A Scoping Review of the Effects of COVID-19 Medications on Pregnancy
Abstract
COVID-19 is a pandemic disease caused by the SARS-CoV-2 which began to appear around in December 2019 in Wuhan, China and spread globally in the last few months. Currently, there is no specific treatment for SARS-CoV-2 which forced clinicians to use old drugs, chosen for their efficacy against similar viruses or their in vitro activity. The majority of information comes from small case series and single center reports which showed that COVID-19 infection in pregnant women can lead to intrauterine growth restriction, premature labor and spontaneous abortion. So, in the view of the urgency of COVID-19 pandemic and the uncertainties about its management during pregnancy, we aimed to provide a literature review on the effectiveness and safety of available medications for COVID-19 in pregnant women. Here, our overview may provide useful information for physicians to choose the best available medications for treatment a pregnant case with COVID-19.
Keywords: COVID-19; Pregnancy; Medications
Introduction
In Wuhan, China, coronavirus disease-2019 (COVID-19) began to appear in December 2019 [1]. It is caused by severe acute respiratory syndrome coronavirus-2 (SARS-Cov-2), this is a new type of enveloped RNA viruses characterized by mild infection in upper respiratory tract and life-threatening pneumonia [2]. The number of the affected pregnant women is increasing as pregnancy is a special immunological case in which the immune system is exposed to great challenges involving maintaining and establishing adaptation to allogenic fetus and preserving fetus from any microbial challenges. The immune system in pregnancy undergoes three stages; pro-inflammatory state in the first trimester, antiinflammatory state in the second trimester and second proinflammatory state in the third trimester [3].
During pregnancy the upper respiratory tract is swollen due to high levels of estrogen and progesterone which restrict lung expansion, and this increase the incidence of viral infection. Recent literature explains that COVID-19 infection is associated with cytokine storm in severe cases in which there is increased plasma concentration of tumor necrosis factor alpha, macrophage inflammatory protein1 alpha, monocyte chemoattractant protein1, granulocyte-colony stimulating factor, interferon gamma inducible protein10, interleukins (IL-2), (IL-7), (IL-10). Based on the proinflammatory state in third and first trimester in pregnancy and cytokine storm in COVID-19 infection the pregnant women are exposed to severe inflammatory state which can affect the fetal brain and leads to several aspects of neuronal dysfunction [3,4]. Also, elevated levels of TNF alpha in mother’s peripheral blood can be toxic to early embryo development and induce preterm delivery in non-human models [5].
Previous studies have explained that COVID-19 infection in pregnant women can lead to intrauterine growth restriction, premature labor and spontaneous abortion [6]. Therefore, treatment must be initiated when potential benefits outweigh potential risks and intra uterine development must be monitored closely during treatment and even after the treatment is stopped [7]. Due to the urgency of COVID-19 pandemic and the uncertainties about its management during pregnancy, we aimed to provide a literature review on the effectiveness and safety of available medications for COVID-19 in pregnant women. After we reviewed the guidelines and protocols from National institution of health (NIH), United Kingdom National Health Service (NHS), Egypt, Saudi Arabia, France, Italy, Spain and China, we limited our search on the most relevant medications mentioned in them. We also limited our search on English-language literature.
Chloroquine and Hydroxychloroquine
Chloroquine and hydroxychloroquine are antimalarial and antirheumatoid drugs. They are weak bases and have deep volume of distribution and half-life around 50 days. These drugs cause defect in the lysosomal activity and autophagy, interfering with stability of cell membrane and causing defect in pathway of signaling and transcriptional activity leading to inhibition of cytokine production and modulating certain co-stimulatory molecules. Both drugs are enantiomers [8]. Chloroquine and hydroxychloroquine are category C according to FDA [9]. Studies showed that they have a broadspectrum antiviral effect by increasing endosomal PH required for virus\cell infusion and causing defect in glycosylation of cellular receptors of SARS-COV. They also have anti-inflammatory effect plus their anti-viral effect which are responsible for their potent effect in treating COVID-19 [10]. Chloroquine can cross the placenta and accumulate in the fetal tissues as hydroxychloroquine which tend to accumulate in melanin containing tissues as retina and choroid leading to loss of vision [11].
