Hostname: page-component-7c8c6479df-fqc5m Total loading time: 0 Render date: 2024-03-28T16:18:05.080Z Has data issue: false hasContentIssue false

COVID-19: can we treat the mother without harming her baby?

Published online by Cambridge University Press:  25 January 2021

Michael D. Wiese
Affiliation:
Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia
Mary J. Berry
Affiliation:
Centre for Translational Physiology & Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand
Pravin Hissaria
Affiliation:
Department of Immunology, SA Pathology, Royal Adelaide Hospital, Adelaide University, Adelaide, South Australia, Australia
Jack R.T. Darby
Affiliation:
Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia Early Origins of Adult Health Research Group, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia
Janna L. Morrison*
Affiliation:
Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia Early Origins of Adult Health Research Group, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia
*
Address for correspondence: Janna L. Morrison, Australian Research Council Future Fellow (Level 3), Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, GPO Box 2471, Adelaide 5001, SA, Australia. Email: Janna.Morrison@unisa.edu.au
Rights & Permissions [Opens in a new window]

Abstract

Medical care is predicated on ‘do no harm’, yet the urgency to find drugs and vaccines to treat or prevent COVID-19 has led to an extraordinary effort to develop and test new therapies. Whilst this is an essential cornerstone of a united global response to the COVID-19 pandemic, the absolute requirements for meticulous efficacy and safety data remain. This is especially pertinent to the needs of pregnant women; a group traditionally poorly represented in drug trials, yet a group at heightened risk of unintended adverse materno-fetal consequences due to the unique physiology of pregnancy and the life course implications of fetal or neonatal drug exposure. However, due to the complexities of drug trial participation when pregnant (be they vaccines or therapeutics for acute disease), many clinical drug trials will exclude them. Clinicians must determine the best course of drug treatment with a dearth of evidence from either clinical or preclinical studies, where at least in the short term they may be more focused on the outcome of the mother than of her offspring.

Type
Review
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
Copyright
© The Author(s), 2021. Published by Cambridge University Press in association with the International Society for Developmental Origins of Health and Disease

Background

Since the beginning of 2020, when most of us had not heard of COVID-19, as of 8 October 2020,1 there have been over 36 million cases of SARS-CoV-2 and 1 million deaths from COVID-19 globally. The devastating impact of COVID-19 on communities worldwide is clear. Although vaccination is a key part of our global response to this crisis, we need a more immediate armamentarium of safe drugs to treat those infected with SARS-CoV-2 now, and during the months or years ahead whilst vaccine development progresses. There is no definite timeline on vaccine development. Even if a vaccine against SARS-CoV-2 is developed, its success depends on the development of lasting immunity, stability of the virus, availability and efficacy of the vaccine, and the willingness of the population to be vaccinated.

Furthermore, it remains important to acknowledge that we as a population are susceptible to novel coronaviruses, with three life-threatening variants emerging in the past 20 years. These novel viruses will require treatment and thus understanding the impact of the disease, its vaccine and treatment on the fetus and child will future-proof our pharmaceutical toolbox. In 2017, the WHO identified 17 diseases for which vaccine development was a priority: MERS and SARS, both coronaviruses, were highly ranked,2 yet neither have an effective vaccine. Of 224 candidate vaccines, only 2.7% have advanced to Phase 1 trials.Reference Maslow3 Thus, despite vaccine candidates for SARS-CoV-2 entering human safety trials, there may be some time before an effective vaccine is available. Vaccines for SARS have been complicated by hyperimmune responses following infection in vaccinated individuals, likely due to antibodies that target the spike protein on the virus.Reference Jiang, He and Liu4 Over the last 20 years, despite societal awareness and engagement, progress with vaccine development programmes (such as for HIVReference Laher, Bekker, Garrett, Lazarus and Gray5 and Zika virusReference Lunardelli, Apostolico, Fernandes and Santoro Rosa6) has been slow, and proportional engagement in clinical trial participation across ethnic and socio-economic groups may not have been achieved.Reference Cobb, Singer and Davis7 Even if a safe, effective SARS-CoV-2 vaccine is found, significant vaccine hesitancy and refusal remains an important issue for both health care workersReference Wilson, Zaytseva and Bocquier8,Reference Lau, Lee and Wong9 and the wider community which may limit vaccine uptakeReference Detoc, Bruel, Frappe, Botelho-Nevers and Gagneux-Brunon10 and virus elimination strategies.Reference Phadke, Bednarczyk, Salmon and Omer11

Critically, whilst vaccine-preventable disease is a major health initiative, pregnant women are traditionally amongst the last to access new vaccinations due to the inherent ethical implications and concerns around potential fetal toxicity. Many vaccines, such as those recommended for seasonal influenza, need to be administered annually, as prior immunisation confers limited longevity of protection, thus immunisation prior to pregnancy is not assured of offering protection during pregnancy. There is emerging evidence of reinfection,Reference Bongiovanni12Reference Goldman, Wang and Roltgen14 which suggests that vaccination for SARS-CoV2 may last for a limited period; however, we are too early in our learnings to fully appreciate the duration of immunity after contracting SARS-CoV-2 or receiving an effective vaccine. Thus, even if current claims of an approved vaccine by the end of 2020 are realised, ensuring global access to an effective vaccine will take far longer, and, even if available, vaccination uptake may be lower than required to slow the spread with a vaccine that is only partially effective, especially in women of reproductive age. Indeed, women of reproductive age, particularly those aged 20–29 years are also the group most likely to be SARS-CoV-2-positive.15 Thus, we must be prepared to provide the best care to pregnant women whilst also reducing harm to their baby. Regardless of whether a vaccine is available, effective and safe, there will be a need to treat pregnant women with symptomatic COVID-19 and/or the next novel coronavirus that enters the human population through zoonotic infection comes along. Understanding the safety of these drugs for pregnant women and their babies will future-proof our clinical toolbox against COVID-19.

