Lifesaving drug for severe bleeding after childbirth could be made accessible for all, study suggests
Intramuscular administration of tranexamic acid (TXA), a drug used to target severe bleeding after childbirth, is safe and quickly reaches therapeutic concentrations in pregnant women, according to a study involving researchers from the London School of Hygiene & Tropical Medicine (LSHTM).
The findings, from the Woman-PharmacoTXA Phase 2 trial, highlight that intramuscular injection may be a potential alternative to current intravenous approaches, which are often unsuitable in home births or rural care settings.
Oral TXA was also well-tolerated, however, on average, took around one hour to reach therapeutic blood concentrations, meaning it could be unsuitable for emergency treatment.
The results are published in the British Journal of Obstetrics and Gynaecology.
Severe bleeding after childbirth, or postpartum haemorrhage (PPH), is one of the leading causes of maternal death worldwide, with most of the 70,000 yearly deaths occurring in low-and middle-income countries (LMICs).
Results from the earlier WOMAN trial, led by researchers from LSHTM with collaboration from 21 countries, provided crucial evidence for the life-saving potential of repurposing TXA for treating PPH.
Originally used in surgery and later in trauma, TXA works by inhibiting the breakdown of blood clots.
Although intravenous administration of TXA is the first port-of-call for treatment, many births in LMICs take place at home, with access to healthcare settings often limited. Subsequently, focus has shifted towards finding alternative administration routes.
In this trial, an international research team, including from LSHTM, recruited over 120 women aged 18 or older who were due to give birth by caesarean section at two hospitals in Pakistan and one in Zambia between December 2020 and June 2021. All women had one or more risk factors for postpartum haemorrhage.
The study is the first trial testing several different routes of administration in women giving birth and notably the first to test the intramuscular route, specifically in pregnant women.
Overall, intramuscular and oral TXA were well tolerated, with no serious side effects for mothers or newborns. Target concentrations of TXA in maternal blood were achieved for both routes, although for oral TXA this took an hour – a characteristic that could prevent its use in emergency treatment. Intramuscular TXA, however, reached therapeutic concentrations within ten minutes of injection, which was maintained for over four hours.
The authors conclude that these findings provide enough evidence to conduct comparative Phase 3 clinical trials (I’M WOMAN) beginning in August this year. These will aim to determine if intramuscular administration is as effective as intravenous routes in reducing postpartum bleeding.
Professor Haleema Shakur-Still, co-author and Professor of Global Health Clinical Trials at LSHTM said: “In many LMICs, women do not give births in healthcare facilities, so if TXA can be given just as successfully intramuscularly as via intravenous injection, this could be of huge significance to the thousands of women who die every year from PPH.”
Professor Rizwana Chaudhri, co-author based at Shifa Tameer-e-Millat University, Islamabad, Pakistan said: “The intramuscular route will be very helpful in Pakistan. With some patients who are experiencing a PPH, it is difficult to get an intravenous line established, so anything that can reduce PPH will be useful. In some cases, it will be the first and last choice.”
Dr Mwansa Ketty Lubeya, co-author based at The University of Zambia-School of Medicine, Women and Newborn Hospital-UTH said: “In Zambia, we are still struggling with access to TXA. Even when it is available, there should be options in terms of administration. There is no point in having TXA when canulation is not an option. We are excited to have the intramuscular option and be able to use it far and wide.”
Dr Ian Roberts, co-author and Professor of Epidemiology at LSHTM said: “We have good reason to believe the intramuscular route will be as effective as the intravenous route to reduce postpartum bleeding. In August, we are starting a large global trial to prove this in the hope that this will change WHO guidelines. We want to make this lifesaving treatment available to all women wherever they give birth.”
JOURNAL
British Journal of Obstetrics and Gynaecology
METHOD OF RESEARCH
Randomized controlled/clinical trial
SUBJECT OF RESEARCH
People
ARTICLE TITLE
Alternative routes for tranexamic acid treatment in obstetric bleeding (WOMAN-PharmacoTXA trial): a randomised trial and pharmacological study in caesarean section births
Respiratory virus plagues SA but new vaccine for pregnant moms saves babies
This is what the MATISSE study conducted in 18 countries including South Africa aimed to find out.
The Maternal Immunization Study for Safety and Efficacy (MATISSE) phase 3 trial evaluated the efficacy and safety of maternal RSVpreF vaccination in preventing RSV-associated lower respiratory tract illness in infants.
