Despite 2.5 million infections and 169,000 deaths worldwide (as of April 20, 2020), no maternal deaths and only a few pregnant women afflicted with severe respiratory morbidity have been reported to be related to COVID-19 disease. Given the disproportionate burden of severe and fatal respiratory disease previously documented among pregnant women following other coronavirus-related outbreaks (SARS-CoV in 2003 and MERS-CoV in 2012) and influenza pandemics over the last century, the absence of reported maternal morbidity and mortality with COVID-19 disease is unexpected.
To describe maternal and perinatal outcomes and death in a case series of pregnant women with COVID-19 disease.
We describe here a multiinstitution adjudicated case series from Iran that includes 9 pregnant women diagnosed with severe COVID-19 disease in their second or third trimester. All 9 pregnant women received a diagnosis of SARS-CoV-2 infection by reverse transcription polymerase chain reaction nucleic acid testing. Outcomes of these women were compared with their familial/household members with contact to the affected patient on or after their symptom onset. All data were reported at death or after a minimum of 14 days from date of admission with COVID-19 disease.
Among 9 pregnant women with severe COVID-19 disease, at the time of reporting, 7 of 9 died, 1 of 9 remains critically ill and ventilator dependent, and 1 of 9 recovered after prolonged hospitalization. We obtained self-verified familial/household cohort data in all 9 cases, and in each and every instance, maternal outcomes were more severe compared with outcomes of other high- and low-risk familial/household members (n=33 members for comparison).
We report herein maternal deaths owing to COVID-19 disease. Until rigorously collected surveillance data emerge, it is prudent to be aware of the potential for maternal death among pregnant women diagnosed as having COVID-19 disease in their second or third trimester.
Over the last several decades, it has been shown that emerging novel strains of influenza and coronaviruses that cause severe respiratory disease typically disproportionately affect pregnant women, in part owing to adaptive immunology and cardiopulmonary physiology of pregnancy. During 3 of the major influenza pandemics of the last 100 years (1918, 1957–1958, and 2009), pregnant women in their second or third trimester were considerably more likely to be hospitalized or die compared with the general population. , For example, in the 1918 H1N1 pandemic, the case fatality proportion among pregnant women was 27%. In the most recent influenza pandemic (2009 H1N1), pregnant women in the United States accounted for 6.4% of all hospitalizations and 4.3%–5.7% of all deaths even though they generally represent only 1% of the population. , In the severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) outbreak, the general population mortality rate was 10.5%, whereas that of pregnant women approximated 25%, with 33% requiring mechanical ventilation. The risks of morbidity with severe lower respiratory tract infections are not limited to maternal outcomes because there is a known increased occurrence of preterm birth, fetal demise, and delivery of low birthweight infants with nearly all maternal severe lower respiratory tract viral infections. ,
Why was this study conducted?
Given the disproportionate burden of severe and mortal respiratory disease previously documented among pregnant women following other related coronavirus outbreaks (severe acute respiratory syndrome coronavirus in 2003 and Middle East respiratory syndrome coronavirus) and influenza pandemics over the last century, the absence of reported maternal morbidity and mortality with coronavirus disease 2019 (COVID-19) is unexpected. The purpose of this study was to describe maternal and perinatal outcomes and death in a case series of pregnant women with severe COVID-19 disease in an adjudicated case series.
Among 9 pregnant women with severe COVID-19 disease, at the time of reporting 7 of 9 died, 1 of 9 remains critically ill and ventilator dependent, and 1 of 9 recovered after prolonged hospitalization.
What does this add to what is known?
Our case series is in contrast to prior reports suggesting no known mortality among pregnant women infected by severe acute respiratory syndrome coronavirus 2. Whether the COVID-19 disease maternal case fatality rate or maternal morbidity estimates will ultimately be the same, less, or greater than that of other populations is as yet unknown but will require extensive population-based surveillance data to accurately determine. However, the fatal cases reported herein demonstrate it is not zero, and should inspire caution against complacency and guide restraint in rushing estimates of relative or attributable risk with pregnancy.
