Teratogenicity is when an agent e.g., a chemical disturbs the development of a developing baby.
After the catastrophe of thalidomide, the medical profession and members of the public are much more cautious about the use of medication during pregnancy. However, sometimes it cannot be avoided.
There is a 3-5 percent background risk for birth defects in all pregnancies. Exposure to a medication may add to this risk. However, many drugs do not show an increase in the background risk.
There is no evidence linking paternal exposures to teratogenicity for the developing foetus, although exposure to some agents can reduce male fertility.
So why are we so worried about taking medicines during pregnancy? I believe that the tragedy of thalidomide has influenced our perception of risk.
Thalidomide was first marketed in the UK in April 1958. Originally it was developed as an anti-convulsant but was found to be ineffective. However, it was a good sedative, promoting sleep. In the UK the drug was prescribed for common symptoms of early pregnancy, particularly morning sickness. Its use was halted in November 1961. To produce teratogenic defects it had to have been taken when the embryo was most sensitive, 34 to 50 days after the beginning of the mother’s last period.
Thalidomide is associated predominantly with limb defects. However, almost any organ of the body could be affected. The death rate before the first birthday among babies exposed to thalidomide in the womb was about 40%, largely due to serious internal malformations. About 10,000 babies were affected worldwide.
The period of greatest risk is between the first and eighth week of pregnancy. With chronic ongoing conditions, the mother should seek pre-conceptual advice about whether to stop her medication, change it, take a higher dose of folic acid or consider the risks of continuing. No drugs have been tested in clinical trials in humans to ascertain whether they will cause abnormalities – it would be unethical to do so. It would also be impossible to recruit enough people to ensure that rare abnormalities were captured by the research. The data we have is retrospectively collected, largely by the completion of ‘yellow cards’. Drugs may be tested on animals, but the results are not always transferable to humans.
So far only 30 drugs have been shown to cause major abnormalities. All pregnancies have a background risk of around 2–3%. In many cases, if the embryo is badly affected the body will naturally miscarry, particularly if the exposure was in the first 14 days after conception (the pre-embryonic period). Many of us worry about what we did between the date of our last period, conception and finding out we are pregnant. What about that bottle of wine? What about the painkillers for that headache? In the vast majority of cases, all will be well buy this doesn’t mean we should take unnecessary risks.
The foetus is most at risk from teratogens in weeks three to eight after conception (the embryonic period) when the major organs are developing. For example, exposure to sodium valproate during this time may result in spina bifida, as the neural tube closes between day 17 and day 30 after conception. Cleft palate is most likely to develop around 36 days after conception.
Week nine up until birth is termed the foetal period and babies are less susceptible to damage, although some structures continue to form. During this period there is more likely to be a reduction in growth or within organs: for example, warfarin may cause bleeding in the brain, while ibuprofen and other non-steroidal anti-inflammatory drugs can cause premature closure of the ductus arteriosus, producing neonatal pulmonary hypertension. Fluoxetine can produce severe drowsiness after birth.
Teratogens can also prevent implantation, cause abortion, produce intrauterine growth retardation or cause foetal death (Lee, 2000). Drugs should be avoided during pregnancy unless they are essential. With some drugs, higher doses of folic acid (5mg daily) are recommended. It may be possible to reduce the number of drugs a mother is taking, or discontinue drugs temporarily (e.g. statins). A discussion of the relative risk of the increase of teratogenicity compared with the risk to the mother’s health should be held using evidence-based resources (Motherisk, OTIS), allowing the (prospective) parents to make an informed choice.
We know that the early stages of pregnancy bring nausea and even hyperemesis for up to 70% of women (Lee, 2000). Symptoms can occur at any time of the day. Nausea in pregnancy resolves by 16 weeks in 90% of cases. Hyperemesis gravidarum occurs in less than 1% of pregnancies but often involves the mother being admitted for rehydration and symptom control with medication, as the Duchess of Cambridge discovered in her first pregnancy.
Cyclizine: It is often the first drug tried for nausea in pregnancy.
Promethazine: No increased risks of congenital abnormalities in the baby above the background rate for the population have been reported when cyclizine or promethazine have been used in therapeutic doses (NICE CKS 2013).
Prochlorperazine: No increased risks of congenital abnormalities, above the background rate for the population, have been reported when prochlorperazine has been used in therapeutic doses (NICE CKS 2013).
Metoclopramide: It is not recommended for mothers younger than 20, as they are more likely to experience side-effects. No increased risks of congenital abnormalities, above the background rate for the population, have been reported when metoclopramide has been used in therapeutic doses (NICE CKS 2013), although one cohort study has shown a higher incidence of premature delivery after metoclopramide exposure.
Domperidone
Pyridoxine (vitamin B6), when compared with placebo, may be effective at reducing nausea, but not vomiting. However, the evidence is of low quality (Mazzotta, 2000). Although no relationship has been found between B6 status and the incidence of morning sickness, using 10–40mg/day appears to reduce the severity of symptoms and is often used as a benchmark to evaluate other treatments. Doses of over 200mg a day are discouraged as sensory neuropathy (loss of sensation in the fingers) is reported with high doses given for extended periods.
Ondansetron: Most studies have found no increased risks of congenital abnormalities above the background rate for the population when ondansetron is used in therapeutic doses. However, a single study has shown an increased risk of isolated cleft palate following first-trimester exposure to ondansetron, which is why it is usually the drug used when all else has failed and the mother and baby are at risk from dehydration.
Extracts taken from “Why Mothers Medication Matters” Jones W Pinter and Martin 2017
