• Users Online: 546
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 
ORIGINAL ARTICLE
Ahead of print publication  

Pharmacological management of COVID-19 in pregnancy


1 Internal Medicine Department, Shiraz University of Medical Sciences, Shiraz, Iran
2 Maternal, Fetal, and Neonatal Research Center, Tehran University of Medical Sciences, Tehran, Iran
3 Maternal, Fetal, and Neonatal Research Center, Tehran University of Medical Sciences; Maternal Health Department, Iran Ministry of Health and Medical Education, Tehran, Iran
4 Breastfeeding Research Center, Tehran University of Medical Sciences, Tehran, Iran

Date of Submission03-Jun-2021
Date of Acceptance15-Sep-2021
Date of Web Publication21-Dec-2021

Correspondence Address:
Nasrin Changizi,
Maternal Fetal and Neonatal Research Center, Vali-Asr Hospital, Imam Khomeini Hospital Complex, Bagher Khan Ave., Tehran 1419733141
Iran
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aihb.aihb_86_21

  Abstract 


Coronavirus disease 2019 (COVID-19) as a severe and rapid spread disease is a global health emergency since December 2019. During the outbreak of COVID-19, infected pregnant women were treated with different pharmacological regimens; however, trial studies are still investigating their safety and effectiveness. In the present study, we reviewed all recently published studies related to the pharmaceutical management of COVID-19 in pregnancy to discuss the rapid evolving pattern of administered medications. A review study was conducted to investigate the pharmacological management of COVID-19 in pregnancy. All types of full English and recent articles through detailed research on Cochrane Library, PubMed, UpToDate, ScienceDirect and Google Scholar databases were collected. Several medical sites were also investigated. The implemented keywords for the search were COVID-19, SARS-CoV-2, coronavirus, pregnancy, management, treatment, medication, drug, antiviral, teratogenicity, possible effect, therapeutic effect, adverse effect and pregnancy outcome. There are no definitely specific approved pharmacological treatments for COVID-19 in pregnancy. Evaluating published literature showed that different treatment options, including chloroquine, favipiravir and ribavirin, convalescent plasma, interferons and remdesivir, have been used to stop or decline viral replication. We reviewed published evidence for drug selection and its safety during pregnancy, but conflicting results associated with numbers of trials show that we need further investigation for newer antiviral drugs for use in pregnancy. It seems that management of COVID-19 needs a multidisciplinary approach, and a consultant medical team should be arranged to decide about medications for the management of COVID-19-infected pregnant women.

Keywords: COVID-19, pharmacological management, pregnancy



How to cite this URL:
Raeisi A, Barekati H, Changizi N, Farahani Z, Farrokhzad N, Sahebi L, Charousaei H, Aghazadeh Attari MM. Pharmacological management of COVID-19 in pregnancy. Adv Hum Biol [Epub ahead of print] [cited 2022 Jan 23]. Available from: https://www.aihbonline.com/preprintarticle.asp?id=333312




  Introduction Top


Coronavirus disease 2019 (COVID-19), as a severe and rapid spread disease, is a global health emergency. Regarding the possibility of vertical transmission, this disease may be responsible for high rates of prenatal mortality and morbidities.[1],[2],[3],[4] An investigation delineated that of 637 COVID-19-infected pregnant women, 10% were ICU hospitalised, 24% showed severe to critical symptoms and 1.6% of them died.[5] Neonatal adverse effects associated with SARS-CoV-2 infection have also been reported in neonates with positive nasopharyngeal reverse transcription–polymerase chain reaction or anti-immunoglobulin-M.[5],[6],[7]

Nowadays, treatment of COVID-19 in pregnancy is a big challenge due to factors associated with both virus and administered antiviral drugs. Biological and mutagenic behaviours of the virus, as well as determination of bioavailability, safety and potential teratogenic effects regarding antiviral drugs or vaccines, should be noticed in the finding of any effective pharmaceutical agent. These challenges are the main reasons that pregnant women mostly were excluded from data collection in recent clinical trials.[8],[9],[10]

Although adequate rest and caloric intake, relief of symptoms, hydration, electrolyte balance, oxygen therapy and other supportive measures are beneficially recommended for infected pregnant cases, no specific antiviral medication was approved by the Food and Drug Administration (FDA).[3] During the outbreak of COVID-19, infected pregnant women were treated with different available antiviral, antimalaria, anti-HIV, anti-parasite, vasodilator and antihypertensive, immunomodulatory, traditional medicines and convalescent plasma; however, several trials are still investigating their safety and effectiveness as well as proposing any other pharmacological treatments.[10],[11],[12] In the present study, we reviewed any published study related to pharmacological management of COVID-19 in pregnancy to discuss evolving of administered medications.


  Materials and Methods Top


A systematic literature review was conducted to investigate the pharmacological management of COVID-19 in pregnancy during the pandemic. All types of full English and recent articles (from December 2019 to 1 February 2021), including pilot study, letters to the editor, case–control, case series, clinical trials, systematic review and meta-analysis, were selected through detailed research on Cochrane Library, PubMed, UpToDate, Scopus, ScienceDirect and Google Scholar databases. Several medical sites, such as the World Health Organization (WHO), American College of Obstetricians and Gynecologists, Royal College of Obstetricians and Gynaecologists (RCOG), National Institutes of Health (NIH), the UK Teratology Information Service (UKTIS), International Society of Ultrasound in Obstetrics and Gynecology, Centers for Disease Control and Prevention, ICMR-National Institute for Research in Reproductive Health, the International Federation of Gynecology and Obstetrics and National Institutes of Health, were investigated regarding the subject. By reviewing the reference lists, some additional relevant studies were also added. The implemented MeSH-based (Medical Subject Headings) keywords for the search were “COVID-19” OR “SARS-CoV-2” OR “COVID-2019” OR “Coronavirus” AND “pregnancy” OR “prenatal” OR “antenatal” AND “management” OR “drug” “medication” OR “antiviral” “medication” “therapeutic effect.” All studies that enrolled pregnant women with confirmed COVID-19 receiving pharmacological management were included. By reviewing the abstracts of all selected articles, studies with irrelevant or duplicate topics or studies without pointing to treatment were excluded. The primary outcome was the determination of different pharmacological management implemented for the treatment of COVID-19 during pregnancy from December 2019 to 1 February 2021.

