key: cord-0904837-a45urpfj authors: D'Souza, Rohan; Ashraf, Rizwana; Rowe, Hilary; Zipursky, Jonathan; Clarfield, Lauren; Maxwell, Cynthia; Arzola, Cristian; Lapinsky, Stephen; Paquette, Katryn; Murthy, Srinivas; Cheng, Matthew P.; Malhamé, Isabelle title: Pregnancy and COVID‐19: Pharmacologic Considerations date: 2020-09-21 journal: Ultrasound Obstet Gynecol DOI: 10.1002/uog.23116 sha: 50982ebf1bfdcf5a7e9ebce22218b7d85436db34 doc_id: 904837 cord_uid: a45urpfj The Severe Acute Respiratory Syndrome‐related Coronavirus‐2 (SARS‐CoV2) pandemic has sparked controversy regarding the use of certain routine and investigational pharmacologic interventions during pregnancy and the postpartum period. In this review, we critically appraise guidance in regard to pharmacologic considerations unique to pregnant and lactating women with coronavirus disease (COVID‐19). We summarize the evidence, which supports the routine use of antenatal corticosteroids, magnesium sulfate and low‐dose aspirin where clinically indicated, and if not contraindicated for medical reasons. We highlight that decision‐making about initiation, dose and duration of prophylactic anticoagulation for pregnant patients with COVID‐19 should be made by a multidisciplinary team and must consider disease severity, timing of delivery in relation to disease onset, inpatient versus outpatient status, underlying comorbidities, and contraindications to the use of anticoagulation. We discuss the rationale behind suggested modifications to the use of peripartum analgesia and anaesthesia at the time of the pandemic, as well as considerations specific to mechanically‐ventilated pregnant patients. Finally, we discuss emerging evidence supporting the reduction in mortality in patients with COVID‐19 with the use of corticosteroids, while tabulating up‐to‐date information on the safety of various investigational therapies for COVID‐19. It is hoped that this comprehensive review while providing guidance to clinicians caring for pregnant and postpartum women during the COVID‐19 pandemic will also encourage researchers to consider their inclusion in clinical trials of therapeutic interventions for COVID‐19. This article is protected by copyright. All rights reserved. As of August 16 th 2020, Severe Acute Respiratory Syndrome-related Coronavirus-2 (SARS-CoV-2) was responsible for 21.3 million cases of coronavirus disease and 761,779 deaths globally 1 . In certain regions of the world, up to 15% of pregnant women were found to have positive polymerase-chain reaction testing for SARS-CoV-2 upon admission for delivery 2 . While pregnant women do not appear to be at substantially higher risk of severe manifestations from COVID-19 3 , the disease has resulted in severe maternal morbidity and mortality in both high and low resource settings 4, 5 . Obstetrics is an essential service and the provision of routine obstetric care must continue through pandemics to ensure optimal maternal and fetal health. The This article is protected by copyright. All rights reserved. The first section focuses on the impact of COVID-19 on the use of medications given for pregnancy care. This will include routinely administered medications in pregnancy such as antenatal corticosteroids for fetal lung maturation, magnesium sulfate for fetal neuroprotection and eclampsia prophylaxis/treatment, and low-dose aspirin which is used for prevention of placentally-mediated complications. Anaesthetic considerations will also be discussed, including the use of nitrous oxide and regional analgesia to avoid the administration of general anaesthesia in emergency situations. We also assess the role of thromboprophylaxis in pregnant women with COVID-19. The second section describes the impact of pregnancy on the use of medications that may be given specifically in the setting of COVID-19. This includes guidance on the use of medications during mechanical ventilation, and the safety of investigational medications for COVID-19 during pregnancy and lactation. As such, this review serves as a guide for health care professionals and researchers in various health care disciplines caring for pregnant and postpartum women during the COVID-19 pandemic. This article is protected by copyright. All rights reserved. generated debate during the COVID-19 pandemic: 1) antenatal corticosteroids; 2) magnesium sulfate (MgSo4); and 3) non-steroidal anti-inflammatory drugs (NSAIDs). Practice recommendations have been summarized in Table 1 . There is strong evidence to support the use of a single course of antenatal corticosteroids (betamethasone or dexamethasone) in women at risk of preterm birth between 24 and 34 weeks of gestation. Antenatal corticosteroids