interestingly, the rate of maternal temperature above 38 °C on admission to the labor and delivery units was not different between SARS-CoV-2–infected patients and controls. A lower rate of fever in pregnant compared to nonpregnant SARS-CoV-2 patients has been demonstrated,29 as well as a lack of difference in temperature between symptomatic and asymptomatic infected pregnant patients.30 This finding may compromise the benefit of temperature screening, which is a common practice before entry to public spaces during the COVID-19 pandemic.

The finding of less neuraxial labor analgesia use in asymptomatic and symptomatic SARS-CoV-2 patients compared to controls was unexpected, given the lack of apparent contraindications and the strong recommendations for proactive use of these techniques by SOAP and other major national professional organizations to avoid unnecessary general anesthesia.31 All participating institutions reported seeking guidance from these recommendations, and none reported explicit policies that discouraged or delayed neuraxial anesthesia. This discrepancy persisted despite controlling for some potential confounders that are known to impact neuraxial anesthetic use such ethnicity.32 The use of general anesthesia for cesarean delivery was conversely increased, although case numbers were small and the cited reason was most often “maternal respiratory failure.” Reasons for not choosing neuraxial labor techniques were not recorded in the registry but might have included delays awaiting laboratory results (eg, platelet counts), the burden of the required additional personal protective equipment, or provider concern about performing procedures on infected patients, particularly during this first wave of the COVID-19 pandemic. It is possible that these outcomes would be different if assessed during the later waves of the pandemic (from June 2020 to present) due to a better understanding of the disease, more international experience with neuraxial anesthesia in the setting of COVID-19, and more liberal use of noninvasive respiratory assist devices. A recent investigation across 6 hospitals found a significant reduction (7.7%–3.7%, P < .001) in general anesthesia rates for cesarean delivery (risk ratio, 0.50; 95% CI, 0.39–0.93) during the pandemic (April to July 2020) compared to 2019 and a decline in conversion from regional to general anesthesia.9 However, this downward trend was preexisting, before the pandemic, and the investigators did not compare the use of these anesthetic techniques in contemporaneous patients with and without SARS-CoV-2 infection, or those with asymptomatic and symptomatic disease.9

Fortunately, neither transmission of SARS-CoV-2 infection to the anesthesiologist nor central nervous system transmission of virus to the patient specifically during obstetric neuraxial procedures has been reported. Although thrombocytopenia has been reported in the cases of SARS-CoV-2,33 severe thrombocytopenia precluding the use of neuraxial anesthesia in obstetric patients is extremely rare.34 When severe thrombocytopenia is present,35 it is often in the context of critical illness with concomitant systemic disease and multiorgan dysfunction. The only patient in our cohort with severe thrombocytopenia had a known alternative etiology: ITP. Although the precise etiology of SARS-CoV-2–related thrombocytopenia is unknown, the current hypothesis is of an immune-mediated mechanism with preserved platelet function.33 Furthermore, other changes in hemostasis related to SARS-CoV-2 infection including enhanced clot formation, hyperfibrinogenemia, and hypofibrinolysis are procoagulant and may be protective against neuraxial bleeding in the absence of disseminated intravascular coagulation (DIC).36 Finally, concern for respiratory challenges associated with neuraxial anesthesia for cesarean delivery in patients with symptomatic SARS-CoV-2 infection could include the loss of accessory respiratory muscle function, the supine position, and a reluctance to use adjunct respiratory aids (eg, high-flow nasal cannula), which appears to be changing. It is worth noting, however, that in our cohort, it appears that most (80%) general anesthetics for cesarean delivery were due to maternal respiratory failure.

