Breakthroughs Blog: Maternal health

Pregnant women in their first trimester are at risk of malaria Eileen Buxton is a Ghanaian nurse who contracted malaria while pregnant with twins. As a health care professional, she recognized the symptoms such as high fever, severe nausea, and vomiting. She sought care and was given artemether-lumefantrine, a medicine that was recently recommended by the World Health Organization (WHO) to treat malaria in the first trimester of pregnancy.Unfortunately, the situation where medicines are available and determined to be safe for use in first-trimester pregnancy is uncommon. According to the Concept Foundation, since the 1990s, only two drugs have been developed specifically for pregnant women. Furthermore, in the clinical research stage of medicine development, pregnant women, especially those in their first trimester, have been historically excluded for fear of causing harm to the mother and the baby. As a result, health care professionals and pregnant women are left with limited information, making it difficult to make informed decisions about the best course of treatment. Well-tolerated and effective antimalarials, as well as medicines for other diseases, must be developed and made available, accessible, and affordable for pregnant women like Eileen. Malaria infection and treatment during the first trimester of pregnancyMalaria, although preventable and treatable, can become fatal if left untreated, and in pregnancy, the disease has severe consequences for both the mother and the baby she is carrying. Malaria in pregnancy (MiP) can result in the severe, rather than uncomplicated, form of the disease for the mother, resulting in gestational hypertension, premature labor, miscarriage, and the fetus being small for its gestational age. Newborns can be born prematurely and with low birth weight, leading to further health complications, such as cognitive delays. During the first trimester, women are especially at risk of malaria infection because they are unprotected, as no preventive therapies are available until later in pregnancy. Data show that around 65 percent of cases of MiP appear late in the first trimester because the placenta becomes more susceptible to infection, demonstrating a clear need for recommended medicines that can both prevent and treat women in early pregnancy. Although the aforementioned effects of malaria in the second and third trimesters are well known, there has been little data collected on the effects of malaria in the first trimester: few women in malaria-endemic countries attend health facilities in early pregnancy due to a mix of cultural and logistical factors, creating an obstacle to generating research.Preventive therapies for the first trimester are urgently needed: currently, there are none. Intermittent preventive treatment of malaria in pregnancy, an intervention used in sub-Saharan Africa, is only recommended by WHO from the second trimester onward to protect pregnant women from the disease.And although WHO recently recommended the artemisinin-based combination therapy (ACT) artemether-lumefantrine for use in the first trimester, the organization’s Strategy to respond to antimalarial drug resistance in Africa also points out that most countries rely on this drug and thus recommends using a wider range of ACTs to mitigate the development of drug resistance. Ethics and regulatory frameworks for including pregnant women in clinical researchThe four main ethical principles of clinical research are beneficence, nonmaleficence, autonomy, and justice. These principles must be adhered to when designing clinical trials that safely and equitably include pregnant women in their first trimester. In fact, excluding this population perpetuates a cycle of underrepresentation in clinical research, while including them adheres to the principle of justice by ensuring that individuals, regardless of status or condition, have equal access to the benefits of medical research. Drug development takes, on average, 10 to 15 years before registration. When pregnant women are excluded from clinical research, there are no data on how well tolerated or effective it is for pregnant women when the drug reaches market. The COVID-19 pandemic demonstrated that it is possible to rapidly develop and distribute drugs, and with the Sustainable Development Goals (SDGs) set to expire in seven years, the malaria community needs to work at an accelerated pace to achieve Target 3.3 of the SDGs: end the epidemics of AIDS, tuberculosis, malaria, and neglected tropical diseases and combat hepatitis, water-borne diseases, and other communicable diseases. Greater priority must be placed on expediting the discovery, development, and delivery of medicines that meet the needs of at-risk groups, like pregnant women in their first trimester.Global health has experienced a paradigm shift: it is now widely acknowledged that pregnant women must be protected through, and not from, research, a principle that is underscored by recent international commitments. In 2022, at the 75th World Health Assembly, WHO member states adopted Resolution 75.8: Strengthening clinical trials to provide high-quality evidence on health interventions and to improve research quality and coordination. While it does not specifically mention pregnancy, this resolution provides a basis for countries in both the Global North and the Global South to develop clinical ecosystems that are “health-needs driven, evidence based, well designed and well implemented and be guided by established ethical guidance.”In 2021, the G7 Health Ministers adopted the G7 Therapeutics and Vaccines Clinical Trials Charter, which commits to “stronger collaboration in large-scale international trials to enable greater diversity of participants, including pregnant people and children” and supporting low- and middle-income countries, where malaria is most prevalent, in sustainably strengthening capacity. Malaria in pregnancy remains a major public health concern that demands urgent attention and action from global health stakeholders. Clinical research plays a critical role in advancing the development of effective interventions with an adequate safety profile. Ensuring that pregnant women are part of this research from the start can help save millions of lives and adhere to fundamental principles of justice and equity. 

