key: cord-0910201-i6eqt6z8
authors: Hantoushzadeh, Sedigheh; Shamshirsaz, Alireza A.; Aleyasin, Ashraf; Seferovic, Maxim D.; Aski, Soudabeh Kazemi; Arian, Sara E.; Pooransari, Parichehr; Ghotbizadeh, Fahimeh; Aalipour, Soroush; Soleimani, Zahra; Naemi, Mahsa; Molaei, Behnaz; Ahangari, Roghaye; Salehi, Mohammadreza; Oskoei, Atousa Dabiri; Pirozan, Parisa; Darkhaneh, Roya Faraji; Laki, Mahboobeh Gharib; Farani, Ali Karimi; Atrak, Shahla; Miri, Mir Mohammad; Kouchek, Mehran; Shojaei, Seyedpouzhia; Hadavand, Fahimeh; Keikha, Fatemeh; Hosseini, Maryam Sadat; Borna, Sedigheh; Ariana, Shideh; Shariat, Mamak; Fatemi, Alireza; Nouri, Behnaz; Nekooghadam, Seyed Mojtaba; Aagaard, Kjersti
title: Maternal Death Due to COVID-19 Disease
date: 2020-04-28
journal: Am J Obstet Gynecol
DOI: 10.1016/j.ajog.2020.04.030
sha: d7a0235faed420dc98c2b7190e9f37a4f88d9f22
doc_id: 910201
cord_uid: i6eqt6z8

Abstract Background Despite 2.5 million infections and 169,000 deaths worldwide (current as of April 20, 2020), no maternal deaths and only a few pregnant women afflicted with severe respiratory morbidity had been reported to be related to COVID-19 disease. Given the disproportionate burden of severe and mortal respiratory disease previously documented among pregnant women following other related coronavirus outbreaks (SARS-CoV in 2003 and MERS-CoV) and influenza pandemics over the last century, the absence of reported maternal morbidity and mortality with COVID-19 disease is unexpected. Objectives To describe maternal and perinatal outcomes and death in a case series of pregnant women with COVID-19 disease. Study design We describe here a multi-institution adjudicated case series from Iran which includes 9 pregnant women diagnosed with severe COVID-19 disease during their latter 2nd or 3rd trimester. All 9 pregnant women were diagnosed with SARS-CoV-2 infection by rRT-PCR nucleic acid testing (NAT). Outcomes of these women were compared to their familial/household members with exposure 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. Results 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 the maternal outcomes were more severe when compared to other high and low-risk familial/household members (n=33 members for comparison). Conclusion We report herein maternal deaths due to COVID-19 disease. Until rigorously collected surveillance data emerges, it is prudent to be aware of the potential for maternal death among pregnant women diagnosed with COVID-19 disease in their latter trimester(s).

pregnancy .

Over the last several decades, it has been shown that emerging novel strains of influenza and coronaviruses which cause severe respiratory disease [1] [2] [3] [4] typically disproportionately affect pregnant women, in part due to the adaptive 35 immunology and cardiopulmonary physiology of pregnancy. [5] [6] [7] During three of the major influenza pandemics of the 36 last 100 years (1918, 1957-58, and 2009 ), pregnant women in their 2 nd or 3 rd trimester of pregnancy were considerably 37 more likely to be hospitalized or die when compared with the general population. 3, 8 For example, in the 1918 H1N1 38 pandemic, the case fatality proportion among pregnant women was 27%. 3 In the most recent influenza pandemic 39 (2009 H1N1), although pregnant women in the U.S. generally represent only 1% of the population, they accounted for 40 6 .4% of all hospitalizations and 4.3-5.7% of all deaths. 6, 8 In the SARS-CoV-1 outbreak, the general population mortality 41 rate was 10.5%, while that of pregnant women approximated 25% with 33% requiring mechanical ventilation. 1 The 42 risks of morbidity with severe lower respiratory infections are not limited to maternal outcomes, as there is a known 43 increased occurrence of preterm birth, fetal demise, and delivery of low birth-weight infants with nearly all maternal 44 severe lower respiratory viral infections. [1] [2] [3] [4] 8 45 46

