As many as nine in every 10 pregnant women take some form of medication. For some it’s a straightforward, over-the-counter pain-reliever or digestive calmer, while others need medicine to manage an underlying medical condition or to minimise a current risk.
Yet all too often, we don’t know what the safest and most effective dose is for this time of life, and to find out we need more health research involving pregnant women. That’s according to Consultant Obstetrician Professor Jennifer Donnelly, who recently co-led a clinical trial to determine the best heparin dose for women at high risk of blood clots during pregnancy.
The reticence to include pregnant participants in health research is understandable, but trials can be done safely, according to Professor Donnelly, who practises obstetrics and maternal-fetal medicine in the Rotunda and Mater hospitals in Dublin.
“[In clinical care and research] There are often questions in relation to consent, concern, care, worry about the fetus,” she says. ‘But it is important to do research in pregnant women in a safe way that respects their rights and the fetus’s rights and wellbeing. We should not be excluding pregnant women from research. We need to have safe and evidence-based treatment for women in pregnancy.”
Poor evidence, poorer outcomes
About 55-60,000 women give birth each year in Ireland, and as many as 90% of them can are thought to take medication of some kind during pregnancy, Professor Donnelly notes. “That could include paracetamol, proton pump inhibitors (for indigestion) or medication for underlying conditions,” she explains.
The issue is that, during pregnancy, understandable concerns about taking medication mean pregnant women are often under-medicated, so they don’t receive the optimum dose of the medicine they need.
But Professor Donnelly stresses that there are many safe options and alternatives and that women should be supported to take those medications in order to optimise their own wellbeing and outcomes.
“The difficulty is that there is a lack of evidence,” she says, highlighting a 2006 study [https://pubmed.ncbi.nlm.nih.gov/16461959/] in France that examined the treatment of all-comers into an Emergency Department with a suspected pulmonary embolism, a potentially life-threatening clot in the lung. The study found that pregnancy was the biggest risk factor for inappropriate treatment, with 70% of pregnant women being under-treated or inappropriately treated due to lack of evidence.
“Oftentimes, pregnant women are excluded from research,” says Professor Donnelly, calling for more inclusive trials with pregnancy in mind. “It is important to ensure that we can use safe, appropriate and effective treatments [in pregnancy] and that we can give them to women with confidence.”
Low or intermediate?
Professor Donnelly and colleagues have been working to gather evidence for treating another type of clot in pregnancy, a venous thromboembolism or VTE, which can cause death or bring long-term consequences for women who survive.
She and colleagues looked at recommendations in different parts of the world that arise from the same set of guidelines on how to treat or prevent VTE in pregnancy. The researchers found enormous discrepancies in how those guidelines translate into clinical practice around the world.
“Prescriptions of preventative medications for VTE varied from 7% up to 37%,” says Professor Donnelly. “So, depending on where you were living you would be recommended a different amount of prophylaxis to reduce the risk of blood clotting in pregnancy.”
To help improve the evidence around clot treatment and prevention in pregnancy. Professor Donnelly and heamatologist Professor Fionnuala Ní Áinle co-led the HRB-funded Irish arm of the international HighLow trial. [https://www.researchgate.net/publication/303801502_Low-molecular-weight_heparin_to_prevent_recurrent_venous_thromboembolism_in_pregnancy_Rationale_and_design_of_the_Highlow_study_a_randomised_trial_of_two_doses].
The randomised controlled trial worked with 1,000 women – 100 of whom were in Ireland – to compare the standard treatments of low or intermediate doses of low molecular-weight heparin at high risk of clotting.
The project took a long time to bring everything and everyone together – the Irish team sent the first application for ethics approval in February 2014, and the study’s findings were published [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)02128-6/abstract] in The Lancet in 2022.
But the hard work, co-ordination and patience paid off, according to Professor Donnelly, because the HighLow study provides the evidence that a low dose is ‘equivalent and non-inferior’ for preventing VTE in pregnancy compared to the higher dose, which itself could being a greater risk of bleeding. “This represents a huge amount of women and healthcare professionals co-ordinating to get evidence, and this will influence practice and guidelines,” she says.
Involve patients
Through her work with the Irish Medicines in Pregnancy Service, Professor Donnelly sees the need for more research, patient involvement, education and training in gathering and using evidence for safe and effective medicines in pregnancy.
The Covid-19 pandemic highlighted the need for robust research around vaccines in pregnancy, she says, particularly as pregnant women tend to be at higher risk from SARS-CoV2 as well as influenza, and we need safe and reliable information for women who can benefit from the vaccines.
Patients themselves are key to informing and driving the research, she adds, citing as a prime example the AI_PREMie [https://aipremie.com/] project. Led by Professor Patricia Maguire in UCD, AI_PREMie is working with pregnant women and biobanked samples and using AI to help identify predictors of pre-eclampsia in pregnancy.
And sometimes the need for new research is a welcome development – strides in treatments for cystic fibrosis in the last 10-15 years means that more women with CF are now having pregnancies, notes Professor Donnelly. She draws attention to research [https://hrbopenresearch.org/articles/5-22] by RCSI doctoral student Jen Balfe, who lives with CF, on fertility and maternity care for women in Ireland with the condition.
More effective reporting structures and policies are also needed to boost the quantity and quality of research and trials that include pregnant women so we can better optimise medications and outcomes, notes Professor Donnelly: “If we are excluding pregnant women from trials, then we are not going to get the evidence that we need.”
This blog has been written on foot of one of a series of presentations given by subject matter experts at the National Office’s ‘Lunch & Learn’ series. This is a learning and educational programme for the National Research Ethics Committee (NREC) members and wider research ethics community in Ireland.