COVID-19 in pregnancy

There is evidence for unique immunological changes in each stages of pregnancy that result in a different response to viral infections compared to non-pregnant women,Reference Mor and Cardenas16 and pregnant women are identified as being part of a vulnerable population by RANZCOG.17 Specifically, they are more susceptible to respiratory infections and thus it is possible they may also be more susceptible to SARS-CoV-2Reference Liu, Wang, Zhao, Kwak-Kim, Mor and Liao18, although susceptibility varies.Reference Ryan, Purandare, McAuliffe, Hod and Purandare19 Whilst there is evidence that pregnancy is not related to severity of disease,Reference Ryan, Purandare, McAuliffe, Hod and Purandare19Reference Molteni, Astley and Ma21 poor maternal outcomes such as ventilation and ECMO have been reported.Reference Ronnje, Länsberg, Vikhareva, Hansson, Herbst and Zaigham22,Reference Zambrano, Ellington and Strid23 The prevalence of SARS-CoV-2 in a community is an important factor when determining risk of exposureReference Rozycki and Kotecha24,Reference Pierce-Williams, Burd and Felder25 and this will vary both across and within countries. In the US and UK, 7–15% of women presenting at hospital for term delivery tested positive for SARS-CoV-2 in March/April 2020.Reference Rozycki and Kotecha24,Reference Prabhu, Cagino and Matthews26,Reference Allotey, Stallings and Bonet27 In New York, 10% of 675 pregnant women (>20 weeks) tested positive and concerningly 78% of them were symptomatic.Reference Prabhu, Cagino and Matthews26 In contrast, other studies suggest that 14–70% of pregnant women who tested positive are asymptomatic.Reference Pettirosso, Giles, Cole and Rees28Reference Smith, Seo and Warty30 The course of COVID-19 in pregnancy has been described and includes fever, coughing and dyspnea with severe cases including acute respiratory disease.Reference Ryan, Purandare, McAuliffe, Hod and Purandare19,Reference Pierce-Williams, Burd and Felder25,Reference Allotey, Stallings and Bonet27,Reference Pereira, Cruz-Melguizo, Adrien, Fuentes, Marin and Perez-Medina31Reference Khalil, Kalafat and Benlioglu34 Pregnant women may have more pulmonary infiltrate than non-pregnant women,Reference Xu, Shao and Bao29 although most experience mild disease.Reference Ryan, Purandare, McAuliffe, Hod and Purandare19,Reference Turan, Hakim, Dashraath, Jeslyn, Wright and Abdul-Kadir35,Reference Trippella, Ciarcià and Ferrari36 A systematic review has highlighted the increased risk of ICU support needed for pregnant women with COVID-19 compared to non-pregnant women of equivalent age.Reference Allotey, Stallings and Bonet27 Symptomatic pregnant women with COVID-19, particularly those who develop pneumonia, may be at increased risk of delivering their baby preterm by caesarean section due to maternal complications.Reference Pierce-Williams, Burd and Felder25,Reference Allotey, Stallings and Bonet27,Reference Smith, Seo and Warty30,Reference Khalil, Kalafat and Benlioglu34,Reference Turan, Hakim, Dashraath, Jeslyn, Wright and Abdul-Kadir35,Reference Della Gatta, Rizzo, Pilu and Simonazzi37Reference Oncel, Akın and Kanburoglu40 Preterm delivery puts the neonate at increased risk of poor immediate and longer-term outcomes.Reference Berry, Foster, Rowe, Robertson, Robson and Pierse41 There is also evidence that these pregnancies are associated with greater risk of fetal distress, stillbirth, miscarriage, low birth weight and respiratory distress in the newborn.Reference Smith, Seo and Warty30,Reference Yang, Wang, Zhu and Liu32,Reference Yan, Guo and Fan33,Reference Trippella, Ciarcià and Ferrari36,Reference Panahi, Amiri and Pouy42 Overall, however, for term-born infants whose mothers have COVID-19, neonatal outcomes are good,Reference Trippella, Ciarcià and Ferrari36 despite a higher risk of bacterial pneumoniaReference Zhang, Dong and Ming43 and, although rates of admission to neonatal intensive care units are high,Reference Allotey, Stallings and Bonet27 few neonatal deaths have been reported.Reference Yan, Guo and Fan33 Based on the time course of the appearance of SARS-CoV-2 across the globe (Fig. 1), most publications to date report data on women who contract COVID-19 in the third trimester.Reference Smith, Seo and Warty30,Reference Khalil, Kalafat and Benlioglu34,Reference Turan, Hakim, Dashraath, Jeslyn, Wright and Abdul-Kadir35,Reference Woodworth, Olsen and Neelan44 Thus, the feto-maternal complications of infection with SARS-CoV-2 in the first or second trimester are currently uncertain.Reference Prabhu, Cagino and Matthews26 Understanding the impact of the timing of infection on the course of a pregnancy and long-term outcomes in the offspring will take many years in the clinical population. Furthermore, few studies have included contemporaneous SARS-CoV-2-negative pregnancies as a control group, reducing the impact of the data. For example, meta-analysis of studies that included a pregnant SARS-CoV-2-negative control group shows no significant relationship between SARS-CoV-2 infection and preterm delivery.Reference Melo and Araújo45 Lastly, there are many systematic reviews of small studies with overlapping reporting dates. Thus, for all who we know regarding SARS-CoV-2 in pregnancy, the true impact is not clear. From this perspective, prevention of SARS-CoV-2 is the best option,Reference Dotters-Katz and Hughes39 and an effective vaccine may allow this to occur.

Fig. 1. Timeline showing the appearance and progression of COVID-19 globally in relation to gestation length to illustrate our current inability to understand the true impact of COVID-19 on offspring. Data sourced from Refs. 46–50.

Vertical transmission of COVID-19 in pregnancy

Many studies have focused on whether COVID-19 is vertically transmitted from mother to her fetus or if the risk of exposure to the baby occurs during the postnatal period. Theoretically, vertical transmission remains possible. Angiotensin converting enzyme 2, a target of SARS-CoV-2 cell entry, and the spike glycoprotein of SARS-CoV2 have been found on the syncytiotrophoblast cells of the placental villi that form the interface between mother and fetus in the placenta.Reference Taglauer, Benarroch and Rop51 Many case or small studies have been performed and systematic reviews of these studies have not identified evidence for vertical transmission.Reference Rozycki and Kotecha24,Reference Prabhu, Cagino and Matthews26,Reference Xu, Shao and Bao29,Reference Yang, Wang, Zhu and Liu32,Reference Zhang, Dong and Ming43,Reference Zheng, Guo, He, Wang, Yu and Ye52Reference Lamouroux, Attie-Bitach, Martinovic, Leruez-Ville and Ville61 There is no evidence that vaginal delivery, breastfeeding or remaining with the mother postnatally increase the risk of neonatal infection, as long as appropriate contact precautions are meticulously applied, whilst the mother remains infectious.Reference Walker, O’Donoghue and Grace62 However, this issue focuses on the concept that the only risk of a SARS-CoV2-positive mother to the fetus is that the fetus/baby may also get COVID-19. Crucially, we do not know the impact of maternal COVID-19 and/or the pharmacological treatment of COVID-19 on the pregnant woman on the developing fetus and how this will impact the offspring across the course of their lives. The principles of developmental origins of health and disease (DOHaD) highlight the importance of taking a life course approach and understanding the mechanisms linking exposures during pregnancy on offspring health in infancy, childhood, adulthood and old age,Reference McMillen and Robinson63Reference Barker, O’Brien, Wheeler and Barker65 and this must be considered in the case of COVID-19.

Drug safety in pregnancy

Historically, most Phase 3 drug trials have included men, and in recent times, non-pregnant women. In many cases, information about the safety of drug use during pregnancy in terms of birth outcomes is collected many years after the drug comes onto the market and is obtained through surveillance programmes such as the now defunct Motherisk programme.Reference Koren66Reference Riggin, Frankel, Moretti, Pupco and Koren69 The problem with this long delay from the drug entering the market and the slow gathering of, in most instances, negative outcomes makes it difficult to understand the true prevalence of poor outcomes and the mechanisms that underlie them. This delays an understanding of the actual impact of drug exposure during pregnancy to the offspring and thus delays changes in practice such as use of another drug, a change in dosing or discussion about termination of pregnancy.Reference Koren66Reference Riggin, Frankel, Moretti, Pupco and Koren69 Inclusion of women of reproductive age and pregnant women in clinical trials is an important feature of minimising harm to the fetus. A recent white paper has been released by the WHO that uses learnings from HIV to propose guidelines for accelerating such data and the key use of physiologically based pharmacokinetic data to inform clinical trials in pregnant women.Reference Eke, Olagunju and Momper70

Any drug given to a pregnant woman, as well as its metabolites, will be distributed to both the maternal and fetal compartments. Fetal development is a dynamic process; the consequences of drug exposure are dependent on the specific stage of fetal development at the time of the exposure. Thus, it is necessary to consider that, in addition to the mother, the fetus is also a patient who will be exposed to the drug.Reference Stefanovic71 Exposure to toxic drug effects may lead to fetal demise, miscarriage, disruption of organ formation (for instance, as seen with devastating consequences with thalidomideReference Lenz72), impaired fetal growth or altered organ function. These all have adverse implications for the wellbeing of the baby and may result in lifelong health impairment. This highlights the importance of the timing of drug exposure during pregnancy (Fig. 2) and the need for preclinical studies that are specifically designed to address questions around safety of maternal drug treatment, at different periods of gestation, on the baby.Reference Darby, Varcoe, Orgeig and Morrison73 These studies cannot simply look for congenital malformations, as drugs may be more nuanced effects with the true extent of problems only manifesting later in life. For example, our previous work has shown that maternal treatment with antidepressants can result in changes in body composition in childhood.Reference Grzeskowiak, Gilbert and Morrison74Reference Grzeskowiak, Morrison and Henriksen77 Some medications proposed for treatment of COVID-19 in pregnancy already have a widely characterised maternal and infant safety profile (e.g., antiretroviral drugs used to reduce vertical transmission rates of HIV), which enables better decision-making between clinicians and their patients. However, many important knowledge gaps around the safety of other drugs that may potentially be used to treat pregnant women infected with SARS-CoV-2 remain.

Fig. 2. The timing, dose and duration of fetal exposure to medications to treat the symptoms of COVID-19 in the mother will interact to determine the impact on the fetus with organ-specific effects that will impact health across the life course of the offspring. Adapted from Refs. 78 and 79.