have been shown to reduce the risk of perinatal death, respiratory distress syndrome, intraventricular haemorrhage, necrotising enterocolitis, need for respiratory support and neonatal intensive care unit (NICU) admission, even in the current era of advanced neonatal care 6 . More recent evidence suggests that the benefits of antenatal corticosteroids might extend to infants born at 22-24 weeks gestation 7 and between 34 and 36+6 weeks of gestation 8 . However not all guidelines recommend their administration at extremes of prematurity. Corticosteroids were associated with an increased risk of mortality in a systematic review of 30 studies examining their use as adjunctive treatment for influenza 9 . However, it included only one RCT, and the certainty of the available evidence from observational studies was deemed to be low, because of the potential for confounding by indication. Furthermore, the doses used were 4-10 times the typical dose administered in pregnancy for fetal lung maturation. So far, there is no evidence from the current or previous coronavirus outbreaks (e.g., Severe Acute Respiratory This article is protected by copyright. All rights reserved. Syndrome-Coronavirus and Middle East Respiratory Syndrome-Coronavirus) that a single course of corticosteroids given for fetal lung maturation causes maternal complications 10 . Moreover, a weak recommendation has been issued for the use of corticosteroids in patients with acute respiratory distress syndrome (ARDS), based on indirect evidence 11 , and more recently, evidence from RCTs has suggested that a course of corticosteroids may be beneficial for certain patients with COVID-19 pneumonia (see section 4.3). Professional societies continue to support the use of antenatal corticosteroids when indicated for lung maturation among women with COVID-19 10, 12-18 . However, risks and benefits of corticosteroids should be carefully weighed for women with critical illness, and their administration should not delay urgent delivery 15, 16 . Given the lack of robust evidence, several societies have recommended against their use after 34 weeks 10, 12, 16, 17 . Magnesium sulfate (MgSO4) has been shown to be effective for prophylaxis and treatment of seizures in preeclampsia at any gestational age 19 , and for fetal neuroprotection (decreasing risk of cerebral palsy) when administered to women at imminent risk for preterm birth 20 , especially under 30 weeks of gestation. Although MgSO4 may be associated with an increased risk of maternal respiratory muscle weakness, no risk of respiratory failure has been demonstrated 21 . Several professional societies support the use of MgSO4 when indicated among pregnant women with COVID-19 10, 12, 15 . An individual patient assessment of risks and benefits must be performed when using MgSO4, particularly in women with hypoxia 12 . Alternate dose regimens for neuroprotection could be considered on an individual basis, such as a single 4 g IV bolus dose of MgSO4 22 . Moreover, prophylaxis with MgSO4 for women with preeclampsia can be safely withheld in the absence of severe features 12 . As per routine practice, the dose of MgSO4 should be adjusted in patients with acute kidney injury, which may be a feature of COVID-19. Aspirin at doses of 75 to 162 mg inhibits the production of cyclooxygenase isoenzyme 1 leading to decreased platelet production of thromboxane A2, a potent vasoconstrictor 23 . As a result, antenatal low-dose aspirin is recommended as primary and secondary prophylaxis for placentally-mediated complications of pregnancy, including preeclampsia, fetal growth restriction and preterm birth 19, 23 . Human pathogenic coronaviruses, including SARS-CoV-2, bind to target cells through angiotensin-converting enzyme 2 (ACE-2) 24 . Given possible increased expression of ACE-2 in patients taking ibuprofen, concerns were initially raised about use of NSAIDs in patients with COVID-19 25 . However, a rapid systematic review conducted by the World Health Organization (WHO) showed that use of NSAIDs was not associated with severe adverse events, increased acute health care utilization, decreased long-term survival, or reduced quality of life in patients with COVID-19 26 . As such, the known benefits of preeclampsia prevention appear to outweigh hypothetical risks of adverse outcomes of COVID-19 infection related to the usage of low-dose aspirin 27 . Accordingly, the International Federation of Gynecology and Obstetrics (FIGO) and the American College of Obstetricians and Gynecologists (ACOG) have stated that there is insufficient data available to recommend against the use of low dose aspirin for prophylaxis against placentally-mediated