What do we actually know about the risk to unborn babies when the mother takes a medication? Not much, and this is a major problem.
More than 1200 medicinal drugs are prescribed to pregnant and breastfeeding women “off-label”, that is, they are prescribed only at the discretion of the doctor because these medications haven’t any regulatory approval for use on pregnant women. That is because the usual formal clinical trials are rarely conducted on this group of patients due to valid ethical concerns over the risk to the unborn child.
This however, means that doctors and their patients are largely in the dark on the potential risks of taking these medicines while pregnant, making doctors suitably cautious in prescribing and in setting dosages.
The sound advice to any patient, pregnant or otherwise, should always be to try to avoid taking medications, if at all possible. But in the case of pregnant women with conditions like epilepsy, depression, anxiety or psychosis, discontinuation of a treatment may put at risk the health and even survival of both mother and baby.
What is needed is more extensive and rigorous research into how vulnerable unborn babies actually are to medical drugs taken by the mother.
At the moment all we have is a number of retrospective epidemiological studies of the behavioural outcomes in infants when the mother had taken medications while pregnant, like for example paracetamol. But these have generally been of poor quality and even if well conducted, they can at best uncover an association, not a cause.
Which is why we have focused our research on understanding exactly how, and how much of a drug moves across from the mother into the bloodstream and brain of a fetus, or in the case of newborns, from breastmilk.
Using rat models as the best proxy we have for humans, our latest published research found that while the placenta plays an effective role in limiting the exposure of a fetus to a drug, unborn babies and newborns lack key biological mechanisms that in adults restrict molecules from crossing from the bloodstream and into the brain.
It means we have a potential pathway to better understanding the vulnerability of fetuses and newborns to different drugs, and eventually a better understanding of safer doses for a pregnant woman.
The initial stages of drug development almost always involve studies in animals. In respect of drugs that might be used in pregnancy the only regulatory requirement is for drugs to be tested in animals at the very early stages of pregnancy in order to assess the risks of potential congenital defects.
This became a mandatory requirement after the thalidomide disaster when in the 1960s it was revealed that thalidomide marketed as a tranquilizer and subsequently as a treatment for morning sickness in pregnancy could cause terrible birth defects.
However, very few animal studies conducted at later stages of development have been published. In relation to drugs that might affect brain development, there are only about 10 published papers in which a drug has been administered to a pregnant animal (usually a rodent) and the brain examined.
Although these studies provide evidence that some drugs do enter the developing brain, they are difficult to interpret because of limitations in the experimental design.
In our study we focused on three drugs – paracetamol, which has been estimated to be taken by 65-75 per cent of women during pregnancy; digoxin, which is used for some cardiac conditions, and cimetidine, which is used to treat “heartburn”, a relatively common condition in pregnancy.
We used doses that are within the normal clinical range in patients either as a single dose or following multiple doses, and administered the medications at the late stages of a rat pregnancy over a period of five days. This is a quarter of the last part of the usual 21-day gestational period in rats.
In addition, experiments were conducted in the first few days after birth and in adult female rats (pregnant and non-pregnant). An early postnatal age was chosen because in terms of brain development in rats this corresponds to 22 to 24 weeks gestation in humans, which is the earliest stage at which a human baby could be viably born.
Newborns are also particularly vulnerable at this stage because of the loss of the protection provided by the placenta.
When we compared the drug levels in the blood of the mother and the fetus we found that for all three drugs the placenta reduced the amount of drug entering the fetus by about 60-70 per cent at the age studied.
But an important question for us is whether in the developing brain there is an additional degree of protection provided by mechanisms that we already know in adults act to restrict a drug entering from the blood. These restrictive mechanisms are the main reason why it has proved difficult to develop new drugs for neuro and psychiatric disorders.
In order to asses this we compared the entry of the drugs with that of molecules of similar physical properties that are known not to be restricted by the mechanisms that affect drug entry into the brain.
From our experiments there is clear evidence that in the adult animals, drugs are indeed restricted from entering the brain, but this effect is much less in young developing brains where we found that all three drugs entered to a greater extent.
We also found that during multiple dose treatment even less of a drug entered the adult brain. This has been shown previously for many drugs and is thought to be due to the protective mechanisms of the adult brain becoming stronger in the wake of repeated exposure.
However, in what is a new finding, our study showed that this strengthening didn’t occur in the developing brain, making young brains potentially even more vulnerable than previously thought.
We need to be cautious in interpreting these results for clinical practice. Our studies so far have not looked at the potential harmful effects of the drugs on brain development and behaviour of the offspring, but we are in the process of doing so. However, significant aspects of such studies in rats are likely to translate to humans because the underlying biological principles are similar.
In summary, our study doesn’t provide evidence that use of these drugs should be discontinued.
Nevertheless, particularly in the case of paracetamol, because it is so widely used in pregnancy, we need to be sure we are following the current guidelines that restrict its use to treating fever (which at some stage of pregnancy may itself cause damage to the fetus), and as only a short-term treatment of severe pain rather than a long-term medication.
We have a long way to go, but what our research shows is that it is possible to assess how vulnerable fetuses and newborns are to drugs, and so eventually adopt more accurate guidelines for taking medications when pregnant to better protect both babies and their mothers.
This research has been made possible by funding from The CASS Foundation.