Efficacy and safety of casirivimab/imdevimab (REGEN-COV) in pregnant individuals with COVID-19: Literature review and insights from the COVID-19 International Drug Pregnancy Registry

Abstract

Introduction

Casirivimab/imdevimab (CAS/IMD) comprises two monoclonal antibodies that neutralize SARS-CoV-2. Pregnant individuals were excluded from initial trials, limiting safety data.

Methods

The COVID-19 International Drug Pregnancy Registry enrolled 53 pregnant women treated with CAS/IMD, with 34 live births.

Results

No safety concerns were identified.

Discussion and conclusions

The findings of the COVID-PR study support the safety of CAS/IMD during pregnancy, adding to the growing body of evidence on COVID-19 treatments for this population. The available literature shows that CAS/IMD is effective in preventing the progression to severe COVID-19 in pregnant individuals. The drugs are well-tolerated, and there is no compelling evidence of adverse maternal or neonatal outcomes. The results from the COVID-PR study are consistent with those of the broader literature.

Keywords

Pregnancy pharmacovigilance monoclonal antibody therapy maternal fetal health obstetric infectious diseases

Introduction

The novel and highly transmissible SARS-CoV-2 virus was first identified in China late in 2019 and quickly spread around the globe resulting in over 7 million deaths worldwide as of August 2024, with over 1.2 million deaths in the United States alone.¹ Infection by the virus may be asymptomatic or give rise to an acute respiratory disease, known as coronavirus disease 2019 (COVID-19), which ranges in severity from mild to fatal.² Pregnancy appears to be a risk factor for developing more serious disease and is associated with an increased rate of hospitalization, ventilatory support, and death.^3–10 COVID-19 is also associated with a higher risk of maternal obstetric mortality and morbidity, including hypertension, postpartum hemorrhage, and additional infections.^4,8,9

There is evidence of an increase in adverse perinatal outcomes such as stillbirth and preterm birth, particularly in association with the Delta variant of the virus.^3,7,10,11 Infection of the placenta by the SARS-CoV-2 virus can lead to malperfusion or placental insufficiency, changes consistent with preeclampsia, which may contribute to stillbirth or neonatal death.^9,11 Nearly 50% of pregnant individuals who are hospitalized with COVID-19 give birth prematurely, although the resulting offspring are generally healthy.⁹ Despite these risks, vaccine hesitancy among pregnant individuals is high.^8,11 Therefore, safe and effective treatments are of paramount importance in this population.

Some monoclonal antibodies (mAbs) have demonstrated therapeutic efficacy against certain viruses, including Ebola and influenza.⁷ When used in the treatment of SARS-CoV-2 infection, they work by preventing the binding of the spike protein to its receptor on target host cells. Additionally, antibody-dependent phagocytosis by macrophages is facilitated, which can reduce the viral load by up to 70%, thereby preventing progression to serious disease.^7,12

Casirivimab/imdevimab (CAS/IMD) is a copackaged formulation of two neutralizing immunoglobulin γ 1 recombinant human mAbs against SARS-CoV-2, sold under the brand name REGEN-COV.^2,8 Both components bind with high affinity to distinct nonoverlapping epitopes of the SARS-CoV-2 spike protein receptor binding domain.^2,13 In vitro studies show that each antibody almost completely blocks the virus from binding to the human ACE2 receptor.² By using two antibodies, the risk of viral resistance should be lowered.¹³

When used either as a treatment or prophylactically in animals, CAS/IMD limited the airway viral load and viral-induced lung pathology in monkeys and prevented loss of bodyweight in hamsters, suggesting therapeutic potential.² Human studies indicate that it also reduces the viral load, shortens the duration of symptoms, and decreases the incidence of both hospitalization and death in susceptible SARS-CoV-2 variants.⁸ The results of in vitro studies suggest that the neutralization potency of CAS/IMD is likely to be retained against several SARS-CoV-2 variants of concern, although the extent to which this correlates with clinical outcomes is unclear.² However, CAS/IMD does not appear to be effective against the Omicron variant.^14,15

CAS/IMD was initially granted emergency use authorization (EUA) in November 2020 by the U.S. Food and Drug Administration (FDA) for the treatment of mild-to-moderate COVID-19 in patients at high risk of progression to severe disease,^2,8,13,15 with similar authorizations subsequently granted in several other countries.² In May 2021, the FDA recognized pregnancy as a high-risk criterion for COVID-19 and authorized the use of CAS/IMD in nonhospitalized patients.^5,6,16 The drug may also be given prophylactically following exposure to the SARS-CoV-2 virus to pregnant individuals who are not fully vaccinated or who are not expected to produce an adequate immune response to vaccination.^7,8,13,15 Following data showing that CAS/IMD is ineffective against the Omicron variant, and Omicron becoming the dominant variant in the United States, in January 2022 the FDA amended EUA for CAS/IMD to exclude its use in U.S. states, territories, and jurisdictions. This step was taken to prevent patients from being exposed to potentially dangerous side effects from a medication not likely to be beneficial against the Omicron variant of the SARS-CoV-2 virus.¹⁴

