Drug safety in pregnancy

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There are many reasons why medications would be needed during pregnancy, such as managing a pregnant person's existing health conditions. However, there is a risk that medicines taken during pregnancy could cause harm to the developing fetus, the severity of which could be determined by considering the drug's properties and the gestational timing, amongst other factors. During this interview, I'd like to explore the current categorisation system for prescribing drugs in pregnancy, as well as other resources clinicians can use that will help inform their discussions with patients.

Hello, and welcome to the Australian Prescriber Podcast. I'm Jo Cheah, a hospital pharmacist in Melbourne, and your host for this episode. It's a pleasure to speak to Dr Debra Kennedy, senior staff specialist and director of MotherSafe at the Royal Hospital for Women in Sydney, and conjoint associate professor at the School of Women's and Children's Health at the University of New South Wales in Sydney. Debra has co-authored an article called Drug Safety in Pregnancy, with Ronald Batagol, and this article is available free in the Australian Prescriber. Welcome, Debra to the program. Thanks for joining us.

Thank you. Pleasure to be here.

Debra, why is it important to consider drug use during pregnancy?

Well, it's important because pregnant people, just like everyone else, may require medications. And in fact, over 90% of women will need to take at least one medication during pregnancy, and I think the average is around 3 [medications]. They could be used to treat pregnancy-related conditions such as nausea, vomiting, constipation, or could be pre-existing ongoing medical problems. And likewise, normal acquired things like cough and cold and flu and allergies.

What patient and/or drug factors do you consider before starting or stopping a medication during pregnancy?

Well, the most important thing really is the severity of a condition, and really balancing up the need to treat versus potential concerns. While people, I think, are aware of the potential concerns of teratogenicity and what could a medication potentially do to a developing fetus, the counterbalance is really, well, what are the risks of an untreated or undertreated condition for the mother, for the pregnancy, and then ultimately for the health of the fetus and then the newborn baby?

And can you briefly describe how drugs can affect developing fetuses, and provide some examples of drugs with known effects?

By definition, we talk about a teratogen, comes from the Greek word teratos. Teratos was actually a monster, so it meant causing malformations. I suppose our definition now is that a teratogen is really any agent that can interfere with fetal development, and that could be causing pregnancy loss or miscarriage, or it could actually be causing structural birth defects. And I think what we are really increasingly interested in is possibly more subtle effects such as affecting neurodevelopment, which are sometimes more difficult to establish, and really need a lot longer in terms of follow-up and research. We know also, even though it's not necessarily part of this, that it's not just medications, so things like viruses, things like rubella and radiation, other exposures can also be defined as teratogens. Depending really on gestational timing, you have a very, very early exposure in the gamete stage. So things like high-dose radiotherapy or chemotherapy can actually cause sterility.

But interestingly, if someone regains their fertility after high-dose radiotherapy or chemotherapy, particularly with things like alkylating agents, there does not appear to be a significantly increased risk of birth defects or chromosomal abnormalities or genetic abnormalities in the offspring. The next period, I suppose when we talk about exposure, is that pre-implantation period, so from the 2 weeks post conception to when the person misses their period. It's 14 to 28 days post LMP [last menstrual period]. And that's a period of relative safety in terms of exposures, so most exposures are not associated with an increased risk of birth defects, and that's why we call it the all-or-nothing period. The main concern there, and the main reason a pregnancy may not be viable, is because of an intrinsic chromosomal abnormality.

The next period where there's really the biggest sensitivity in terms of structural birth defects is the embryonic period, which is from about 4 to 10 weeks post LMP. That's when all of the major organ systems are developing. That's when things like major cardiac defects, neural tube defects, clefting is going to occur in that period. Beyond that, the conceptus is a fetus, so the organs are formed, brain and the nervous system continue to grow and develop, and that's the period when we are more concerned about exposures that could cause neurodevelopmental problems. Agents such as nonsteroidal anti-inflammatory drugs and angiotensin receptor blockers don't necessarily increase risks of structural defects, but can affect fetal urine output and therefore cause oligohydramnios, so inadequate fluid around the babies. Other agents that can cause fetal problems, apart from viruses are infectious agents, are agents that could cause hypotension, so things like vasoconstrictors where you can get things like limb defects, limb reduction, or transverse defects due to vascular perfusion problems.

