Author: Magnús Jóhannsson, physician. This article was originally published in November 2011.

In some countries, records are kept of the medicines women receive during pregnancy, gradually building up information about the risks associated with each medicine. Around 30 medicines are known or strongly suspected to have harmful effects on the foetus. These include many cancer medicines, most antiepileptic medicines, some blood pressure medicines, some painkillers, some antidepressants and several others.

History

Until the 1940s–1950s, it was generally believed that the placenta protected the foetus from foreign substances originating outside the body. From around 1940, many began to question this, and in 1941 strong evidence emerged that foreign compounds and viruses (the rubella virus) could harm the foetus. In 1961, thalidomide was shown to have caused severe malformations in thousands of human foetuses, and in 1970, diethylstilbestrol (DES) was shown to cause cancer in girls exposed to the medicine before birth. In the early 1970s, it was conclusively demonstrated that alcohol can cause malformations. Since then, the same has been found to apply to many medicines and natural substances (food supplements).

Animal studies

For half a century, all new medicines have been investigated for potential harmful effects on the foetus. Before that, few such studies were conducted. Some of these studies use cultured cells, while others must be conducted in animals, most commonly rats. These studies examine the effects of the medicine on nucleic acids (genetic material), fertility, the foetus and the infant around and immediately after birth. Studies of this kind reveal marked differences in sensitivity between species. Laboratory animals vary in sensitivity (rats, mice and rabbits), and human foetuses are sometimes more sensitive and sometimes less sensitive than animal foetuses. Animal studies can therefore only provide an indication of the risks. The hormone cortisone causes malformations in mice but not in humans. Thalidomide has a strong tendency to cause malformations in humans, but much less so in animals. Sometimes the risk is similar in humans and animals, as is the case with vitamin A and related substances. The effects of medicines on human foetuses can only be studied indirectly. In some countries, careful records are kept of the medicines and food supplements women take during pregnancy, gradually building up information about the risks associated with each medicine.

What kinds of harm can occur to the foetus?

Malformations naturally attract the most attention, but various other effects can occur. Other known toxic effects on the foetus or child include foetal death, impaired foetal development, underdevelopment or overdevelopment of individual organs, abnormal bodily functions in the newborn, malignancy in childhood and impaired intellectual development.

When is the risk greatest?

Time is usually measured from conception, and the risk of malformations is very low during the first 2 weeks. During weeks 3–8, the organs develop and take on their final form. The risk of malformations is therefore greatest during this period of just under two months. The first trimester is often referred to in this context, meaning the first 3 months or the first 13 weeks. Other types of harmful effects may occur later in pregnancy.

How common is harm to the foetus?

Major malformations are estimated to occur in 2–3% of births. A major malformation is one that is noticeable and/or requires surgery. Minor malformations are much more common but are difficult to define. Medicines have been estimated to account for approximately 1–2% of all malformations, while most (98–99%) have unknown causes. When advising on medicine use during pregnancy, it is essential to consider both the baseline risk that is always present and any potential increase in risk associated with the medicine concerned.

Which medicines cause harm to the foetus, and how great is the risk?

Around 30 medicines are known or strongly suspected to have harmful effects on the foetus. These include many cancer medicines, most antiepileptic medicines, some blood pressure medicines, some painkillers, some antidepressants and several others. Two types of medicines stand out in terms of risk: thalidomide and vitamin A and related substances (vitamin A derivatives, such as isotretinoin). If these medicines are taken during weeks 3–8 of pregnancy, the risk of malformations is 20–30%. For other medicines with confirmed teratogenic effects, the risk is much lower, at only 1–5%. Dosage also matters, and when medicines are necessary during pregnancy, doses should be kept as low as possible.

Do women have a choice?

Sometimes an untreated illness in the mother poses a greater risk to the foetus than the medicines used to treat it. This applies, for example, to epilepsy and pregnancy-related nausea with severe vomiting. Sometimes it is possible to choose a medicine considered less risky than others. Food supplements (natural substances) are rarely a suitable alternative to medicines because less is generally known about their potential effects on the foetus. In addition, many food supplements are known to have harmful effects on the foetus.

Classification of medicines by risk

Medicines have long been classified according to their risk to the foetus, based on the best available evidence at the time. The most widely used classification is based on a Swedish system in which medicines are assigned to four categories, A, B, C or D, according to the level of risk. A: the risk is considered low or negligible, based on information from humans and animals. B: the risk is unknown because use during pregnancy has been limited, but there is no evidence of harm to the foetus in humans or animals. C: the medicine’s effects are considered to pose a risk of harm to the foetus, but no information is available on teratogenic effects. D: the medicine is considered known to cause malformations or other serious harm to the foetus. These letters are not used in the Icelandic Medicinal Product Information database or in package leaflets. Instead, more or less standardised wording describes the risk.

Medicines and breastfeeding

For many reasons, breast milk is the best source of nutrition for an infant during the first months of life. This must be considered when making decisions about the mother’s medicine use and breastfeeding. It must also be borne in mind that some medicines affect infants differently from older children and adults. Some medicines are excreted in breast milk, while others are not. Sometimes it is not known whether a medicine is present in breast milk or in what quantity. It may be possible to time the mother’s doses so that the infant receives as little of the medicine as possible. Sometimes another medicine with a comparable effect can be chosen that is not excreted in breast milk. Taking all these factors into account, medicines are often divided into four categories, with appropriate standardised wording:

I: The medicine is not excreted in breast milk.

II: The medicine is excreted in breast milk, but the risk to the infant is considered negligible at normal doses.

III: The medicine is excreted in breast milk in quantities considered to pose a risk to the infant, even at normal doses.

IV: Information on excretion of the medicine in breast milk is missing or too incomplete to assess the potential risk to the infant.