CAS/IMD must be administered in a single intravenous infusion, although the two components can also be given consecutively by subcutaneous injection. For both the treatment and prevention of COVID-19, the recommended dose is 600 mg of each component. For subjects who require ongoing protection, the initial dose can be followed every four weeks by subsequent doses of 300 mg/300 mg CAS/IMD.^2,13

Following intravenous administration of a 1200 mg dose, population pharmacokinetic analysis suggests a mean half-life of around 30 days for CAS and 26 days for IMB.^2,13,17 Both mAbs are expected to follow endogenous IgG and degrade into small peptides and amino acids. Neither metabolization by CYP450 enzymes nor significant renal or hepatic excretion is predicted; thus, interactions with other drugs are unlikely. Patient characteristics, including age, sex, bodyweight, ethnicity, albumin level, and the presence of renal or mild hepatic impairment, do not appear to have any clinically relevant impact on CAS/IMD exposure.^2,13 While most adverse events (AEs) observed in clinical trials of CAS/IMD were related to COVID-19,¹³ there have been reports of administration-related reactions and anaphylaxis in some individuals,^13,15 with measurable levels of anti-CAS and anti-IMD antibodies being observed in a small proportion of patients.²

Studies of other mAbs indicate that transfer across the placenta is minimal in the first trimester and occurs mainly by simple diffusion. Later in pregnancy, maternal IgG antibodies are increasingly and actively transferred, with the highest rate occurring after 36 weeks of gestation. Cord blood concentrations are inversely correlated with the time since the last maternal dose, and mAb levels at birth can often be higher in the infant than in the mother.¹⁸

Current guidelines do not support the withholding of COVID-19 treatments, including mAbs, from pregnant women on the grounds of theoretical safety concerns.^7,19 However, as pregnant individuals were excluded from the studies leading to the emergency use approval of mAbs, there is little information on the use of these drugs during pregnancy.^5,7,13,16 Most mAbs, including CAS/IMD, cross the placenta easily, although there is no evidence of adverse pregnancy outcomes following their usage.^9,11,18 Nonetheless, mothers and fetuses exposed to mAbs during pregnancy should be carefully monitored.

In this article, we present results from the first 30 months of the COVID-19 International Drug Pregnancy Registry (COVID-PR) study, as well as provide an overview of the existing data relating to the safety and efficacy of CAS/IMD treatment during pregnancy.

Methods

The COVID-PR study

The COVID-PR is an ongoing, international, noninterventional, postmarketing cohort study designed to collect safety data from pregnant or recently pregnant individuals treated during pregnancy with either the mAbs CAS/IMD or sotrovimab, or the antiviral drugs remdesivir or molnupiravir, for mild, moderate, or severe COVID-19.^20,21 Study participants are aged 18 years or older and must be pregnant or have concluded a pregnancy within the previous 30 days at the time of enrollment. For participants treated with mAbs, the exposure window also includes the 90 days preceding the first day of the last menstrual period.

Participants complete online questionnaires at enrollment, during pregnancy, and for up to 12 months following the live birth of an infant via a dedicated web portal. These questionnaires collect self-reported information on sociodemographic and health characteristics, COVID-19 symptoms, and obstetric, neonatal, and infant outcomes. The questionnaire is based on the one used in the earlier International Registry of Coronavirus Exposure in Pregnancy (IRCEP) study,²² with improvements made in response to feedback from an ad hoc pilot study conducted with volunteer participants prior to the main study launch, as well as from IRCEP participants and study personnel. Additional comments are collected from COVID-PR participants at the end of each questionnaire module to identify concerns about question wording or to clarify instructions.

Where applicable, participants are asked to provide medical records to verify reported conditions. The relationship between reported AEs, both in the mothers and resulting offspring, and treatment with CAS/IMD during pregnancy is assessed by the COVID-PR Safety Physician using the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) Causality Assessment System (https://www.who.int/publications/m/item/WHO-causality-assessment). Serious AEs are defined as an untoward medical occurrence which follows treatment, and which does not necessarily have a causal relationship with the usage of the therapy that:

Results in death;

Is life-threatening;

Requires inpatient hospitalization or prolongation of hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions);

Results in congenital anomaly/birth defect;

Requires intervention to prevent permanent impairment or damage.

