Skip to main content
Download PDF

Volume 14 Supplement 3

Proceedings from the Global Forum on Bioethics in Research (GFBR)’s “Ethics of Research in Pregnancy” meeting

Protected to death: systematic exclusion of pregnant women from Ebola virus disease trials

Reproductive Health volume 14, Article number: 172 (2017) Cite this article

Abstract

Background

For 30 years, women have sought equal opportunity to be included in trials so that drugs are equitably studied in women as well as men; regulatory guidelines have changed accordingly. Pregnant women, however, continue to be excluded from trials for non-obstetric conditions, though they have been included for trials of life-threatening diseases because prospects for maternal survival outweighed potential fetal risks. Ebola virus disease is a life-threatening infection without approved treatments or vaccines. Previous Ebola virus (EBOV) outbreak data showed 89–93% maternal and 100% fetal/neonatal mortality. Early in the 2013–2016 EBOV epidemic, an expert panel pointed to these high mortality rates and the need to prioritize and preferentially allocate unregistered interventions in favor of pregnant women (and children). Despite these recommendations and multiple ethics committee requests for their inclusion on grounds of justice, equity, and medical need, pregnant women were excluded from all drug and vaccine trials in the affected countries, either without justification or on grounds of potential fetal harm. An opportunity to offer pregnant women the same access to potentially life-saving interventions as others, and to obtain data to inform their future use, was lost. Once again, pregnant women were denied autonomy and their right to decide.

Conclusion

We recommend that, without clear justification for exclusion, pregnant women are included in clinical trials for EBOV and other life-threatening conditions, with lay language on risks and benefits in information documents, so that pregnant women can make their own decision to participate. Their automatic exclusion from trials for other conditions should be questioned.

Background

The 2013–2016 Ebola virus (EBOV) epidemic was estimated to have caused 28,616 confirmed, probable, and suspected cases and 11,310 deaths [1], but the true burden of EBOV may have been higher. The number of cases and deaths exceeded by more than two orders of magnitude those across all 29 previous outbreaks [1,2,3]. No approved treatments or vaccines were available and a large number of trials were initiated.

Inclusion of women in trials submitted for US registration improved after 1993, when new regulatory guidelines required that a representative sample of patients likely to receive a drug be included in clinical studies and data be analyzed to determine gender differences in response [4,5,6,7,8]. The gender guidelines were developed amidst growing concerns that the drug development process did not provide adequate information about the effects of drugs or biological products in women, particularly HIV treatments, and a general consensus that women should have autonomy to determine participation in clinical trials for themselves [5, 8, 9]. Women are now generally included in trials—provided they are not pregnant and commit, as necessary, to effective birth control [9]. Exclusion of pregnant women is still usual practice in trials that do not address obstetric conditions, largely due to concern about birth defects after specific drug exposure in utero and the view that high fetal risk without important medical benefits for the mother is not acceptable [4, 9, 10]. Exclusion, therefore, should not apply to women with life-threatening diseases, as illustrated by early HIV/AIDS drug trials which included pregnant women in the earliest phases—before completion of animal-reproduction studies—because any risk to the fetus was balanced by an overwhelming potential benefit (prolonging life) to the mother [11]. The absence of data on general medical conditions in pregnancy means that pregnant women continue to be treated for non-obstetric conditions with drugs which did not undergo rigorous scientific testing in pregnancy, and for which safe and effective therapeutic doses in pregnancy and maternal and fetal risks are largely unknown [8,9,10, 12, 13]. More pregnant women and their future offspring are therefore exposed to potential harms through off-label use of medications than would be the case with rigorous scientific testing of medications used during pregnancy [14, 15].

In this paper, we review the case fatality data for pregnant women and fetuses/neonates from previous outbreaks and the pregnancy-related eligibility criteria of the therapeutic and vaccine studies in EBOV-affected countries. In the absence of registered treatments or vaccines to control this lethal disease, the World Health Organization (WHO) coordinated and supported research to expedite identification of interventions that could control the outbreak and improve future control efforts. Furthermore, WHO supported many of these studies, which therefore required WHO Ethics Review Committee (WHO-ERC) approval [16]. We reflect on how WHO-ERC made decisions regarding the eligibility of pregnant women during the 2013–2016 outbreak and provide an overview of the case fatality data now available to inform research during future outbreaks.

Data on maternal and pregnancy outcomes informing study protocols in the 2013–2016 EBOV epidemic

Table 1 summarizes published data from EBOV outbreaks on maternal and pregnancy outcomes, Section A for the previous epidemics, Section B for the 2013-6 epidemic. In the 1976 outbreak, the case fatality rate (CFR) in EBOV-infected pregnant women was 89% (73/82) [17]. Almost half of all EBOV-infected women were pregnant (46%: 82/177). The high risk in pregnancy was later attributed to the repeated use of needles for vitamin injections in routine antenatal care without sterilization between patients [17, 18]. In the 1995 outbreak, 15/105 (14%) EBOV-infected women were pregnant [17]. The CFR for EBOV-infected pregnant women was 93% (14/15) compared with 70% (28/40) for EBOV-infected non-pregnant women and an overall 77.5% CFR (245/316) [17]. The differences in CFR are not statistically significant.