Respiratory syncytial virus (RSV) is the most common cause of hospitalisation in children under five years of age, and even more so in those younger than six months.
Researchers at the Wits Vaccines and Infectious Diseases Analytics Research Unit (Wits VIDA) at the University of the Witwatersrand, Johannesburg, led the MATISSE trial in South Africa.
The researchers wanted to find out if administering Pfizer’s Bivalent Prefusion F Vaccine in pregnancy could reduce the burden of RSV-associated lower respiratory tract illness in new-borns and infants and, if so, how well, and for how long?
In this trial, as part of a multi-centred study, Wits VIDA report that vaccination of pregnant women with the RSV vaccine is safe, and reduces the risk of severe RSV associated lower respiratory tract infection by 82% in infants aged through to six months old.
The findings were published in the New England Journal of Medicine (NEJM) on 5 April 2023.
“This study adds to the portfolio of research on vaccination of pregnant women to protect the mother, foetus and new-born,” says study author and Director of Wits VIDA, Professor Shabir Madhi. “The release of these study findings, in which South African scientists played a prominent role, comes at a time when RSV is back with a vengeance in SA, with paediatric wards being filled with children in whom illness can now be prevented with this new RSV vaccine.”
The urgency to immunise against RSV
Lower respiratory tract infections (LRTI) are the most common cause of hospitalisation and death in children 1-59 months of age, particularly in low- and middle-income countries (LMICs).
RSV is the most common cause of LRTI hospitalisation in children, occurring in some 30-80% of cases.
Approximately two-thirds of children will be infected at least once by RSV in the first two years of life, a third of whom will develop LRTI.
In 2019, it was estimated that there were 101 400 RSV-attributable deaths, 99% of which occurred in LMICs and 50% of which were in children less than 6 months of age.
Death from RSV is likely to be underestimated in low-income settings. There has been no change in the burden of RSV over the past two decades.
RSV-LTRI immunisation a global priority and a LMIC urgency
Vaccines to prevent RSV-LRTI are considered a priority by the World Health Organization.
There is currently no antiviral treatment for children with RSV infection, and management of RSV-LRTI is symptom based.
Palivizumab, a costly monoclonal antibody, is the only licensed effective strategy to reduce the risk of RSV-LRTI hospitalisation in South Africa.
The MATISSE study shows that the RSV prefusion F protein-based vaccine (RSVpreF) administered during the late second or third trimester of pregnancy may protect infants from severe RSV illness during the first few months of life – this would be particularly important in low- and middle-income countries, where the burden of RSV-associated lower respiratory tract illness is highest.
About the MATISSE Clinical Trial
Funded by Pfizer; MATISSE ClinicalTrials.gov number, NCT04424316. DOI: 10.1056/NEJMoa2216480
About Wits VIDA
Established in 1997 as the Pneumococcal Diseases Research Unit and then the Respiratory and Meningeal Pathogens Research Unit, it rebranded in 2019 to the Vaccines and Infectious Diseases Analytics Research Unit (Wits VIDA). Research focuses on clinical and molecular epidemiology of vaccine preventable disease; clinical development and evaluation of vaccines; the study of the immunology of vaccines including in people living with HIV; and basic science research aimed at discovering vaccine candidates. In 2017, Wits VIDA established a health and demographic surveillance platform (HDSS) to understand the context in which infections occur and how disease trends affect population dynamics, both in children and pregnant women. The HDSS platform was integral to understanding Covid-19 epidemiology, its effects, and excess mortality across age groups. An established social-behavioural science stream at Wits VIDA is currently exploring motivations and barriers to vaccination and behaviours impacting maternal and infant health, amongst others.
JOURNAL
New England Journal of Medicine
METHOD OF RESEARCH
Randomized controlled/clinical trial
SUBJECT OF RESEARCH
People
ARTICLE TITLE
Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants
Vaccination during pregnancy could prevent RSV illness in infants
Clinical study shows vaccine to be effective and well tolerated
Peer-Reviewed PublicationIt is estimated that about 50 to 70 percent of children in Germany contract RSV in the first year of life, and nearly every child will have been infected at least once before reaching two years of age. Illness generally starts with mild cold-like symptoms before progressing to the lower respiratory tract and lungs. The disease can cause acute breathing problems and shortness of breath. Around the world, some 100,000 children under the age of five years died as a result of RSV infection in 2019, about 97 percent of them in low- and middle-income countries.