However, based on initial reports largely from China, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) does not appear to follow these historical patterns of worsened disease risk in pregnancy. We identified 16 reports of SARS-CoV-2 infection or coronavirus disease 2019 (COVID-19) in pregnancy or in neonates (as of April 8, 2020). Unexpectedly, although these case reports or retrospective case series include some information on a total of 154 pregnant women and 118 live-born neonates (1 set of twins, 1 second trimester termination, 1 fetal death, 34 undelivered), we identified only a few gravidae reported as having experienced morbidity requiring respiratory support and critical care. For example, in a detailed case series of 9 gravida from Wuhan, China, all delivering at 36 to 40 weeks’ gestation with symptomatic COVID-19 viral pneumonia, Chen and colleagues reported that none required mechanical ventilation or respiratory support. Of note, however, the upper confidence interval limit for zero mortality in a series of 9 women would be 33%. The sole reported severe cardiopulmonary maternal morbidity reported from China was experienced by a gravida admitted at 34 weeks’ gestation with severe COVID-19 pneumonia. Subsequent to this patient’s cesarean delivery for a stillborn fetus while in septic shock, her cardiopulmonary status acutely deteriorated with multiple organ system dysfunction requiring extracorporeal membrane oxygenation (ECMO). At the time her care was reported, she remained on ECMO heart-lung bypass. In a recently published 2-week surveillance cohort from paired clinical affiliate institutions in New York City, Breslin and colleagues reported that among 43 confirmed cases of SARS-CoV-2 infection during pregnancy, the estimated rate of severe maternal disease approximated that of the nonpregnant population at 9.3%. Interestingly, 2 gravidae who progressed to critical disease (4.3%) were among the 14 of 43 (32.6%) women who were initially asymptomatic, and both required intensive care unit (ICU) admission in the postpartum period.
SARS-CoV-1 (the viral pathogen of the 2003 SARS epidemic) and SARS-CoV-2 are both enveloped virions containing 1 positive-strand RNA genome belonging to the Betacoronavirus genus of the Coronaviridae family. SARS-CoV-2 uses the same angiotensin-converting enzyme 2 (ACE2) as its putative cell entry host receptor as SARS-CoV-1 and bears 80%–85% nucleotide homology to SARS-CoV-1. , Although both SARS-CoV-1 and SARS-CoV-2 bind to ACE2 through the viral surface spike glycoprotein (S protein, 76% protein identity), there are some suggested distinctions regarding the role of specific serine and cysteine proteases in cleavage of the S protein in priming for enhanced cell entry. Specifically, while the S protein of both SARS-CoV-1 and SARS-CoV-2 is cleaved by the same transmembrane protease serine 2 (TMPRSS2) to facilitate efficiency of entry and viral replication, there is emerging evidence that SARS-CoV-2 co-opts and recruits additional host proteases for transmissibility. , Nonetheless, given the overall phylogenetic and functional similarities between the viruses, the suggestion of zero pregnant fatalities is unexpected and further inconsistent with data documenting severe disease and death among similarly aged adults who are not pregnant and of low risk.
Although accurate case fatality rates and attributable and relative risk of maternal mortality following SARS-CoV-2 infection will be reported in the future, 1 of the critical immediate questions faced by providers caring for pregnant women in the midst of the current pandemic is straightforward: are pregnant women at risk of death with COVID-19? We detail herein 7 maternal deaths in a case series of 9 women with severe COVID-19 and compare these deaths to self-verified outcomes among their familial/household members.
The intent of this retrospective case series was to document maternal death and describe maternal, fetal, neonatal, and familial self-reported characteristics among 9 patients known to have experienced severe maternal cardiopulmonary morbidity or mortality after admission to any 1 of 7 level III maternity hospitals in Iran over a 30-day period of time (mid-February to mid-March, 2020; precise dates of admission gated to protect patient identity).
This case series and its detailed reporting were approved by the Ethics Committee of Tehran University of Medical Sciences (IRB IR.TUMS.VCR.1398.1082; IRB PI S.H.) and Baylor College of Medicine (IRB H-47407); a data use agreement (DUA) between Baylor College of Medicine and Tehran University of Medical Sciences was executed for the purpose of this reporting. Subject consent was waived by both review boards, and all familial data was voluntarily self-reported and no familial medical records were reviewed. Additional protection for participants beyond no disclosure of exact dates of admission or death included gating maternal age in 5-year increments and using controlled-access encrypted electronic records for data transfer of primary source data, including digital images of patients’ medical records. Index case subjects were assigned as case 1 to 9 for the purposes of publication and communication of nonidentifying information and reflect neither the order of their care nor presentation of first symptoms. The hospital in which each patient received her care is similarly not reported in an effort to protect subject identity.
