key: cord-282862-kve6fa49
authors: Pastick, Katelyn A; Nicol, Melanie R; Smyth, Elizabeth; Zash, Rebecca; Boulware, David R; Rajasingham, Radha; McDonald, Emily G
title: A Systematic Review of Treatment and Outcomes of Pregnant Women with COVID-19 – A Call for Clinical Trials
date: 2020-08-13
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofaa350
sha: 
doc_id: 282862
cord_uid: kve6fa49

BACKGROUND: Data pertaining to COVID-19 in pregnancy are limited; to better inform clinicians, we collated data from COVID-19 cases in pregnancy and summarized clinical trials enrolling this population. METHODS: We performed a systematic literature review of PubMed/MEDLINE to identify cases of COVID-19 in pregnancy or the postpartum period and associated outcomes. We then evaluated the proportion of COVID-19 clinical trials (from Clinicaltrials.gov) excluding pregnant or breastfeeding persons (both through June 29(th), 2020). RESULTS: We identified 11,308 published cases of COVID-19 in pregnancy. Of those reporting disease severity, 21% (416/1999) were severe/critical. Maternal and neonatal survival were reassuring (98% [10437/10597] and 99% [1155/1163], respectively). Neonatal disease was rare with only 41 possible cases of infection reported in the literature. Of 2351 ongoing COVID-19 therapeutic clinical trials, 1282 were enrolling persons of reproductive age and 65% (829/1282) excluded pregnant persons. Pregnancy was an exclusion criterion for 69% (75/109) of chloroquine/hydroxychloroquine, 80% (28/35) of lopinavir/ritonavir, and 48% (44/91) of convalescent plasma studies. We identified 48 actively recruiting or completed drug trials reporting inclusion of this population. CONCLUSIONS: There are limited published reports of COVID-19 in pregnancy despite more than 14 million cases worldwide. To date, clinical outcomes appear reassuring, but data related to important long-term outcomes are missing or not yet reported. The large number of clinical trials excluding pregnant persons, despite interventions with safety data in pregnancy, is concerning. In addition to observational cohort studies, pregnancy specific adaptive clinical trials could be designed to identify safe and effective treatments.

A c c e p t e d M a n u s c r i p t 3

Worldwide, it is estimated that there are nearly two billion women of reproductive age and women comprise upwards of 70% of the total healthcare workforce [1, 2] . Pregnant women and women of reproductive potential are therefore at a high risk of contracting COVID-19. In a recent Centers for Disease Control and Prevention (CDC) report of 7,162 patients with COVID- 19 in the United States, as many as 2% of cases occurred in pregnant women [3] . In prior work examining influenza, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS), pregnant women had increased morbidity and mortality when compared with non-pregnant women [4] [5] [6] . Currently, there is insufficient evidence to determine whether the same is true for pregnant women with COVID-19. It is hypothesized that the natural physiologic state of immune tolerance associated with pregnancy may increase the risk of infection and severe complications [7] .

There is a need to identify safe and effective treatment options for pregnant persons with COVID-19, as there is for all populations, but there are multiple barriers preventing their inclusion in clinical trials. Due to safety concerns for the mother and the potential for teratogenicity, both pregnant and breastfeeding people are frequently excluded from clinical research studies, often in spite of established pharmacological safety data in pregnancy.

However, drug metabolism (and therefore efficacy) in pregnancy differs from the general population, arguing for their inclusion in trials; optimal dosing requires special attention to physiologic changes (e.g. increased glomerular filtration rate or decreased plasma albumin concentrations), which can alter pharmacokinetics and pharmacodynamics of drug concentrations. Fetal organogenesis also needs to be factored in when possible. Finally, as pregnancy is a state of immunologic change to accommodate the fetus, it is unclear how therapeutic immune modulators used in COVID-19 (e.g. tocilizumab and sarilumab) may impact maternal and fetal outcomes.