complications of pregnancy 15, 17 . Indomethacin is a tocolytic that can be used to suppress preterm labour in order to facilitate administration of antenatal corticosteroids or transfer to a tertiary centre 28 . Although the administration of a single course of indomethacin for the purpose of tocolysis is unlikely to lead to serious maternal adverse events in the context of COVD-19 and pregnancy, its use is associated with an increased risk of neonatal morbidity, including severe intraventricular haemorrhage, necrotizing enterocolitis, and periventricular leukomalacia 29 . Indomethacin can also cause reversible premature closure of the ductus arteriosus if administered after 32 weeks' gestation 28 . Where possible, alternate tocolytics should be used. High rates of thrombotic complications have been reported in patients with severe and critical COVID-19 30 . These events are the result of at least two mechanisms -pulmonary microvascular thrombosis (immunothrombosis) and hospital-associated venous thromboembolism (VTE) 31 . Since pregnancy is a prothrombotic state, the possibility of an This article is protected by copyright. All rights reserved. increased risk of thrombosis in pregnant women with COVID-19 has become an area of concern. However, published data do not suggest that pregnant women have an increased risk of thrombotic complications related to COVID-19 4, 32 . Low molecular weight heparin (LMWH) is the drug of choice for thromboprophylaxis in pregnant women with COVID-19. Its utility, however, is only established for the treatment of VTE, and LMWH may have little or no effect for immunothrombosis. This explains why thrombotic events have been described in those on prophylactic, and even therapeutic LMWH, and suggests that the thrombotic risk from immunothrombosis is unlikely to be lowered by increasing the dose of LMWH, but by consideration of anti-cytokine and anti-viral therapy in carefully selected patients, in an experimental setting 31 . Decisions about initiation and duration of prophylactic anticoagulation in the context of pregnancy and COVID-19 should be made by a multidisciplinary team which includes haematologists, internists/intensivists and obstetricians, and must consider disease severity, the timing of delivery in relation to disease onset, whether the patient is admitted to hospital or self-isolating at home, the underlying prothrombotic risk secondary to comorbidities and the presence of major bleeding from obstetrical or nonobstetrical causes including coagulopathies. We have recently reviewed the published literature and international guidelines, and made clinical practice recommendations for antepartum and postpartum thromboprophylaxis in ambulatory and inpatient pregnant women with COVID-19 (Table 2 ). In summary, based on published literature, there is insufficient evidence to recommend the use of intermediate or therapeutic doses of LMWH, which may increase bleeding risk without reducing thrombotic risk in pregnant patients with COVID-19. There is also insufficient evidence to comment on the role of low-dose aspirin in thromboprophylaxis or anticytokine and antiviral agents in preventing immunothrombosis. These unanswered questions should be addressed in clinical trials. Neuraxial labor analgesia: Neuraxial analgesia is the first choice for intrapartum analgesia in pregnant women with COVID-19 33 . Concerns about the risk of meningitis or encephalitis in the context of active viremia remain theoretical 34 . Thrombocytopenia has been described in certain cohorts of patients with COVID-19, and as such a platelet count should be available to confirm eligibility for the procedure. The platelet cut-off for neuraxial analgesia should be determined by the clinical context, keeping in mind that the risk of clinical deterioration with general anesthesia is far greater than the risk of epidural hematoma with thrombocytopenia 35 . Pre-procedure ultrasound-assistance can be considered to facilitate epidural insertion 36 , while following current guidelines for cleaning and preparing equipment 37 . An early epidural placement may reduce the need for general anaesthesia in case of conversion to caesarean delivery 3, 36 . Although no pharmacological changes in regular dosing have been recommended, a modified epidural infusion regimen (local anesthetic concentration, adjuvants and/or pump settings) may be considered in order to minimize in-person contact with patients with COVID-19 36 . While neuraxial procedures are not considered to be aerosolized generating medical procedures (AGMP), healthcare providers should use droplet precautions and the patient should wear a surgical mask 36 . Nitrous oxide for labour and