Drug treatment of SARS-CoV-2

Until now, treatment of COVID-19 has focused on the use of antiviral medications (e.g., remdesivirReference Pierce-Williams, Burd and Felder80) and immunomodulators (e.g., dexamethasone, hydroxychloroquine, tocilizumab and anakinra) to dampen an exaggerated immune response to SARS-CoV-2 infection in acutely unwell patients.Reference Wu, Wang and Kuo81 Other than the use of dexamethasone in patients with severe COVID-19, there is no conclusive evidence that any of these therapies increase survival, although most of the trials that have been conducted have yet to report their findings. Prophylaxis against infection will no doubt be a strategy that is explored, although early positive signs with hydroxychloroquine were followed by evidence of a lack of efficacyReference Boulware, Pullen and Bangdiwala82 and concerns about increased mortality, development of cardiac arrythmias and cardiac death.Reference Mehra, Desai, Ruschitzka and Patel83

Selection criteria for drugs to treat the symptoms of COVID-19 in pregnant women

When a pregnant woman requires management of COVID-19, the clinician will be presented with two patients: a pregnant woman and a fetus. However, it is the pregnant woman who will be experiencing the symptoms of COVID-19 and who will require treatment with the primary concern being the mothers’ wellbeing. Her symptoms of COVID-19 may result in hypoxemia, hyperthermia or hypoglycemia in the fetus, and these could all have negative consequences during fetal as well as postnatal life. However, it is important to consider that some treatments for the symptoms of COVID-19 in the mother may have greater or fewer effects on the fetus. These effects may be short or long term and may manifest as congenital malformations, or changes in the structure and function of organ systems that persist throughout the life course and confer a greater risk of chronic disease later in life. This later point raises concerns for COVID-19 in the context of the DOHaD hypothesis (Fig. 3). Thus, it is important to ensure that preclinical studies are performed to fill the gaps in our knowledge about the effects of these drugs on the pregnant mother, the developing fetus and the offspring from childhood to adulthood. This will allow the clinician the opportunity to pair this knowledge with the best evidence around treatment of COVID-19 to select a treatment strategy that will result in the best outcomes for the pregnant woman with the least risk of negative outcomes for the offspring.

Fig. 3. It is necessary to identify COVID-19 drug therapies for pregnant women who do not harm their babies’ growth and development or the health of their offspring throughout their life. Studies in humans will take years to decades to perform, but preclinical studies in appropriate models will accelerate our knowledge.

We referred to the current guidelines for care of COVID-19 patients and inspected the clinical trials registries (e.g., ClinicalTrials.gov and ANZCTR.org.au) as well as publications on emerging clinical evidence for effectiveness in treatment of COVID-19. Here, we summarise some of the medications used in the treatment of COVID-19 and the knowledge base about their use in pregnancy and the impact on the fetus and offspring. Clearly, this is a dynamic area, and drugs for use in treating COVID-19 may change as data emerge from ongoing clinical trials, and thus Table 1 is not comprehensive but reflects the current knowledge base.

Table 1. Drug treatments for COVID-19 and our knowledge about their safety for use in pregnancy

No or limited data of many of the medications in clinical trials for the treatment of COVID-19 in pregnant women and their offspring

Clinical prioritisation means that in most settings, the immediate health needs of the mother outweigh theoretical health implications of drug exposure to the fetus. For example, a PubMed search of ‘Remdesivir and pregnancy’ produced 13 results (6 October 2020), including 4 case reports with polypharmacy treatment of COVID-19 which contained little to no fetal outcome data and one case series of 64 pregnant women with severe or critical COVID-19, 16 of whom received remdesivir (including 65% of those women assessed as being critical) an average of 10.5 days after symptoms emerged.Reference Pierce-Williams, Burd and Felder80,Reference Anderson, Schauer, Bryant and Graves84 In this case, series pregnancy and neonatal outcomes were reported, but the sample was not large enough to disentangle the effects of a mother with COVID-19 from those of exposure to remdesivir (and other treatments) on the fetus and there was no follow-up after birth. Concerningly, despite an absence of knowledge of placental transfer, remdesivir is deemed safe for the treatment of COVID-19 in pregnancy based on very limited data, with evidence of safety in pregnancy arising from a single study in a pregnant patient with Ebola, published in 2017.Reference Mulangu, Dodd and Davey85,Reference Louchet, Sibiude, Peytavin, Picone, Tréluyer and Mandelbrot86

Many of the candidate drugs are also used in other immune-mediated or inflammatory conditions, many of which affect women of reproductive age. Thus, even if these drugs are not used in COVID-19, better understanding of the effects of these drugs in pregnancy will be a significant and clinically valuable contribution to fetal safety of drugs used in women. There is an urgent need to utilise appropriate animal models, rather than women facing life-threatening illness, to establish the acute and longer-term outcomes of fetal drug exposure.

Preclinical models for determining the safety of drug treatments in pregnancy

Unfortunately, many studies of the effects of drugs during pregnancy in humans simply focus on gross pregnancy outcomes (e.g., gestational age at birth) and the overall physical condition of the baby at birth (e.g., congenital malformations). The long latency and other confounding factors between fetal drug exposure and later-life wellbeing prohibit most human long-term follow-up studies. Preclinical studies of the effects of maternal drug treatment on her offspring prior to birth and throughout the life course (Fig. 2) must be performed in a species where the timing of fetal development aligns with that of humans. Although non-human primates such as Macaca fascicularis Reference Barbier and Bélanger87 may be the gold standard for drug testing, due to ethical concerns and logistical constraints, they may not be appropriate for characterisation of fetal impact of drug exposures (myometrial contraction after fetal surgery for catheter placement and technical limitations of fetal size (adults weigh 1.5–2 kg)).

Sheep and guinea pigs have been extensively used in preclinical studies that have been used to build an evidence base for therapies in obstetrics and paediatrics,Reference Morrison, Berry and Botting88,Reference Morrison, Botting and Darby89 most notably the use of antenatal steroids in women at risk of preterm delivery. The effects of a range of maternal drug treatments, including antidepressants,Reference Morrison, Chien, Gruber, Rurak and Riggs90Reference Morrison, Rurak and Chien93 rosiglitazone,Reference Muhlhausler, Morrison and McMillen94 resveratrol,Reference Darby, Saini and Soo95 betamethasoneReference Berry, Polk, Ikegami, Jobe, Padbury and Ervin96,Reference Berry, Gray, Wright, Dyson and Wright97 and methamphetamine,Reference Soo, Wiese and Dyson98 on physiological outcomes in the fetus and juvenile have been studied in sheep and guinea pigs. There are advantages and disadvantages to each model. In sheep models, fetal surgery can be performed to allow collection of paired blood samples from the maternal and fetal circulation and determine the fetal response to maternal drug treatment in real time.Reference Morrison, Chien, Gruber, Rurak and Riggs90Reference Morrison, Rurak and Chien93,Reference Morrison, Riggs and Rurak99 In guinea pigs, one can comprehensively assess the longer-term effects of fetal drug exposure to primary school age equivalencyReference Berry, Gray, Wright, Dyson and Wright97,Reference Soo, Wiese and Dyson98,Reference Dyson, Palliser and Wilding100Reference Shaw, Palliser, Dyson, Hirst and Berry103 or adulthood.Reference Sarr, Thompson, Zhao, Lee and Regnault104Reference Thompson, Sarr, Piorkowska, Gros and Regnault106 Detailed fetal physiological studies are not possible in human pregnancy and similarly, waiting several years for the effects of fetal exposure in humans to become manifest is unethical and may result in ongoing harm whilst pregnant women continue to receive drugs that are not appropriate for use in pregnancy.

Separation of vertical versus early postnatal transmission of SARS-CoV-2 remains challenging.Reference Della Gatta, Rizzo, Pilu and Simonazzi37,Reference Di Mascio, Khalil and Saccone38 However, the impact of COVID-19 on the fetus per se appears to primarily relate to the overall clinical condition of the mother. Thus, the primary aim of preclinical studies is to identify which of the potential therapeutic options for COVID-19 are likely to have minimal or no effect on the fetus and thus the child and later life adult. Some agents under review for use in COVID-19 are already used in pregnancy for other conditions (e.g., lopinavir and ritonavir are used in HIV treatment). However, despite widespread clinical use, it is not always clear whether any adverse effects on her child are due to the effects of maternal viral infection, the mothers’ other co-morbidities, or the effects of the candidate drug on fetal or childhood growth or physiological function; such studies must be performed in rigorous preclinical models of pregnancy in a physiologically relevant species.