The study is being conducted in any country where at least one of the drugs of interest is available. The aim is to enroll 200 participants for each study drug, with 100 of these participants having received treatment during the first trimester of pregnancy. The sample size was determined by estimating baseline risks of the primary outcomes using data from previous studies and the general population to calculate the minimum detectable effect sizes. The final sample size is considered the minimum required to detect differences with 80% power at a two-sided significance level of 0.05. The COVID-PR is expected to last for five years; recruitment for CAS/IMD began on 4 December 2021, and this report is based on data collected until 31 May 2024.

Descriptive analyses were conducted on the data collected in the study. For each variable, the number of responses in each category was recorded and corresponding percentages were calculated. For certain outcome variables, such as obstetric outcomes, categories were predefined, and any response that did not fit a predefined category was recorded as “other.” In contrast, for variables such as AEs and serious AEs, responses were collected in an open-ended (ad libitum) format.

Literature review

On 15 May 2024, we conducted a PubMed search for English-language manuscripts on the use of CAS/IMD during pregnancy, using the keywords “Casirivimab,” “Imdevimab,” “REGEN-COV,” and “Pregnancy.” Relevant articles were initially identified through abstracts, followed by a review of the full text. Articles were considered relevant if they provided information on the use of CAS/IMD during pregnancy and reported results related to either efficacy or safety in pregnant populations. Data were extracted and tabulated separately for efficacy and safety. Additional articles were identified by reviewing the reference lists of selected manuscripts. The primary aim of this article is to present the results of our study and contextualize them within the existing literature. Although we sought to offer a broad narrative overview of the available evidence, we recognized that a full systematic review would substantially increase the manuscript's length. Therefore, this is a narrative review and does not fully adhere to PRISMA guidelines.²³

Results

The COVID-PR study

During the study timeframe, a total of 53 participants, all residing in the United States, who were treated with CAS/IMD during pregnancy were enrolled in the study. Details of the baseline characteristics of the participants are given in Table 1. It is notable from this table that there was a high level of missing data, which averaged around 20% for most variables but was as high as 36% for existing medical conditions at the onset of pregnancy. Participants ranged in age from 19 to 43 years, with a mean age of 30.94 years (SD 5.01). The majority of participants described themselves as white, had completed at least a college education, were employed full-time before their pregnancy, did not use tobacco or alcohol, took a daily vitamin supplement, and considered themselves to be in good health. However, over 80% of the participants were obese before their pregnancy, and a similar proportion reported at least one preexisting medical condition, with asthma (n = 10) and polycystic ovary syndrome (n = 7) being the most frequently reported conditions. Just over one-third of the participants were treated with CAS/IMD during the first trimester of pregnancy, with the remainder receiving treatment during the second or third trimesters.

Table 1.

Baseline characteristics of COVID-PR participants treated with casirivimab/imdevimab.

Characteristic	Number	%
Age (years)
18–19	1	1.9
20–24	4	7.5
25–29	18	34.0
30–34	16	30.2
35–39	13	24.5
40–44	1	1.9
Ethnicity^a
White/Caucasian	38	71.7
Hispanic/Latina/Spanish origin	5	9.4
Black/African American	3	5.7
American Indian/Alaska Native	2	3.8
Middle Eastern/North African	1	1.9
Other/multirace	1	1.9
Missing data	9	17.0
Highest level of education attained
Graduate/professional	9	17.0
College	26	49.1
High school	9	17.0
Missing data	9	17.0
Employment status at onset of pregnancy
Employed but on maternity leave	1	1.9
Employed full time (35 or more hours per week)	26	49.1
Employed part time (fewer than 35 h per week)	6	11.3
Not employed, not looking for work	8	15.1
Not employed, looking for work	1	1.9
Disabled, not able to work	2	3.8
Missing data	9	17.0
Gestational timing of treatment
First trimester	2	3.8
Second trimester	14	26.4
Third trimester	25	47.2
After pregnancy	12	22.6
Tobacco use:
No	29	54.7
Yes, before this pregnancy	10	18.9
Yes, before and during this pregnancy	1	1.9
Yes, during this pregnancy	1	1.9
Missing data	12	22.6
Alcohol use during pregnancy
Never	39	73.6
Once per month	1	1.9
Once per week	1	1.9
A few days per week	0	0.0
Every day	0	0.0
Missing data	12	22.6
Vitamin use during pregnancy
Never	0	0.0
1–3 times per week	4	7.5
4–6 times per week	6	11.3
Every day	31	58.5
Missing data	12	22.6
Prepregnancy body mass index
18.5–24.9	8	15.1
25.0–29.9	16	30.2
≥30.0	20	37.7
Missing data	12	22.6
Self-reported prepregnancy health
Excellent	13	24.5
Very good	19	35.8
Good	10	18.9
Fair	0	0.0
Poor	2	3.8
Missing data	9	17.0
Existing medical conditions at onset of pregnancy^a
None	7	13.2
At least one medical condition	27	50.1
Arrhythmia	2	3.8
Asthma	10	18.9
Diabetes type II	2	3.8
Endometriosis	2	3.8
High blood pressure (started before pregnancy)	1	1.9
Low thyroid hormone	3	5.7
Polycystic ovary syndrome	7	13.2
Rheumatoid arthritis	1	1.9
Other	6	11.3
Missing data	19	35.8
Healthcare coverage at onset of pregnancy
No	3	5.7
Yes	41	77.4
Missing data	9	17.0