However, based on initial reports largely from China, 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 COVID-19 disease in 48 pregnancy or in neonates (current as of April 8, 2020). [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] Unexpectedly, although these case reports or retrospective 49 case series include some information on a total of 154 pregnant women and 118 live born neonates (1 set of twins, 1 50 2 nd trimester termination, 1 fetal death, 34 undelivered), we identified only a few gravidae reported as having suffered 51 morbidity requiring respiratory support and critical care. [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] For example, in a detailed case series of nine gravida from 52 Wuhan, China, all delivering at 36 to 40 weeks gestation with symptomatic COVID-19 viral pneumonia, Chen and 53 colleagues 10 reported that none required mechanical ventilation nor respiratory support. Of note, however, the upper 54 confidence interval limit for zero mortality in a series of nine women would be 33%. The sole reported severe 55 cardiopulmonary maternal morbidity reported from China was suffered by a gravida admitted at 34 weeks gestation 56 with a severe COVID-19 pneumonia. 12 respectively; more granular details are found in Table 1 and Table 2 . The 2 adjudicated cases of severe morbidity 158 without death (cases 8 and 9) are documented in Supplemental Figure S1 , and Supplemental Tables S1 and S2. Key in two others. 9,14 Because our study is a case series and not a surveillance cohort, while our report demonstrating any 296 occurrence of morbidity or death generally aligns with the reported trend of severe maternal outcomes (9.3% of the 297 surveillance cohort) and critical morbidity (4.7%) of Breslin and colleagues, we cannot report on the rate of occurrence 298 in any of our hospitals or centers. 18 When considering our maternal deaths relative to these and others reports, [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] 299 there are two key distinguishing features of our series. First, ours is a case series reporting death of pregnant women affiliate hospitals, 1/3 of which were asymptomatic and diagnosed by universal surveillance testing on routine 303 obstetrical admission. Second, all of our subjects were delivered (or died with their periviable fetuses in utero); other 304 case series totaled 22% undelivered gravida at the time of reporting and retained only sparse maternal outcomes 305 data. [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] Longer term follow-up may be important in revealing instances of severe maternal outcomes, since most of 306 our patients died days to weeks after initial symptoms and often in the post-partum interval.

There are additional characteristics of the patients in our case series which are distinct, but unlikely to be confounding 309 our reported SARS-CoV-2 associated mortality. Five of our gravidae were 35 years of age or older, with two of these 310 five being of elder advanced maternal age (>40 years). However, of the 2 of 9 still alive, both were 35 years or older 311 ( who.int/china/health-topics/maternal-health). Maternity care delivered in Iran during the pandemic has remained a 320 high national and regional priority, and ICU capacity at all of the centers was non-limiting and in no instance was 321 admission, ICU transfer, delivery, intubation, nor medication delayed for lack of availability of resources.

Rather, we think it more probable that delays in reporting or underreporting, alongside non-random selection bias, 324 may be contributing to these first-pass differences. Assessment of epidemiologic characteristics including case-fatality 325 ratios during the course of a pandemic may be affected by right (Type I) censoring and ascertainment bias. 30 As 326 recently demonstrated by Mizumoto et al, 30 breakdowns in an overwhelmed healthcare delivery system with the SARS-