In this systematic review, we sought to highlight the heterogeneity of treatment and outcome data for pregnant persons with COVID-19 and summarize the literature related to COVID-19 in pregnancy. We provide an overview of the proportion of completed and actively recruiting interventional clinical trials permitting the inclusion of pregnant or breastfeeding individuals to A c c e p t e d M a n u s c r i p t 4 underscore how frequently this population is ineligible for trial participation and to discuss the potential implications.

A systematic literature review was conducted to identify cases of COVID-19 in pregnancy that were reported as of June 29 th , 2020 following the PRISMA checklist. The first author searched PubMed/MEDLINE for all language publications and pre-prints using a combination of the following MeSH keywords: "pregnancy," "postpartum," "COVID-19," and "SARS-CoV-2."

The first and third authors screened abstracts and reviewed the potential publications and references for relevance to identify any missing articles that were not identified using the above listed keywords. Details as they pertained to presenting symptoms, any treatments received, and maternal, fetal/neonatal outcomes were recorded. Studies unrelated to cases of COVID-19 in pregnancy or the peripartum period were excluded.

A second search was conducted to identify COVID-19 clinical trials as of June 29th, 2020 that reported pregnancy/breastfeeding as an exclusion criterion. Clinicaltrials.gov was searched for relevant studies, using the preprogrammed search terms "COVID-19," "SARS-CoV-2," "2019-nCoV," "2019 novel coronavirus," and "severe acute respiratory syndrome coronavirus 2." Inclusion and exclusion criteria were examined to determine whether pregnant and/or breastfeeding patients were excluded from the study. Studies listed as interventional clinical trials were then analyzed. Information related to specific therapeutic intervention and the status of recruitment were summarized. Of the actively ongoing interventional clinical trials investigating the use of a drug (including dietary supplements and biologic agents) that did not report the exclusion of pregnant or breastfeeding women, the first author contacted study personnel for each of these studies by email to discern whether or not pregnant or breastfeeding women were eligible to be enrolled.

A c c e p t e d M a n u s c r i p t 5 Patient consent is not applicable as this article is a systematic review.

In our systematic literature review, we identified 11,308 reported cases of COVID-19 in pregnancy and the postpartum period from a total of 52 case reports, 44 case series, 25

prospective/retrospective cohort studies, three governmental or national reports, and two case control studies (Table 1, Figure 1 ). Of those that reported estimated gestational age at the time of diagnosis (n=2824), 77% (2184/2824) were in the third trimester of pregnancy (>28 weeks), with the majority in the peripartum/postpartum period; 20% (574/2824) were in the second and 2% (66/2824) were in the first trimester.

The most common symptoms reported were cough (24%, 2704/11308) and fever (18%, 2051/11308), followed by fatigue, malaise, or myalgias (13%, 1525/11308), headache (13%, 1448/11308), and shortness of breath or dyspnea (12%, 1391/11308); overall, fewer than 5% were reported as entirely asymptomatic (366/11308 or 3%). Not all studies reported maternal symptoms. The majority of these COVID-19 cases were mild to moderate in severity (79% M a n u s c r i p t 6 there were 8 reported neonatal deaths. Neonatal testing for SARS-CoV-2 varied widely, making it challenging to draw any definitive conclusions about maternal fetal transmission. In many case series and case reports, SARS-CoV-2 was tested but not detected in: amniotic fluid, breast milk, umbilical cord blood, placental tissue, maternal vaginal secretions, nor in neonatal: serum, plasma, whole blood, feces, gastric secretions, or throat swabs. Overall, we only identified 41 neonates with possible SARS-CoV-2 infection based on positive PCR or antibody tests performed on neonatal specimens (e.g. nasopharyngeal/oropharyngeal swabs, blood, stool and/or unspecified sites) (Supplemental Table 1 ) [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] . The following specimens were also found to be SARS-CoV-2 PCR or IgG/IgM positive: 9 placental specimen [10, 13, 19, [26] [27] [28] , 3 umbilical cord blood [18, 19, 27] , 3 breast milk [13, 19, 29] , 3 maternal stool or rectal/anal swabs [18, 29] , and 1 sample of maternal vaginal secretions [13] . Several reports discussed placental pathology associated with maternal SARS-CoV-2 infection, but did not specifically assess the placenta for the microbiologic presence of SARS-CoV-2 [13, 16, 27, 28, [30] [31] [32] .