Participants were permitted to give more than one answer, so the number of answers may exceed the number of participants.

By 31 May 2024, 32 participants had given birth to live infants, one participant had withdrawn from the study, 19 were lost to follow-up, and the status of the remaining participant was undetermined (the due date had been reached, but no information on the birth outcome was available). Nine of the live births were delivered by caesarean section. There were no pregnancy terminations, either elective or spontaneous. Two participants were carrying twins, resulting in a total of 34 live infants born.

The birthweights of the 34 live infants ranged from 1332 g to 4366 g, with a mean birthweight of 3271 g (SD 746 g). One baby was born at a gestational age exceeding 42 weeks, 21 were born at 39–42 weeks, nine at 37–38 weeks, and three at 32–36 weeks. Three babies were considered to have been born prematurely.

Safety outcomes

Details of the AEs reported by both the mothers and their infants are given in Table 2.

Table 2.

Adverse events reported for casirivimab/imdevimab treatment during the first 24 months of the COVID-PR study.

Adverse event	Number (%)	Serious adverse event	Related to casirivimab/imdevimab treatment
Maternal events
All events	33 (100.0)	—	—
COVID-19	4 (12.1)	Yes; No; No; No	No; No; No; No
Premature delivery	4 (12.1)	Yes; No; No; No	No; No; No; No
Chills	2 (6.1)	No; No	Yes; Yes
Gestational diabetes	2 (6.1)	Yes; Yes	No; No
Nausea	2 (6.1)	No; No	Yes; Yes
Prolonged labor	2 (6.1)	Yes; No	No; No
Ageusia	1 (3.0)	No	Yes
Anosmia	1 (3.0)	No	Yes
Arrhythmia	1 (3.0)	Yes	Yes
Cholestasis of pregnancy	1 (3.0)	Yes	No
Confusional state	1 (3.0)	No	Yes
Dizziness	1 (3.0)	No	Yes
Hyperhidrosis	1 (3.0)	No	Yes
Injury	1 (3.0)	Yes	No
Nasal discomfort	1 (3.0)	No	Yes
Oligohydramnios	1 (3.0)	Yes	No
Placental disorder	1 (3.0)	No	No
Placental infarction	1 (3.0)	No	No
Placental insufficiency	1 (3.0)	Yes	No
Postpartum hemorrhage	1 (3.0)	Yes	No
Preeclampsia	1 (3.0)	No	No
Preterm rupture of membranes	1 (3.0)	No	No
Pyrexia	1 (3.0)	No	Yes
Infant/fetal events
All events	60 (100.0)	—	—
Ear infection	9 (15.0)	No; No; No; No; No; No; No; No; No	No; No; No; No; No; No; No; No; No
Premature baby	6 (10.0)	Yes; Yes; Yes; Yes; No; No	No; No; No; No; No; No
COVID-19	5 (8.3)	No; No; No; No; No	No; No; No; No; No
Large for dates baby	4 (6.7)	No; No; No; No	No; No; Unassessable; Unassessable
Acoustic stimulation tests abnormal	3 (5.0)	No; No; No	No; No; No
Neonatal dyspnea	3 (5.0)	Yes; Yes; Yes	No; No; No
Blood glucose decreased	2 (3.3)	Yes; Yes	No; No
Breech presentation	2 (3.3)	Yes; Yes	No; No
Fetal heart rate deceleration abnormality	2 (3.3)	Yes; Yes	No; No
Infantile apnea	2 (3.3)	Yes; Yes	No; No
Respiratory syncytial virus infection	2 (3.3)	No; No	No; No
Anemia neonatal	1 (1.7)	No	No
Candida infection	1 (1.7)	No	No
Croup infectious	1 (1.7)	Yes	No
Drug hypersensitivity	1 (1.7)	No	No
Ear malformation	1 (1.7)	Yes	Unassessable
Fetal heart rate decreased	1 (1.7)	Yes	No
Gastroenteritis	1 (1.7)	No	No
Gastroesophageal reflux disease	1 (1.7)	No	No
Hydronephrosis	1 (1.7)	Yes	No
Immature respiratory system	1 (1.7)	Yes	No
Jaundice neonatal	1 (1.7)	No	No
Low birth weight baby	1 (1.7)	Yes	No
Nasopharyngitis	1 (1.7)	No	No
Neonatal aspiration	1 (1.7)	Yes	No
Neonatal pneumonia	1 (1.7)	Yes	No
Neonatal respiratory distress	1 (1.7)	Yes	No
Poor feeding infant	1 (1.7)	Yes	No
Pulmonary artery stenosis congenital	1 (1.7)	Yes	No
Pyelocaliectasis	1 (1.7)	Yes	No
Pyrexia	1 (1.7)	No	No

