Di Gennaro et al. BMC Infectious Diseases (2023) 23:776 BMC Infectious Diseases
https://doi.org/10.1186/s12879-023-08747-2
RESEARCH Open Access
Efficacy and safety of therapies
for COVID-19 in pregnancy: a systematic review
and meta-analysis
Francesco Di Gennaro1, Giacomo Guido1, Luisa Frallonardo1, Francesco Vladimiro Segala1, Rosalba De Nola2,
Gianluca Raffaello Damiani2, Elda De Vita1, Valentina Totaro1, Mario Barbagallo3, Emanuele Nicastri4,
Antonella Vimercati2, Ettore Cicinelli2, Giuseppina Liuzzi4, Nicola Veronese3 and Annalisa Saracino1
Abstract
Background Clinical evidence suggests that pregnant women are more vulnerable to COVID-19, since they are
at increased risk for disease progression and for obstetric complications, such as premature labor, miscarriage, preec-
lampsia, cesarean delivery, fetal growth restriction and perinatal death. Despite this evidence, pregnant women are
often excluded from clinical trials, resulting in limited knowledge on COVID-19 management. The aim of this system-
atic review and meta-analysis is to provide better evidence on the efficacy and safety of available COVID-19 treatment
in pregnant women.
Methods Four authors searched major electronic databases from inception until 1 st November-2022 for con-
trolled trials/observational studies, investigating outcomes after the administration of anti-SARS-CoV-2 treat-
ments in pregnant women affected by COVID-19. The analyses investigated the cumulative incidence of delivery
and maternal outcomes in pregnant women, comparing those taking active medication vs standard care. Risk
ratios (RRs) with 95% confidence intervals were calculated. Statistical significance was assessed using the random
effects model and inverse-variance method. This systematic review and meta-analysis was conducted in accordance
with the updated 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The
protocol has been registered in Prospero (number registration: CRD42023397445).
Results From initially 937 non duplicate records, we assessed the full texts of 40 articles, finally including ten stud-
ies. In six studies, including 1627 patients, the use of casirivimab/imdevimab (CAS/IMD), remdesivir, and IFN-alpha
2b significantly decreased the need of cesarean section ((RR = 0.665; 95%CI: 0.491–0.899; p = 0.008; I 2 = 19.5%;)
(Table 1, (Fig. 1). Treatments did not decrease the risk of preterm delivery, admission to neonatal ICU, or stillbirth/
perinatal loss (p-values > 0.50 for all these outcomes) and did not prevent the progression of disease towards severe
degrees (k = 8; 2,374 pregnant women; RR = 0.778; 95%CI: 0.550–1.099; p = 0.15; I 2 = 0%). Moreover, the use of medica-
tions during pregnancy did not modify the incidence of maternal death in two studies (Table 2).
Conclusions To our analysis, CAS/IMD, remdesivir, and IFN alpha 2b reduced the number of cesarean sections
but demonstrated no effect on disease progression and other obstetric and COVID-19 related outcomes. The inability
to evaluate the influence of viral load on illness development in pregnant women was attributed to lack of data. In
Correspondence:
Luisa Frallonardo
luisana.frallonardo@gmail.com
Full list of author information is available at the end of the article
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Di Gennaro et al. BMC Infectious Diseases (2023) 23:776 Page 2 of 9
our systematic review, no major side effects were reported. Though, it is essential for the medical community to focus
more on clinical trials and less on episodic case reports and case series, with standardization of fetal and maternal
outcomes.
Keywords COVID-19, Pregnancy, SARS-CoV-2, Monoclonal antibodies, Antivirals, Maternal morbidity
Introduction In fact, still three years after the outbreak of the
The physiological changes occurring in pregnancy, e.g., COVID-19 pandemic, the choice of the appropriate
immunological, respiratory, coagulative, and cardio- treatment for pregnant patients is a relevant clinical issue
vascular, can make pregnancy a risk factor for several that should consider the drug’s safety for the patient and
courses of SARS-CoV-2 infection, both for mother and the fetus.
child, consequently requiring hospitalization, medical This systematic review and meta-analysis aimed to pro-
interventions, and intensive care admission [1]. This vide better evidence of COVID-19 treatment in pregnant
assertion is supported by clinical evidence indicat- women, in terms of efficacy and safety.