Reports in the literature on treatment received by peripartum women with COVID-19 varied greatly or were not reported on. Overall, we found reports of 106 women who received hydroxychloroquine, 39 lopinavir/ritonavir, 13 remdesivir, 13 interleukin-1 (IL-1) or IL-6 inhibitors, and 9 intravenous immunoglobulin (IVIG) or gamma globulin either during pregnancy or the postpartum period.

As of June 29 th , 2020, there were 2351 ongoing COVID-19 related clinical trials registered on Clinicaltrials.gov [33] . Approximately 55% (1282/2351) were interventional clinical trials investigating the therapeutic use of a drug, device, procedure, screening/diagnostic tool, or behavioral intervention in reproductive age adults (18- Table 2 ).

Of the 453 interventional studies registered on Clinicaltrials.gov that did not specifically mention the exclusion of pregnant or breastfeeding women, only 50% (227/453) were studies investigating the therapeutic use of a drug. Of these, 77 were not yet recruiting, 4 were withdrawn, and 1 was suspendedthese studies were removed from further analyses. Of the remaining 145 trials, only 7% (10/145) reported specific inclusion of pregnant or breastfeeding patients. The remainder were contacted by email to verify whether or not pregnant and breastfeeding persons could be enrolled.

A further 38 studies whose investigators were contacted by email verified the inclusion of pregnant and breastfeeding patients; 18 were investigating use of convalescent plasma, 16 chloroquine/hydroxychloroquine, 10 various other drugs, 2 IL-6 inhibitors, and 2 remdesivir.

The two remdesivir studies clarified that pregnant patients could be enrolled on a request for compassionate use basis only. One study assessing thromboprophylaxis clarified that only breastfeeding patients could be enrolled, and one hydroxychloroquine post-exposure prophylaxis study reported inclusion of pregnant persons into the control arm only. Overall, 62 trials did not respond to email inquiries, 18 reported the exclusion of pregnant or breastfeeding women, 15 had no email address provided and could not be contacted, and 2 trials were either unsure or reported that they would discuss with an ethics committee (Figure 2) . A total of 48 completed or actively recruiting clinical trials reported the inclusion of pregnant or breastfeeding persons ( Table 2) .

Data regarding the clinical presentation, disease evolution, treatment, and outcomes for COVID-19 in pregnancy and lactation are scarce. Despite nearly 14 million cases of COVID-19 worldwide [38] , we identified only a few thousand reported cases of pregnant or breastfeeding persons with COVID-19. In general, published data mainly consisted of case series and reports, and the information was heterogeneous, with outcome reporting subject to major bias and was sometimes missing entirely. From the limited available literature, we found that when outcomes were reported, maternal and fetal/neonatal survival was overall excellent (98% and 99%) and that fetal/neonatal infection was rare but described.

A c c e p t e d M a n u s c r i p t 8 We found nearly two thirds of completed or ongoing interventional COVID-19 related clinical trials have excluded pregnant or breastfeeding persons. This finding reaffirms prior reports [39] . Despite available safety data in pregnancy for hydroxychloroquine and lopinavir/ritonavir, we were surprised to find 68% and 80% of the respective clinical trials had excluded pregnant or breastfeeding persons. While some clinical trials may have had multiple study arms that might have prohibited the enrollment of this population due to known teratogenicity of other medications, many trials were singularly investigating hydroxychloroquine or lopinavir/ritonavir. Both the American College of Obstetrics and Gynecology and the American College of Rheumatology endorse the use of hydroxychloroquine in pregnancy for treatment and management of systemic lupus erythematosus [34, 35] and lopinavir/ritonavir is one of the few drugs with an actual indication for pregnancy per the U.S.