“Previously, only symptomatic treatment was available for RSV. In severe cases, supplemental oxygen is vital, but in poorer countries, it is often not administered fast enough or to an adequate extent,” says Dr. Beate Kampmann, head of the Institute of International Health at Charité and Einstein Professor for Global Health. “This means we urgently need an vaccine to provide effective protection against RSV severe disease for the most vulnerable group, namely children under six months old.”
One promising option is vaccination during pregnancy, which is already recommended for diseases such as the flu, whooping cough, and COVID-19. Expectant mothers generate antibodies after receiving the vaccine and then pass them along to the unborn child through the placenta. The baby is born with effective immune defenses that persist through the first few months of life.
Extensive vaccination study in 18 countries
Now, a pharmaceutical company has developed this kind of vaccine to be administered during pregnancy, targeting RSV. The new vaccine, called RSV-preF, was the subject of an extensive international study performed in 18 countries between 2020 and 2022, which investigated its tolerability and efficacy. Kampmann played an instrumental role in the study as part of her longstanding research work within the vaccines and immunity theme with the Medical Research Council (MRC) Unit The Gambia, part of the London School of Hygiene and Tropical Medicine (LSHTM).
In the phase 3 trial that has now been published, the vaccine was administered to 3,682 randomly selected participants during the second or third trimester of pregnancy as a shot in the upper arm. A similarly sized comparison group received a placebo shot containing no vaccine. Neither the participants nor the heads of the study knew at any time up to the conclusion of the trial who had received the vaccine and who had been given the placebo. That makes it a placebo-controlled randomized double-blind trial, which is aligned with the very highest standards of quality.
The children were examined regularly and upon any signs of respiratory illness for one to two years after birth. They were also tested for RSV, and the severity of illness was assessed according to a predefined scale used for the study.
Approval for RSV vaccine sought
“The results of the vaccine trial are extremely positive,” Kampmann says. “In over 80 percent of children, maternal immunization during pregnancy prevented severe RSV disease in the first three months of life, and over two-thirds were still protected at six months of age. The vaccine was also very well tolerated.” The maker of the vaccine has applied to the European and U.S. drug authorities for approval. Results of the review are expected later this year.
Nearly half of the study’s participants came from the United States, while 30 percent live in low- or middle-income countries. Kampmann’s team recruited about 200 participants in Gambia, for example. “We were able to use the platform for vaccine trials involving pregnant women that we had already established in Gambia for the RSV vaccine study as well,” she says. Kampmann, a proven expert in childhood infectious disease, has been working in the West African country for more than a decade now. Her activities have included initiating a program for immunization during pregnancy to combat whooping cough (pertussis) during childhood. The goal is to prevent these kinds of diseases and lower infant mortality rates.
“It’s important to perform vaccine trials in the countries where the vaccines are to be used later on,” Kampmann says. “Especially in socioeconomically disadvantaged countries, people often suffer from chronic gastrointestinal conditions due to poor hygiene conditions. That can lower the effectiveness of vaccination, as in the case of the rotavirus vaccine. And there are comorbidities such as malaria and HIV that impair the transfer of antibodies through the placenta. All these factors affect how well a vaccine works in the end.” When it comes to national vaccination bodies, it is also important for a vaccine to have proven effective within that region so it can be recommended later on.
“The RSV vaccine was tolerated extremely well overall by the participants, and its effectiveness in preventing severe RSV disease in infants was persuasive. We’d like to thank all the women who participated in the study, and we hope the vaccine will be in use soon, saving many young lives.” That applies to children in Gambia and around the world, since the 2022/23 season that just concluded highlighted the consequences of RSV infections. In Germany alone, intensive care admissions among infants and toddlers increased by as much as 350 percent, according to the Robert Koch Institute, Germany’s federal public health agency. The situation pushed healthcare systems to their limits at times.
*Kampmann B et al. Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants. NEJM, 2023 Apr 05. doi: 10.1056/NEJMoa2216480
About the study
The phase 3 clinical trial (Maternal Immunization Study for Safety and Efficacy – MATISSE) was sponsored and funded by the pharmaceutical company Pfizer. Kampmann and her team did not receive any personal fees for the study.
Links
Original publication
Institute of International Health
London School of Hygiene and Tropical Medicine (LSHTM)
IMPRINT – IMmunising PRegnant women and INfants network
MRC The Gambia
JOURNAL
New England Journal of Medicine
METHOD OF RESEARCH
Randomized controlled/clinical trial
SUBJECT OF RESEARCH
People
ARTICLE TITLE
Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants
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