The present study was registered at Tehran University of Medical Sciences and ethics approval was obtained according to Helsinki Declaration (IR.TUMS.VCR.REC1399.504).


  Results Top


One hundred and sixty studies (articles, guidelines and websites database) were yielded through the computerised search. After exclusion of duplicate references (n=45), irrelevant studies without pointing to treatment protocols or lack of information (n=46), finally 69 Full-text studies were remained that met the eligibility criteria [Figure 1].
Figure 1: Flow chart of the included studies in a systematic review.

Click here to view


A data extraction list was designed to records information related to the first author's name, country, publication date, study design and medical treatments for COVID-19 in pregnancy [Table 1].
Table 1: A data extraction list with information related to first author's name, country, publication date, study design and medical treatments for coronavirus disease 2019 in pregnancy

Click here to view


Although there are no definitely specific approved pharmacological antiviral treatments for COVID-19 in pregnancy, evaluating published literature showed that different antiviral treatment options had been used to stop or decline viral replication. These drugs are categorised and summarised below.

Lopinavir/ritonavir (Kaletra)

Lopinavir/ritonavir (in B category in the FDA for pregnancy) is an anti-HIV drug with protease inhibitor effect.[9] Liang and Acharya, Chen et al. and Wang et al. showed that this treatment as a preferred drug (two capsules; 200 mg/50 mg per capsule) was beneficially and safely recommended for COVID-19-infected pregnant women in China.[21],[22],[30] Dashraath et al. noted the benefits of lopinavir/ritonavir in the treatment of COVID-19. The authors stated that this treatment would be safe because of no reported foetal anomalies, preterm birth or low birth weight amongst HIV-positive pregnant women using these medications.[38] Zhao et al. in April 2020 reported that lopinavir/ritonavir is a preferred and safe antiviral treatment for COVID-19 during pregnancy. Hence, this drug with no potential risk factors for preterm labour or birth defects could be recommended.[28] López et al., in June 2020, pointed to lopinavir/ritonavir (two tablets; 100 mg/25 mg; every 12 h for 7–14 days) as the recommended pharmacological treatment for pregnant women in Spain.[39] Conversely, Api et al. in June 2020 confirmed a need for a high dose with very limited efficiency of lopinavir/ritonavir in the management of pregnant patients with COVID-19.[11] Jamaica Guideline for the management of pregnancy during the COVID-19 pandemic in March 2020 noted little to no beneficial effects related to lopinavir/ritonavir in the treatment of COVID-19 infection.[63] The International Society of Infectious Disease in Obstetrics and Gynecology (ISIDOG) in April 2020 also recommended that lopinavir/ritonavir should be administered as the second antiviral choice because of its potential maternal adverse effects, drug interactions and adverse birth outcome.[27] Although Public Health England in May 2020 reported the beneficial effects with no potential risks for foetal malformation or neurodevelopmental impairment associated with administration of lopinavir/ritonavir in pregnancy, its latest update (in January 2021) reported no beneficial effects of this drug on the treatment of COVID-19 in pregnancy.[64] Favilli et al. noted that sufficient data related to the effectiveness of lopinavir/ritonavir in the treatment of COVID-19 for pregnant women were not available.[9] Louchet et al., in a systematic review (June 2020), have also reported no significant benefits related to lopinavir/ritonavir in COVID-19-infected cases except from severe adverse effects like gastrointestinal complications.[2] The Federation of Obstetric and Gynaecological Societies of India, published in July 2020, recommended lopinavir/ritonavir for only high-risk pregnant women with underlying diseases like diabetes.[44] Berghella, in August 2020, stated that despite successful use of lopinavir/ritonavir in combination with other medications against the COVID-19 virus, a low level of lopinavir-ritonavir can cross the placenta and may increase the risk of preterm birth.[50] Lopinavir-ritonavir was not also recommended for treatment of COVID-19 in pregnancy by later update of UpToDate version.[65]