Table 1 Published data on maternal and pregnancy outcomes after EBOV infection
Full size table

In aggregate, any EBOV-infected pregnant woman had survived only after spontaneous miscarriage, elective abortion, stillbirth, or with a neonatal death (Table 1 SectionA). All EBOV-infected pregnant women developed vaginal and uterine bleeding and were at high risk for spontaneous abortion and pregnancy-related hemorrhage [19]. In the 1976 outbreak, the rate of spontaneous abortions was 23% (19/82). The remaining pregnancy outcomes were stillbirths or neonatal deaths—no neonate survived longer than 19 days [18]. In 1995, the spontaneous abortion rate was 67% (10/15), with three elective abortions, one premature stillborn, and one live-born, full-term neonate who died at three days [17]; one of the three elective abortions followed an incomplete spontaneous abortion and the woman survived [17]. Four EBOV-infected mother-baby pairs were traced after the 2000–2001 outbreak in Uganda: all mothers and babies had died [20, 21].

Clinical trials of potential treatments and vaccines during the 2013–2016 epidemic in Guinea, Liberia, and Sierra Leone

At the time of this epidemic, there were no approved specific treatments or vaccines for Ebola virus disease (EVD). Clinical management consisted of supportive care, particularly fluid and electrolyte management, correction of coagulopathy, treatment of secondary infections, and management of other complications [19]. Treatments proposed had not undergone clinical trials in EBOV populations or at all [22,23,24]. Vaccines were in very early development with few having entered Phase I safety and immunogenicity trials [24,25,26,27,28,29].

Table 2 lists the trials conducted during the 2013–2016 epidemic in Liberia, Guinea, and Sierra Leone and their pregnancy-related eligibility criteria. All drug and vaccine trials excluded pregnant women. Two of three convalescent plasma studies, funded by the European Union, included pregnant women [30]. Pregnant women were granted access to new treatments only within ‘Monitored Emergency Use of Unregistered Interventions’ (MEURI) [31] protocols implemented by Médecins Sans Frontières (MSF) for MIL77 (three chimeric monoclonal antibodies targeting different epitopes on the surface of EBOV glycoprotein) and favipiravir [16, 31].

Table 2 Drug and vaccines trials proposed, initiated, or completed during the 2013–2016 Ebola virus disease epidemic in Guinea, Liberia, and Sierra Leone
Full size table

WHO ethics review committee considerations

The WHO-ERC reviewed all protocols for studies supported or sponsored by WHO, four protocols at the request of the Médecins Sans Frontières Ethics Review Board and one for the Rapid Assessment of Potential Interventions & Drugs for Ebola (RAPIDE) Consortium [16, 31, 32]. The WHO-ERC applied the Council for International Organizations of Medical Sciences guidelines [33] and followed the recommendations of a WHO panel of external experts convened to provide ethical guidance on use of unregistered interventions for treatment or prevention of EBOV in a context in which patients were managed with no, or limited, clinical trial data [34]. The WHO panel counselled use of unregistered interventions in the epidemic, conditional upon evidence from laboratory and animal studies. The panel also emphasized that in prioritizing and allocating interventions “children and pregnant women should be considered particularly vulnerable [because of their higher mortality rates]... and given special protection when receiving such interventions” [34]. In the face of the long history of exclusion of pregnant women from clinical trials [9, 15, 35,36,37], this recommendation was remarkable and important; the WHO-ERC understood that these groups were to be provided preferential access to interventions. For the WHO-ERC, the virtual certainty of fetal/neonatal loss invalidated exclusion of pregnant women because of risk to the fetus; the high maternal mortality in past Ebola outbreaks favored their inclusion for clinical and ethical reasons. Other ethical considerations dictated that pregnant women should be accorded the same autonomy as non-pregnant adults: pregnant women had a greater interest in and right to decide about their own and their fetus’ health than sponsors, researchers, regulators or ethics committees. The WHO-ERC considered these points equally applicable to vaccine trials in EVD-affected countries that would enroll uninfected participants based on data from Phase I safety and immunogenicity trials and noted that other ethics committees took the same view [31].