Maternal outcomes

Among the 53 study participants treated with CAS/IMD, 23 (43.3%) reported a total of 33 AEs. The most frequently reported AEs were COVID-19 reinfection and premature delivery, each observed in four participants (one of the mothers gave birth to premature twins, and one AE was coded as preterm premature rupture of membranes instead of premature delivery based on details of the event) hence the number of premature deliveries is lower than the number of premature babies). Of these, 11 AEs (reported by 11 participants, or 20.8%) were classified as serious. Only one of these serious AEs, a report of arrhythmia, could potentially be related to CAS/IMD administration. Additionally, 11 of the nonserious AEs might be attributable to the treatment.

Neonatal outcomes

In total, 60 AEs were reported in 20 (58.8%) of the 34 infants born to study participants, occurring either in utero or after delivery. The most frequently reported AEs were ear infections (n = 9), premature baby (n = 6), and COVID-19 infection (n = 5). Out of these, 27 AEs (reported in 15 infants, or 44.1%) were classified as serious. These included four premature births, three cases of neonatal dyspnea, two cases each of decreased blood glucose, breech presentation, fetal heart rate deceleration abnormality, and infantile apnea, and one case each of infectious croup, ear malformation, decreased fetal heart rate, hydronephrosis, immature respiratory system, low birth weight, neonatal aspiration, neonatal pneumonia, neonatal respiratory distress, poor feeding, congenital pulmonary artery stenosis, and pyelocaliectasis. None of these serious AEs appeared to be related to CAS/IMD treatment, although there was insufficient evidence to determine the relationship between treatment and the observed ear malformation. None of the nonserious AEs were considered likely related to CAS/IMD, though for two of these AEs, there was insufficient information to assess causality.

Literature review: Efficacy and safety of CAS/IMD during pregnancy

Efficacy in pregnant people

Table 3 summarizes the available evidence on the efficacy of CAS/IMD during pregnancy.

Table 3.

Evidence relating to the efficacy of casirivimab/imdevimab in pregnant populations.

Author, year, reference	Study type	Number of treated patients	Treatment details	Outcomes
Hirshberg, 2021⁶	Retrospective chart review	4	CAS/IMD infusion	One patient experienced disease progression from mild to moderate after mAb therapy; none required additional outpatient visits or hospitalization
Mayer, 2021⁸	Case series	2	Infusion of 600 mg CAS/IMD	Symptoms resolved within two weeks in both patients; neither required hospitalization
Chang, 2022⁴	Retrospective chart review	20	CAS/IMD infusion; 10 additional patients treated with other mAbs	Results not given specifically for CAS/IMD patients; subjective improvement in symptoms reported in 25 patients; two patients admitted to hospital for supplemental oxygen
Levey, 2022⁷	Retrospective cohort study	36	CAS/IMD infusion, including two patients who received postexposure prophylactic treatment	Patients in treated group less likely to require ICU admission and had shorter hospital stays; no difference in requirement for additional pharmacological treatment or ventilatory support; nine treated patients admitted to hospital, eight of these within 24 h of treatment
Magawa, 2022¹¹	Case-control series	8	CAS/IMD infusion; anticoagulants, antivirals, and steroids if required	No treated patients reported worsening of symptoms, all experienced a significant reduction in fever 24–48 h after treatment; no significant differences between treatment and control groups in blood test parameters, either at admission to hospital or three to five days after treatment
McCreary, 2022¹⁹	Retrospective cohort study	110	CAS/IMD infusion	Results not given specifically for CAS/IMD patients; frequency of COVID-19-associated outcomes similar between treated and control groups; one control participant died
Riccardo, 2022¹⁰	Prospective case series	13	Single infusion of 4000 mg/4000 mg CAS/IMD; low molecular weight heparin, steroids, and antibiotics if required	Symptoms resolved in all patients after treatment; no patients required ICU admission; no recorded deaths
Richley, 2022¹²	Case series	14	CAS/IMD infusion	No patients progressed to severe disease
Folkman, 2023⁵	Case series	7	Infusion of either 600 mg or 1200 mg CAS/IMD	Improvement of symptoms after median four days in five patients; one patient required ICU admission due to disease progression and respiratory failure
Williams, 2023¹⁶	Retrospective cohort study	88	CAS/IMD infusion	Outcomes similar in treated and control groups: one patient (1.1%) and eight patients (1.2%) respectively required hospitalization; one patient (1.1%) and six patients (0.9%) respectively required supplemental oxygen; one patient (1.1%) and seven patients (1.0%) respectively developed severe disease
Buonomo, 2024³	Retrospective case series	12	Infusion of 1200 mg/1200 mg CAS/IMD; low molecular weight heparin and antibiotics if required	No patients progressed to severe disease or required oxygen therapy