It is known that up to 99% of women take a prescribed or over the counter medication during pregnancy.Reference Gagne, Maio, Berghella, Louis and Gonnella107,Reference Lacroix, Damase-Michel, Lapeyre-Mestre and Montastruc108 In addition to this existing medication use, women with COVID-19 will be treated with a range of medications for symptom management. Furthermore, as social isolation is known to adversely impact on mental health, pregnant women during the pandemic, with or without COVID-19, may therefore also require treatment for mental health disorders.Reference Berthelot, Lemieux, Garon-Bissonnette, Drouin-Maziade, Martel and Maziade109 Thus, complications relating to polypharmacy is a concern, especially if access to usual health care providers is hampered as a result of the pandemic. SARS-CoV-2 infection and the need for pharmacological intervention need to account not only for the medications required to treat the infection, but their interaction with a panoply of medications needed to treat other non-COVID-19 diseases.

Concluding remarks

If clinicians have the choice of medications believed to have equitable efficacy for maternal symptoms, the fetal and postnatal impact of the drug will inform important maternal therapy choices. Ensuring rigorously tested, high-quality information is available for clinicians, women and their families is paramount to avoid the unintended consequences of poorly designed, inappropriately tested drug regimens becoming an accepted part of clinical care.Reference Zhai, Lye and Kesselheim110 Treatment of COVID-19 represents a profound challenge to physicians across the globe. The best treatments are yet to be established, leading to an unprecedented explosion in new drug therapy trials. Pregnant women are especially vulnerable to the effects of COVID-19, yet we are without clear guidance on drugs that are effective for the mother but are also safe for her developing fetus. Given the well-documented issues surrounding drug research participation during pregnancy,Reference Heyrana, Byers and Stratton111 pregnant women, despite vulnerability to COVID-19, are likely to be amongst the last clinical groups to have access to robust scientific evidence to guide clinical decision-making.Reference Zhai, Lye and Kesselheim110 Simply waiting for an effective vaccine to become available, or for herd immunity to take effect, is an unacceptably risky strategy. To reduce the latency in human safety and efficacy trials, we highlight the need to capitalise on well-established perinatal translational platforms to firstly test the acute fetal effects (sheepReference Morrison, Berry and Botting88) and secondly assess any adverse pregnancy or longer-term outcomes on offspring (guinea pigsReference Morrison, Botting and Darby89).

Financial support

JLM was funded by an ARC Future Fellowship (Level 3; FT170100431).

Conflicts of interest

The authors have no competing interests to disclose.