Food and Drug Administration (FDA) [40] . While recent evidence suggests these drugs may not be effective in treating or preventing COVID-19 [41] [42] [43] [44] , the large percentage of clinical trials that excluded pregnant persons should serve as a wake-up call to us all, including Institutional Review Boards, regulatory authorities, and clinical trial investigators.

is not without risk of harm to the fetus/neonate, the blanket exclusion of pregnant or breastfeeding persons from COVID-19 clinical trials has serious implications [39] . Although we found that severe complications and death were rare (1-2%), uncommon complications are important on a population level during a pandemic because of the sheer volume of cases (a 1% mortality rate still equates to 10000 deaths if one was to examine 1 million cases). Furthermore, while published outcomes were reassuring, outcomes may be worse in developing countries with less access to critical care resources, making a safe and effective drug therapy all the more important.

Only when drugs are intended to be used in pregnancy, does the FDA require pharmaceutical companies to demonstrate safety and efficacy in pregnancy [45] . Between 1960-2013, only 1% of pharmacokinetic clinical trials were conducted with the inclusion of pregnant women [46] .

Through observation alone, it can take an average of 27 years to develop enough data to estimate the teratogenicity risk of a drug [45] , which is a prohibitively long timeline during a pandemic.

Enrolling pregnant persons into clinical trials with their informed consent can help circumvent this delay. In our search, we came across three observational cohort studies specifically capturing A c c e p t e d M a n u s c r i p t 9 information regarding the treatment of pregnant women (NCT04323839, NCT04319016, NCT04315870). While these studies will greatly increase our knowledge of the treatment and outcomes of this population, mores studies are needed, including examining the safety and efficacy of any potential vaccine.

To improve care for pregnant persons with COVID-19, pregnancy-specific adaptive clinical trials, similar to those for human immunodeficiency virus (HIV) [47], should be considered.

These can allow for pregnancy-specific expertise in recruitment, consent, and assessment of pregnancy related outcomes. Such studies could assess pharmacokinetics at varying stages in pregnancy to ensure dose optimization and can accommodate the rapid inclusion of promising new drugs that may emerge. These studies would complement ongoing clinical trials enrolling pregnant persons. A similar approach is currently underway for children (NCT04278404). For future and ongoing trials that include or enroll pregnant persons, there should be a mechanism in place to systematically capture longitudinal pregnancy outcomes. This may include consenting women for long term follow-up should they become pregnant during the course of the trial. The availability of safety and efficacy data for investigational drugs for use in COVID-19 is paramount in order to properly counsel people who become pregnant during infection and/or following an unintentional exposure.

Our review of the literature was timely and is the first study (to our knowledge) to systematically examine and compile the available data related to treatment and outcomes of COVID-19 in pregnancy and related clinical trials. While we conducted a comprehensive search, our study has limitations. The major limitation relates to the data included in the published studies. There are several inherent biases (e.g. recollection and publication bias) present in case series and observational studies. These may be especially prevalent in our review, given the extent of missing data and the lack of uniform reporting on important pregnancy and neonatal outcomes. Asymptomatic or mild cases of COVID-19 may have been underreported and for cases that did not report outcomes, we cannot assume that none of these were without severe While we found reassuring maternal and fetal/neonatal outcomes with COVID-19, more rigorous, harmonized data collection and publication regarding all aspects of the disease, its treatment and outcomes in pregnant and breastfeeding individuals are needed. Consideration should be given to establishing an international registry and pregnancy specific adaptive clinical trials with coordinated data collection for important outcomes. We urge investigators and regulatory health agencies to work together to find a sound ethical approach to include this population of consenting adults in interventional trials. This will ensure that trial results are generalizable, and that we have the necessary knowledge to guide safe, effective treatment in order to counsel the many pregnant and breastfeeding individuals who may go on to develop COVID-19 during this evolving pandemic.