You mentioned in your answer there chemotherapy, radiotherapy, NSAIDs [nonsteroidal anti-inflammatory drugs], ACE [angiotensin converting enzyme] inhibitors. Obviously, thalidomide is a really well-known teratogen. Were there any other drug classes that you wanted to highlight in relation to their use in pregnancy?

The major teratogen that is on the market today is isotretinoin, or Roaccutane, the acne medication. And the population who use it are primarily of childbearing age, so it's a significant problem. And one of the other problems, there's often quite poor contraceptive advice given to women on some of these major teratogens, and not being on appropriate contraception. And women actually understanding or knowing that there was a teratogenic risk but not necessarily taking appropriate precautions with contraception.

We know that isotretinoin has at least a 30 to 50% chance of causing major anomalies when taken at the wrong time, which is in the first trimester. And significant neurodevelopmental sequelae, which may not necessarily be associated with structural defects. Even if someone has a reassuring 18 to 20-week morphology ultrasound scan, you can't always be reassuring that the isotretinoin has not caused neurodevelopmental sequelae in the exposed fetus.

That's a really good point, and a good reminder for prescribers and pharmacists when counselling patients on isotretinoin if they're a childbearing age. Really important. Thanks for mentioning that. What is the current categorisation of medications prescribed during pregnancy in Australia?

In Australia, we've got the A to X categorisation, and that came out really as a result of the thalidomide tragedy because there was an awareness that there could be teratogenic concerns around medication use in pregnancy. So the decision was made to categorise drugs, and that came not only in Australia, but in Europe and also in America. Interestingly, in America, the FDA [Food and Drug Administration] made the decision to abandon their categorisation, which was a little different, but fundamentally the same as the Australian one. And the Americans now favour a labelling with more descriptive labelling for products in Australia that A to X is widely used [for]. While it's a guide, I think unfortunately it tends to be used as a Bible, and there are some discrepancies and there are some things that are probably not great about it.

One thing, it's not applicable to breastfeeding. For the other thing, I think it's confusing because most people are pretty happy [with] category A’s... Lots of pregnant women have used it without an apparent increased risk in birth defects.

Category B is the largest category, so most medications are in that category. And that category is really that there's inadequate human data so that the information that we are giving is around animal data. The reason we don't have much human data is because pregnant women have been actively excluded from clinical drug trials really following thalidomide because of concerns around potential teratogenicity. But what that's resulted in is really I think that pregnant women, or women planning pregnancy, have missed out. Essentially, they're guinea pigs because a lot of the data comes at postmarketing rather than pre-marketing, and the information we get is often from inadvertent exposures because we can't do clinical trials.

Category B is really animal data. B1 is that there's reassuring animal data. B2 is it's not much. And B3 is actually animal data suggests that there could be an increase in birth defects, the significance of which is considered uncertain for humans. That's not very reassuring, yet many prescribers would be more happy to prescribe a B3 than a C medication, because B comes before C in the alphabet. And that's really misleading.

Because what category C is, is really that these are drugs that may be associated with pharmacological issues without causing malformation. They're going to be things where there could be fetal or neonatal withdrawal, or adaptation problems. Basically, most of the antidepressants, opioids, are category C. Beta blockers, for example. And that makes sense because there could be fetal or neonatal withdrawal, but not actually malformations. At MotherSafe, we get referrals or questions because people have been switched from a category C to a category B3 medication because B comes before C in the alphabet. That's misleading and not particularly helpful.

Category D could cause malformations, and that's when it needs to get put in clinical context. So needs to balance the risk of potential teratogenicity versus risks of an untreated or undertreated medical condition. So drugs like warfarin, valproate, carbamazepine are category D because they have been associated with birth defects, but equally there may be a situation where they may be of benefit and that outweighs the potential risk.