CAS/IMD: casirivimab/imdevimab; ICU: intensive care unit; mAb: monoclonal antibody.

One of the earliest evaluations of the efficacy of CAS/IMD involved four pregnant women with mild or moderate COVID-19 at the time of treatment. Although one participant experienced disease progression from mild to moderate after mAb therapy, none required additional outpatient visits or hospitalization.⁶

A case series of two unvaccinated pregnant women found that COVID-19 symptoms resolved within two weeks following intravenous infusion of CAS/IMD. Neither patient progressed to severe disease or required hospitalization.⁸

A retrospective chart review of 30 pregnant women with mild-to-moderate COVID-19, including 20 treated with CAS/IMD, reported subjective improvement in symptoms within seven days of infusion for 25 patients. Ten patients were subsequently admitted to the hospital: two required supplemental oxygen but did not develop severe COVID-19, while the remaining eight were admitted for non-COVID-related issues.⁴

A retrospective cohort study compared outcomes in two groups of pregnant women: 36 who received CAS/IMD and 50 who did not. The treated group included 10 participants in the first trimester, 11 in the second trimester, and 15 in the third trimester. Patients in the control group were more likely to require ICU admission and had longer hospital stays, although neither difference reached statistical significance. The groups did not differ in their requirement for additional pharmacological treatment or ventilatory support. Nine treated patients were admitted to the hospital, eight within 24 h of CAS/IMD administration, making it unclear if hospitalization would have occurred regardless of treatment.⁷

A case series of eight pregnant women with mild-to-moderate COVID-19 who received CAS/IMD was compared to 10 untreated pregnant controls. None of the treated cases reported worsening of their disease following CAS/IMD administration. Instead, a significant reduction in fever was observed 24 and 48 h after treatment. No significant differences were found in blood test parameters between the two groups, measured at admission to the hospital and 3–5 days after CAS/IMD administration or hospitalization, as appropriate.¹¹

A cohort study with 552 participants, 20% of whom received CAS/IMD, found that the risk-adjusted frequency of 28-day COVID-19-associated outcomes was similar between the treated group and untreated controls. Although the rate of non-COVID-19-related hospital admissions was higher in treated patients, it was not possible to determine if these were related to mAb administration. One control participant died.¹⁹

The efficacy of CAS/IMD administered as a single intravenous infusion of 4000 mg/4000 mg in pregnant women with severe COVID-19 was evaluated in a prospective case series of 13 hospitalized unvaccinated individuals. Participants were also treated with low molecular weight heparin, steroids, and antibiotics, as required. Despite most patients having risk factors for disease progression, such as lymphopenia and elevated C-reactive protein levels, symptoms resolved in all 13 cases after treatment. None required ICU admission, and there were no deaths.¹⁰

A case series of 14 pregnant women treated with CAS/IMD reported that none progressed to severe disease.¹²

A small case series reported on seven unvaccinated pregnant people treated with either 600 mg or 1200 mg of CAS/IMD during the second or third trimester. Five patients improved at a median of four days posttreatment, while COVID-19 progressed in one patient who subsequently required ICU admission due to respiratory failure.⁵

A retrospective cohort study compared outcomes following CAS/IMD administration in 88 pregnant women and 676 untreated participants. The outcomes were similar, with 1.1% of treated patients and 1.2% of the untreated group subsequently requiring hospitalization for COVID-19. Admission rates in both groups were considerably lower than those previously reported in nonpregnant populations. The proportion of each group developing severe disease or requiring supplemental oxygen was also comparable.¹⁶

The efficacy of CAS/IMD was investigated in a retrospective case series involving 12 unvaccinated patients with mild-to-moderate COVID-19, all in the second or third trimester. None were hospitalized, and all received an intravenous infusion of 1200 mg/1200 mg of CAS/IMD, as well as low molecular weight heparin and antibiotics if required. None progressed to severe disease or required oxygen therapy.³

Safety in pregnant people

The data available on the safety of CAS/IMD in pregnant people is limited, but the drugs appear to be well-tolerated.^{3–7,9,11,12,19} Table 4 presents a summary of the safety data related to maternal and neonatal pregnancy outcomes.