This work was supported in part by the Doris Duke Charitable Foundation through a grant M a n u s c r i p t M a n u s c r i p t 

Women of reproductive age (15-49 years) population (thousands)

World Health Organization. Women in the health workforce

Preliminary Estimates of the Prevalence of Selected Underlying Health Conditions Among Patients with Coronavirus Disease 2019 -United States

Pandemic influenza and pregnant women

Severe Acute Respiratory Syndrome and pregnancy

Potential Maternal and Infant Outcomes from (Wuhan) Coronavirus 2019-nCoV Infecting Pregnant Women: Lessons from SARS, MERS, and Other Human Coronavirus Infections

Why are pregnant women susceptible to COVID-19? An immunological viewpoint

Clinical characteristics of 19 neonates born to mothers with COVID-19

Clinical Findings and Disease Severity in Hospitalized Pregnant Women With Coronavirus Disease 2019 (COVID-19)

Vertical transmission of COVID-19: SARS-CoV-2 RNA on the fetal side of the placenta in pregnancies with COVID-19 positive mothers and neonates at birth

Novel coronavirus-related acute respiratory distress syndrome in a patient with twin pregnancy: A case report

Characteristics and outcomes of pregnant women admitted to hospital with confirmed SARS-CoV-2 infection in UK: national population based cohort study

Probable congenital SARS-CoV-2 infection in a neonate born to a woman with active SARS-CoV-2 infection

A snapshot of the Covid-19 pandemic among pregnant women in France

Re: Novel Coronavirus COVID-19 in late pregnancy: Outcomes of first nine cases in an inner city London hospital

COVID-19 and HELLP: Overlapping Clinical Pictures in Two Gravid Patients

Vaginal delivery in SARS-CoV-2-infected pregnant women in Northern Italy: a retrospective analysis

Pre-labor anorectal swab for SARS-CoV-2 in COVID-19 pregnant patients: is it time to think about it?

Neonatal Late Onset Infection with Severe Acute Respiratory Syndrome Coronavirus 2

Severe COVID-19 during Pregnancy and Possible Vertical Transmission

Antibodies in Infants Born to Mothers With COVID-19 Pneumonia

Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive study

A case report of neonatal COVID-19 infection in China

Association of COVID-19 with pregnancy outcomes in health-care workers and general women

Possible Vertical Transmission of SARS-CoV-2 From an Infected Mother to Her Newborn

Detection of SARS-COV-2 in Placental and Fetal Membrane Samples

SARS-CoV-2 infection of the placenta

Report of Positive Placental Swabs for SARS-CoV-2 in an Asymptomatic Pregnant Woman with COVID-19

Coronavirus disease 2019 among pregnant Chinese women: case series data on the safety of vaginal birth and breastfeeding

Placental Pathology in COVID-19

Placental abruption in a twin pregnancy at 32 weeks' gestation complicated by COVID-19, without vertical transmission to the babies

The use of convalescent plasma therapy and remdesivir in the successful management of a critically ill obstetric patient with novel coronavirus 2019 infection: A case report

Immune Modulating Therapies in Pregnancy and Lactation

American College of Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases

Safety and efficacy of lopinavir/ritonavir during pregnancy: a systematic review

World Health Organization. Coronavirus disease (COVID-19) Situation Report -180

Importance of inclusion of pregnant and breastfeeding women in COVID-19 therapeutic trials

Food and Drug Administration. Kaletra (lopinavir and ritonavir)

A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19

Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19: A Randomized Trial

Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre, randomized

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

Should pregnant women be included in phase IV clinical drug trials?

Obstetric Pharmacokinetic Dosing Studies are Urgently Needed