In our large cohort, 5.7% of all cases and 15.9% of the symptomatic cases required ICU admission, highlighting the impact of the subgroup of patients studied. Published ICU admission rates for obstetric patients with SARS-CoV-2 infection range from 1.5% when both ambulatory and inpatient patients are included20 to 13.5% in a subset of patients with significant comorbidities.37 The CDC recently reported for symptomatic women, after adjusting for confounders, a higher risk of being admitted to the ICU (10.5 vs 3.9 per 1000 cases; adjusted risk ratio [aRR], 3.0; 95% CI, 2.6–3.4), receiving invasive ventilation (2.9 vs 1.1 per 1000 cases; aRR, 2.9; 95% CI, 2.2–3.8) and maternal death (1.5 vs 1.2 per 1000 cases; aRR, 1.7; 95% CI, 1.2–2.4), although reason for ICU admission was not identified.20 Similarly, a multicenter case-control study with propensity score matching concluded that admission to the hospital and ICU was increased for pregnant versus for nonpregnant women, although the investigators acknowledged that the threshold for admission of pregnant patients with SARS-CoV-2 to the hospital and the ICU may be lower.38

Strengths of this study include the focus on a large cohort of hospitalized peripartum patients from geographically diverse US locations with varied SARS-CoV-2 status and a contemporaneous control cohort that were selected by a random process to maximize representation. Our study does have important limitations. Inter- and intrainstitution ascertainments of SARS-CoV-2 status differed over time evolving from testing for symptoms to universal testing. Whereas all included “positive” patients and >79% of control patients were tested for SARS-CoV-2 infection, not all the control patients were tested. In some centers, this may mean that a control patient could have been an asymptomatic carrier. Asymptomatic carrier status is currently not well understood, and in some women, PCR positive testing appears to persist for several weeks beyond the initial infection.39 Whereas we adjusted outcomes for several identifiable confounders, there is always the potential for unmeasured confounders. In addition, findings with large CIs for some outcomes suggest that our study may have been underpowered to find clinically significant differences that might exist between the groups. Finally, we acknowledge that some patients in our cohort have been included in previous reports20,30,40; however, to our knowledge, these reports lack anesthetic management or a robust a control population against which to compare.

In conclusion, our study demonstrates that, in this multicenter cohort of peripartum patients with and without SARS-CoV-2 infection, differences between obstetric and neonatal outcomes seem to be mostly driven by symptomatic patients. The lower utilization of neuraxial analgesia in laboring patients with asymptomatic or symptomatic infection compared to patients without infection warrants further investigation.

ACKNOWLEDGMENTS

The authors acknowledge the following individuals for their assistance with data extraction, Research Electronic Data Capture (REDCap) management, and data entry: Rachel Achu, MD (Department of Anesthesiology, Boston Medical Center); Sara E. Carlson, MD (Department of Obstetrics and Gynecology, Mayo Clinic); Alejandro Contreras, MD (Department of Anesthesiology, NYU Langone); Germaine Cuff, PhD (Department of Anesthesiology, NYU Langone); Thomas Folino, DO (Department of Anesthesiology, NYU Langone); Lola Franco, BS (Department of Anesthesiology, NYU Langone); Karen Frey, BS (Department of Anesthesiology, Washington University School of Medicine); Chloe Getrajdman, BS (Department of Anesthesia, Mount Sinai); Matthew Hartnett, BS (Department of Anesthesia, Mount Sinai); Alexandra Hohmann, BA (Department of Anesthesiology, Weill Cornell Medicine); Nisha Kumar, MD (Department of Anesthesiology, Boston Medical Center); Steven Margolis, MD (Department of Anesthesiology, NYU Langone); Taron Matevosyan, MD (Department of Anesthesiology, NYU Langone); Ariel Mueller, MA (Department of Anesthesia, Massachusetts General Hospital); Christopher Mukasa, BS (Columbia University); Samantha Parsons, BS (Columbia University); Kendra Petrick, RN (Department of Anesthesiology, University of Maryland); Allyson Preston, MD (Department of Obstetrics and Gynecology, Massachusetts General Hospital-North Shore); Corinne Rabbin-Birnbaum, BS (Department of Anesthesiology, Weill Cornell Medicine); Ben S. Shatil, DO (Department of Anesthesiology, Emory University); Maria Sheikh, MD (Department of Anesthesiology, Stanford University); Matthew Sison, BS (Department of Anesthesia, Mount Sinai); LaToya Stubbs, BS (Department of Anesthesiology, University of Maryland); Dale Tager, BS (Department of Anesthesiology, Emory University); and Allen Wang, MD (Department of Anesthesiology, Boston Medical Center).