ing that pregnant women who have been infected with
previous coronaviruses, such as Severe Acute Respira-
tory Syndrome (SARS) and Middle Eastern Respira- Materials and methods
tory Syndrome (MERS), were regarded as potentially This systematic review and meta-analysis was con-
more susceptible to experiencing a severe disease [2]. ducted in accordance with the updated 2020 Preferred
Pregnant women have a higher risk of miscarriage, rup- Reporting Items for Systematic Reviews and Meta-
ture of membranes, premature prelabor, preeclampsia, Analyses (PRISMA) guideline [12]. The protocol has
cesarean delivery, fetal growth restriction and perinatal been registered in Prospero (number registration:
death [3]. CRD42023397445).
There are other factors that could potentially clarify
the underlying risk that SARS-CoV-2 poses to pregnant
women and their fetuses. First, the temporary overex- Search strategy
pression of the ACE-2 receptor in the placenta allows Four independent reviewers, by couples, searched Pub-
the virus to cause histopathological and perfusion Med, Embase, Web of Science, and Scopus from incep-
changes, massive perivillous fibrin depositions, necro- tion until 01st November 2022. The full search strategy
sis of syncytiotrophoblast, and diffuse chronic intervil- and the search terms used are the following: “(COVID-
lositis, all of which could have negative consequences 19 OR Novel Coronavirus–Infected Pneumonia OR 2019
for the foetus and the continuation of pregnancy [4, 5]. novel coronavirus OR 2019-nCoV OR SARS-CoV-2)
Furthermore, the reduction of total lung capacity and AND (Lopinavir OR ritonavir OR Darunavir/cobicistat
the consequent hyperventilation, also due to the grow- OR Methylprednisolone OR Prednisone OR Hydrocor-
ing uterus, can cause one to inhale more air within tisone OR Hydroxychloroquine OR Dexamethasone
the same period of time with more exposure to SARS- OR Enoxaparin OR. Low molecular weight heparins
CoV- infection [6, 7], while also affecting the mater- OR Remdesivir OR Anakinra OR Baricitinib. OR Sari-
nal immune system (an increase in maternal serum lumab OR Tocilizumab OR Casirivimab OR Imdevimab
levels of toll-like receptors TLR-1 and TLR-7, and the OR Regdanvimab. OR bamlanivimab OR etesevimab
increase of angiotensin-converting enzyme 2 [ACE-2]), OR Sotrovimab OR Tixagevimab OR Cilgavimab. OR
which can decrease the efficacy of viral clearance [8, 9] Nirmatrelvir OR Molnupiravir OR Favipiravir OR Col-
and increase the risk of several diseases. chicine OR. Chloroquine OR Nafamostat mesylate OR
Furthermore, the state of hypercoagulability, which Camostat mesylate OR Infliximab OR. Tofacitinib OR
occurs primarily in the third trimester and the immedi- Bebtelovimab OR Ruxolitinib OR Nitazoxanide OR.
ate postpartum period, is a risk factor for thrombotic Plitidepsin OR Zotatifin OR Niclosamide OR nelfina-
events and thus contributes to the worsening of the vir OR inhibitors of HIV protease OR Hyperimmune
clinical course of SARS-CoV-2 infection [10, 11]. plasma OR Interferon OR ibuprofen OR Celecoxib) AND
Despite concerns about the increased vulnerabil- (("Pregnancy"[Mesh] OR "Pregnant Women"[Mesh] OR
ity of pregnant women to COVID-19, this population pregnanc))”. Discrepancies in the literature search pro-
remains an underrepresented group in the study of cess were resolved by a third investigator (N.V.). Rayyan,
drug therapy, with pregnant people excluded from vac- a free-access website, was used for title/abstract screen-
cine and therapy trials. ing (https:// www. rayyan. ai/).
Di Gennaro et al. BMC Infectious Diseases (2023) 23:776 Page 3 of 9
Inclusion and exclusion criteria fluid complications, ectopic pregnancy, placental com-
Studies were included based on the following PICO plications, eclampsia or pre-eclampsia, severe bleeding,
question: obstetric fistula, infections.