By the end of the EBOV epidemic, the WHO-ERC had reviewed 14 protocols for interventional trials as well as two MEURI protocols [16]. These included studies of brincidofovir [32] and favipiravir [38], a study with convalescent plasma [39] and several phases of the rVSVΔG/ZEBOV-GP vaccine [40,41,42,43] and the ChAd3-EBO-Z vaccine [44, 45]. All vaccine protocols, including those in affected countries, excluded pregnant women. The brincidofovir trial excluded pregnant women on the basis of embryotoxicity in animal studies without comment on the relevance of these data for a disease resulting in 100% human fetal loss; the favipiravir trial could not include pregnant women because the sponsors were unable to get insurance coverage despite strong recommendations for inclusion from the WHO-ERC, MSF Ethics Review Board, and Inserm Institutional Review Board [31]. The WHO-ERC requested investigators of all treatment and vaccine trials in the affected countries to reconsider exclusion of pregnant women based on benefit-risk assessment, but the requested amendments were not submitted. Therefore, the WHO-ERC faced the difficult dilemma of granting approval for immediate trial start (with potential benefit for the many participants the protocols included) or withholding approval until pregnant women were either included or their exclusion justified. The latter choice would delay trial start in the context of an epidemic for which mortality was high and speed of intervention was essential. Since agreement to include pregnant women would require consensus between numerous parties (including sponsors), which would take time and delay trial start substantially (or possibly indefinitely), WHO-ERC did not make inclusion of pregnant women a prerequisite for WHO-ERC clearance [16]. When interim analysis of the efficacy and safety data in non-pregnant adults in the rVSVΔG/ ZEBOV-GP vaccine trial showed benefit, the WHO-ERC (and the Data Safety Monitoring Board) pointed out the high incidence and mortality rates in children and pregnancy and unsuccessfully sought inclusion of the latter, or justification of exclusion. Forty-two pregnant women were denied participation [43]. However, since the trial excluded pregnant women on the basis of self-reported pregnancy status (pregnancy tests were offered, but not obligatory), more than 20 other pregnant women received the vaccine [Henao-Restrepo and MSF, personal communication] [43].

Data from the 2013–2016 EVD epidemic that will inform the design of studies in future EBOV outbreaks

The 2013–2016 EVD epidemic permitted better estimates of CFRs and factors impacting survival rates and determination of persistence of EBOV in different body fluids.

The CFR across both sexes was 62.9% (95% CI: 61.9–64.0%) declining from 69.8% (95% CI: 58.6–79.2) to around 39% (95% CI: 25.7–54.3%) from July 2015 to September 2015. Survival was highest in those under 5 years (75.6%) and above 75 years (83.8%), a pattern similar in all three countries [2]. Both sexes were equally susceptible to infection [46]. In all countries, time from initial symptoms to hospitalization was approximately 0.5 days shorter for women [46]. CFRs were significantly lower for women: 63% (95% CI: 61.6–64.4, n = 4756) versus 67.1% for men (95% CI, 65.8–68.5, n = 4637), p < 0.001; the survival difference was significant after adjustment for age, clinical symptoms, and intervals between onset and hospitalization [46].

Despite the size of the epidemic, and the opportunity, information on pregnancy and pregnancy outcomes was not systematically obtained. Available data are shown in Table 1B; some analyses are ongoing. The maternal CFR estimated from these data is 55% (44/80) [46,47,48,49,50,51,52,53,54,55,56,57,58] excluding approximately 20 pregnant vaccinated women [43]; maternal CFR is not statistically significantly different from the CFR of women overall. All surviving mothers experienced miscarriages or stillbirths [49,50,51, 57, 58] and two women died with the fetus in utero [47, 48]. The only surviving baby was born to a woman who had received favipiravir under a MEURI protocol and died. Authorization was given to MSF to treat the newborn, but not the mother, with ZMapp [56] [59]. The reasons for high fetal mortality may be related to EBOV placental preference and consequent high viral load in utero, as samples from amniotic fluid, placenta, and fetuses tested positive for EBOV [52]. Live-born babies appear to have been preterm births and preterm babies normally have a high mortality risk. In EBOV-affected countries where babies are often exclusively breastfed immediately after birth (and there may not be a safe alternative to breastfeeding available), the absence of a surviving mother or the inability of an EBOV-infected survivor to breastfeed places a surviving baby at risk of death.

As of 2 February 2016, between 10,000 and 17,000 EBOV survivors were reported compared with 1000 survivors from all previous epidemics combined [2, 60, 61]. Compared to blood used for determining cure, clearance of EBOV is delayed (sometimes for months) in immunologically protected fluids/body compartments including semen [62, 63], ocular tissues [64], breastmilk [65], vaginal secretions [66] and the central nervous system [60, 67]. Mother-to-child transmission of EBOV can occur through body fluids in utero, during delivery, contact after birth, and breastmilk, even when the woman is asymptomatic [48]. Among 70 EBOV survivors who conceived post-recovery, 15/68 miscarried and two survivors elected to terminate their pregnancies; four neonates were stillborn (3/4 conceived within two months of discharge of the Ebola Treatment Unit). While still sparse, the data suggest that pregnancies shortly after recovery also increase the risk for poor outcomes [68].

Conclusions

In this epidemic, a positive diagnosis meant a high probability of mortality; interventions yet to be proven effective provided the best chance of avoiding death. Despite an 89% maternal CFR and near certain fetal loss in previous outbreaks (i.e. little chance of harming the fetus by administering an experimental intervention), pregnant women were systematically excluded from all drug and vaccine trials. Their automatic disqualification denied pregnant women the potential for benefit given to others. EBOV-infected pregnant women as a class were also harmed because knowledge to protect them (and their fetuses) now lags behind knowledge for other groups. Results from studies that excluded pregnant women cannot be automatically extrapolated to pregnancy. This lack of data specific to pregnancy will negatively impact the health of pregnant women and their access to interventions in the next outbreak.