References

WHO. Annual review of diseases prioritized under the Research and Development Blueprint. Information consultation, 24–25 January 2017. 2017. http://www.who.int/blueprint/what/research-development/2017-Prioritization-Long-Report.pdf?ua=1 Google Scholar
Maslow, JN. The cost and challenge of vaccine development for emerging and emergent infectious diseases. Lancet Glob Health. 2018; 6 (12), e1266e1267.CrossRefGoogle ScholarPubMed
Jiang, S, He, Y, Liu, S. SARs vaccine development. Emerg Infect Diseases. 2005; 11 (7), 10161020.CrossRefGoogle ScholarPubMed
Laher, F, Bekker, LG, Garrett, N, Lazarus, EM, Gray, GE. Review of preventative HIV vaccine clinical trials in South Africa. Arch Virol. 2020; doi: 10.1007/s00705-020-04777-2.CrossRefGoogle ScholarPubMed
Lunardelli, VAS, Apostolico, JS, Fernandes, ER, Santoro Rosa, D. Zika virus-an update on the current efforts for vaccine development. Hum Vaccin Immunother. 2020; doi: 10.1080/21645515.2020.1796428.Google ScholarPubMed
Cobb, EM, Singer, DC, Davis, MM. Public interest in medical research participation: differences by volunteer status and study type. Clin Transl Sci. 2014; 7 (2), 145149.CrossRefGoogle ScholarPubMed
Wilson, R, Zaytseva, A, Bocquier, A, et al. Vaccine hesitancy and self-vaccination behaviors among nurses in southeastern France. Vaccine. 2020; 38 (5), 11441151.CrossRefGoogle ScholarPubMed
Lau, LHW, Lee, SS, Wong, NS. The continuum of influenza vaccine hesitancy among nursing professionals in Hong Kong. Vaccine. 2020; doi: 10.1016/j.vaccine.2020.08.038.CrossRefGoogle ScholarPubMed
Detoc, M, Bruel, S, Frappe, P, Botelho-Nevers, E, Gagneux-Brunon, A. Intention to participate in a COVID-19 vaccine clinical trial and to get vaccinated against COVID-19 in France during the pandemic. medRxiv. 2020; doi: 10.1101/2020.04.23.20076513.Google Scholar
Phadke, VK, Bednarczyk, RA, Salmon, DA, Omer, SB. Association between vaccine refusal and vaccine-preventable diseases in the United States: a review of measles and pertussis. JAMA. 2016; 315 (11), 11491158.CrossRefGoogle ScholarPubMed
Bongiovanni, M. COVID-19 re-infection in an healthcare worker. J Med Virol. 2020; doi: 10.1002/jmv.26565.Google Scholar
Bruni, M, Cecatiello, V, Diaz-Basabe, A, et al. Persistence of anti-SARS-CoV-2 antibodies in non-hospitalized COVID-19 convalescent health care workers. J Clin Med. 2020; 9 (10).CrossRefGoogle ScholarPubMed
Goldman, JD, Wang, K, Roltgen, K, et al. Reinfection with SARS-CoV-2 and failure of humoral immunity: a case report. medRxiv. 2020; doi: 10.1101/2020.09.22.20192443.Google ScholarPubMed
Mor, G, Cardenas, I. The immune system in pregnancy: a unique complexity. Am J Reprod Immunol. 2010; 63 (6), 425433.CrossRefGoogle ScholarPubMed
Liu, H, Wang, LL, Zhao, SJ, Kwak-Kim, J, Mor, G, Liao, AH. Why are pregnant women susceptible to COVID-19? An immunological viewpoint. J Reprod Immunol. 2020; 139, 103122.CrossRefGoogle ScholarPubMed
Ryan, GA, Purandare, NC, McAuliffe, FM, Hod, M, Purandare, CN. Clinical update on COVID-19 in pregnancy: A review article. J Obstet Gynaecol Res. 2020; 46 (8), 12351245.CrossRefGoogle ScholarPubMed
Qiancheng, X, Jian, S, Lingling, P, et al. Coronavirus disease 2019 in pregnancy. Int J Infect Dis. 2020; doi: 10.1016/j.ijid.2020.04.065.CrossRefGoogle ScholarPubMed
Molteni, E, Astley, CM, Ma, W, et al. SARS-CoV-2 (COVID-19) infection in pregnant women: characterization of symptoms and syndromes predictive of disease and severity through real-time, remote participatory epidemiology. medRxiv. 2020; doi: 10.1101/2020.08.17.20161760.Google ScholarPubMed
Ronnje, L, Länsberg, JK, Vikhareva, O, Hansson, SR, Herbst, A, Zaigham, M. Complicated COVID-19 in pregnancy: a case report with severe liver and coagulation dysfunction promptly improved by delivery. BMC Pregnancy Childbirth. 2020; 20 (1), 511.CrossRefGoogle ScholarPubMed
Zambrano, LD, Ellington, S, Strid, P, et al. Update: characteristics of symptomatic women of reproductive age with laboratory-confirmed SARS-CoV-2 infection by pregnancy status — United States. MMWR Morb Mortal Wkly Rep. 2020; 69, 16411647.CrossRefGoogle ScholarPubMed
Rozycki, HJ, Kotecha, S. Covid-19 in pregnant women and babies: what pediatricians need to know. Paediatr Respir Rev. 2020; 35, 3137.Google ScholarPubMed
Pierce-Williams, RAM, Burd, J, Felder, L, 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 (3), 100134.CrossRefGoogle ScholarPubMed
Prabhu, M, Cagino, K, Matthews, KC, et al. Pregnancy and postpartum outcomes in a universally tested population for SARS-CoV-2 in New York City: a prospective cohort study. Bjog. 2020; doi: 10.1111/1471-0528.16403.CrossRefGoogle Scholar
Allotey, J, Stallings, E, Bonet, M, et al. Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis. BMJ. 2020; 370, m3320.CrossRefGoogle ScholarPubMed
Pettirosso, E, Giles, M, Cole, S, Rees, M. COVID-19 and pregnancy: a review of clinical characteristics, obstetric outcomes and vertical transmission. Aust N Z J Obstet Gynaecol. 2020; doi: 10.1111/ajo.13204.CrossRefGoogle ScholarPubMed
Xu, S, Shao, F, Bao, B, et al. Clinical manifestation and neonatal outcomes of pregnant patients with coronavirus disease 2019 pneumonia in Wuhan, China. Open Forum Infect Dis. 2020; 7 (7), ofaa283.CrossRefGoogle ScholarPubMed
Smith, V, Seo, D, Warty, R, et al. Maternal and neonatal outcomes associated with COVID-19 infection: a systematic review. PLoS One. 2020; 15 (6), e0234187.CrossRefGoogle ScholarPubMed
Pereira, A, Cruz-Melguizo, S, Adrien, M, Fuentes, L, Marin, E, Perez-Medina, T. Clinical course of coronavirus disease-2019 in pregnancy. Acta Obstet Gynecol Scand. 2020; 99 (7), 839847.CrossRefGoogle ScholarPubMed
Yang, Z, Wang, M, Zhu, Z, Liu, Y. Coronavirus disease 2019 (COVID-19) and pregnancy: a systematic review. J Matern Fetal Neonatal Med. 2020; doi: 10.1080/14767058.2020.1759541.CrossRefGoogle ScholarPubMed
Yan, J, Guo, J, Fan, C, et al. Coronavirus disease 2019 (COVID-19) in pregnant women: a report based on 116 cases. Am J Obstet Gynecol. 2020; doi: 10.1016/j.ajog.2020.04.014.CrossRefGoogle ScholarPubMed
Khalil, A, Kalafat, E, Benlioglu, C, et al. SARS-CoV-2 infection in pregnancy: a systematic review and meta-analysis of clinical features and pregnancy outcomes. EClinicalMedicine. 2020; 25, 100446.CrossRefGoogle ScholarPubMed
Turan, O, Hakim, A, Dashraath, P, Jeslyn, WJL, 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; doi: 10.1002/ijgo.13329.CrossRefGoogle ScholarPubMed
Trippella, G, Ciarcià, M, Ferrari, M, et al. COVID-19 in pregnant women and neonates: a systematic review of the literature with quality assessment of the studies. Pathogens. 2020; 9.CrossRefGoogle ScholarPubMed
Della Gatta, AN, Rizzo, R, Pilu, G, Simonazzi, G. COVID19 during pregnancy: a systematic review of reported cases. Am J Obstet Gynecol. 2020; doi: 10.1016/j.ajog.2020.04.013.Google ScholarPubMed
Di Mascio, D, Khalil, A, Saccone, G, et al. Outcome of Coronavirus spectrum infections (SARS, MERS, COVID 1–19) during pregnancy: a systematic review and meta-analysis. Am J Obstet Gynecol MFM. 2020; doi: 10.1016/j.ajogmf.2020.100107.CrossRefGoogle Scholar
Dotters-Katz, SK, Hughes, BL. Considerations for obstetric care during the COVID-19 pandemic. Am J Perinatol. 2020; doi: 10.1055/s-0040-1710051.Google ScholarPubMed
Oncel, MY, Akın, IM, Kanburoglu, MK, et al. A multicenter study on epidemiological and clinical characteristics of 125 newborns born to women infected with COVID-19 by Turkish Neonatal Society. Eur J Pediatr. 2020; doi: 10.1007/s00431-020-03767-5.Google ScholarPubMed
Berry, MJ, Foster, T, Rowe, K, Robertson, O, Robson, B, Pierse, N. Gestational age, health, and educational outcomes in adolescents. Pediatrics. 2018; 142 (5).CrossRefGoogle ScholarPubMed
Panahi, L, Amiri, M, Pouy, S. Risks of Novel Coronavirus Disease (COVID-19) in pregnancy; a narrative review. Arch Acad Emerg Med. 2020; 8 (1), e34.Google ScholarPubMed