➙Participants: pregnant women; Statistical analysis
➙Intervention: pharmacological intervention for the The analyses investigated the cumulative incidence of
treatment of acute SARS-CoV2 infection; delivery and maternal outcomes in pregnant women
➙Comparison: placebo or standard of care; comparing those taking an active medication vs standard
➙Outcomes: delivery and maternal health end- care. We calculated the risk ratios (RRs) with their 95%
points; confidence intervals (CIs), Statistical significance was
➙Study design: randomized controlled trials, clini- assessed using the random effects model and inverse-var-
cal controlled trials, observational studies. iance method [12, 16].
Statistical heterogeneity of outcome measurements
Published articles were excluded if they (i) were between different studies was assessed using the s I 2. The
reviews, letters, in vivo or in vitro experiments, commen- classification of data as having low heterogeneity was
taries, or conference abstracts; (ii) absence of a control based on I2 from 30 to 49%, moderate heterogeneity from
group or active control group (e.g., another medication); 50 to 74%, and high heterogeneity from 75% and above
(iii) data non meta-analyzable. [17]. In case of high heterogeneity and having at least
10 studies for an outcome [17], we plan to run a meta-
Data extraction and risk of bias regression analysis to explore potential sources of vari-
Four authors extracted data independently which ability that could affect estimate rates among studies [18].
included name of first author, date of publication, coun- Publication bias was assessed by visually inspecting
try of origin, population included, type of study, follow- funnel plots and using the Egger bias test [19]. In case
up (standardized in weeks), mean or median age of the of statistically significant publication bias, the trim-and-
women included, gestational age (weeks), number of fill analysis was planned [20]. For all analyses, a P-value
vaccinated women, name and dosage of the intervention less than 0.05 was considered statistically significant.
drugs. Disagreements between authors were resolved by All analyses were performed using STATA version 14.0
one independent reviewer (N.V.). (StataCorp).
The Newcastle–Ottawa Scale (NOS) was used to assess
the study quality/risk of bias [13]. The NOS assigns a Results
maximum of 9 points based on three quality parame- Literature search
ters: selection, comparability, and outcome. The evalua- The literature search is fully reported in the PRISMA
tion was made by one investigator (FVS) and checked by flow-chart (Fig. 1). We initially identified 937 non dupli-
another (NV), independently. The risk of bias was con- cate records. After excluding 897 works from their titles
sequently categorized as high (< 5/9 points), moderate and abstracts, we assessed the full-texts of 40 articles,
(6–7), or low (8–9) [14]. finally including ten studies [19–28]. The absence of a
control group was the main reason of the exclusion after
Outcomes full-text screening.
Outcomes were the evaluation of maternal, fetal, deliv-
ery and neonatal outcomes according to the Interna- Descriptive findings
tional Federation of Gynecology and Obstetrics (FIGO) Table 1 shows the descriptive characteristics of the
classification. (Safe Motherhood and Newborn Health studies included. Overall, 2,463 pregnant women with
Committee. FIGO Consensus Guidelines on Intrapartum a mean/median age of 30 years were followed-up for
Fetal Monitoring. Available online: https:// www.j sog. or. an average period of three weeks. Their mean gesta-
jp/ intern atio nal/p df/ CTG. pdf (accessed on 25 September tional age was 25 weeks (range: 6 to 29.8 weeks). Over-
2022) [15]. The outcomes of our interest were divided in all, only seven studies reported the vaccination status,
delivery outcomes, i.e., preterm delivery, Cesarean sec- with about one third of the pregnant women being vac-
tion, admission to neonatal ICU (intensive care unit), cinated against COVID-19 (36.7%). Regarding the study
stillbirth/perinatal loss, obstructed labor and maternal design, only one had a prospective design [20], whilst the
outcomes, i.e., COVID-19 progression to severe dis- other studies had a retrospective or case–control design.
ease (admission to ICU, respiratory failure and need for Among the interventions used, the drug most used was
invasive ventilation, involvement of multiple organ sys- the combination of casirivimab/imdevimab (four stud-
tems), maternal death, miscarriage/fetal loss, amniotic ies), followed by remdesivir (two studies) and IFN alpha
Di Gennaro et al. BMC Infectious Diseases (2023) 23:776 Page 4 of 9
Fig. 1 Flow-chart of the studies included
2b (two studies) (Table 1). However, no outcome had a Efficacy and safety of medications in pregnant women
high heterogeneity. on maternal outcomes
Table 3 shows the efficacy and safety of medications used
Efficacy and safety of medications in pregnant women in pregnancy taking maternal outcomes as endpoints.