Category X are the shouldn't be used. Isotretinoin is a good example. There are a few other category X medications where the data's really based on animal studies and it's not necessarily that robust, but nevertheless, it's a fairly good guide. I think that we do run into problems with a categorisation because it's not black and white, and I think it's nuanced, and that's why it does need interpretation. And that's why services like mine exist, so that we can help guide both consumers and clinicians around making these sorts of decisions.

Very interesting. As you were saying, pregnant women are excluded from clinical trials and we find things out in a postmarketing setting rather than pre-marketing. Where could we find information about inadvertent use of medications in pregnancy if we wanted to? Would we have to search for cases in the literature or is there a database where all of this information is collated?

There are quite a few databases. There's one called Reprotox, and TERIS, and Shepard’s, and they collate information. There's also textbooks, so Brigg’s Drugs in Pregnancy and Lactation. In New South Wales, they're all accessible through CIAP [Clinical Information Access Portal], through New South Wales Health, otherwise they are on subscription. There are also teratogen information services. In America, it's called MotherToBaby, it's a group of teratogen information services, and they have quite good fact sheets that are freely available online. And likewise in the UK, there's a UK TIS [teratogen information service], and they have a service called Bumps [best use of medicines in pregnancy], which is the best use of medicines in pregnancy. And so, you can get information from there as well. And they're well referenced, so there's good information there.

And I think really a big take-home message is that we should not be getting this sort of information from drug labelling and product information, because drug companies probably don't particularly care whether pregnant women use or don't use their product. It's a very small market. They don't want to be sued, so they're going to be erring on the side of caution and saying don't use in pregnancy, even for medications that are category A.

If I could jump back to the isotretinoin example, just out of interest. I thought it might be worth mentioning that the teratogenic risk doesn't just occur whilst a patient is on isotretinoin. Is that right? It continues even after the drug has stopped for a period of time?

Some of the retinoids, so not isotretinoin, but some of the other retinoids do have a longer half-life. Isotretinoin itself, the half-life is around 24 hours. We generally say after 5 half-lives you're going to have pretty low levels. In the past we were more prescriptive about telling women that they had to stop the drug. And obviously we advise women planning pregnancy to stop the drug when they're trying to conceive. That doesn't always happen.

Going back to where do we get the information, we do get information when services like mine and the clinical services around the world collaborate and collect cases of inadvertent or other exposure. A group in Germany actually, over 10 years ago now, published data on women who had exposure in that all-or-nothing period. Pretty much stopped by the time they missed their period. And in the past we would've said there's a significant risk, and that paper was actually quite reassuring. We now, for women who stop literally the minute they pee on a stick and find out they're pregnant, we're pretty reassuring around isotretinoin exposure. Obviously, there are some people who are going to metabolise it a little bit differently. And possibly, whether they're taking 10 or 20 mg a day might make a little bit of a difference. But generally, we would be relatively reassuring if they stop at that point.

Just highlights the complexity of the issue that the information provided depends on the patient, the drug, the dose, the half-life, and all of these other clinical context that is important. In terms of practical tips for our listeners, how would you advise them to approach conversations about medications in pregnancy with their patients?

Well, I think the first thing that I really like to emphasise is that ideally this should be done in a preconception setting. Particularly women on chronic medications should have the conversation when they're planning, because I think that's ideal to optimise medications. If they are on a potential teratogen, to try and see if there's a better alternative prior to pregnancy. Once they're pregnant, it comes down to clinical context. It's really important to date a pregnancy. Obviously, again, knowing that lots of pregnancies are not necessarily timed or planned as well as they might be. And given that early ultrasound is so accurate now, so doing a beta-HCG [human chorionic gonadotrophin] blood test is not particularly helpful. Dating ultrasound is the most accurate to plus or minus a few days. And that can often be the most reassuring thing for people if they do have an inadvertent exposure to something that they rather would've not have been.