delivery: Nitrous oxide is a non-flammable gas commonly used for analgesia and general anaesthesia. However, evidence on whether it constitutes an AGMP is currently lacking 38 patients with respiratory symptoms such as the increased risk of respiratory depression, as well as the increased risk of vomiting, which could potentially generate aerosols 41 . Remifentanil should be used on a case-by-case basis, and in the absence of respiratory compromise. Initial concerns around the use of NSAIDs for postpartum analgesia have been allayed by the WHO's rapid systematic review detailed above 26 . NSAIDs can be used for analgesia in postpartum women with COVID-19. Acetaminophen is another safe. Opioids should be used with caution because of the risks of respiratory depression. Pharmacological strategies for the management of Post-dural Puncture Headache should be implemented prior to considering an epidural blood patch. Concerns have been raised about injecting blood in the epidural space in the setting of ongoing viremia 42 . However, providers can proceed with epidural blood patch in cases of debilitating and severe headache. Nasal sphenopalatine ganglion block should be discouraged as it is a potential AGMP 33 . Neuraxial techniques: In order to avoid tracheal intubation and extubation (AGMP) during general anesthesia, neuraxial anesthesia remains the first choice for caesarean delivery. Both spinal or epidural anesthesia are adequate options depending on the clinical context (elective, emergency, or intrapartum). Only essential drugs and equipment should be available in the operating room in order to prevent contamination and wastage. The dosing regimen must be given according to standard of care, while minimising the risk of conversion to general anesthesia. Importantly, significant intraoperative hypotension was reported in pregnant women with COVID-19 43 . As such, an adequate prophylactic strategy, such as a phenylephrine infusion, is strongly recommended 44 . COVID-19 should be rigorously followed to minimise aerosols, which can increase the potential for human-to-human viral transmission 45 . Proper pre-oxygenation and stable hemodynamics should be ensured to maintain optimal placental perfusion. Moreover, rapid neuromuscular block (rocuronium 1.2 mg/kg or succinylcholine 1 mg/kg), and strategies to maximise first pass success such as video-laryngoscope should be performed to prevent cough and limit aerosolization 45, 46 . Section 2. The impact of pregnancy on the pharmacologic management of patients with COVID-19 This article is protected by copyright. All rights reserved. The mainstay of COVID-19 therapy remains optimal supportive care. Optimal mechanical ventilation of the pregnant patient with respiratory failure may require analgesic, sedative and neuromuscular blocking medications. The current critical care approach to sedation is to minimize the use of sedative drugs, because of benefit to mother and fetus. The optimal analgesic and sedative intensive care unit (ICU) regimen during pregnancy is not known. Some drugs are described under "Anaesthesia" above, but safety considerations differ when comparing short-term to long-term use in the ICU. A recent U.S. Federal Drug Administration (FDA) Drug Safety announcement 47 suggested potential risk to the fetal neurodevelopment with long-term maternal sedation, although this report did not specifically mentioning ICU sedation. The ACOG takes issue with this statement, identifying the lack of clinical evidence 48 . Opioids and benzodiazepines are commonly used drugs in the ICU, and there are risks of infant sedation and neonatal abstinence syndrome. However, most will not require NICU admission or medications, if born at term. Case reports describe the use of propofol during mechanical ventilation with no significant harm other than hypotension with an associated decrease in uteroplacental perfusion. A report of propofol infusion in two pregnant women undergoing prolonged neurosurgical procedures describes development of acidosis, but atypical of propofol infusion syndrome 49 . Dexmedetomidine, a sedative alpha-2-agonist, has been used during caesarean delivery and as an infusion in the ICU for a ventilated pregnant woman 50 . This drug crosses the placenta and can induce uterine contractions 51 . Non-depolarizing neuromuscular blocking agents cross the placenta in variable amounts: the fetal-maternal drug concentration ratio of atracurium, vecuronium, rocuronium and pancuronium varies between 0.07 and 0.26 51 . Little is known about the fetal effects of neuromuscular block infusion during pregnancy. While an older report described fetal paralysis and neonatal arthrogryposis