Each case of EBOV infection during pregnancy in previous outbreaks has resulted in the death of the woman or her fetus; no mother-baby pair has ever survived. Therefore, EBOV infection satisfied two conditions that should have driven inclusion of pregnant women in trials: firstly, EBOV is a life-threatening infection and chance of survival constitutes an important medical benefit. Secondly, with 100% fetal/neonatal death without intervention, investigational treatment of the mother could not place the fetus at “greater than minimal” added risk. Importantly, by excluding pregnant women, sponsors, investigators, insurance companies, and others influencing protocol provisions violated the autonomy of pregnant women and their right to decide on research participation for themselves, a fundamental ethical principle.

The largest ever EVD epidemic provided ideal conditions to deviate from usual practice for the immediate potential benefit of EBOV-infected pregnant women and the potential benefit of pregnant women in future outbreaks or epidemics. This opportunity was lost. It is time to stop “protecting” pregnant women by excluding them from trials without their consent, and time to insist on rigorous justification of exclusion, thus according pregnant women the same rights and opportunities we offer other adults.

Abbreviations

EBOV:

Ebola virus

EVD:

Ebola virus disease

MEURI:

Monitored Emergency Use of Unregistered and Experimental Interventions

WHO:

World Health Organization

WHO-ERC:

World Health Organization Ethics Review Committee

References

  1. World Health Organization. Ebola situation report . 11 may 2016. 2016. http://apps.who.int/gho/data/view.ebola-sitrep.ebola-summary-20160511?lang=en. Accessed 7 May 2017.

    Google Scholar 

  2. Garske T, Cori A, Ariyarajah A, Blake IM, Dorigatti I, Eckmanns T, et al. Heterogeneities in the case fatality ratio in the west African Ebola outbreak 2013–2016. Philos Trans R Soc London B Biol Sci. 2017; doi: 10.1098/rstb.2016.0308.

  3. Coltart CEM, Lindsey B, Ghinai I, Johnson AM, Heymann DL. The Ebola outbreak, 2013-2016: old lessons for new epidemics. Philos Trans R Soc B. 2017:372. doi: 10.1098/rstb.2016.0297.

  4. U.S. Food and Drug Administration. Center for Drug Evaluation and Research. In: Guideline for the study and evaluation of gender differences in the clinical evaluation of drugs. Washington: Federal Register; 1993. 58(139):39406-16.

  5. Sherman LA, Temple R, Merkatz RB. Women in clinical trials: an FDA perspective. Science (80- ). 1995; doi:10.1126/science.7638593.

  6. Merkatz RB, Temple R, Sobel S, Kessler DA. Working group on women in clinical trials. Women in clinical trials of new drugs: a change in Food and Drug Administration policy. N Engl J Med. 1993;9:292–6.

    Article  Google Scholar 

  7. Merkatz RB, Junod SW. Historical background of changes in FDA policy on the study and evaluation of drugs in women. Acad Med. 1994;69:703–7.

    CAS  Article  PubMed  Google Scholar 

  8. Merkatz RB. Inclusion of women in clinical trials: a historical overview of scientific, ethical, and legal issues. J Obstet Gynocology Neonatal Nurs. 1998;27:78–84.

    CAS  Article  Google Scholar 

  9. Shields KE, Lyerly AD. Exclusion of pregnant women from industry-sponsored clinical trials. Obstet Gynecol. 2013;122:1077–81.

    Article  PubMed  Google Scholar 

  10. Adam MP, Polifka JE, Friedman JM. Evolving knowledge of the teratogenicity of medications in human pregnancy. Am J Med Genet Part C Semin Med Genet. 2011;157:175–82.

    Article  Google Scholar 

  11. Merkatz R, Temple R, Sobel S, Feiden K, Kessler DA. Trials WG on W in C. Women in clinical trials of new drugs: a change in Food and Drug Administration policy. N Engl J Med. 1993;329:292–6.

    CAS  Article  PubMed  Google Scholar 

  12. Lyerly AD, Little MO, Faden RR. Reframing the framework: toward fair inclusion of pregnant women as participants in research. Am J Bioeth. 2011;11:50–2.

    Article  PubMed  Google Scholar 

  13. Cragan JD. Medication use during pregnancy. BMJ. 2014;349 doi: 10.1136/bmj.g5252.

  14. Holmes LB. Human teratogens: Update 2010. Birth Defects Res Part A - Clin Mol Teratol. 2011;91:1–7.

    CAS  Article  PubMed  Google Scholar 

  15. Macklin R. Enrolling pregnant women in biomedical research. Lancet. 2010;375:632–3.

    Article  PubMed  Google Scholar 

  16. Alirol E, Kuesel AC, Guraiib MM, de la Fuente-Núñez V, Saxena A, Gomes MF. Ethics review of studies during public health emergencies - the experience of the WHO ethics review committee during the Ebola virus disease epidemic. BMC Med Ethics. 2017;18

  17. Mupapa K, Mukundu W, Bwaka MA, Kipasa M, De Roo A, Kuvula K, et al. Ebola hemorrhagic fever and pregnancy. JID. 1999;179 Suppl 1:22–3.