Because if you can say, well, look, actually this happened in that all-or-nothing period in that 2 to 4 weeks post-LMP, so first 2 weeks post conception, would be incredibly reassuring. And beyond that, it's around what are the risks? Because people say, well, if there's any risk, it's not acceptable. But no pregnancy comes without a risk. About 2 or 3 liveborn babies out of 100 will be born with a major birth defect, such as cleft lip, spina bifida. Up to 5% could have some sort of neurodevelopmental problem that might not be obvious in the first year of life. That's the background. So you've always got to think about that in relation to any medication you're taking. And again, flip side, what are the risks of an untreated condition, be it bipolar, epilepsy? And except probably for isotretinoin, genetic conditions, a recessive or a dominant condition is going to have a much higher chance of having a child with a potential problem than the vast majority of potential exposures.

And we know that untreated depression has significant impacts on the maternal health. That all has to be weighed up against, well, what are the actual risks of taking an SSRI [selective serotonin reuptake inhibitor] or another medication that a mother's been stable on? And the other thing I suppose is around dosing. And there's a tendency to think, well, if I lower the dose, it's less likely to be teratogenic. And for most medications within the normal prescribing dosing, increasing a dose is not going to increase the risk of teratogenicity. There's a few exceptions, possibly lamotrigine with doses over 300 mg a day. Valproate over 1,000 mg. Warfarin.

But in general, I say to people, underdosing is the worst to both worlds because you're still exposing yourself and your baby to the medication, but you're not getting the maximum benefit. And thinking about pharmacodynamics and pharmacokinetics, as a pregnancy goes on, oftentimes you might excrete more free drug renally, you might need to increase doses to get the same therapeutic levels that you were getting at the start of a pregnancy.

Yeah, very important if you had a patient who was pregnant and needing medications, to monitor them regularly and provide advice depending on where they are in their pregnancy. But as you said, no pregnancy is risk-free, and all these things need to be weighed up.

Yep.

Really interesting. And just out of interest as well, is the current categorisation system, the A to X, related to both pregnancy and breastfeeding, or is it just pregnancy?

It's only pregnancy, lactation does not have a categorisation. There are some really good resources for breastfeeding. Thomas Hale, who's a clinician from the United States, has got lots of information online. And then there's the Drugs in Pregnancy and Lactation, Briggs, but also Lactmed, which is freely available through NIH [National Institutes of Health]. Actually, it's a website, and you can just look up very well-referenced monographs on the vast majority of prescribed medications.

If you can't get information about breastfeeding from those sources, then sometimes you can get other information. For example, if it's a very large molecule or for most of the biologicals. Even if they get into the milk, which they're not likely to because they're huge molecules, but even if there’s small amount gets into the milk, they're likely to be destroyed in the infant's gut. Again, we can be quite reassuring often based on the pharmacokinetic properties of medications if there is limited information otherwise.

Definitely a reminder for our listeners to have a look at the resources listed in Table 2 of the article.

And there's always services too, and I think that's really important that patients can call. In New South Wales, our service is available to consumers as well as to healthcare providers. Different states have slightly different services, but there's information out there. And we always say, look, it's much better to get someone to get information and say you don't know. The thing you don't want is someone being told to terminate an otherwise wanted pregnancy because they've been given really terrible advice, and unfortunately we still see that as well.

Oh, dear.

I think it's really, really important. There's good specialist services and information out there, you just need to know how to access them.

Yes, definitely. And a good reminder that some of these services do take calls from consumers, it's not just for healthcare professionals. Debra, that takes us to the end of the episode. I really appreciate your time and insight into the topic.

Pleasure. Thank you.

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Debra and Ronald's full article is available on the Australian Prescriber website. The views of the hosts and the guests on the podcast are their own and may not represent Australian Prescriber or Therapeutic Guidelines. Debra Kennedy is the director of MotherSafe, a statewide teratogen information service based at the Royal Hospital for Women, which provides telephone advice and counselling to women and healthcare providers on drug and nondrug exposures during pregnancy and breastfeeding.

I'm Jo Cheah, and thanks again for joining us on the Australian Prescriber Podcast.