on delivery outcomes Overall, the use of medications during pregnancy did not
Table 2 shows the effect of any medication on delivery modify progression towards severe COVID-19 (k = 8; 2,374
outcomes. In particular, in six studies including 1627 pregnant women; RR = 0.778; 95%CI: 0.550–1.099; p = 0.15;
pregnant women, the use of casirivimab/imdevimab I2 = 0%). Moreover, the use of medications during preg-
(four studies), remdesivir (one study) and IFN alpha 2b nancy did not modify the incidence of maternal death in
(one study) significantly decreased the need of Cesar- two studies. Finally, one study reported that no difference
ean section (RR = 0.665; 95%CI: 0.491–0.899; p = 0.008; in placental complications, eclampsia or pre-eclampsia, or
I2 = 19.5%; Fig. 2 for the forest plot). When including only severe bleeding was observed (Table 3). As summarized
the studies using casirivimab/imdevimab, the re-calcu- in Table 3, no data were reported regarding other mater-
lated effect size was similar. This outcome did not suffer nal outcomes of interest, i.e., miscarriage/fetal loss, ectopic
on any publication bias (Table 2). On the contrary, the pregnancy, obstetric fistula or bacterial infections.
use of medications did not decrease the risk of preterm
delivery, admission to neonatal ICU, or stillbirth/perina- Risk of bias
tal loss (p-values > 0.50 for all these outcomes). Finally, no Supplementary Table 1 and Table 1 reported the evalu-
study reported data regarding obstructed labor (Table 2). ation of the risk of bias. Overall, the median value of
Di Gennaro et al. BMC Infectious Diseases (2023) 23:776 Page 5 of 9
Table 1 Descriptive characteristics for the studies included
Author, year Population Type of study Follow-up Mean/median age Gestational Number of Drug used as Dosage of the Quality of
(weeks) (years) age (weeks) vaccinated intervention intervention drug the studies
(number-unit) (0–9)
Nasrallah, 2021 [20] hospitalized women Prospective cohort 8 32 (range 16–44) 29.2 NR Remdesivir 200 mg day 5
with moderate 1 + 100 mg days 2–5
COVID-19
Kravchenko, 2021 [27] hospitalized women Case–control study NA 31.18 (range NA) 27.7 NA IFN alpha 2b 3,000,000 UI 6
with moderate rectal supposito-
COVID-19 ries bid + 4000 UI
gel five times/day
on the nasal mucosa
Magawa, 2022 [29] hospitalized women Retrospective cohort 0.7 30.25 (range 20–37) 28 0/8 Casirivimab/ 600 mg/600 mg 7
with moderate imdevimab
COVID-19
Eid, 2022 [30] non-hospitalized Retrospective cohort NA 29.2 ± 8.2 26 43/115 Casirivimab/ NR 5
women with mild imdevimab
COVID-19
Valsecchi, 2022 [31] hospitalized women Retrospective cohort 4 30.3 ± 4.43 29.77 0/20 Nitric Oxide 200 ppm × 2 6
with severe COVID-19
Tumash, 2022 [28] hospitalized women Retrospective cohort NA 33 (range NA) 32 NA Remdesivir 200 mg day 5
with moderate 1 + 100 mg days 2–5
COVID-19
Sinchikhin, 2022 [25] non-hospitalized Prospective cohort 3 25 (range NA) NR 7/37 IFN alpha 2b 5000 ui 6
pregnant women
exposed to COVID-19
Levey, 2022 [32] non-hospitalized Retrospective cohort 0 29.2 (range NA) NR 0/36 Casirivimab/ 600 mg/600 mg 5
pregnant women imdevimab
positive or exposed
to COVID-19
Williams, 2022 [33] non-hospitalized Retrospective cohort NA NA NA 0/88 Casirivimab/ 600 mg/600 mg 6
women with mild imdevimab
COVID-19
McCreary, 2022 [34] non-hospitalized Retrospective cohort 4 30 (range 26- 33) 6 265/552 Bamlanivimab NA 7
women with mild and etesevimab.