    Google Scholar 

  18. Report of an International Commission. Ebola haemorrhagic fever in Zaire, 1976. Bull World Health Organ. 1978;56:271–93.

    PubMed Central  Google Scholar 

  19. Jamieson DJ, Uyeki TM, Callaghan WM, Meaney-Delman D, Rasmussen SA. What obstetrician–gynecologists should know about Ebola. Obstet Gynecol. 2014;124:1005–10.

    Article  PubMed  Google Scholar 

  20. Francesconi P, Yoti Z, Declich S, Onek PA, Fabiani M, Olango J, et al. Ebola hemorrhagic fever transmission and risk factors of contacts, Uganda. Emerg Infect Dis. 2003;9:1430–7.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Nelson JM, Griese SE, Goodman AB, Peacock G. Live neonates born to mothers with Ebola virus disease: a review of the literature. J Perinatol. 2016;36:411–4.

    CAS  Article  PubMed  Google Scholar 

  22. World Health Organization. Potential Ebola therapies and vaccines: interim guidance. 2014. http://apps.who.int/iris/handle/10665/137590. Accessed 15 Dec 2014.

    Google Scholar 

  23. Bausch DG, Sprecher AG, Jeffs B, Boumandouki P. Treatment of Marburg and Ebola hemorrhagic fevers: a strategy for testing new drugs and vaccines under outbreak conditions. Antivir Res. 2008;78:150–61.

    CAS  Article  PubMed  Google Scholar 

  24. Jones SM, Feldmann H, Ströher U, Geisbert JB, Fernando L, Grolla A, et al. Live attenuated recombinant vaccine protects nonhuman primates against Ebola and Marburg viruses. Nat Med. 2005;11:786–90.

    CAS  Article  PubMed  Google Scholar 

  25. Qiu X, Fernando L, Alimonti JB, Melito PL, Feldmann F, Dick D, et al. Mucosal immunization of cynomolgus macaques with the VSVΔG/ZEBOVGP vaccine stimulates strong ebola GP-specific immune responses. PLoS One. 2009; doi: 10.1371/journal.pone.0005547.

  26. Geisbert TW, Daddario-Dicaprio KM, Lewis MG, Geisbert JB, Grolla A, Leung A, et al. Vesicular stomatitis virus-based ebola vaccine is well-tolerated and protects immunocompromised nonhuman primates. PLoS Pathog. 2008;4:e1000225.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Kobinger GP, Feldmann H, Zhi Y, Schumer G, Gao G, Feldmann F, et al. Chimpanzee adenovirus vaccine protects against Zaire Ebola virus. Virology. 2006;346:394–401.

    CAS  Article  PubMed  Google Scholar 

  28. Geisbert TW, Bailey M, Hensley L, Asiedu C, Geisbert J, Stanley D, et al. Recombinant adenovirus serotype 26 (Ad26) and Ad35 vaccine vectors bypass immunity to Ad5 and protect nonhuman primates against ebolavirus challenge. J Virol. 2011;85:4222–33.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Martin JE, Sullivan NJ, Enama ME, Gordon IJ, Roederer M, Koup RA, et al. A DNA vaccine for Ebola virus is safe and immunogenic in a phase I clinical trial. Clin Vaccine Immunol. 2006;13:1267–77.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. van Griensven J, Edwards T, Baize S. Efficacy of convalescent plasma in relation to dose of Ebola virus antibodies. N Engl J Med. 2016; doi: 10.1056/NEJMc1609116.

  31. Schopper D, Ravinetto R, Schwartz L, Kamaara E, Sheel S, Segelid MJ, et al. Research ethics governance in times of Ebola. Public Health Ethics. 2016; doi: 10.1093/phe/phw039.

  32. Dunning J, Kennedy SB, Antierens A, Whitehead J, Ciglenecki I, Carson G, et al. Experimental treatment of ebola virus disease with brincidofovir. PLoS One. 2016;11:1–10.

    Article  Google Scholar 

  33. Council for International Organizations of Medical Sciences (CIOMS). International ethical guidelines for biomedical research involving human subjects. CIOMS. https://cioms.ch/shop/product/international-ethical-guidelines-for-health-related-research-involvinginvolvinghumans/. Accessed 14 Aug 2014

  34. Ethical considerations for use of unregistered interventions for Ebola virus disease - Report of an advisory pannel to WHO. 2014.

  35. Mastroianni AC, Faden R, Federman D. Women and Health Research: ethical and legal issues of including women in clinical studies, volume I. Washington, DC: National Academy Press; 1994.