On follow up of infants that their mothers took hydroxychloroquine during gestation and lactation, Hart and Naughton presenting that the main complication is preterm delivery (20.5%), no significant neonatal infections or congenital anomalies were observed, including infants that were breastfed. They concluded that hydroxychloroquine seems to be safe during pregnancy and preterm delivery reflects the state of maternal disease [12]. Suhonen reported a case receiving hydroxychloroquine phosphate in the first six weeks of pregnancy to control discoid systemic lupus erythematosus and fetus was born with no anomalies and grew without any mental or physical abnormalities [13]. Ross and Garotos examined autopsy from 14-week aborted fetus as his mother taking chloroquine showing no anomalies in oropharynx [14].
Additionally, eight patients who were presented to American Rheumatism Association, these patients had 28 pregnancies, they were receiving chloroquine, three of them underwent incomplete pregnancy or neonatal death as they came during period of activity of the disease, one had still birth fetus, four underwent spontaneous abortion and six had full term standard deliveries [15]. A meta-analysis conducted on hydroxychloroquine included seven cohort studies and one randomized controlled trial showed no significant increase in the rates of major congenital, craniofacial, genitourinary, cardiovascular, nervous system malformations, stillbirth or prematurity. Unfortunately, there is no data about the effect of chloroquine on pregnant women with COVID-19.
Remdesivir
Remdesivir is small molecule broad spectrum antiviral drug which act as RdRp inhibitor targeting viral genome process of replication. It is recommended to be safe during pregnancy in COVID-19 infection as in trials conducted of Marburg virus and Ebola virus [16]. In reproductive non-clinical toxicity, there is no adverse effects were noticed on embryo-fetal development in male infertility or pregnant animal with Remdesivir. In photoactivated localization microscopy study of acute Ebola virus disease, 26% of children and 3% of pregnant women received Remdesivir without any notable adverse effect [17].
Interferons (IFN-α and IFN-β mainly)
Type I interferons (IFN-α/β) have broad spectrum antiviral activities against RNA viruses by inducing an antiviral response across a wide range of cell types and stimulating the host adaptive immune response [18]. Data from several pregnancy registries showed no association between preconception or during pregnancy exposure to interferon-beta-1b and an increased risk of adverse birth outcomes [19]. A meta-analysis conducted to observe whether type I interferon has adverse effects on pregnant women with primary thrombocytopenia. The results showed that IFN-α did not significantly increase the risk of malformations, miscarriages, stillbirths, or premature births [20]. Another large systematic review included 50 studies that identified 761 pregnancies exposed to interferon β. Results reported that exposure to interferon β was associated with shorter mean birth length, lower mean birth weight, and preterm birth (<37 weeks); however, there was no increased risk of serious pregnancy complications of spontaneous abortion, cesarean delivery or birth weight < 2.5 kg [21].
A recent study included data from 26 European countries evaluated pregnancy outcomes of 948 pregnant women with multiple sclerosis receiving IFN I-β during pregnancy or within one month before conception. Results did not show an increased risk of fetal malformations or spontaneous abortion [22]. Currently, IFN type I is classified as US FDA pregnancy category C.
Janus Kinase Inhibitors (e.g., Baricitinib)
Baricitinib is a potent and selective janus Kinase Inhibitor that is used for treatment of rheumatoid arthritis and currently being investigated for treatment of COVID-19 cases due to its antiinflammatory and antiviral activities [23] as it would likely prevent the dysregulated production of pro-inflammatory cytokines in COVID-19 cases [24]. There are limited human data on the use of baricitinib to evaluate the drug-associated risk for major birth defects or miscarriage. In animal studies of embryo-fetal development, there was increased embryo lethality in some species that were given baricitinib at very high doses, above the maximum human recommended dose [25]. Baricitinib is not assigned in the US FDA pregnancy categorization. But It is classified as AU TGA (Australian categorization) pregnancy category: D.
Interleukin-1 Inhibitors (e.g., Anakinra)
Interleukin-1 is a pro inflammatory cytokine binds to IL-1 receptor and modulate its action so inhibitors of interleukin-1 are used to treat rheumatoid arthritis and currently being investigated for treatment of COVID-19 due to its potential effect to interfere with the cytokine storm in severe cases of COVID-19 [26]. There is limited evidence about the use of Interleukin-1 inhibitors(IL-1) in pregnancy but unintentional first trimester exposure is unlikely to be harmful [27]. According to an International multi-center study of the pregnancy outcomes in pregnant women exposed to interleukin-1 inhibitors, the use of interleukin-1 inhibitors may not significantly affect pregnancy outcomes or infant development. The study identified a total of 43 pregnancies with IL-1 inhibitors exposure in 7 countries, including 8 maternal from 14 with canukinumab and 23 maternal from 29 with anakinra. Seven healthy infants of normal gestational age and birthweight delivered from eight pregnancies exposed to canukinumab. Twenty-one healthy infants, and one baby with unilateral renal agenesis and ectopic neurohypophysis delivered from 23 pregnancies exposed to anakinra [28]. Anakinra is classified as US FDA pregnancy category B and AU TGA pregnancy category: B1.