DISCLOSURES

Name: Daniel Katz, MD.

Contribution: This author helped contribute to the data, write the manuscript, and edit the critical content.

Conflicts of Interest: None.

Name: Brian T. Bateman, MD, MSc.

Contribution: This author helped contribute to the data, design the study, assist in drafting the manuscript, and edit the critical content.

Conflicts of Interest: None.

Name: Klaus Kjaer, MD.

Contribution: This author helped contribute to the data, assist in study design, and edit the critical content.

Conflicts of Interest: None.

Name: Dana P. Turner, PhD.

Contribution: This author helped design the study, perform data analysis, create the tables, and edit the critical content.

Conflicts of Interest: D. P. Turner reports grants from the National Institute of Neurological Disorders and Stroke (NINDS) and is a consultant to Headache: The Journal of Head and Face Pain.

Name: Nicole Z. Spence, MD.

Contribution: This author helped contribute to the data and edit the critical content.

Conflicts of Interest: None.

Name: Ashraf S. Habib, MBBCh.

Contribution: This author helped contribute to the data and edit the critical content.

Conflicts of Interest: None.

Name: Ronald B. George, MD.

Contribution: This author helped contribute to the data, assist in study design, and edit the critical content.

Conflicts of Interest: None.

Name: Roulhac D. Toledano, MD, PhD.

Contribution: This author helped contribute to the data and edit the critical content.

Conflicts of Interest: None.

Name: Gilbert Grant, MD.

Contribution: This author helped contribute to the data and edit the critical content.

Conflicts of Interest: None.

Name: Hannah E. Madden, BS.

Contribution: This author helped manage the data, create the figure, and edit the manuscript.

Conflicts of Interest: None.

Name: Alex J. Butwick, MBBS, MS.

Contribution: This author helped contribute to the data, assist in study design, and edit the critical content.

Conflicts of Interest: None.

Name: Grant Lynde, MD.

Contribution: This author helped contribute to the data, assist in study design, and edit the critical content.

Conflicts of Interest: None.

Name: Rebecca D. Minehart, MD, MSHPEd.

Contribution: This author helped contribute to the data and edit the critical content.

Conflicts of Interest: None.

Name: Yaakov Beilin, MD.

Contribution: This author helped contribute to the data, assist in study design and draft the manuscript, and edit the critical content.

Conflicts of Interest: None.

Name: Timothy T. Houle, PhD.

Contribution: This author helped design the study, perform data analysis, and edit the critical content.

Conflicts of Interest: None.

Name: Emily E. Sharpe, MD.

Contribution: This author helped contribute to the data and edit the critical content.

Conflicts of Interest: None.

Name: Bhavani Kodali, MD.

Contribution: This author helped contribute to the data and edit the critical content.

Conflicts of Interest: None.

Name: Shobana Bharadwaj, MBBS.

Contribution: This author helped contribute to the data and edit the critical content.

Conflicts of Interest: None.

Name: Michaela K. Farber, MD, MS.

Contribution: This author helped contribute to the data and edit the critical content.

Conflicts of Interest: None.

Name: Arvind Palanisamy, MD.

Contribution: This author helped contribute to the data and edit the critical content.

Conflicts of Interest: None.

Name: Malavika Prabhu, MD.

Contribution: This author helped contribute to the data and edit the critical content.

Conflicts of Interest: None.

Name: Nikolai Y. Gonzales, MD.

Contribution: This author helped contribute to the data and edit the critical content.

Conflicts of Interest: None.

Name: Ruth Landau, MD.

Contribution: This author helped contribute to the data, design the study, assist in draft the manuscript, and edit the critical content.

Conflicts of Interest: None.

Name: Lisa Leffert, MD.

Contribution: This author founded the registry and helped contribute to the data, design the study, write the manuscript, and edit the critical content.

Conflicts of Interest: None.

This manuscript was handled by: Jill M. Mhyre, MD.

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