Table 4.

Evidence on the safety of casirivimab/imdevimab in pregnant populations: Maternal and neonatal outcomes.

Author, year, reference	Study type	Number of treated patients	Treatment details	Outcomes
Hirshberg, 2021 ⁶	Retrospective chart review	4	CAS/IMD infusion	One case of preterm delivery; no abnormalities in fetal growth or anatomy identified on ultrasound or at delivery
Mayer, 2021 ⁸	Case series	2	Infusion of 600 mg CAS/IMD	One baby admitted to NICU due to intermittent tachypnea and associated oxygen requirement
Chang, 2022 ⁴	Retrospective chart review	20	CAS/IMD infusion; 10 additional patients treated with other mAbs	Four caesarean full-term deliveries, one caesarean preterm delivery and two vaginal preterm deliveries reported; one preterm infant admitted to NICU; no growth or anatomical abnormalities identified; no significant adverse pregnancy outcomes
Levey, 2022 ⁷	Retrospective cohort study	36	CAS/IMD infusion, including two patients who received postexposure prophylactic treatment	No significant difference between treated group and controls for rates of severe maternal morbidity, need for oxygen support, ICU admission or length of hospital stay; rate of caesarean delivery 25% in treated group and 40% in controls; no significant difference between treated group and controls for rates of preterm birth, fetal growth restriction, birthweight, 5-min Apgar score less than 7, need for resuscitation at delivery, NICU admission and neonatal demise; no miscarriages reported
Magawa, 2022 ¹¹	Case-control series	8	CAS/IMD infusion; anticoagulants, antivirals, and steroids if required	Four caesarean deliveries reported (three due to previous caesarean delivery); two babies were small for gestational age
McCreary, 2022 ¹⁹	Retrospective cohort study	110	CAS/IMD infusion	No differences between treated and control groups for gestational age at delivery, birthweight, NICU admission, stillbirths, severe maternal morbidity, hypertension at delivery, or maternal ICU admission
Momin, 2022 ⁹	Case report	1	CAS/IMD infusion	Patient experienced miscarriage several days after treatment
Riccardo, 2022 ¹⁰	Prospective case series	13	Single infusion of 4000 mg/4000 mg CAS/IMD; low molecular weight heparin, steroids and antibiotics if required	No miscarriage or fetal loss reported; three caesarean deliveries and two preterm deliveries reported
Richley, 2022 ¹²	Case series	14	CAS/IMD infusion	Two cases of fetal growth restriction reported; one preterm caesarean delivery reported (due to worsening respiratory status and nonreassuring fetal heart tracing); two consecutive fetal heart decelerations recorded in fetus of mother who experienced breathing difficulty following treatment
Folkman, 2023 ⁵	Case series	7	Infusion of either 600 mg or 1200 mg CAS/IMD	Two preterm caesarean deliveries reported (one to avoid COVID-19 progression, one due to cardiotocography)
Williams, 2023 ¹⁶	Retrospective cohort study	88	CAS/IMD infusion	Rates of preterm delivery, caesarean delivery, NICU admission and small for gestational age all nonsignificantly lower in treated group compared to controls
Buonomo, 2024 ³	Retrospective case series	12	Infusion of 1200 mg/1200 mg CAS/IMD; low molecular weight heparin and antibiotics if required	Eight caesarean deliveries and five preterm births were reported (two spontaneous, two due to preeclampsia, and one due to ICP); no cases of NICU admission or fetal/neonatal death reported

CAS/IMD: casirivimab/imdevimab; ICP: intrahepatic cholestasis of pregnancy; ICU: intensive care unit; mAb: monoclonal antibody; NICU: neonatal intensive care unit.

Most studies have observed low rates of AEs in pregnant individuals either during or shortly after treatment with CAS/IMD.^{4–7,11,12,16,19} Reported symptoms include breathing issues, sometimes accompanied by mild oxygen desaturation,^7,12 and hypotension and dizziness.⁴ These symptoms differ from the indications of hypersensitivity and anaphylaxis, such as pruritus, flushing, rash, urticaria, and facial swelling, observed in nonpregnant individuals,^8,12,13 and it is unclear whether they represent infusion-related reactions or disease progression.⁷ Contemporaneous heart trace abnormalities have also been observed in the fetuses of some patients who experienced adverse reactions themselves, although a definitive link to CAS/IMD could not be established.¹² There are no reports of severe reactions to CAS/IMD infusion in pregnant women.^3,19

A single case report of miscarriage following CAS/IMD administration⁹ has not been reflected in other studies.^7,10 Rates of severe maternal morbidity, hypertension at delivery, or maternal ICU admission are similar in treated and untreated individuals.^7,19