CoV-2 pandemic may result in an underestimated death risk in epidemic epicenters even within a given country (right 328 censoring). We emphasize that large upper limit confidence intervals will always accompany small case series with zero 329 mortality, and this could additionally lead to a false reassurance regarding risk of death in early reporting. [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] 330 331 Strengths and limitations. We acknowledge that our series is limited by lack of surveillance data and is prone to 332 adverse outcome ascertainment bias. Accordingly, we are not attempting to quantify risk or estimate rates in our small 333 series and explicitly discourage others from doing so. Surveillance data will ultimately define the impact of pregnancy 334 among women who died or experienced severe morbidity attributed to COVID-19 disease. Our case series lends critical 335 information to the current narrative based on previously published reports, which presently suggests zero mortality 13 among pregnant women. [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] Determining the proportionate case fatality rate and risk of severe morbidity in pregnancy 337 will require rigorous population-wide surveillance data from many countries, inclusive of data identifying potential maternal mortality is not zero, and suggest caution against complacency and early assumptions of protection with Despite these limitations, there are a number of strengths to our report. First, we took a rigorous approach to 343 collecting primary source data and adjudicating each case and its outcomes. Second, we compared our outcomes to 344 familial/household members as a proxy for comparative risk (Figure 2 and Figure S1, panel B) . Given the R0 estimate 345 of SARS-CoV-2 ranging from 2.1-3.11, [25] [26] [27] [28] [29] [30] it would be anticipated that the same viral strain infected the case and her 346 familial/household cohort and access to quality care and baseline demographic variances would be anticipated to be small. We recognize that ideally we would compare our outcomes to all severely ill non-pregnant subjects over the 

Wholesale Market. In that instance, the patient wore an N95 mask during the delivery, and there was no maternal-albeit inclusive of serologic testing with IgM antibodies with yet unproven SARS-CoV-2 specificity which unexpectedly 370 declined in their levels within the first two weeks of postnatal life. 24 We acknowledge that when considering the potential for vertical transmission, both the placenta and stool/meconium 373 maybe of importance, as a less lethal common Coronaviridae (229E) is known to be transplacentally transmitted but its mRNA is more highly expressed in early gestation human placental syncytiotrophoblasts, and ACE protein localizes to 376 fetal endothelium, the placental expression of host proteases (such as TMPRSS2 and others) necessary for cleavage of 377 the S protein and receptor priming is unknown but has generally only been described in lung and airway cells, or their 378 progenitors. [26] [27] [28] As a result, whether the necessary and sufficient host molecular machinery to enable efficient 379 transplacental vertical transmission is present or absent in the second or third trimester human placenta is presently 380 unknown, and our current case series offers no further insight. With regards to fecal-oral transmission, we were struck 381 by a recent report suggesting that as great as 23.2% of non-pharyngeal detected SARS-CoV-2 may be detected by rRT-

PCR NAT in the stool. 33 In this case series of 73 SARS-CoV-2 infected patients ranging from aged 10 months to 78 years, 

We make no conclusions regarding the relative likelihood (or not) that pregnant women may be at higher risk for 391 infection with SARS-CoV-2. While it is frequently stated that pregnant women are 'immunosuppressed', such 392 assumptions are incorrect. 7 Rather, human pregnancy represents highly adaptive immunity, allowing the mother to Table 1 and Table S1 and 

GDM, gestational diabetes mellitus; HCQ, hydroxychloriquine; IFN, interferon-alpha nebulizers; plasma, under a separate IRB, received immunotherapy through convalescent plasma transfusion from a recovered COVID-19 donor with known seropositivity; unk, unknown values; AMA, advanced maternal age; NAT, nucleic acid testing by rRT-PCR; WBC, white blood cell count; Cr, serum creatinine. For antiviral and antibiotic regiments, please see methods and case narratives. +For protection of patient identification, maternal age was gated in inclusive 5 year blocks. ^Case 1 did not receive seasonal influenza vaccination, but did have negative influenza testing during hospitalization for SARS-CoV-2. *For all laboratory values, the initial value at the time of admission is provided, with the trough and peak from the hospitalization interval (trough, peak). # Lymphopenia was defined as 10%; & Elevated C-reactive protein (CRP) was defined as >10 mg/L. ^^SaO2 values are as reported at the time of diagnosis of ARDS and intubation. As detailed in the case description, case 3 was negative on day of life 1, but converted to positive on day of life 7. In no instance was magnesium sulfate given intrapartum nor antenatal for the purpose of neuroprotection, and not patient in the series had preeclampsia. 

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