COVID-19 casirivimab
and imdevimab.
or sotrovimab treat-
ment compared
with no mAb treat-
ment
NA: not applicable, NR: not reported
Di Gennaro et al. BMC Infectious Diseases (2023) 23:776 Page 6 of 9
Table 2 Meta-analysis of the delivery outcomes for the studies included
Outcome Number of Sample size Risk ratio (95% CI) p-value I2 Egger’s test
studies (SE), p-value
Cesarean section 6 1627 0.665 0.008 19.5 1.62 (1.10)
(0.491–0.899) P = 0.22
Preterm delivery 7 2501 0.874 0.50 43.5 -1.09 (1.17)
(0.591- 1.294) P = 0.40
Admission to neonatal ICU 4 2284 1.099 0.54 4.2 -1.47 (1.00)
(0.810–1.490) P = 0.28
Stillbirth/perinatal loss 4 1449 0.932 0.93 15.4 2.99 (5.19)
(0.200–4.347) P = 0.62
Obstructed labor Not reported
Fig. 2 Meta-analysis of medications versus standard care in preventing Cesarean section
the NOS was 5, indicating a poor quality of the studies were first approved for general population and only later
included. The risk of bias, in factwas high in four stud- for pregnant women.
ies and moderate in the other six. The most common In fact, over time, with the increase of efficacy of
sources of bias were the lack of comparability between COVID-19 treatment and vaccines, it has seen a growing
treated and controls and the short follow-up. interest in the use and efficacy also in pregnant women
as well.
Discussion Several studies have assessed the immunogenicity,
In this systematic review with meta-analysis includ- safety, and efficacy of COVID-19 vaccines in pregnant
ing about 2,500 pregnant women, we examined the effi- women, [8] resulting in a lower risk of premature deliv-
cacy and safety of treatments for COVID-19 infection in ery and the occurrence of a small-for-gestational-age
pregnancy. foetus in pregnant women who receive vaccinations
Pregnant women constitute a unique population compared to unvaccinated [21]. Additionally the safety
not only because of their increased disease risk of results revealed that pregnant and breastfeeding individ-
COVID-19 disease [9], but also in regard to the exclu- uals experienced mild vaccine-related local and systemic
sion from any pre-licensure trials. Moreover, pregnant responses subsequent to the administration [22].
women resulted in being the one with fewer treatment Additional studies with larger samples and longer
options against SARS-CoV-2 during the first periods of follow-ups are needed to clarify the effect of multiple
COVID-19 pandemic, where treatment and vaccines doses (booster included) on obstetrical and perinatal
Di Gennaro et al. BMC Infectious Diseases (2023) 23:776 Page 7 of 9
Table 3 Maternal outcomes for the studies included
Outcome Number of Sample size Risk ratio (95% CI) p-value I2 Egger’s test (SD), p-value
studies
COVID-19 progression 8 2374 0.778 0.15 0 -0.98 (0.52) P = 0.11
(0.550–1.099)
Maternal death 2 1017 0.450 0.49 0 Not possible
(0.048–4.264)
Miscarriage/fetal loss Not reported
Amniotic fluid complications 1 283 0.381 0.13 Not possible Not possible
(0.109–1.337)
Ectopic pregnancy Not reported
Placental complications 1 89 0.208 0.30 Not possible Not possible
(0.011–3.918)
Eclampsia or pre-eclampsia 1 296 0.928 0.84 Not possible Not possible
(0.446 -1.929)
Severe bleeding 1 280 0.310 0.13 Not possible Not possible
(0.068–1.407)
Obstetric fistula Not reported
Infections Not reported
outcomes and the difference between trimesters, taking Nevertheless, as demonstrated by M. Gao et Al.
into account the time between vaccination and delivery. Casirivimab-Imdevimab accelerates symptom resolution
The lack of treatment during pregnancy has obliged the and showed considerable advantages in terms of prevent-
U.S. Food and Drug Administration (FDA) to permit the ing hospitalization and mortality in COVID 19 disease
emergency authorization of the administration of mono- [35, 36]. The role of viral load reduction in viral respira-
clonal antibodies (casirivimab/imdevimab or sotrovimab) tory infections during pregnancy in reducing the risk of
against COVID-19, assessing pregnancy at high risk for disease progression is still under discussion as the results
severe disease as an inclusion criterion for the prescrip- are discordant, considering that in our analysis the vacci-
tion of monoclonal antibodies [23, 24]. nation history of both groups was discontinuously known
In our analysis, casirivimab and imdevimab (CAS/ [34, 37].