Preterm caesarean deliveries have been reported in three women shortly after they received CAS/IMD,^5,12 but two of these were for preexisting pregnancy complications or to avoid a potential COVID-19 progression.⁵ All the delivered babies were healthy.^5,12 Although there have been other reports of preterm delivery some weeks after CAS/IMD treatment,^3,6,10,16 overall, there is no convincing evidence of an increased incidence of caesarean or preterm delivery in treated women,^{4,5,7,10,16,19} and the rates may actually be lower than in untreated controls.^7,16 Stillbirths, the need for resuscitation at delivery, admission to a neonatal ICU, and neonatal demise do not appear to be more common in infants born to mothers treated with CAS/IMD during pregnancy compared to untreated controls.^3,7,16,19 One infant was admitted to a neonatal ICU due to intermittent tachypnea and a requirement for oxygen, which was not related to COVID-19 infection.⁸ Although some studies have reported no influence on birthweight^6,16,19 or birth abnormalities,⁶ several cases of fetal growth restriction have been reported in babies born to mothers who received CAS/IMD during pregnancy.^11,12 However, infant growth and anatomy appear to be unaffected by maternal treatment.⁴

Discussion

As of 31 May 2024, only one of the 11 serious maternal AEs and none of the AEs reported in infants enrolled in the COVID-PR study appeared likely to have a causal relationship with CAS/IMD treatment during pregnancy. Many maternal AEs were short-term symptoms that may have been related to the participants’ existing COVID-19 infections or represented transient reactions to CAS/IMD infusion. Infections, including COVID-19, were frequently reported in the infants. Overall, the results from the COVID-PR study for CAS/IMD align broadly with those from other studies in pregnant populations, suggesting that the use of CAS/IMD during pregnancy is not associated with a significant risk of serious side effects.^{3–7,10–12,16,19}

A major limitation of our study is the failure to recruit the planned number of participants. Analyses are based on low numbers and may lack sufficient statistical power to detect less common outcomes. Furthermore, the enrollment process may favor self-selection, as participants choose to enroll based on their own experiences. Additionally, the sample may lack representativeness, particularly as all participants came from the same country, limiting the generalizability of the results to other populations.

The small sample size has been further compounded by the high level of losses to follow-up. However, the study protocol allows for ongoing attempts to reengage with these subjects, which may improve the situation as the study progresses. Missing information has also impacted the completeness of the data. This may be remedied in the future as participants are encouraged to provide relevant medical records to verify their self-reported experiences and outcomes.

Despite these drawbacks, we believe that the COVID-PR provides valuable data on the use of CAS/IMD during pregnancy, contributing to the limited information currently available.

Our review of the available literature on the use of CAS/IMD for the treatment of COVID-19 in pregnant individuals suggests that the treatment is generally effective in preventing progression to severe disease and reducing the need for hospitalization and supplemental oxygen. No deaths were reported among study participants treated with CAS/IMD. The drugs also appear to be well-tolerated, with low reported rates of AEs. Additionally, there is no compelling evidence of an increased risk of any individual adverse maternal or neonatal outcomes in treated patients compared to controls. The results from the COVID-PR study align with those reported in the broader literature.

Conclusions

Our analysis of outcome and safety data from 53 participants enrolled in the COVID-PR study who were treated with CAS/IMD during pregnancy has revealed no concerning safety issues. As COVID-19 becomes endemic, treatments will still be required and there appears to be no compelling reason to advise against the use of CAS/IMD in pregnant individuals with COVID-19 where the circulating strains are known to be susceptible to CAS/IMD.

Footnotes

Acknowledgments

We gratefully acknowledge the scientific support provided by the Roche/Genentech and Regeneron teams, which was instrumental in the development of this article. Editorial assistance for this manuscript was provided by Alison Thornton.

Consent for publication

Informed consent was obtained from all participants included in the study.

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DFW, CR, and AF are employees of Thermo Fisher Scientific, a company that receives funding from Genentech, Roche, Regeneron, and various other pharmaceutical companies. LPS reports no conflicts of interest. VY is employed by Genentech, Inc., DK is employed by Regeneron Pharmaceuticals, Inc., and JI is employed by Roche Products Limited.

Ethical approval

This study received ethics approval by the Western IRB, Copernicus Group Institutional Review Board (WCG IRB) (20214420).

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The COVID-PR receives funding from Gilead Sciences, Merck Sharp and Dohme, Genentech/Roche, Regeneron Pharmaceuticals, and GSK.

Guarantor

DFW is the guarantor of the study.

Informed consent

Eligible subjects sign an electronic consent form prior to enrolling in the study.

ORCID iD

Diego F Wyszynski .

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