Chloroquine, chloroquine phosphate and hydroxychloroquine

These antimalarial drugs (C category) with approved antiviral and immunomodulatory properties are the most frequent drugs which were initially implemented in managing COVID-19 in the clinical trial studies.[8],[9] Although there was not much evidence regarding their therapeutic effects for the treatment of COVID-19 during pregnancy, published studies related to the treatment of malaria can provide some informative data about their safety and adverse effects.[9] A review study from China by Li et al. has shown that chloroquine as a safe medicine with doses lower than 500 mg could be used for COVID-19-infected pregnant women. The recommended dose for hydroxychloroquine in treatment of COVID-19 during pregnancy was reported 200 mg twice or three times a day. It was also noted that regarding the probability of hydroxychloroquine accumulation in the foetus, its cons and pros should be weighed.[59] Jamaica Guideline for the management of pregnancy during the COVID-19 pandemic has also pointed to antiviral effects of both chloroquine and hydroxychloroquine with more beneficial and fewer side effects for hydroxychloroquine. Different recommended regimens associated with hydroxychloroquine were reported such as 200 mg three times a day for 10 days, 400 mg two times a day on the 1st day followed by daily for 5 days, 400 mg two times a day on the 1st day followed by 200 mg bid for 4 days and 600 mg bid on the 1st day followed by 400 mg daily for 4 days. Furthermore, the additional benefit was reported by a combination of azithromycin and hydroxychloroquine in the treatment of COVID-19 during the pregnancy period.[63] The guideline published by the Federation of Obstetric and Gynaecological Societies of India (June 2020) also recommended a combination of daily hydroxychloroquine (600 mg) and azithromycin (500 mg) for 10 days along with supportive treatment for COVID-19-infected pregnant women.[66] Zhao et al. in April 2020 have reported results of several clinical trials, meta-analysis studies and WHO records to indicate no to mild side effects of chloroquine and hydroxychloroquine on pregnancy outcome. The authors concluded that hydroxychloroquine as an effective drug could be prescribed for pregnant women with COVID-19.[28] Mei et al. reported that chloroquine with interfering effects on the terminal glycosylation of ACE2 could be safely recommended during pregnancy without any adverse effects on neonatal birth weight, gestational age, growth and neurological development.[8] Breslin et al., by a case series study, reported two asymptomatic cases who were hospitalised for labour induction but showed critical symptoms related to COVID-19. Both cases received hydroxychloroquine (600 mg twice daily for 1 day followed by 400 mg daily over the next 4 days). Respiratory function in a patient improved, and she was discharged from the hospital 4 days after delivery while the other patient remained in hospital for oxygen supplementation requirement and acute kidney injury.[32] Regarding teratogenicity of hydroxychloroquine, Malhamé et al., in June 2020, pointed to a meta-analysis and reported no major congenital anomalies, stillbirth or preterm birth amongst infants born from 740 treated mothers with hydroxychloroquine.[67] López et al. have also recommended hydroxychloroquine sulphate (400 mg every 12 h the 1st day followed by 200 mg every 12 h for the following 4 days) as the pharmacological treatment of COVID-19 during pregnancy.[39] Dashraath et al. pointed to chloroquine and remdesivir as the strongest candidates for the treatment of COVID-19 during pregnancy. The authors noted that chloroquine which was used across China, could effectively improve the clinical, radiological and serological findings in COVID-19-infected pregnant cases (in each trimester) without any increased risk of adverse perinatal outcomes. However, the side effects associated with a high dose of this drug, like systolic hypotension, should be considered.[38] An investigation by Louchet et al. reported a uteroplacental transfer of chloroquine with a mean ratio of concentrations of 1:1 and increased time and dose-dependent risks of maternal ototoxicity, cardiac toxicity and hypotension; however, no teratogenic/fetotoxic risks, miscarriage or neonatal ocular damage were observed. On the other hand, the dose of 200 mg once or twice a day would be safe for use in pregnancy with no increased prenatal risks, including miscarriage, congenital malformation or visual problems. The foetal-to-maternal concentration ratio for hydroxychloroquine was reported 1:04.[2] The therapeutic doses for chloroquine, chloroquine phosphate and hydroxychloroquine in treatment of COVID-19 during pregnancy were also recommended by the ISIDOG: 600 mg chloroquine at diagnosis and 300 mg 12 h later, followed by 300 mg twice a day up to day 5; 1000 mg chloroquine phosphate at diagnosis and 500 mg 12 h later, followed by 300 mg twice a day for 5 days; and 400 mg hydroxychloroquine at diagnosis and 400 mg 12 h later, followed by 200 mg twice a day for 5 days. Based on the ISIDOG guideline (published on 22 April 2020), hydroxychloroquine may recommend as the first-line treatment; however, its adverse effects such as cardiotoxicity/arrhythmia (lengthening of QTc interval) and drug interactions should be considered.[27] LaCourse et al. pointed to a meta-analysis study reporting a minimal foetal or maternal risk associated with hydroxychloroquine in 800 pregnant women except from spontaneous abortion, which was significantly increased.[47] The United States FDA in April 2020 also warned the health staff against severe adverse effects of hydroxychloroquine or chloroquine, including heart complications, haemodynamic and lymphatic system disorders, kidney/liver failure and death. Moreover, based on the FDA recommendation, the cardiotoxicity and ventricular tachycardia associated with hydroxychloroquine or chloroquine may deteriorate when these drugs are administered in combination with the antibiotics like azithromycin.[68] Favilli et al. reported the mild beneficial effects of chloroquine and hydroxychloroquine in the treatment of COVID-19 during pregnancy with no adequate evidence related to adverse prenatal and neonatal outcomes.[9] UKTIS in May 2020 pointed to a meta-analysis study and reported no significant increased risks of the craniofacial, cardiovascular, nervous system, genitourinary and other malformations as well as stillbirth, low birth weight or prematurity in pregnant women using hydroxychloroquine. However, based on a recent update of the guideline, it was reported that because of lack of data, foetal monitoring would be necessary on a case-by-case basis.[64] Api et al. and Pierce-Williams et al. noted that although hydroxychloroquine is considered a safe drug to use in pregnancy, clinical data regarding its effectiveness, risks and benefits for the treatment of COVID-19 in pregnancy were insufficient.[11],[48] Two case series studies from Iran also reported the administration of hydroxychloroquine for poor prognosis COVID-19-hospitalised pregnant patients. However, the cases died.[23],[42] Furthermore, NIH and UpToDate, in the last updated guidelines, recommended against the use of chloroquine or hydroxychloroquine for the treatment of inpatient and outpatient COVID-19-infected cases.[50],[69]

Favipiravir and ribavirin

These guanosine analogue antiviral agents by inhibiting virus RNA synthesis were reported as the other administered drugs for the treatment of COVID-19. Zao et al., in April 2020, noted the contradiction of ribavirin (in X category) during pregnancy because of several congenital malformations, including torticollis, hypospadias, polydactyly, glucose-6-phosphate dehydrogenase deficiency, ventricular septal defect and ventricular brain cyst.[28] Mei et al. and Li et al. have reported that the COVID-19 virus may show resistance to the typical dose of administered ribavirin or favipiravir.[8],[59] Api et al. in June 2020 noted that although favipiravir has been widely administered in many hospitals and recommended in several national protocols for treatment of moderate-to-severe COVID-19 symptoms, it is contraindicated for pregnant cases because of its mutagenic properties, teratogenicity and embryotoxicity.[11] Louchet et al., in June 2020, showed teratogenic effects of favipiravir for pregnant women with COVID-19.[2] This warning against teratogenic effects of ribavirin or favipiravir was also noted by several other studies.[13],[38],[50]