Zhang, L, Dong, L, Ming, L, et al. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during late pregnancy: a report of 18 patients from Wuhan, China. BMC Pregnancy Childbirth. 2020; 20 (1), 394.CrossRefGoogle ScholarPubMed
Woodworth, K, Olsen, EO, Neelan, V, et al. Birth and infant outcomes following laboratory-confirmed SARS-CoV-2 infection in pregnancy — SET-NET. MMWR Morb Mortal Wkly Rep 2020; 69, 16351640.CrossRefGoogle ScholarPubMed
Melo, GC, Araújo, K. COVID-19 infection in pregnant women, preterm delivery, birth weight, and vertical transmission: a systematic review and meta-analysis. Cad Saude Publica. 2020; 36 (7), e00087320.CrossRefGoogle ScholarPubMed
Lillie, PJ, Samson, A, Li, A, et al. Novel coronavirus disease (Covid-19): the first two patients in the UK with person to person transmission. J Infect. 2020;80 (5), 578606.CrossRefGoogle ScholarPubMed
Remuzzi, A, Remuzzi, G. COVID-19 and Italy: what next? Lancet. 2020; 395 (10231), 12251228.CrossRefGoogle ScholarPubMed
Alicandro, G, Remuzzi, G, La Vecchia, C. Italy’s first wave of the COVID-19 pandemic has ended: no excess mortality in May, 2020. Lancet. 2020; 396 (10253), e27e28.CrossRefGoogle ScholarPubMed
Indolfi, C, Spaccarotella, C. The outbreak of COVID-19 in Italy: fighting the pandemic. JACC Case Rep. 2020; 2 (9), 14141418.CrossRefGoogle ScholarPubMed
Taglauer, E, Benarroch, Y, Rop, K, et al. Consistent localization of SARS-CoV-2 spike glycoprotein and ACE2 over TMPRSS2 predominance in placental villi of 15 COVID-19 positive maternal-fetal dyads. Placenta. 2020; 100, 6974.CrossRefGoogle ScholarPubMed
Zheng, T, Guo, J, He, W, Wang, H, Yu, H, Ye, H. Coronavirus disease 2019 (COVID-19) in pregnancy: 2 case reports on maternal and neonatal outcomes in Yichang city, Hubei Province, China. Medicine (Baltimore). 2020; 99 (29), e21334.CrossRefGoogle ScholarPubMed
Yang, Z, Liu, Y. Vertical transmission of severe acute respiratory syndrome Coronavirus 2: a systematic review. Am J Perinatol. 2020; 37 (10), 10551060.Google ScholarPubMed
Zaigham, M, Andersson, O. Maternal and perinatal outcomes with COVID-19: a systematic review of 108 pregnancies. Acta Obstet Gynecol Scand. 2020; doi: 10.1111/aogs.13867.CrossRefGoogle ScholarPubMed
Yoon, SH, Kang, JM, Ahn, JG. Clinical outcomes of 201 neonates born to mothers with COVID-19: a systematic review. Eur Rev Med Pharmacol Sci. 2020; 24 (14), 78047815.Google ScholarPubMed
Thomas, P, Alexander, PE, Ahmed, U, et al. Vertical transmission risk of SARS-CoV-2 infection in the third trimester: a systematic scoping review. J Matern Fetal Neonatal Med. 2020; doi: 10.1080/14767058.2020.1786055.CrossRefGoogle ScholarPubMed
Tang, JY, Song, WQ, Xu, H, Wang, N. No evidence for vertical transmission of SARS-CoV-2 in two neonates with mothers infected in the second trimester. Infect Dis (Lond). 2020; doi: 10.1080/23744235.2020.1798499.CrossRefGoogle ScholarPubMed
Simões, ESAC, Leal, CRV. Is SARS-CoV-2 vertically transmitted? Front Pediatr. 2020; 8, 276.CrossRefGoogle Scholar
Marín Gabriel, MA, Cuadrado, I, Álvarez Fernández, B, et al. Multicentre Spanish study found no incidences of viral transmission in infants born to mothers with COVID-19. Acta Paediatr. 2020; doi: 10.1111/apa.15474.CrossRefGoogle ScholarPubMed
Lopes de Sousa, Á F, Carvalho, HEF, Oliveira, LB, et al. Effects of COVID-19 infection during pregnancy and neonatal prognosis: what is the evidence? Int J Environ Res Public Health. 2020; 17 (11).CrossRefGoogle ScholarPubMed
Lamouroux, A, Attie-Bitach, T, Martinovic, J, Leruez-Ville, M, Ville, Y. Evidence for and against vertical transmission for severe acute respiratory syndrome coronavirus 2. Am J Obstet Gynecol. 2020; 223 (1), 91.e9191.e94.CrossRefGoogle ScholarPubMed
Walker, KF, O’Donoghue, K, Grace, N, et al. Maternal transmission of SARS-COV-2 to the neonate, and possible routes for such transmission: a systematic review and critical analysis. BJOG. 2020; doi: 10.1111/1471-0528.16362.CrossRefGoogle Scholar
McMillen, IC, Robinson, JS. Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiolog Rev. 2005; 85 (2), 571633.CrossRefGoogle ScholarPubMed
Barker, DJ. The fetal and infant origins of adult disease. BMJ. 1990; 301 (6761), 1111.CrossRefGoogle ScholarPubMed
Barker, DJ. Fetal programming and public health. In Fetal programming influences on development and disease in later life (eds. O’Brien, PMS, Wheeler, T, Barker, DJ), 1999; pp. 311. Royal College of Obstetrics and Gynaecology Press: London.Google Scholar
Koren, G. “Prozac Baby” - 25 years of motherisk research into SSRIs and alcohol in pregnancy. J Popul Ther Clin Pharmacol. 2014; 21 (3), e526532.Google ScholarPubMed
Nulman, I, Rovet, J, Stewart, DE, et al. Neurodevelopment of children exposed in utero to antidepressant drugs. N Engl J Med. 1997; 336 (4), 258262.CrossRefGoogle ScholarPubMed
Pastuszak, A, Schick-Boschetto, B, Zuber, C, et al. Pregnancy outcome following first-trimester exposure to fluoxetine (Prozac). Jama. 1993; 269 (17), 22462248.CrossRefGoogle Scholar
Riggin, L, Frankel, Z, Moretti, M, Pupco, A, Koren, G. The fetal safety of fluoxetine: a systematic review and meta-analysis. J Obstetr Gynaecol Canada. 2013; 35 (4), 362369.CrossRefGoogle ScholarPubMed
Eke, AC, Olagunju, A, Momper, J, et al. Optimizing pharmacology studies in pregnant and lactating women using lessons from HIV: a consensus statement. Clin Pharmacol Ther. 2020; doi: 10.1002/cpt.2048.Google ScholarPubMed
Stefanovic, V. COVID-19 infection during pregnancy: fetus as a patient deserves more attention. J Perinat Med. 2020; 48 (5), 438440.CrossRefGoogle ScholarPubMed
Lenz, W. A short history of thalidomide embryopathy. Teratology. 1988; 38 (3), 203215.CrossRefGoogle Scholar
Darby, JRT, Varcoe, TJ, Orgeig, S, Morrison, JL. Cardiorespiratory consequences of intrauterine growth restriction: Influence of timing, severity and duration of hypoxaemia. Theriogenology. 2020.CrossRefGoogle ScholarPubMed
Grzeskowiak, LE, Gilbert, AL, Morrison, JL. Neonatal outcomes after late-gestation exposure to selective serotonin reuptake inhibitors. J Clin Psychopharmacol. 2012; 32 (5), 615621.CrossRefGoogle ScholarPubMed
Grzeskowiak, LE, Gilbert, AL, Morrison, JL. Prenatal exposure to selective serotonin reuptake inhibitors and risk of childhood overweight. J Dev Orig Health Dis. 2012; 3 (4), 253261.CrossRefGoogle ScholarPubMed
Grzeskowiak, LE, Gilbert, AL, Sorensen, TI, et al. Prenatal exposure to selective serotonin reuptake inhibitors and childhood overweight at 7 years of age. Ann Epidemiol. 2013; 23 (11), 681687.CrossRefGoogle ScholarPubMed
Grzeskowiak, LE, Morrison, JL, Henriksen, TB, et al. Prenatal antidepressant exposure and child behavioural outcomes at 7 years of age: a study within the Danish National Birth Cohort. BJOG. 2016; 123 (12), 19191928.CrossRefGoogle ScholarPubMed
Morrison, JL. Sheep models of intrauterine growth restriction: fetal adaptations and consequences. Clin Exp Pharmacol Physiol. 2008; 35 (7), 730743.CrossRefGoogle ScholarPubMed
Darby, JRT, Varcoe, TJ, Orgeig, S, Morrison, JL. Cardiorespiratory consequences of intrauterine growth restriction: Influence of timing, severity and duration of hypoxaemia. Theriogenology. 2020; 150, 8495.CrossRefGoogle ScholarPubMed
Pierce-Williams, RAM, Burd, J, Felder, L, et al. Clinical course of severe and critical COVID-19 in hospitalized pregnancies: a US cohort study. Am J Obstet Gynecol MFM. 2020; doi: 10.1016/j.ajogmf.2020.100134.Google ScholarPubMed
Wu, R, Wang, L, Kuo, HD, et al. An update on current therapeutic drugs treating COVID-19. Curr Pharmacol Rep. 2020; doi: 10.1007/s40495-020-00216-7.CrossRefGoogle ScholarPubMed
Boulware, DR, Pullen, MF, Bangdiwala, AS, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. N Engl J Med. 2020; doi: 10.1056/NEJMoa2016638.CrossRefGoogle ScholarPubMed