Interleukin-6 Inhibitors (e.g., Tocilizumab)
Interleukin-6 (IL-6)is a pro-inflammatory cytokine that activates its downstream Janus kinase (JAK) signal by binding the transmembrane (cis-signaling) or soluble form (trans-signaling) of the IL-6 receptor [29]. Tocilizumab is a monoclonal antibody used for the treatment of rheumatoid arthritis and currently being investigated for treatment of some cases of severe COVID-19 with good results [30]. There are insufficient data to determine if there is a drug-associated risk for major birth defects or miscarriage [31]. A study analyzed pregnancy-related reports of 399 women with Tocilizumab exposure shortly before or during pregnancy. Pregnancy outcomes were reported in 288 pregnancies (72.2%) and showed no indication for a substantially increased malformation risk but the data do not yet prove safety [32]. Another Japanese retrospective study included 61 pregnancies with rheumatic disease exposed to tocilizumab during conception. Results showed no increased rates of spontaneous abortion or congenital abnormalities [33]. Tocilizumab is classified as US FDA pregnancy category C and AU TGA pregnancy category: C.
HIV Protease Inhibitors (e.g., Lopinavir/Ritonavir Darunavir/Cobicistat)
Lopinavir and Darunavir work as competitive inhibitors through binding directly to HIV protease and prevent subsequent cleavage of polypeptides, which in turn reduce viral replication and spread. Ritonavir and Cobicistat are metabolism-based enhancer to increase the exposure of Lopinavir and Darunavir [34]. Both drugs are used for treatment of HIV-infected women during pregnancy and prevention of mother-to-child transmission. In spite of their efficacy in vitro against SARS-CoV, they have poor selectivity index requiring higher than the tolerable level to achieve the clinically significant inhibition in vivo; however, based on systemic review and clinical studies found when given early to be associated with lower hospital stay and lower mortality rates [35-37].
Lopinavir is one of the main HIV protease inhibitors recommended in pregnancy with a good safety profile. Pharmacokinetics studies reported lower exposure of LPV in pregnancy [38] due to moderate decrease of total Lopinavir concentrations despite the dose increase [39]. However, the exposure of unbound LPV did not change significantly regardless of trimester or dose [40]. Two cohort studies of 21 women conducted with steady pharmacokinetic evaluations concluding that improving the oral bioavailability of the tablets may compensate for the reduction in exposure during the later stages of pregnancy [41]. Therefore, a population pharmacokinetic analysis conducted to assess the statically significance doesn’t show clinically meaningful difference between Lopinavir exposure in pregnant women receiving the tablet and non-pregnant receiving the capsule and dose adjustment isn’t needed [42]. However increased doses may be preferable in obesity (>100kg) and with a previous history of LPV/RTV use and/or compliance issues [43]. Bearing in mind that increasing the dose didn’t correlate with frequent adverse effects Lopinavir is one of the main HIV protease inhibitors recommended in pregnancy with a good safety profile. Pharmacokinetics studies reported lower exposure of LPV in pregnancy [38] due to moderate decrease of total Lopinavir concentrations despite the dose increase [39]. However, the exposure of unbound LPV did not change significantly regardless of trimester or dose [40]. Two cohort studies of 21 women conducted with steady pharmacokinetic evaluations concluding that improving the oral bioavailability of the tablets may compensate for the reduction in exposure during the later stages of pregnancy [41]. Therefore, a population pharmacokinetic analysis conducted to assess the statically significance doesn’t show clinically meaningful difference between Lopinavir exposure in pregnant women receiving the tablet and non-pregnant receiving the capsule and dose adjustment isn’t needed [42]. However increased doses may be preferable in obesity (>100kg) and with a previous history of LPV/RTV use and/or compliance issues [43]. Bearing in mind that increasing the dose didn’t correlate with frequent adverse effects according to a random clinical trial [44] and didn’t result in greater neurodevelopmental risks for HIV positive mothers or uninfected infants [45].
Iris Publishers
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