Remdesivir

Remdesivir (not classified in FDA categories) is a novel nucleoside analogue that inhibits RNA transcription and viral replication.[9],[10] Until April 2020, remdesivir was not recommended against COVID-19 virus by the International Pharmaceutical Federation (FIP), WHO, CDC, FDA or Chinese Guidance. FDA, on 22 October 2020, approved remdesivir for the treatment of COVID-19 in adults.[70] Trials evaluating the safety of remdesivir against Ebola and Marburg virus disease during pregnancy speculated that this drug could be safe against COVID-19. Pierce-Williams et al., by a cohort study from 5 March to 20 April 2020, showed the significant successful management (P < 0.001) of COVID-19 by using remdesivir in 16 of 64 (25%) pregnant women with severe or critical symptoms.[48] Malhamé et al., in June 2020, pointed to an RCT study showing no increased risks of teratogenicity or foetal toxicity in 6 pregnant women receiving remdesivir for treatment of Ebola virus disease.[67] Api et al. have reported that despite no FDA approval and no adequate investigation related to the use of remdesivir in pregnancy until 10 June 2020, preliminary data from several randomised trials indicated a shorter time to clinical recovery in patients receiving remdesivir compared to those in the control group.[11] Louchet et al., in June 2020, pointed to several clinical trials to show a significant reduction of time to clinical improvement in COVID-19 patients using a loading dose of 200 mg remdesivir followed by 100 mg daily for 10 days. On the other hand, different adverse effects were reported (from 21% to 66%), including renal dysfunction, elevated liver enzymes and cardiac arrest in treated patients. They suggested that with the possibility of placental transfer, the safety of remdesivir in pregnancy should be evaluated.[2] Li et al. reported a good recovery and clinical improvement in patients with severe COVID-19. The authors noted that remdesivir should be administered to pregnant women if the potential benefits outweigh the potential risks.[47] It has been reported that remdesivir was administered for SARS, MERS and coronavirus-infected pregnant cases without any reported risks of foetal toxicity.[67] By ISIDOG guideline and UKTIS, the majority of published recent investigations pointed to the use of remdesivir only in clinical trials because of unclear safety and efficacy during pregnancy.[8],[17],[19],[27],[30],[33],[40] Jamaica Guideline (published in March 2020) reported that none of the antiviral drugs, including remdesivir, has been approved by the Ministry of Health and Wellness for use during pregnancy and clinical effects of remdesivir on COVID-19 need more investigation[63] (https://www.moh.gov.jm; March 2020). Based on the later update of WHO (on 15 October 2020), it was demonstrated little or no therapeutic effects related to remdesivir on the decrease of mortality or improvement of hospitalised COVID-19 patients.[71] An investigation in January 2021 also indicated that there is still ambiguity regarding the beneficial effects of remdesivir for pregnant patients.[54]

Interferons

Type I interferons, including interferon (IFN) α and β (in C category in the FDA for pregnancy) with activating the host adaptive immune system against RNA viruses and stimulating antiviral protein genes, could show antiviral properties in the treatment of MERS-CoV, SARS-CoV-1 as well as SARS-CoV-2.[8],[9] Louchet et al. reported the beneficial effects of IFN-β (subcutaneous injection ranged from 30 mg/0.5 mL per week to 30 mg/0.5 mL three times a week) in treatment of SARS-CoV-2 infection in pregnancy with no uteroplacental cross (due to its high molecular weight) and adverse outcomes.[2] The results of a retrospective descriptive study reported good obstetrical and neonatal outcomes in 7 COVID-19 symptomatic/hospitalised pregnant women with mean gestational age 39 + 1 weeks who received IFNs (40 μg daily) in combination with oseltamivir, ganciclovir, arbidol, traditional Chinese medicines, antibiotic and corticosteroid treatments.[20] Chen et al. also pointed to the use of α-IFN combined with other antiviral agents as an effort of Chinese health officials to reduce the number of deaths amongst severe COVID-19 patients. At the same time, the administration of this drug in early pregnancy needs more caution regarding the risk of foetal growth and development retardations.[22] Zhao et al., based on the results of published meta-analyses, showed the efficacy of IFN (with stronger antiviral effects related to IFN-β1a than IFN-α) against COVID-19 during pregnancy without any increased risks of major malformations, stillbirths, miscarriages or premature births.[28] Mei et al. and Favilli et al. showed IFN-α as a potent in vitro and in vivo antiviral agent without any adverse perinatal or foetal outcomes. However, the authors also confirmed that pregnant women with COVID-19 should be strongly informed about the possible drug's benefits and risks.[8],[9] Furthermore, the UKTIS guideline in May 2020 has also confirmed no increased risks of miscarriage, low birth weight, congenital malformation or neurodevelopment complications following in utero exposure to IFN-β.[64] On the other hand, Li et al. have reported that the use of IFN-α in a pregnant woman should be postponed until weighing the benefits and risks according to her clinical situation.[59] Moreover, based on a study published in 2021, it should be noted that the available data associated with the use of IFN-α may not be generalisable to pregnant cases.[62] Therefore, more investigations are needed.

Convalescent plasma

The plasma of convalescent subjects containing antibodies has been previously prescribed for critically ill patients with SARS, MERS, Ebola, influenza, measles and other infectious diseases. This FDA-approved treatment protocol is also implemented for COVID-19-infected subjects to decrease the viral load, absorption of lung lesions, improve the oxygenation, decline of lymphocyte count and C-reactive protein levels resulting in relief of symptoms and better outcomes.[9],[10] Louchet et al. indicated a useful treatment with a higher discharge rate in SARS-CoV-infected subjects who received a transfusion of immunoglobulins from recovered patients. The authors also confirmed that the transplacental transfer of this immunoglobulin G might protect the foetus and neonate against infection.[2] Favilli et al. and Pierce-Williams et al. have noted that despite no observed adverse reactions in Ebola-infected pregnant women who received plasma convalescent therapy, further investigation and more RCTs are required to assess the safety and efficacy of this protocol in COVID-19 pregnant subjects.[9],[48] Furthermore, Api et al. confirmed considering insufficient data associated with the use of COVID-19 convalescent plasma, and this protocol should not be recommended for infected pregnant subjects.[11] Based on UpToDate recommendation in September 2020, convalescent plasma in combination with other specific drugs and supportive care is the other successful treatment in pregnant women. However, its safety and efficacy for pregnant women should be evaluated by more clinical trials with larger sample sizes.[50]