Mehra, MR, Desai, SS, Ruschitzka, F, Patel, AN. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. 2020; 20, 3118031186.Google Scholar
Anderson, J, Schauer, J, Bryant, S, Graves, CR. The use of convalescent plasma therapy and remdesivir in the successful management of a critically ill obstetric patient with novel coronavirus 2019 infection: A case report. Case Rep Womens Health. 2020; doi: 10.1016/j.crwh.2020.e00221.CrossRefGoogle ScholarPubMed
Mulangu, S, Dodd, LE, Davey, RT Jr, et al. A randomized, controlled trial of ebola virus disease therapeutics. N Engl J Med. 2019; 381 (24), 22932303.CrossRefGoogle ScholarPubMed
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 (3), 100159.CrossRefGoogle ScholarPubMed
Barbier, O, Bélanger, A. The cynomolgus monkey (Macaca fascicularis) is the best animal model for the study of steroid glucuronidation. J Steroid Biochem Mol Biol. 2003; 85 (2–5), 235245.CrossRefGoogle Scholar
Morrison, JL, Berry, MJ, Botting, KJ, et al. Improving pregnancy outcomes in humans through studies in sheep. Am J Physiol Regul Integr Comp Physiol. 2018; 315 (6), R1123R1153.CrossRefGoogle ScholarPubMed
Morrison, JL, Botting, KJ, Darby, JRT, et al. Guinea pig models for translation of the developmental origins of health and disease hypothesis into the clinic. J Physiol. 2018; 596 (23), 55355569.CrossRefGoogle ScholarPubMed
Morrison, JL, Chien, C, Gruber, N, Rurak, D, Riggs, W. Fetal behavioural state changes following maternal fluoxetine infusion in sheep. Dev Brain Res. 2001; 131 (1–2), 4756.CrossRefGoogle ScholarPubMed
Morrison, JL, Chien, C, Riggs, KW, Gruber, N, Rurak, D. Effect of maternal fluoxetine administration on uterine blood flow, fetal blood gas status, and growth. Pediatr Res. 2002; 51 (4), 433442.CrossRefGoogle Scholar
Morrison, JL, Riggs, KW, Chien, C, Gruber, N, McMillen, IC, Rurak, DW. Chronic maternal fluoxetine infusion in pregnant sheep: effects on the maternal and fetal hypothalamic-pituitary-adrenal axes. Pediatr Res. 2004; 56 (1), 4046.CrossRefGoogle ScholarPubMed
Morrison, JL, Rurak, DW, Chien, C, et al. Maternal fluoxetine infusion does not alter fetal endocrine and biophysical circadian rhythms in pregnant sheep. J Soc Gynecol Investig. 2005; 12 (5), 356364.CrossRefGoogle Scholar
Muhlhausler, BS, Morrison, JL, McMillen, IC. Rosiglitazone increases the expression of Peroxisome Proliferator-Activated Receptor-{gamma} target genes in adipose tissue, liver and skeletal muscle in the sheep fetus in late gestation. Endocrinology. 2009; 150 (9), 42874294.CrossRefGoogle ScholarPubMed
Darby, JRT, Saini, BS, Soo, JY, et al. Subcutaneous maternal resveratrol treatment increases uterine artery blood flow in the pregnant EWE and increases fetal but not cardiac growth. J Physiol. 2019; 597 (20), 50635077.CrossRefGoogle Scholar
Berry, LM, Polk, DH, Ikegami, M, Jobe, AH, Padbury, JF, Ervin, MG. Preterm newborn lamb renal and cardiovascular responses after fetal or maternal antenatal betamethasone. Am J Physiol. 1997; 272 (6), R1972R1979.Google ScholarPubMed
Berry, M, Gray, C, Wright, K, Dyson, R, Wright, I. Premature guinea pigs: a new paradigm to investigate the late-effects of preterm birth. J Dev Orig Health Dis. 2015; 6 (2), 143148.CrossRefGoogle ScholarPubMed
Soo, JY, Wiese, MD, Dyson, RM, et al. Methamphetamine administration increases hepatic CYP1A2 but not CYP3A activity in female guinea pigs. PLoS One. 2020; 15 (5), e0233010.CrossRefGoogle Scholar
Morrison, JL, Riggs, KW, Rurak, DW. Fluoxetine during pregnancy: impact on fetal development. Reprod Fertil Dev. 2005; 17 (6), 641650.CrossRefGoogle ScholarPubMed
Dyson, RM, Palliser, HK, Wilding, N, et al. Microvascular circulatory dysregulation driven in part by cystathionine gamma-lyase: a new paradigm for cardiovascular compromise in the preterm newborn. Microcirculation (New York, NY : 1994). 2019; 26 (2), e12507.CrossRefGoogle ScholarPubMed
Shaw, JC, Dyson, RM, Palliser, HK, Gray, C, Berry, MJ, Hirst, JJ. Neurosteroid replacement therapy using the allopregnanolone-analogue ganaxolone following preterm birth in male guinea pigs. Pediatr Res. 2019; 85 (1), 8696.CrossRefGoogle ScholarPubMed
Shaw, JC, Palliser, HK, Dyson, RM, Berry, MJ, Hirst, JJ. Disruptions to the cerebellar GABAergic system in juvenile guinea pigs following preterm birth. Int J Dev Neurosci. 2018; 65, 110.CrossRefGoogle Scholar
Shaw, JC, Palliser, HK, Dyson, RM, Hirst, JJ, Berry, MJ. Long-term effects of preterm birth on behavior and neurosteroid sensitivity in the guinea pig. Pediatr Res. 2016; 80 (2), 275283.CrossRefGoogle ScholarPubMed
Sarr, O, Thompson, JA, Zhao, L, Lee, TY, Regnault, TR. Low birth weight male guinea pig offspring display increased visceral adiposity in early adulthood. PLoS One. 2014; 9 (6), e98433.CrossRefGoogle ScholarPubMed
Thompson, JA, Gros, R, Richardson, BS, Piorkowska, K, Regnault, TR. Central stiffening in adulthood linked to aberrant aortic remodeling under suboptimal intrauterine conditions. Am J Physiol Regul Integr Comp Physiol. 2011; 301 (6), R17311737.CrossRefGoogle ScholarPubMed
Thompson, JA, Sarr, O, Piorkowska, K, Gros, R, Regnault, TR. Low birth weight followed by postnatal over-nutrition in the guinea pig exposes a predominant player in the development of vascular dysfunction. J Physiol. 2014; 592 (Pt 24), 54295443.CrossRefGoogle ScholarPubMed
Gagne, JJ, Maio, V, Berghella, V, Louis, DZ, Gonnella, JS. Prescription drug use during pregnancy: a population-based study in Regione Emilia-Romagna, Italy. Eur J Clin Pharmacol. 2008; 64 (11), 11251132.CrossRefGoogle Scholar
Lacroix, I, Damase-Michel, C, Lapeyre-Mestre, M, Montastruc, JL. Prescription of drugs during pregnancy in France. Lancet. 2000; 356 (9243), 17351736.CrossRefGoogle ScholarPubMed
Berthelot, N, Lemieux, R, Garon-Bissonnette, J, Drouin-Maziade, C, Martel, É, Maziade, M. Uptrend in distress and psychiatric symptomatology in pregnant women during the coronavirus disease 2019 pandemic. Acta Obstet Gynecol Scand. 2020; 99 (7), 848855.CrossRefGoogle ScholarPubMed
Zhai, MZ, Lye, CT, Kesselheim, AS. Need for transparency and reliable evidence in emergency use authorizations for coronavirus disease 2019 (COVID-19) therapies. JAMA Intern Med. 2020; doi: 10.1001/jamainternmed.2020.2402.CrossRefGoogle ScholarPubMed
Heyrana, K, Byers, HM, Stratton, P. Increasing the participation of pregnant women in clinical trials. JAMA. 2018; 320 (20), 20772078.CrossRefGoogle ScholarPubMed
Spinner, CD, Gottlieb, RL, Criner, GJ, et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial. JAMA. 2020; 324 (11), 10481057.CrossRefGoogle ScholarPubMed
Goldman, JD, Lye, DCB, Hui, DS, et al. Remdesivir for 5 or 10 days in patients with severe Covid-19. N Engl J Med. 2020; doi: 10.1056/NEJMoa2015301.CrossRefGoogle ScholarPubMed
Wang, Y, Zhang, D, Du, G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020; 395 (10236), 15691578.CrossRefGoogle ScholarPubMed
Easterlin, MC, De Beritto, T, Yeh, AM, Wertheimer, FB, Ramanathan, R. Extremely preterm infant born to a mother with severe COVID-19 pneumonia. J Investig Med High Impact Case Rep. 2020; 8, 2324709620946621.Google ScholarPubMed
Cao, B, Wang, Y, Wen, D, et al. A trial of Lopinavir-Ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. 2020; 382 (19), 17871799.CrossRefGoogle ScholarPubMed
Hung, IF, Lung, KC, Tso, EY, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 2020; 395 (10238), 16951704.CrossRefGoogle ScholarPubMed
Sibiude, J, Mandelbrot, L, Blanche, S, et al. Association between prenatal exposure to antiretroviral therapy and birth defects: an analysis of the French perinatal cohort study (ANRS CO1/CO11). PLoS Med. 2014; 11 (4), e1001635.CrossRefGoogle Scholar