    Google Scholar 

  36. Little MO, Lyerly AD, Faden RR. Pregnant women & medical research: a moral imperative. Bioethica Forum. 2009;2:60–5.

    Google Scholar 

  37. Blehar MC, Spong C, Grady C, Goldkind SF, Sahin L, Clayton JA. Enrolling pregnant women: issues in clinical research. Womens Heal Issues. 2013; doi: 10.1016/j.whi.2012.10.003.

  38. Sissoko D, Laouenan C, Folkesson E, Lebing AM, Malme K, Manfrin E, et al. Experimental treatment with Favipiravir for Ebola virus disease (the JIKI trial): a historically controlled, single-arm proof-of- concept trial in Guinea. PLoS Med. 2016;13 doi: 10.1371/journal.pmed.1001967.

  39. van Griensven J, Edwards T, de Lamballerie X, Semple MG, Gallian P, Baize S, et al. Evaluation of convalescent plasma for Ebola virus disease in Guinea. N Engl J Med. 2016; doi: 10.1056/NEJMoa1511812.

  40. Huttner A, Dayer JA, Yerly S, Combescure C, Auderset F, Desmeules J, et al. The effect of dose on the safety and immunogenicity of the VSV Ebola candidate vaccine: a randomised double-blind, placebo-controlled phase 1/2 trial. Lancet Infect Dis. 2015; https://doi.org/10.1016/S1473-3099(15)00154-1.

  41. Agnandji ST, Huttner A, Zinser ME, Njuguna P, Dahlke C, Fernandes JF, et al. Phase 1 trials of rVSV Ebola vaccine in Africa and Europe — preliminary report. N Engl J Med. 2015; doi: 10.1056/NEJMoa1502924.

  42. Henao-Restrepo AM, Longini IM, Egger M, Dean NE, Edmunds WJ, Camacho A, et al. Articles efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein : interim results from the Guinea ring vaccination cluster-randomised trial. Lancet. 2015;6736:1–10.

    Google Scholar 

  43. Henao-Restrepo AM, Longini IM, Egger M, Dean NE, Edmunds WJ, Camacho A, et al. Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!). Lancet. 2017; doi: 10.1016/S0140-6736(16)32621-6.

  44. De Santis O, Audran R, Pothin E, Warpelin-Decrausaz L, Vallotton L, Wuerzner G, et al. Safety and immunogenicity of a chimpanzee adenovirus-vectored Ebola vaccine in healthy adults: a randomised, double-blind, placebo-controlled, dose-finding, phase 1/2a study. Lancet Infect Dis. 2015; doi: 10.1016/S1473-3099(15)00486-7.

  45. Tapia MD, Sow SO, Lyke KE, Haidara FC, Diallo F, Doumbia M, et al. Use of ChAd3-EBO-Z Ebola virus vaccine in Malian and US adults, and boosting of Malian adults with MVA-BN-Filo: a phase 1, single-blind, randomised trial, a phase 1b, open-label and double-blind, dose-escalation trial, and a nested, randomised, double-bli. Lancet Infect Dis. 2015; doi: 10.1016/S1473-3099(15)00362-X.

  46. Ebola Response Team WHO. Ebola virus disease among male and female persons in West Africa. N Engl J Med. 2016; doi: 10.1056/NEJMc1510305.

  47. Maganga GD, Kapetshi J, Berthet N, Kebela Ilunga B, Kabange F, Mbala Kingebeni P, et al. Ebola virus disease in the Democratic Republic of Congo. N Engl J Med. 2014;371:2083–91.

    CAS  Article  PubMed  Google Scholar 

  48. Akerlund E, Prescott J, Tampellini L. Shedding of Ebola virus in an asymptomatic pregnant woman. N Engl J Med. 2015;372:2467–9.

    CAS  Article  PubMed  Google Scholar 

  49. Caluwaerts S, Lagrou D, Lledo P, Black B, Decroo T, Modet A, et al. Blood, birthing and body fluids : delivering and staying alive in an Ebola management Centre. 2015. https://www.msf.org.uk/sites/uk/files/3._28_caluwaerts_ebola_ocb_sv_final.pdf. Accessed 10 May 2017.

    Google Scholar 

  50. Baize S, Pannetier D, Oestereich L, Rieger T, Koivogui L, Magassouba N, et al. Emergence of Zaire Ebola virus disease in Guinea. N Engl J Med. 2014;371:1418–25.

    CAS  Article  PubMed  Google Scholar 

  51. Baggi FM, Taybi A, Kurth A, Van Herp M, Di Caro A, Wölfel R, et al. Management of pregnant women infected with Ebola virus in a treatment centre in Guinea, June 2014. Euro Surveill 2014; 19 (49): pii=20983.

  52. Caluwaerts S, Fautsch T, Lagrou D, Moreau M, Camara AM, Günther S, et al. Dilemmas in managing pregnant women with ebola: 2 case reports. Clin Infect Dis. 2016;62:903–5.