Other drugs

Several other medications were also reported in included studies while the results are conflicting. Although the usual steroids prophylaxis may protect pregnancies against the risks of premature rupture of membranes, preterm delivery and foetal growth restriction, some steroids may delay the virus clearance or cause hyperglycaemic status in pregnant subjects. Based on the WHO reports, antenatal administration of short time and low doses of dexamethasone (in C category) (or betamethasone) with blood glucose monitoring would be beneficial, safe and without any adverse maternal/foetal outcomes.[9],[34],[39],[60] UpToDate also suggested the use of glucocorticoids (dexamethasone or betamethasone followed by either prednisolone or hydrocortisone) for maternal treatment of COVID-19 in pregnant women with increased risk of preterm delivery at 24 + 0 and 33 + 6 weeks of gestation.[50] On the contrary, a study reported that the use of high doses of corticosteroids should be postponed after delivery because of its possible effects on foetal malformation or low birth weight.[20]

Concerning the thrombotic nature of pregnancy, prophylaxis with low-molecular-weight heparin was also recommended for all hospitalised positive COVID-19 pregnant women without a clear contraindication. Furthermore, this treatment was also recommended to continue for 2 weeks after hospitalisation based on D-dimer levels.[9],[34],[39],[44],[48],[50],[51],[52],[55] However, other investigations indicated that the efficacy of low-molecular-weight heparin to improve the prenatal outcomes in pregnancies complicated with severe COVID-19 requires further investigation before formal recommendation.[35],[62]

Antibacterial agents such as amoxicillin, ceftriaxone and azithromycin (belongs to class B by FDA) were also recommended for COVID-19 pregnant cases with secondary bacterial infection or comorbidities.[9],[27],[30],[44] Host-directed therapy and immunomodulatory agents such as tocilizumab, sarilumab, siltuximab, infliximab, colchicine, metformin, statins, glitazones and pioglitazone were also used in cases with cytokines storm while data regarding the use of these pharmacological agents in pregnancy are very limited.[2],[9],[11],[28],[39] Arbidol with antiviral effects by inhibition of enveloped virus membrane fusion has also been administered for pregnant women with COVID-19, but its safety during pregnancy needs further investigation.[2],[8],[16],[20],[35] An investigation suggested that due to no adequate related data, arbidol should not be recommended for pregnant women.[44] Ivermectin (in category C) as an anti-parasitic agent may show inhibitory effects on viral replication resulting in the reduction of viral load; however, due to a lack of convincing evidence regarding its safety, it is not recommended for pregnant women.[60] Herbal medicines such as Jinyebaidu, granules and Lianhuaqingwen were also recommended by few studies, while more evidence is needed to confirm the safety of these traditional medicines for the treatment of COVID-19 in pregnant women.[12],[15]


  Discussion Top


In the present study, we reviewed lots of published evidence (until February 2021) for drug selection, their effectiveness and safety during pregnancy that may provide useful, informative data.

The results of the present study indicated conflicting findings of a number of investigations and trials that are still debating different therapeutic regimens. Administered medications have been rapidly evolved during the COVID-19 pandemic, and different treatment modalities were added. Earlier studies have indicated the beneficial effects without adverse maternal/foetal outcomes regarding the use of anti-HIV, antimalarial and antiviral agents such as lopinavir/ritonavir, chloroquine, chloroquine phosphate, hydroxychloroquine and remdesivir during pregnancy. At the same time, the recent investigation focused on the therapeutics effects of immunomodulatory agents, plasma of convalescent subjects and immune system activators. Antibacterial, anti-thrombotic and steroid prophylaxis have also been reported by several included studies as useful treatments preventing secondary bacterial infection, comorbidities, thrombotic events, premature rupture of membranes and preterm delivery.

It should be mentioned that until now, there are no unique antiviral medications approved by both the FDA and WHO for the treatment of COVID-19 during pregnancy. In October 2020, the WHO reported little or no therapeutic effects related to remdesivir, hydroxychloroquine, lopinavir/ritonavir and IFN regimens on the decrease of mortality or improvement of hospitalised COVID-19 patients[71] while the FDA approved remdesivir for the treatment of COVID-19 in adult and paediatric patients older than 12 years.[70] These controversies show that we still need further investigation and trials determining the effective antiviral drugs for use in pregnancy.

It is supposed that a consultant medical team (including obstetrician/gynaecologist, infectious disease specialist, anaesthesiologist, intensivist, radiologist, paediatrician or neonatologist) should be arranged to decide about medications for the management of COVID-19-infected pregnant women. According to the CDC and ACOG guidelines (updated 14 December 2020), the administered medications should be responsible for decreasing viral load, enhancing the immune system, preventing thrombotic events as well as secondary bacterial infection or comorbidities. Moreover, decisions regarding the use of corticosteroids should be made by the consultant team.[31],[72] This therapeutic management of hospitalised mothers should be scheduled based on the best evidence, balancing medications' cons and pros, considering contraindications and adverse effects in the case by case, as well as informing patients. Finally, it seems that including not excluding pregnant women in clinical trials may introduce a potentially beneficial treatment for infected pregnant women with COVID-19.

The main strength of our study was collecting different types of articles besides several guidelines to show the rapid evolution of administered medications.


  Conclusion Top


In the present study, lots of published evidence were reviewed for drug selection, their effectiveness and safety during pregnancy. Administered medications have been rapidly evolved during the COVID-19 pandemic, and different treatment modalities, including anti-HIV, antimalarial, antiviral, antibacterial, anti-thrombotic, immunomodulatory agents and steroids, have been implemented for infected pregnant women. Although conflicting results of a number of trials are still debating different therapeutic regimens, these controversies show that we need further investigation for newer drugs for use in pregnancy. Moreover, it is supposed that a consultant medical team (including obstetrician/gynaecologist, infectious diseases specialist, anaesthesiologist, intensivist, radiologist, paediatrician or neonatologist) should be arranged to decide about medications for the management of COVID-19-infected pregnant women.

Acknowledgement

This study was supported by the Tehran University of Medical Sciences (TUMS) and Maternal-Fetal and Neonatal Research Center. We acknowledge their kindly supports in this study.