Interested in more global health innovation news? Every week GHTC scours media reports worldwide to deliver essential global health R&D news and content to your inbox. Sign up now to receive our weekly R&D News Roundup email.A recent study found that an inexpensive, widely available antibiotic could sharply reduce the number of pregnant individuals in low- and middle-income countries who develop sepsis in childbirth, which is among the three leading causes of maternal deaths globally. The study, conducted in seven countries mostly in sub-Saharan Africa and Asia, showed that a single dose of the drug azithromycin during labor cut the risk of the mother developing sepsis by around 35 percent. Azithromycin is a generic drug, it has a long half-life, and it does not require refrigeration, making it an inexpensive and easy-to-deliver tool that could be widely adopted even in low-resource settings.Following the recent discovery of an outbreak of H5N1 on a Spanish mink farm, scientists have identified that the strain of the virus behind the outbreak contains a mutation that could make the virus more adaptable to mammals. While experts have stressed that there is no need panic, the outbreak is a reminder of the importance of disease surveillance and preparedness measures, especially as a new variant of H5N1 has spread among bird populations and spilled over into humans in recent years. Scientists have not detected any transmission of this latest strain among humans, although the mutation could increase the potential risk.Fungal pathogens are a growing threat to global public health, according to experts and the World Health Organization (WHO), which published a list of priority fungal pathogens last year. Resistance is exacerbating the threat. For example, Candida auris, Aspergillus fumigatus, and Cryptococcus neoformans, which WHO ranks among the four highest priority threats, have all shown resistance to current tools. There are also no vaccines for the top four critical infections identified. As aging populations and the climate crisis contribute to growing antimicrobial resistance, there is a strong need for improving surveillance capacity and investing in developing diagnostics, medicines, and other interventions for fungal infections, which currently account for less than 1.5 percent of all infectious disease research spending, according to WHO.

Malaria in pregnancy threatens the health of mothers and babiesWhen a woman finds out she is pregnant, it is often an exciting, emotional, and nerve-racking time. For women in malaria-endemic countries, however, there is an additional concern: the risk of contracting malaria during pregnancy. This was a major worry for Kenyan mother Elyne Kaingu. Fortunately, during her second pregnancy, she received intermittent preventive treatment of malaria in pregnancy (IPTp) at the health clinic, enabling her to have a malaria-free pregnancy. However, not all women are as fortunate as Kaingu.According to the World Health Organization’s (WHO’s) 2021 World Malaria Report, 34 percent of the more than 33 million pregnancies worldwide in 2020 were exposed to malaria, meaning more than 11 million women and babies were at risk for the serious complications that malaria in pregnancy (MiP) may entail, including anemia, the development of severe malaria, and risk of miscarriage or low infant birth weight. Insufficient prevention and treatment options for MiP Despite the urgent need, options for preventing and treating MiP are currently limited. Pregnant women are usually excluded from clinical trials to protect them and their babies from potential adverse effects of new drugs in development, making it difficult to determine the safety and appropriate dose to guide recommendations of new and existing drugs for use in pregnant women. While WHO recommends artemisinin-based combination therapies (ACTs) to treat uncomplicated malaria and sulfadoxine-pyrimethamine (SP) for IPTp for women in their second and third trimesters, these treatments fall short in some critical areas: neither is recommended for use in the first trimester of pregnancy1 and SP should not be used by pregnant women with HIV/AIDS receiving prophylaxis against opportunistic infections or by women in areas where SP drug resistance is reported.Protecting and treating pregnant women: Researching, repurposing and recombining antimalarials  To improve the availability of well-tolerated and effective antimalarials for pregnant women, changes in drug development approaches are urgently needed. Through MMV’s MiMBa strategy, the product development partnership is advocating for and advancing several innovative research approaches.What has first been required is a mindset shift—a clear agreement to change the way we approach de-risking of compounds so that there is robust data on pregnancy as soon as possible in the drug development process. Starting at the earliest phase (discovery), MMV is prioritizing new antimalarials for progression to development based on their low-risk profile for birth defects. In addition, MMV is using translational pregnancy models to optimize and accelerate their clinical development by providing information on