Cases were not selected by any form of systematic surveillance but rather arose from a voluntary reporting of maternal cases with known morbidity or mortality attributable to COVID-19. Our definition of severe disease was comparable with that of others (see further definitions below). Severe cardiopulmonary disease was defined as need for ventilator support and/or cardiopulmonary collapse. With IRB approval from the Ethics Committee of Tehran University of Medical Sciences, starting in February 2020, the Iranian Perinatology Society generated a secure reporting structure to share cases, outcomes, and management of pregnant women with severe morbidity or death. For the purposes of this case series, all 9 known cases with severe COVID-19 over a 30-day span of time at any of the 7 hospitals or centers are reported herein. Severe disease was classified by provision of having met inclusion criteria of (1) severe morbidity (dyspnea, blood oxygen saturation [SaO 2 ] ≤93% on room air, or partial pressure of arterial oxygen to fraction of inspired oxygen <300), (2) an available death certificate, and (3) at least 1 positive SARS-CoV-2 nucleic acid testing (NAT) result. Centers were not selected for participation a priori, and all reporting of cases was voluntary. Ultimately, all 9 cases arose from 7 centers that provide high-level maternity care in Iran and are staffed by perinatology (maternal-fetal medicine) consultant specialists and critical care specialists. These 7 centers included Shariati Hospital and Imam Khomeini Hospital at Tehran University of Medical Sciences, Tehran, Iran; Shohada Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Baqiyatallah Hospital, Baqiyatallah University of Medical Sciences, Tehran, Iran; Mousavi Hospital, Zanjan University of Medical Sciences, Zanjan, Iran; Kamkar-Arabnia Hospital, Qom University of Medical Science, Qom, Iran; and Alzahra Hospital, Guilan University of Medical Sciences, Rasht, Iran. Of these 9 known cases of severe COVID-19 from this 30-day time period, 7 resulted in maternal death (as of April 20, 2020).
General case management
All pregnant women in this series had a positive result for SARS-CoV-2 by reverse transcription polymerase chain reaction (RT-PCR) NAT on nasopharyngeal, with or without oropharyngeal and sputum specimens; some subjects were tested multiple times. All collected specimens were tested for SARS-CoV-2 using TIB-Molbiol (Germany) and/or Sansure Biotech 2019-nCov (China) reagents and protocols, complying with the World Health Organization’s (WHO) guidelines for use. According to the COVID-19 national guidelines issued by Iran’s National Ministry of Health and Medical Education on March 8, 2020, a 3-drug regimen for all COVID-19 pneumonia was recommended and allowed extension for up to 14 days. This included oral administration of 75-mg oseltamivir every 12 hours for 5 days; 400-mg hydroxychloroquine sulfate daily, or 1000-mg chloroquine sulfate tablet as a single dose, and 400-100-mg lopinavir/ritonavir every 12 hours for 5 days. Changing to a 4-drug regimen was recommended with the presence of any of the following signs indicative of severe disease: loss of consciousness, tachypnea (respiratory rate >24, hypotension [blood pressure <90/60 mm Hg], multilobar lung infiltration with consolidation by chest imaging [computed tomography [CT] or radiograph], or hypoxemia [SaO2 <90%]). The 4-drug regimen added 1200-mg ribavirin PO twice daily for 5 days. Antibiotic administration (choice, dose, and duration) was deferred at the attending physician’s best clinical judgment, and corticosteroids were not recommended. All but 1 patient in this series was first admitted before March 8. In addition, all subjects received either enoxaparin (40 mg subcutaneous, daily) or heparin (5000 units subcutaneous, twice daily) for thromboprophylaxis.