Financial support and sponsorship

This research has been supported by the Tehran University of Medical Sciences and health service as well as the Maternal Fetal and Neonatal Research Center.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Matar R, Alrahmani L, Monzer N, Debiane LG, Berbari E, Fares J, et al. Clinical presentation and outcomes of pregnant women with coronavirus disease 2019: A systematic review and meta-analysis. Clin Infect Dis 2021;72:521-33.  Back to cited text no. 1
    
2.
Louchet M, Sibiude J, Peytavin G, Picone O, Tréluyer JM, Mandelbrot L. Placental transfer and safety in pregnancy of medications under investigation to treat coronavirus disease 2019. Am J Obstet Gynecol MFM 2020;2:100159.  Back to cited text no. 2
    
3.
Rasmussen SA, Jamieson DJ. Pregnancy, postpartum care, and COVID-19 vaccination in 2021. JAMA 2021;325:1099-100.  Back to cited text no. 3
    
4.
Bwire GM, Njiro BJ, Mwakawanga DL, Sabas D, Sunguya BF. Possible vertical transmission and antibodies against SARS-CoV-2 among infants born to mothers with COVID-19: A living systematic review. J Med Virol 2021;93:1361-9.  Back to cited text no. 4
    
5.
Turan O, Hakim A, Dashraath P, Jeslyn WJ, Wright A, Abdul-Kadir R. Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review. Int J Gynaecol Obstet 2020;151:7-16.  Back to cited text no. 5
    
6.
Zeng H, Xu C, Fan J, Tang Y, Deng Q, Zhang W, et al. Antibodies in infants born to mothers with COVID-19 pneumonia. JAMA 2020;323:1848-9.  Back to cited text no. 6
    
7.
Kimberlin DW, Stagno S. Can SARS-CoV-2 infection be acquired in utero?: More definitive evidence is needed. JAMA 2020;323:1788-9.  Back to cited text no. 7
    
8.
Mei Y, Luo D, Wei S, Liao X, Pan Y, Yang X, et al. Obstetric management of COVID-19 in pregnant women. Front Microbiol 2020;11:1186.  Back to cited text no. 8
    
9.
Favilli A, Mattei Gentili M, Raspa F, Giardina I, Parazzini F, Vitagliano A, et al. Effectiveness and safety of available treatments for COVID-19 during pregnancy: A critical review. J Matern Fetal Neonatal Med 2020;1-14.  Back to cited text no. 9
    
10.
Abd El-Aziz TM, Stockand JD. Recent progress and challenges in drug development against COVID-19 coronavirus (SARS-CoV-2) – An update on the status. Infect Genet Evol 2020;83:104327.  Back to cited text no. 10
    
11.
Api O, Sen C, Debska M, Saccone G, D'Antonio F, Volpe N, et al. Clinical management of coronavirus disease 2019 (COVID-19) in pregnancy: Recommendations of WAPM-World Association of Perinatal Medicine. J Perinat Med 2020;48:857-66.  Back to cited text no. 11
    
12.
Luo Y, Yin K. Management of pregnant women infected with COVID-19. Lancet Infect Dis 2020;20:513-4.  Back to cited text no. 12
    
13.
Segars J, Katler Q, McQueen DB, Kotlyar A, Glenn T, Knight Z, et al. Prior and novel coronaviruses, Coronavirus Disease 2019 (COVID-19), and human reproduction: What is known? Fertil Steril 2020;113:1140-9.  Back to cited text no. 13
    
14.
Li Y, Zhao R, Zheng S, Chen X, Wang J, Sheng X, et al. Lack of vertical transmission of severe acute respiratory syndrome coronavirus 2, China. Emerg Infect Dis 2020;26:1335-6.  Back to cited text no. 14
    
15.
Chen H, Guo J, Wang C, Luo F, Yu X, Zhang W, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: A retrospective review of medical records. Lancet 2020;395:809-15.  Back to cited text no. 15
    
16.
Wang X, Zhou Z, Zhang J, Zhu F, Tang Y, Shen X. A case of 2019 novel coronavirus in a pregnant woman with preterm delivery. Clin Infect Dis 2020;71:844-6.  Back to cited text no. 16
    
17.
Mullins E, Evans D, Viner RM, O'Brien P, Morris E. Coronavirus in pregnancy and delivery: Rapid review. Ultrasound Obstet Gynecol 2020;55:586-92.  Back to cited text no. 17
    
18.
Liu W, Wang J, Li W, Zhou Z, Liu S, Rong Z. Clinical characteristics of 19 neonates born to mothers with COVID-19. Front Med 2020;14:193-8.  Back to cited text no. 18
    
19.
Hughes L. Coronavirus (COVID-19) and Pregnancy: What Maternal-Fetal Medicine Subspecialists Need to Know 4.11. 20 (This is an Update from Draft Posted on 3-17-2020). Washington, DC: The Society for Maternal-Fetal Medicine; 2020.  Back to cited text no. 19
    
20.
Yu N, Li W, Kang Q, Xiong Z, Wang S, Lin X, et al. Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: A retrospective, single-centre, descriptive study. Lancet Infect Dis 2020;20:559-64.  Back to cited text no. 20
    
21.
Wang SS, Zhou X, Lin XG, Liu YY, Wu JL, Sharifu LM, et al. Experience of clinical management for pregnant women and newborns with novel coronavirus pneumonia in Tongji Hospital, China. Curr Med Sci 2020;40:285-9.  Back to cited text no. 21
    
22.
Chen D, Yang H, Cao Y, Cheng W, Duan T, Fan C, et al. Expert consensus for managing pregnant women and neonates born to mothers with suspected or confirmed novel coronavirus (COVID-19) infection. Int J Gynaecol Obstet 2020;149:130-6.  Back to cited text no. 22
    
23.
Karami P, Naghavi M, Feyzi A, Aghamohammadi M, Novin MS, Mobaien A, et al. Mortality of a Pregnant Patient Diagnosed with COVID-19: A Case Report with Clinical, Radiological, and Histopathological Findings. Travel Medicine and Infectious Disease; 2020.  Back to cited text no. 23
    
24.
Banaei M, Ghasemi V, Saei Ghare Naz M, Kiani Z, Rashidi-Fakari F, Banaei S, et al. Obstetrics and neonatal outcomes in pregnant women with COVID-19: A systematic review. Iran J Public Health 2020;49:38-47.  Back to cited text no. 24
    