the potential need to adjust drug dosing for pregnant women, as well as the possibility of fetal exposure. Further, MMV performs developmental and reproductive toxicity studies that evaluate the effects of potential drugs on one complete life cycle (from conception in one generation through the following generation) earlier in the development process. Compounds which are shown to be well-tolerated in developmental and reproductive toxicity studies will be evaluated in pregnant women. It is hoped that if compounds can be appropriately de-risked, then in future dedicated clinical trials in pregnancy might be conducted in parallel to phase 3 trials, also known as confirmatory studies, which “aim to confirm the efficacy and safety of the candidate compound in a large patient population.” This approach would allow for the collection of information to establish the benefit/risk balance of a new antimalarial at an earlier stage and will help ensure that the needs of pregnant women are addressed in a more timely and equitable manner in the future.Existing antimalarials: Filling the data gapMMV has undertaken research on existing drugs for their potential use in pregnant women. With its pharmaceutical partner Shin Poong and other research partners, MMV conducted a real-life study (CANTAM) on pyronaridine-artesunate (Pyramax®) in five countries in Africa with results indicating high safety, tolerability, and efficacy for the 11 women who were unknowingly pregnant. Finally, MMV is currently providing input in an ongoing study, PYRAPREG, led by the University of Sciences, Techniques and Technologies of Bamako, which is looking at the efficacy and safety of four ACTs, including Pyramax, in the second and third trimesters of pregnancy. Further, MMV is supporting follow-up studies on ACTs already on the market. For example, MMV and the Liverpool School of Tropical Medicine’s Timika facility in Indonesia continues to monitor women during and after their pregnancies.Finally, MMV has set up a pregnancy registry, launched last year in Kenya with the Liverpool School of Tropical Medicine and extended to Burkina Faso at the beginning of 2022. Through this registry, MMV aims to obtain robust data on the use of a range of ACTs for the treatment of uncomplicated malaria in pregnancy. The information generated will serve to better understand the benefit/risk ratio and contribute to informing policymakers, regulators, clinicians, and pregnant women on the use of ACTs, particularly during the first trimester. According to Hellen Barsosio, a senior clinical research scientist based in Kenya, “Pregnancy registries are vital in providing safety information on drugs and vaccines used during pregnancy, particularly within the first trimester, a critical period for the growing baby due to the limited safety data available by the time drugs reach the market.”Facilitating access to antimalarialsFor antimalarials to be useful in preventing and treating MiP, healthcare workers and patients must be aware of their protective effects and be able to access them. MMV works with governments, pharmaceutical companies, and implementing partners to ensure that antimalarials are available as quickly as possible after launch, especially in hard-to-reach areas. A recent success in facilitating access to antimalarials for pregnant women is the achievement of WHO prequalification for SP by Universal Corporation Ltd, a Kenyan pharmaceutical company, supported by Unitaid and MMV. Universal Corporation Ltd is the first pharmaceutical company in Africa to achieve prequalification for SP. As alternatives to SP advance, it will be crucial to enable manufacturers in endemic countries to produce quality-assured medicines so that they are readily available for pregnant women. The World Health Summit serves as a reminder that those who are the most vulnerable to diseases must be at the center of drug discovery and development efforts. Developing antimalarials to address the needs of pregnant women is vital to achieving malaria eradication by ensuring that everyone can access the care they need. 1. On 25 November, WHO released its updated guidelines for malaria, which include a strong recommendation for the use of an ACT, artemether-lumefantrine, to treat uncomplicated malaria in women in their first trimester

The ability of women to choose whether, when, and how many children to have is essential to advancing the health and well-being of women and their families. In fact, research shows that expanding global access to contraception could reduce maternal deaths by nearly one-third and child deaths by one-quarter. Yet today, 218 million women in low- and middle-income countries have an unmet need for modern contraceptives. New contraceptive innovations are urgently needed to help close this contraceptive gap, including tools that are suitable and convenient for women who live far from health care settings and multipurpose products that combine contraception with HIV prevention. In recognition of World Contraception Day, GHTC is testing our readers’ knowledge of the history of contraceptive innovation. Your challenge for each question below: Name that contraceptive method.