Case ascertainment and adjudication of outcomes
After IRB and DUA approval, digital and electronic images of all available patient information from the time of admission to discharge, death, or reporting was securely sent to a single investigator (A.A.S.) and encrypted. All records were converted to paper form, subsequently stripped of any identifiers, and assigned a unique study code. A systematic process of independent interpretation/translation to distill essential elements of clinical care and outcomes from Farsi to English was undertaken by 2 bilingual investigators boarded in obstetrics and gynecology (A.A.S., S.E.A.); this included conversion of dates from the Solar Hijri calendar (Iranian chronology) to the Gregorian calendar (Western chronology). The deidentified and translated data were then independently adjudicated by 2 boarded and practicing maternal-fetal medicine clinicians (K.M.A., A.A.S.). A series of clarifying questions generated by any of the 3 case interpreters/adjudicators (K.M.A., A.A.S., S.E.A.) were communicated to the coauthors in Farsi through 3 means: video (Skype/WhatsApp/FaceTime), e-mail, and/or direct verbal communication by phone. Once all coauthors and the primary adjudicators reached consensus of all known and reportable outcomes, the case was considered fully adjudicated.
A total of 9 pregnant women are reported in this case series: 7 died and 2 survived and were alive at the time of reporting (April 20, 2020). A schematic summary of each of the 7 fatal adjudicated cases (cases 1–7) and comparative outcomes relative to their familial/household members (self-reported) are provided in Figures 1 and 2 , respectively; more granular details are presented in Tables 1 and 2 . The 2 adjudicated cases of severe morbidity without death (cases 8 and 9) are documented in Supplemental Figure 1 and Supplemental Tables 1 and 2 . Key clinical aspects relative to the interpretation and findings of each case are as follows:
|Characteristics and outcomes||Case 1||Case 2||Case 3||Case 4||Case 5||Case 6||Case 7|
|Maternal age (y) a||25–29||25–29||40–44||30–34||30–34||35–39||45–49|
|Gravida, para||G2 P1001||G1 P0||G2 P1001||G3 P0020||G2 P1001||G2 P0010||G2 P1001|
|Comorbidities||None||Obesity||Subclinical hypothyroid |
|None||GDMA2 (metformin)||AMA||AMA |
|Blood type (Rh)||A (+)||B (+)||A (+)||B (+)||A (+)||O (+)||A (-)|
|Influenza vaccinated||No b||Yes||No||No||Yes||Unknown||No|
|Admission BMI (kg/m 2 )||23||36||26||unk||23||24||18|
|Laboratory or relevant clinical values c|
|Hemoglobin (g/dL)||9.6 (9.2, 9.6)||9.0 (8.5, 10)||11.6 (10.8, 11.8)||10.8 (10.2, 14.3)||9.9 (8.2, 10)||8.1 (8, 10.2)||12.3 (9.9, 12.5)|
|Platelets (× 10 3 /μL)||51 (48,43.4)||68 (62,280)||224 (220,265)||206 (206,333)||305 (265,328)||177 (122,188)||380 (172,380)|
|WBC (x 10 9 /L)||3.8 (3.2, 7.8)||8 (7.2,8.2)||7 (4.2, 13.3)||13.3 (13, 35.6)||20.3 (13.7, 26)||7 (7, 8.6)||16.4 (8.8, 18)|
|Lymphocyte (% 10 9 /L) d||6.8% (5.5, 7.8)||Unknown||5% (5, 6.8)||7.7% (unk)||8.5% (7.5, 8.8)||9% (8.8, 9)||7% (6.2, 8.4)|
|CRP (mg/L) e||41 (38, 87)||18 (18, 22)||25 (20, 25)||56 (unk)||64 (60, 68)||117.5 (37, 12)||81.9|
|AST (U/L)||52 (47, 58)||60 (52, 76)||160 (152, 220)||28 (unk)||40 (32, 48)||29 (22, 29)||66 (52, 68)|
|ALT (U/L)||68 (62, 78)||40 (32, 65)||143 (123, 148)||26 (unk)||17 (15, 40)||18 (14, 22)||38 (34, 62)|
|Cr (mg/dL)||0.8 (0.8–1.6)||0.5 (0.5–1.1)||0.6 (0.6–1.4)||0.7 (0.6–6.0)||0.8 (0.8–1.3)||0.9 (0.9–1.4)||0.7 (0.6–1.5)|
|O 2 Sat, % (SaO 2 ) f||85||70||50–60||83||70–75||65||60–65|
|Maternal status (as of April 20, 2020)|
|Death, intubated, or inpatient recovery||Death||Death||Death||Death||Death||Death||Death|