25.
Peng F, Tu L, Yang Y, Hu P, Wang R, Hu Q, et al. Management and treatment of COVID-19: The Chinese experience. Can J Cardiol 2020;36:915-30.  Back to cited text no. 25
    
26.
Lowe B, Bopp B. COVID-19 vaginal delivery – A case report. Aust N Z J Obstet Gynaecol 2020;60:465-6.  Back to cited text no. 26
    
27.
Donders F, Lonnée-Hoffmann R, Tsiakalos A, Mendling W, Martinez de Oliveira J, Judlin P, et al. ISIDOG recommendations concerning COVID-19 and pregnancy. Diagnostics (Basel) 2020;10:243.  Back to cited text no. 27
    
28.
Zhao X, Jiang Y, Zhao Y, Xi H, Liu C, Qu F, et al. Analysis of the susceptibility to COVID-19 in pregnancy and recommendations on potential drug screening. Eur J Clin Microbiol Infect Dis 2020;39:1209-20.  Back to cited text no. 28
    
29.
Baud D, Greub G, Favre G, Gengler C, Jaton K, Dubruc E, et al. Second-trimester miscarriage in a pregnant woman with SARS-CoV-2 infection. JAMA 2020;323:2198-200.  Back to cited text no. 29
    
30.
Liang H, Acharya G. Novel corona virus disease (COVID-19) in pregnancy: What clinical recommendations to follow? Acta Obstet Gynecol Scand 2020;99:439-42.  Back to cited text no. 30
    
31.
Rasmussen SA, Smulian JC, Lednicky JA, Wen TS, Jamieson DJ. Coronavirus disease 2019 (COVID-19) and pregnancy: What obstetricians need to know. Am J Obstet Gynecol 2020;222:415-26.  Back to cited text no. 31
    
32.
Breslin N, Baptiste C, Miller R, Fuchs K, Goffman D, Gyamfi-Bannerman C, et al. Coronavirus disease 2019 in pregnancy: Early lessons. Am J Obstet Gynecol MFM 2020;2:100111.  Back to cited text no. 32
    
33.
Singh AK, Singh A, Singh R, Misra A. Remdesivir in COVID-19: A critical review of pharmacology, pre-clinical and clinical studies. Diabetes Metab Syndr 2020;14:641-8.  Back to cited text no. 33
    
34.
Ortiz EI, Herrera E, De La Torre A. Coronavirus (COVID 19) infection in pregnancy. Colomb Med (Cali) 2020;51:e4271.  Back to cited text no. 34
    
35.
Rajewska A, Mikołajek-Bedner W, Lebdowicz-Knul J, Sokołowska M, Kwiatkowski S, Torbé A. COVID-19 and pregnancy – Where are we now? A review. J Perinat Med 2020;48:428-34.  Back to cited text no. 35
    
36.
Dong L, Tian J, He S, Zhu C, Wang J, Liu C, et al. Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn. JAMA 2020;323:1846-8.  Back to cited text no. 36
    
37.
Abdollahpour S, Khadivzadeh T. Improving the quality of care in pregnancy and childbirth with coronavirus (COVID-19): A systematic review. J Matern Fetal Neonatal Med 2020;1-9.  Back to cited text no. 37
    
38.
Dashraath P, Wong JL, Lim MX, Lim LM, Li S, Biswas A, et al. Coronavirus disease 2019 (COVID-19) pandemic and pregnancy. Am J Obstet Gynecol 2020;222:521-31.  Back to cited text no. 38
    
39.
López M, Gonce A, Meler E, Plaza A, Hernández S, Martinez-Portilla RJ, et al. Coronavirus disease 2019 in pregnancy: A clinical management protocol and considerations for practice. Fetal Diagn Ther 2020;47:519-28.  Back to cited text no. 39
    
40.
Chawla D, Chirla D, Dalwai S, Deorari AK, Ganatra A, Gandhi A, et al. Perinatal-neonatal management of COVID-19 infection – Guidelines of the Federation of Obstetric and Gynaecological Societies of India (FOGSI), National Neonatology Forum of India (NNF), and Indian Academy of Pediatrics (IAP). Indian Pediatr 2020;57:536-48.  Back to cited text no. 40
    
41.
Poon LC, Yang H, Kapur A, Melamed N, Dao B, Divakar H, et al. Global interim guidance on coronavirus disease 2019 (COVID-19) during pregnancy and puerperium from FIGO and allied partners: Information for healthcare professionals. Int J Gynaecol Obstet 2020;149:273-86.  Back to cited text no. 41
    
42.
Hantoushzadeh S, Shamshirsaz AA, Aleyasin A, Seferovic MD, Aski SK, Arian SE, et al. Maternal death due to COVID-19. Am J Obstet Gynecol 2020;223:109.e1-16.  Back to cited text no. 42
    
43.
Alberca RW, Pereira NZ, Oliveira LM, Gozzi-Silva SC, Sato MN. Pregnancy, viral infection, and COVID-19. Front Immunol 2020;11:1672.  Back to cited text no. 43
    
44.
Khoiwal K, Kapur D, Gaurav A, Chaturvedi J. Management of pregnant women in times of covid-19: A review of current literature. J Obstet Gynaecol India 2020;70:262-6.  Back to cited text no. 44
    
45.
Zaigham M, Andersson O. Maternal and perinatal outcomes with COVID-19: A systematic review of 108 pregnancies. Acta Obstet Gynecol Scand 2020;99:823-9.  Back to cited text no. 45
    
46.
Ashraf MA, Keshavarz P, Hosseinpour P, Erfani A, Roshanshad A, Pourdast A, et al. Coronavirus disease 2019 (COVID-19): A systematic review of pregnancy and the possibility of vertical transmission. J Reprod Infertil 2020;21:157-68.  Back to cited text no. 46
    
47.
LaCourse S, John-Stewart G, Adams Waldorf KM. Importance of inclusion of pregnant and breastfeeding women in COVID-19 therapeutic trials. Clin Infect Dis 2020;71:879-81.  Back to cited text no. 47
    