following 10-day administration of d-tubo-curarine (as well as several sedatives) 52 , a more recent report described good outcomes after a 10-hour infusion of pancuronium during the third trimester 51 . Prolonged infusion of neuromuscular blocking agents should be avoided or used with caution. Neuromuscular blockade should be used for the shortest duration possible and reversal agents should be available on hand if delivery is imminent. According to the preliminary results of the Randomized Evaluation of Covid-19 Therapy A number of antivirals and host-directed therapies have been repurposed and studied for COVID-19 55 . Although primarily intended for the treatment of other conditions, these drugs have the potential to prevent viral replication, minimize serious morbidity, and offer symptomatic relief to patients with COVID-19 56 . These and several other agents are currently under study with over 3,000 clinical trials registered on the International Clinical Trials Registry Platform for This article is protected by copyright. All rights reserved. commendable but also concerning, due to the risk of unnecessary duplication and the risk of several studies being underpowered. Further, as only a minority of studies include pregnant women, there is also a risk that the data are not generalizable to the pregnant and postpartum population 57, 58 . A summary of available information on the safety of the most widely studied investigational drugs in pregnant and lactating women is presented in Table 3 . With regard to pregnancy, the risk has been described in terms of teratogenicity (congenital malformations) and other toxicity (fetal/neonatal loss, prematurity and concerns about growth and development). An attempt has been made to summarize the highest quality data available, in the absence of which data has been extrapolated from case reports and animal studies. Drug transfer into breast milk and safety in lactation primarily depends upon the medication's molecular weight, protein binding, half-life, fat solubility, maternal plasma concentration and neonatal oral bioavailability 59 . The most useful and accurate measure of exposure is the relative infant dose (RID), which provides a weight-based approximation of the neonatal dose as a percentage of the maternal dose 59 . This is calculated as [(infant dose in mg/kg per day)/(maternal dose in mg/kg per day)], and expressed as a percentage of the mother's dose. It has been recommended that an RID of more than 10% should be the theoretical level of This article is protected by copyright. All rights reserved. concern for most medications 60 ; however, this level should be considered relative, and each situation should be evaluated individually, according to the overall toxicity of the medication 59 This article is protected by copyright. All rights reserved. activity, and may have a role in decreasing the cytokine release associated with organ damage in COVID-19. This is being currently investigated as part of a randomized trial 71 Although many of these medications are considered safe for use during pregnancy and lactation, most clinical trials exclude women that are pregnant or lactating 57, 58 , due to concerns regarding the effect of these medications on mothers and fetuses. Since women during pregnancy do not lack the capacity to make an informed choice about participation in research 73 , data outlined in Table 3 This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. • Continue to administer antenatal corticosteroids when indicated for fetal lung maturation. • Insufficient evidence to strongly recommend use after 34 weeks of gestation. • Caution should be applied among women with critical illness. • Since respiratory muscle weakness is a potential side effect of magnesium sulfate, it should be used judiciously among women with established respiratory distress. Non-steroidal antiinflammatory drugs (NSAIDs) • There is insufficient data available to recommend against low dose aspirin prevention of placentally-mediated complications. • There are no COVID-19-specific contraindications for indomethacin use as a tocolytic. • No contraindication to the use of NSAIDs for postpartum analgesia. This article is protected by copyright. All rights reserved. Registry data indicates 7 birth defects in 85 exposed women and 4 in 95 women whose partners were exposed 81 . WHO. 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All rights reserved. levels in milk; no infant safety data in lactation at this time. Case series and registry data suggest no increased rate of congenital abnormalities [84] [85] [86] [87] Case series and registry data suggests no increased rate of spontaneous abortions 84