What do we know about medicines in pregnancy?
Updated: Jan 17
When I started asking questions, around 2003, I first talked to a health journalist I knew. She told me that in order to prove that valproate caused my daughter’s problems I’d need to have empirical evidence of the mechanism of teratogenicity unless there had been long term epidemiological studies made. I smiled politely, had no idea what that meant. 17 years later and I’ve read hundreds of papers and still not found that evidence. I now know that all that time I’d been following the wrong leads.
Journey
My daughter became a participant in a group litigation against Sanof in 2005. But in 2010 legal aid was withdrawn. We then campaigned, blaming one organisation, action, or policy for what happened to us. Everyone we sought to blame had a ‘yes but’ excuse and we were by then fighting what seemed like a losing battle with Vicky Pollard about the location of her homework. We then decided to take a different approach. Instead of politely seeking answers we took direct action and staged a protest outside the MHRA offices.
Review
Our noise was eventually heard. The government ordered a Review in 2017 into the safety of medicines and medical devices, led by Baroness Cumberlege, an Oxford socio-legal researcher and a PR professional. Slowly, evidence emerged, coming together piece by piece until a picture started to emerge. My contact at Leigh Day Law provided us with help to write our 200 page submission. Academics from all disciplines stepped in to do their jobs, often voluntarily. Relevant bodies were identified and called to submit evidence. Surprisingly, most were genuinely keen to change the system, and many understood that it was flawed.
The report was published on 20th July 2020 and was given the name “First Do No Harm”. But despite consulting over 100 organisations closely involved, many puzzle pieces were missing. Rebecca Bromley, Neurodevelopmental Scientist at Manchester gave evidence and made a statement that shocked me. She stated that it takes 27 years for a medicine to be established as a teratogen.
Animal studies on valproate had shown that it was highly teratogenic already in the early stages of licensing. It was fully accepted that it was dangerous - to animals. The drug was put on the market on the assumption that doctors and neurologists would ensure that due care was taken when prescribing.
Regulation and gendered research
Following the Thalidomide disaster in 1958 the establishment of the UK Committee on Safety of Medicines in 1963, the US FDA were concerned that women should not take part in clinical trials. They issued “General Considerations for the Clinical Evaluation of Drugs” in 1977. This stated that women of child-bearing potential should be excluded from Phase 1 and early Phase 2 research except for life-threatening illness. Women were considered a “vulnerable population”. The study of long term outcomes after pregnancy and using epidemiological models then also disappeared. This massive 27 year information gap was not related to logistics or technology, it related to policy and WHO on their website, acknowledge that lack of research on the effects of medicines on women and on pregnancy is a global problem.
Data Challenges
This fits in with my experience of seeking UK research on the fetal effects of sodium valproate, all professionals I asked accepted this norm, explained in words to the effect of “you can’t test drugs on pregnant women”. In the UK data linking was severely restricted, hampered by conservative and libertarian values and could not be shared without consent. This meant that the larger data sets were not able to be linked, such as the development of the child and the medication of the mother. Only specific registries in countries where data could be linked, could examine the levels of valproate on the child this.Some registries were established much later, in the US and Australia, but the UK epilepsy and pregnancy register was not set up until 2001.
In a *recent study, the teratogenic risk in human pregnancy was "undetermined" for 97.7% of drug treatments approved between 2000 and 2010. Furthermore, the amount of data available regarding safety in pregnancy was rated as "none" for 73.3% of these drugs. For those drugs approved between 1980 and 2000, only 23 (5%) changed a full risk category or more in10 years. The mean time for a treatment initially classified as having an "undetermined" risk to be assigned a more precise risk was 27 years.
Despite sodium valproate being highly teratogenic,doctors worked from guidelines given to them, they didn’t read the studies or compare relative risk. A quick check in the BNF is usually all that’s done. They were dependent on those up the chain of expertise to give them guidelines. Against a backdrop of flawed research policies and a focus on seizure control and birth control, risks to the unborn baby were unlikely to filter through to the patient.
The UK Medicines Bill is now complete, and affects rulings across the UK regarding consent for data. The health policies is now devolved and the devolved nations decide on how they incorporate it into their healthcare policies.