Tookey, PA, Thorne, C, van Wyk, J, Norton, M. Maternal and foetal outcomes among 4118 women with HIV infection treated with lopinavir/ritonavir during pregnancy: analysis of population-based surveillance data from the national study of HIV in pregnancy and childhood in the United Kingdom and Ireland. BMC Infect Dis. 2016; 16, 65.CrossRefGoogle ScholarPubMed
Fowler, MG, Qin, M, Fiscus, SA, et al. Benefits and risks of antiretroviral therapy for perinatal HIV prevention. N Engl J Med. 2016; 375 (18), 17261737.CrossRefGoogle ScholarPubMed
Powis, KM, Kitch, D, Ogwu, A, et al. Increased risk of preterm delivery among HIV-infected women randomized to protease versus nucleoside reverse transcriptase inhibitor-based HAART during pregnancy. J Infect Dis. 2011; 204 (4), 506514.CrossRefGoogle ScholarPubMed
Horby, P, Lim, WS, Emberson, JR, et al. Dexamethasone in hospitalized patients with Covid-19 - preliminary report. N Engl J Med. 2020; doi: 10.1056/NEJMoa2021436.Google Scholar
Morrison, JL, Botting, KJ, Soo, PS, et al. Antenatal steroids and the IUGR fetus: are exposure and physiological effects on the lung and cardiovascular system the same as in normally grown fetuses? J Pregnancy. 2012; 2012, 839656.CrossRefGoogle ScholarPubMed
Huang, WL, Beazley, LD, Quinlivan, JA, Evans, SF, Newnham, JP, Dunlop, SA. Effect of corticosteroids on brain growth in fetal sheep. Obstet Gynecol. 1999; 94 (2), 213218.Google ScholarPubMed
Huang, WL, Harper, CG, Evans, SF, Newnham, JP, Dunlop, SA. Repeated prenatal corticosteroid administration delays astrocyte and capillary tight junction maturation in fetal sheep. Int J Dev Neurosci. 2001; 19 (5), 487493.CrossRefGoogle ScholarPubMed
Ramiro, S, Mostard, RLM, Magro-Checa, C, et al. Historically controlled comparison of glucocorticoids with or without tocilizumab versus supportive care only in patients with COVID-19-associated cytokine storm syndrome: results of the CHIC study. Ann Rheum Dis. 2020; 79 (9), 11431151.CrossRefGoogle ScholarPubMed
Saito, J, Yakuwa, N, Takai, C, et al. Tocilizumab concentrations in maternal serum and breast milk during breastfeeding and a safety assessment in infants: a case study. Rheumatology (Oxford). 2018; 57 (8), 14991501.CrossRefGoogle Scholar
Nakajima, K, Watanabe, O, Mochizuki, M, Nakasone, A, Ishizuka, N, Murashima, A. Pregnancy outcomes after exposure to tocilizumab: a retrospective analysis of 61 patients in Japan. Mod Rheumatol. 2016; 26 (5), 667671.CrossRefGoogle ScholarPubMed
Hoeltzenbein, M, Beck, E, Rajwanshi, R, et al. Tocilizumab use in pregnancy: analysis of a global safety database including data from clinical trials and post-marketing data. Semin Arthritis Rheum. 2016; 46 (2), 238245.CrossRefGoogle ScholarPubMed
Nemchand, P, Tahir, H, Mediwake, R, Lee, J. Cytokine storm and use of anakinra in a patient with COVID-19. BMJ Case Rep. 2020; 13 (9).CrossRefGoogle Scholar
Navarro-Millán, I, Sattui, SE, Lakhanpal, A, Zisa, D, Siegel, CH, Crow, MK. Use of anakinra to prevent mechanical ventilation in severe COVID-19: a case series. Arthritis Rheumatol. 2020; doi: 10.1002/art.41422.CrossRefGoogle ScholarPubMed
Cauchois, R, Koubi, M, Delarbre, D, et al. Early IL-1 receptor blockade in severe inflammatory respiratory failure complicating COVID-19. Proc Natl Acad Sci U S A. 2020; 117 (32), 1895118953.CrossRefGoogle ScholarPubMed
Langer-Gould, A, Smith, JB, Gonzales, EG, et al. Early identification of COVID-19 cytokine storm and treatment with anakinra or tocilizumab. Int J Infect Dis. 2020; 99, 291297.CrossRefGoogle ScholarPubMed
Iglesias-Julián, E, López-Veloso, M, de-la-Torre-Ferrera, N, et al. High dose subcutaneous Anakinra to treat acute respiratory distress syndrome secondary to cytokine storm syndrome among severely ill COVID-19 patients. J Autoimmun. 2020; doi: 10.1016/j.jaut.2020.102537.CrossRefGoogle ScholarPubMed
Erden, A, Ozdemir, B, Karakas, O, et al. Evaluation of seventeen patients with COVID-19 pneumonia treated with anakinra according to HScore, SOFA, MuLBSTA and Brescia-COVID respiratory severity scale (BCRSS) scoring systems. J Med Virol. 2020; doi: 10.1002/jmv.26473.Google ScholarPubMed
Clark, KEN, Collas, O, Lachmann, H, Singh, A, Buckley, J, Bhagani, S. Safety of intravenous anakinra in COVID-19 with evidence of hyperinflammation, a case series. Rheumatol Adv Pract. 2020; 4 (2), rkaa040.CrossRefGoogle ScholarPubMed
Huet, T, Beaussier, H, Voisin, O, et al. Anakinra for severe forms of COVID-19: a cohort study. Lancet Rheumatol. 2020; 2 (7), e393e400.CrossRefGoogle ScholarPubMed
Cavalli, G, De Luca, G, Campochiaro, C, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol. 2020;2(6), e325e331.CrossRefGoogle ScholarPubMed
Gerosa, M, Argolini, LM, Artusi, C, Chighizola, CB. The use of biologics and small molecules in pregnant patients with rheumatic diseases. Expert Rev Clin Pharmacol. 2018;11(10), 987998.CrossRefGoogle ScholarPubMed
Cantini, F, Niccoli, L, Matarrese, D, Nicastri, E, Stobbione, P, Goletti, D. Baricitinib therapy in COVID-19: a pilot study on safety and clinical impact. J Infect. 2020;81(2), 318356.CrossRefGoogle ScholarPubMed
Cantini, F, Niccoli, L, Nannini, C, et al. Beneficial impact of Baricitinib in COVID-19 moderate pneumonia; multicentre study. J Infect. 2020;81(4), 647679.CrossRefGoogle ScholarPubMed
Titanji, BK, Farley, MM, Mehta, A, et al. Use of Baricitinib in Patients with Moderate and Severe COVID-19. Clin Infect Dis. 2020; doi: 10.1093/cid/ciaa879.Google Scholar
Dashraath, P, Wong, JLJ, Lim, MXK, et al. Coronavirus disease 2019 (COVID-19) pandemic and pregnancy. Am J Obstet Gynecol. 2020; doi: 10.1016/j.ajog.2020.03.021.Google ScholarPubMed
Costanzo, G, Firinu, D, Losa, F, Deidda, M, Barca, MP, Del Giacco, S. Baricitinib exposure during pregnancy in rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2020; 12, 1759720x19899296.CrossRefGoogle ScholarPubMed
Fiolet, T, Guihur, A, Rebeaud, ME, Mulot, M, Peiffer-Smadja, N, Mahamat-Saleh, Y. Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis. Clin Microbiol Infect. 2020; doi: 10.1016/j.cmi.2020.08.022.Google ScholarPubMed
Nicolas, P, Maia, MF, Bassat, Q, et al. Safety of oral ivermectin during pregnancy: a systematic review and meta-analysis. Lancet Glob Health. 2020;8(1), e92e100.CrossRefGoogle ScholarPubMed
Fan, H, Gilbert, R, O’Callaghan, F, Li, L. Associations between macrolide antibiotics prescribing during pregnancy and adverse child outcomes in the UK: population based cohort study. Bmj. 2020; 368, m331.CrossRefGoogle ScholarPubMed
Pérez, R, Palma, C, Núñez, MJ, Cox, J. Pharmacokinetics of ivermectin after maternal or fetal intravenous administration in sheep. J Vet Pharmacol Ther. 2008;31(5), 406414.CrossRefGoogle ScholarPubMed
Shanmugaraj, B, Siriwattananon, K, Wangkanont, K, Phoolcharoen, W. Perspectives on monoclonal antibody therapy as potential therapeutic intervention for Coronavirus disease-19 (COVID-19). Asian Pac J Allergy Immunol. 2020;38(1), 1018.Google Scholar
Figure 0

Fig. 1. Timeline showing the appearance and progression of COVID-19 globally in relation to gestation length to illustrate our current inability to understand the true impact of COVID-19 on offspring. Data sourced from Refs. 46–50.

Figure 1

Fig. 2. The timing, dose and duration of fetal exposure to medications to treat the symptoms of COVID-19 in the mother will interact to determine the impact on the fetus with organ-specific effects that will impact health across the life course of the offspring. Adapted from Refs. 78 and 79.

Figure 2

Fig. 3. It is necessary to identify COVID-19 drug therapies for pregnant women who do not harm their babies’ growth and development or the health of their offspring throughout their life. Studies in humans will take years to decades to perform, but preclinical studies in appropriate models will accelerate our knowledge.

Figure 3

Table 1. Drug treatments for COVID-19 and our knowledge about their safety for use in pregnancy