48.
Pierce-Williams RA, Burd J, Felder L, Khoury R, Bernstein PS, Avila K, et al. Clinical course of severe and critical coronavirus disease 2019 in hospitalized pregnancies: A United States cohort study. Am J Obstet Gynecol MFM 2020;2:100134.  Back to cited text no. 48
    
49.
Knight M, Morris RK, Furniss J, Chappell LC. Include pregnant women in research-particularly covid-19 research. United Kingdom: British Medical Journal Publishing Group; 2020.  Back to cited text no. 49
    
50.
Berghella V. Coronavirus disease 2019 (COVID-19): Pregnancy issues. UpToDate Internet 2020.  Back to cited text no. 50
    
51.
Narang K, Enninga EA, Gunaratne MD, Ibirogba ER, Trad AT, Elrefaei A, et al., editors. SARS-CoV-2 infection and COVID-19 during pregnancy: A multidisciplinary review. Mayo Clinic Proceedings. USA: Elsevier; 2020.  Back to cited text no. 51
    
52.
Hirshberg A, Kern-Goldberger AR, Levine LD, Pierce-Williams R, Short WR, Parry S, et al. Care of critically ill pregnant patients with coronavirus disease 2019: A case series. Am J Obstet Gynecol 2020;223:286-90.  Back to cited text no. 52
    
53.
Pastick KA, Nicol MR, Smyth E, Zash R, Boulware DR, Rajasingham R, et al., editors. A systematic review of treatment and outcomes of pregnant women with COVID-19 – A call for clinical trials. Open forum infectious diseases. US: Oxford University Press; 2020.  Back to cited text no. 53
    
54.
Wu D, Fang D, Wang R, Deng D, Liao S. Management of pregnancy during the COVID-19 pandemic. Glob Chall 2020;5:2000052.  Back to cited text no. 54
    
55.
Fogacci S, Fogacci F, Favari E, Toth PP, Borghi C, Cicero AF. Management of pregnancy-related hypertensive disorders in patients infected with SARS CoV-2: Pharmacological and clinical issues. Eur Heart J Cardiovasc Pharmacother 2021;7:346-51.  Back to cited text no. 55
    
56.
Burwick RM, Yawetz S, Stephenson KE, Collier AY, Sen P, Blackburn BG, et al. Compassionate use of remdesivir in pregnant women with severe covid-19. Clin Infect Dis 2020;ciaa1466.  Back to cited text no. 56
    
57.
Craig AM, Hughes BL, Swamy GK. Coronavirus disease 2019 vaccines in pregnancy. Am J Obstet Gynecol MFM 2021;3:100295.  Back to cited text no. 57
    
58.
Taylor MM, Kobeissi L, Kim C, Amin A, Thorson AE, Bellare NB, et al. Inclusion of pregnant women in COVID-19 treatment trials: A review and global call to action. Lancet Glob Health 2021;9:e366-71.  Back to cited text no. 58
    
59.
Li L, Wang X, Wang R, Hu Y, Jiang S, Lu X. Antiviral agent therapy optimization in special populations of COVID-19 patients. Drug Des Devel Ther 2020;14:3001-13.  Back to cited text no. 59
    
60.
Manchanda K, Singh J, Bhagat R, Tiwana IK, Singh H. Safety of pharmacological options for the management of COVID-19 in pregnant women: An Indian perspective. Int J Risk Saf Med 2021;32:3-17.  Back to cited text no. 60
    
61.
Rasmussen SA, Kelley CF, Horton JP, Jamieson DJ. Coronavirus disease 2019 (COVID-19) vaccines and pregnancy: What obstetricians need to know. Obstet Gynecol 2021;137:408-14.  Back to cited text no. 61
    
62.
D'Souza R, Ashraf R, Rowe H, Zipursky J, Clarfield L, Maxwell C, et al. Pregnancy and COVID-19: Pharmacologic considerations. Ultrasound Obstet Gynecol 2021;57:195-203.  Back to cited text no. 62
    
63.
Available from: https://www.moh.gov.jm. [Last accessed on 2021 Feb 01].  Back to cited text no. 63
    
64.
Available from: http://www.uktis.org/www.medicinesinpregnancy.org. [Last accessed on 2021 Jan 10].  Back to cited text no. 64
    
65.
Available from: https://www.uptodate.com. [Last accessed on 2021 Feb 01].  Back to cited text no. 65
    
66.
Gandhi A, Ganatra A, Tank P. FOGSI GCPR on Pregnancy with COVID-19 Infection Version 2. Federation of Obstetric and Gynaecological Societies of India 2020; 2020.  Back to cited text no. 66
    
67.
Malhamé I, D'Souza R, Cheng MP. The moral imperative to include pregnant women in clinical trials of interventions for COVID-19.Annals of International Medicine; 2020: 836-837.  Back to cited text no. 67
    
68.
Food U, Administration D. Hydroxychloroquine or Chloroquine for Covid-19: Drug Safety Communication: FDA Cautions Against Use Outside of the Hospital Setting or a Clinical Trial due to Risk of Heart Rhythm Problems. Washington: US Food and Drug Administration; 2020.  Back to cited text no. 68
    
69.
Available from: https://www.covid19treatmentguidelines.nih.gov/whats-new/. [Last accessed on 2021 Feb 01].  Back to cited text no. 69
    
70.
Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-covid-19. [Last accessed on 2021 Feb 01].  Back to cited text no. 70
    
71.
Available from: https://www.who.int/news/item/. [Last accessed on 2020 Sep 15].  Back to cited text no. 71
    
72.
Available from: https://www.acog.org/. [Last accessed on 2021 Feb 01].  Back to cited text no. 72
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1]



 

 
Top
 
 
  Search
 
     Search Pubmed for
 
    -  Raeisi A
    -  Barekati H
    -  Changizi N
    -  Farahani Z
    -  Farrokhzad N
    -  Sahebi L
    -  Charousaei H
    -  Aghazadeh Attari MM
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
Abstract
Introduction
Materials and Me...
Results
Discussion
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed192    
    PDF Downloaded7    

Recommend this journal