    Article  PubMed  Google Scholar 

  53. Chertow DS, Kleine C, Edwards JK, Scaini R, Ruggero G, Sprecher A. Ebola virus disease in West Africa - clinical manifestations and management. N Engl J Med. 2014; doi: 10.1056/NEJMp1413084.

  54. Caluwaerts S, Van Hern M, Cuesta JG, Crestani R, Ronsse A, Lagrou D, et al. Pregnancy and Ebola: management and survival of pregnant patients admitted to Médecins Sans Frontières Ebola treatment Centres in the 2014-2016 West Africa epidemic. In: Schwartz D, Anoko J, Abramowitz S, editors. Pregnant in the time of Ebola. Springer New York: Women and Their Children in the 2013–2015 West African Epidemic; 2017. p. [in press].

    Google Scholar 

  55. Schieffelin JS, Shaffer JG, Goba A, Gbakie M, Gire SK, Colubri A, et al. Clinical illness and outcomes in patients with Ebola in Sierra Leone. N Engl J Med. 2014;371:2092–100.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. Dörnemann J, Burzio C, Ronsse A, Sprecher A, De Clerck H, Van Herp M, et al. First newborn baby to receive experimental therapies survives Ebola virus disease. J Infect Dis. 2017;215:jiw493.

    Article  Google Scholar 

  57. Oduyebo T, Pineda D, Lamin M, Leung A, Corbett C, Jamieson DJ. A pregnant patient with Ebola virus disease. Obstet Gynecol. 2015;126:1273–5.

    Article  PubMed  Google Scholar 

  58. Bower H, Grass JE, Veltus E, Brault A, Campbell S, Basile AJ, et al. Delivery of an ebola virus-positive stillborn infant in a rural community health center, Sierra Leone, 2015. Am J Trop Med Hyg. 2016;94:417–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. Medicins Sans Frontières. NUBIA first newborn to survive Ebola. 2015. https://msf.exposure.co/nubia. Accessed 1 May 2017.

    Google Scholar 

  60. Vetter P, Kaiser L, Schibler M, Ciglenecki I, Bausch DG. Sequelae of Ebola virus disease: the emergency within the emergency. Lancet Infect Dis. 2016;16:e82–91.

    Article  PubMed  Google Scholar 

  61. Fowler R, Mishra S, Chan AK. The crucial importance of long-term follow-up for Ebola virus survivors. Lancet Infect Dis. 2016;16:987–9.

    Article  PubMed  Google Scholar 

  62. Deen GF, Knust B, Broutet N, Sesay FR, Formenty P, Ross C, et al. Ebola RNA persistence in semen of Ebola virus disease survivors — preliminary report. N Engl J Med. 2015; doi: 10.1056/NEJMoa1511410.

  63. Sow MS, Etard J-F, Baize S, Magassouba N, Faye O, Msellati P, et al. New evidence of long-lasting persistence of Ebola virus genetic material in semen of survivors. J Infect Dis. 2016; doi: 10.1093/infdis/jiw078.

  64. Mattia JG, Vandy MJ, Chang JC, Platt DE, Dierberg K, Bausch DG, et al. Early clinical sequelae of Ebola virus disease in Sierra Leone: a cross-sectional study. Lancet Infect Dis. 2015; doi: 10.1016/S1473-3099(15)00489-2.

  65. Bausch DG, Towner JS, Dowell SF, Kaducu F, Lukwiya M, Sanchez A, et al. Assessment of the risk of Ebola virus transmission from bodily fluids and fomites. J Infect Dis. 2007;196(Supp.2):S142–7.

    Article  PubMed  Google Scholar 

  66. Thorson A, Formenty P, Lofthouse C, Broutet N. Systematic review of the literature on viral persistence and sexual transmission from recovered Ebola survivors: evidence and recommendations. BMJ Open. 2016;6:e008859.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Howlett P, Brown C, Helderman T, Brooks T, Lisk D, Deen G, et al. Ebola virus disease complicated by late-onset encephalitis and polyarthritis, sierra leone. Emerg Infect Dis. 2016;22:150–2.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. Fallah MP, Skrip LA, Dahn BT, Nyenswah TG, Flumo H, Glayweon M, et al. Pregnancy outcomes in Liberian women who conceived after recovery from Ebola virus disease. Lancet Glob Heal. 2016;4:e678–9.

    Article  Google Scholar 

  69. WHO/International Study Team. Ebola haemorrhagic fever in Sudan, 1976. Bull World Health Organ. 1978;56:247–70.

    Google Scholar 

  70. Muehlenbachs A, de la Rosa VO, Bausch DG, Schafer IJ, Paddock CD, Nyakio JP, et al. Ebola virus disease in pregnancy: clinical, Histopathologic, and Immunohistochemical findings. J Infect Dis. 2016;215:64–9.

    Article  PubMed  Google Scholar 

  71. Kratz T, Roddy P, Oloma AT, Jeffs B, Ciruelo DP, De La Rosa O, et al. Ebola virus disease outbreak in Isiro, democratic Republic of the Congo, 2012: signs and symptoms, management and outcomes. PLoS One. 2015;10:1–18.