IMD) were the most commonly administered treatment Di Girolamo et al. provides in a systematic review an
in pregnant women with COVID-19 infection, result- extensive analysis of the guidelines on management and
ing in a safe and effective option. From our data, CAS/ approved therapeutic options in COVID-19 in pregnancy
IMD, together with Remdesivir and IFN alpha 2b [25], [38], illustrative of useful approaches regarding the time-
significantly reduced the need for a cesarean section, sug- liness of delivery and hospitalization in cases of severe
gesting that COVID-19 medications in pregnancy might SARS-CoV2 infection. Nevertheless, the finding related
prevent or reduce vascular damage in the placenta. These to the use of corticosteroids and LMWH provides a vali-
data are very relevant if we evaluate that SARS-CoV-2 dation of existing knowledge [39].
is responsible for a state of systemic inflammation and Other meta-analysis have been conducted, on the eval-
hypercoagulability [10], similar characteristics of pre- uating the maternal fetal outcome and the effects on the
eclampsia that can cause abruption and might end up in placenta in SARS-CoV2 infection [40] however, the lack
a caesarean section [26]. Namely pregnant women with of standardization of these therapies highlights the need
COVID-19 show vascular changes in placenta compared to identify opportunities for improving COVID-19 vacci-
to pregnant women who did not develop infection [27]. nation, implementation of treatment of pregnant women,
It is assumed that the role of these treatments is to decrease and inclusion of pregnant women in clinical trials.
viral load of SARS-CoV-2, preventing complications and Further research and evidence are required to stratify
worse outcomes [27, 28] this assumption is still under dis- pregnant populations who have received treatments
cussion as Magawa et al. [29] could not demonstrate a sup- that specifically target the risk reduction of COVID-19
pression in viral activity immediately after the administration disease.The findings of our study must be interpreted
of CAS/IMD, while Levey et al. [32] showed a promising within its limitations. Beside all these observations, in
reduction of viral load in patients with hypoxemia. our meta-analysis, there was not a significant decrease
Di Gennaro et al. BMC Infectious Diseases (2023) 23:776 Page 8 of 9
in the risk of preterm delivery, admission to the neo- Declarations
natal ICU, or stillbirth or perinatal loss. Both maternal
and fetal outcomes need an in-depth debate since they Ethics approval and consent to participateNot required.
are not standardized in the studies on COVID-19 in
pregnancy, resulting in a difficult analysis of the impli- Consent for publication
cations of COVID-19 treatments. Furthermore, our Not applicable.
metanalysis is meant to overcome a limitation encoun- Competing interests
tered in many studies where anti-COVID-19 medica- The authors declare no competing interests. This research was partially sup-
tions were administered to pregnant women with no ported by EU funding within the NextGenerationEU-MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases (Project no. PE00000007,
comparison with a control group; this inclusion criteria INF-ACT).
has resulted in a small and heterogeneous sample size
with a lack of compatibility in terms of follow-up and Author details1 Clinic of Infectious Diseases, Department of Precision and Regenerative
between the treated and control groups. Medicine and Ionian Area - (DiMePRe-J), University of “Aldo Moro”, University
of Bari “Aldo Moro”, Piazza Giulio Cesare N. 11 Cap 70124, Bari, Italy. 2 Clinic
of Obstetrics & Gynaecology, University of Bari “Aldo Moro”, Bari, Italy. 3 Geriat-
rics Section, Department of Internal Medicine, University of Palermo, Palermo,
Conclusions Italy. 4 National Institute for Infectious Diseases ‘Lazzaro Spallanzani’ (IRCCS),
In the last two years, the interest in COVID-19 in preg- Rome, Italy.
nant women has been progressively increasing, as has the
number of publications on this topic. Nevertheless, the Received: 3 May 2023Accepted: 25 October 2023
scientific world needs a different quality of study about
COVID-19 in pregnancy, less keen on case reports and
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