    Google Scholar 

  72. Ebola ca suffit ring vaccination trial consortium. The ring vaccination trial: a novel cluster randomised controlled trial design to evaluate vaccine efficacy and effectiveness during outbreaks, with special reference to Ebola. BMJ. 2015; doi: 10.1136/bmj.h3740.

  73. Duraffour S, Malvy D, Sissoko D. How to treat Ebola virus infections? A lesson from the field. Curr Opin Virol. 2017;24:9–15.

    Article  PubMed  Google Scholar 

  74. Mentré F, Taburet A-M, Guedj J, Anglaret X, Keïta S, de Lamballerie X, et al. Dose regimen of favipiravir for Ebola virus disease. Lancet 2015; 15 February 150–151.

  75. Bai CQ, Mu JS, Kargbo D, Bin SY, Niu WK, Nie WM, et al. Clinical and Virological characteristics of Ebola virus disease patients treated with Favipiravir (T-705) - Sierra Leone, 2014. Clin Infect Dis. 2016;63:1288–94.

    Article  PubMed  Google Scholar 

  76. Dunning J, Sahr F, Rojek A, Gannon F, Carson G, Idriss B, et al. Experimental treatment of Ebola virus disease with TKM-130803: a single-arm phase 2 clinical trial. PLoS Med. 2016;13:1–19.

    Article  Google Scholar 

  77. PREVAIL II Writing Group, Multi-National PREVAIL II Study Team. A randomized, controlled trial of ZMapp for Ebola virus infection. N Engl J Med. 2016;375:1448–56.

    Article  Google Scholar 

  78. Edwards T, Semple MG, De Weggheleire A, Claeys Y, De Crop M, Menten J, et al. Design and analysis considerations in the Ebola_Tx trial evaluating convalescent plasma in the treatment of Ebola virus disease in Guinea during the 2014–2015 outbreak. Clin Trials. 2016; doi: 10.1177/1740774515621056.

Download references

Acknowledgements

We are grateful to S. Caluwaerts for providing us with a pre-publication copy of her book chapter, to J.S. Schieffelin for having provided the maternal outcome of the patient in his article, and to A-M Hanao-Restrepo and MSF for information on vaccinated women in the trial. We also gratefully acknowledge the contribution to the WHO-ERC Ebola-research review of M.R. Balakrishnan, A. Baller, P. Bouvier, K. Fernandez, K. Kennedy, O. Mach, N. Magrini, C. Maure, E. Mumford, B. Ramirez, N. Rollins, M. Senga, J.U. Sommerfeld, S. Suri, and J. Wang-Cavallanti.

Funding

The publication cost of this article was funded by the Wellcome Trust.

Availability of data and materials

Not applicable

About this supplement

This article has been published as part of Reproductive Health Volume 14 Supplement 3, 2017: Proceedings from the Global Forum on Bioethics in Research (GFBR)‘s “Ethics of Research in Pregnancy” meeting. The full contents of the supplement are available online at https://reproductive-health-journal.biomedcentral.com/articles/supplements/volume-14-supplement-3.

Author information

Authors and Affiliations

  1. World Health Organization, Geneva, Switzerland

    Melba F. Gomes

  2. Department for Ageing and Life Course, World Health Organization, Geneva, Switzerland

    Vânia de la Fuente-Núñez

  3. Department for Information Evidence and Research, World Health Organization, Geneva, Switzerland

    Abha Saxena

  4. UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases, World Health Organization, Geneva, Switzerland

    Annette C. Kuesel

Authors
  1. Melba F. Gomes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vânia de la Fuente-Núñez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Abha Saxena
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Annette C. Kuesel
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Authors contributed to WHO-ERC reviews of Ebola-related research as members of the WHO-ERC secretariat (VF-N, AS), the WHO-ERC (ACK) or as WHO-ERC chair (MFG). ACK and VF-N prepared Table 2. ACK and MFG prepared Table 1 and drafted the manuscript, the final version of which was read, reviewed and approved by all authors.

Corresponding author

Correspondence to Melba F. Gomes.

Ethics declarations

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This is an open access article distributed under the terms of the Creative Commons Attribution IGO License (http://creativecommons.org/licenses/by/3.0/igo/legalcode), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any reproduction of this article there should not be any suggestion that WHO or this article endorse any specific organization or products. The use of the WHO logo is not permitted. This notice should be preserved along with the article’s original URL.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Gomes, M.F., de la Fuente-Núñez, V., Saxena, A. et al. Protected to death: systematic exclusion of pregnant women from Ebola virus disease trials. Reprod Health 14, 172 (2017). https://doi.org/10.1186/s12978-017-0430-2

Download citation

  • Published:

  • DOI: https://doi.org/10.1186/s12978-017-0430-2

Keywords

  • Pregnancy
  • Exclusion-criteria
  • Ebola
  • Ethics
  • Risk-benefit
  • Epidemic
  • Trials
  • Research

Reproductive Health

ISSN: 1742-4755