Clinical Pharmacology and Therapeutics. Группа авторов
Table 1.10 Influence of anti‐epileptic drug treatment on rates of congenital malformations.
| Major congenital malformation rate (%) | |
|---|---|
| No anti‐epileptic drug | 3.5 |
| Monotherapy | 3.7 |
| Polytherapy | 6.0 |
1 Management should begin before conception:Use the lowest effective dose of medicationAvoid valproate before conceptionWithdraw any unnecessary medication and use monotherapy wherever possibleIt may be possible to wean women who have been seizure free for several years and require low doses of medication after careful counselling and discussion with a neurologistDo not change if well controlled and already pregnant
2 Discuss increased incidence of congenital malformations using drug specific rates (Table 1.9). In general, the benefits of drug therapy on mother and foetus outweigh the risks
3 All women require to take folic acid 5 mg preconceptually
4 Antenatal screening for neural tube defects by detailed anatomy scan should be performed at 12 weeks and again at 18–20 weeks
5 Vitamin K supplementation during the last month of pregnancy for enzyme‐inducing anticonvulsants
6 Monitor therapy by seizure frequency and adjust doses accordingly
7 Continue anticonvulsant medication during labour
8 Minimise triggers of seizures
9 Neonate should receive vitamin K and breastfeeding should be encouraged
Hypertension
Many drugs routinely used in the treatment of hypertension are associated with teratogenicity and therefore contraindicated in pregnancy. Labetalol, a beta‐blocker, is used as first‐line treatment of hypertension in pregnant women. Second‐line therapies include nifedipine, a calcium channel blocker and methyldopa. The latter is rarely used outside pregnancy because of adverse effects such as fatigue and dizziness but is safe in pregnancy.
Pregnant women with hypertension should also be offered low‐dose aspirin from 12 weeks to prevent or delay the risk of pre‐eclampsia.
Hydralazine is used intravenously for acute or severe hypertension and also orally as a second‐line agent for chronic hypertension in pregnancy. It can cause tachycardia and headache if given intravenously. Its maternal and foetal effects compare unfavourably with nifedipine and labetalol. There are also reported cases of maternal and foetal lupus‐like syndromes associated with its use.
ACE inhibitors and angiotensin II inhibitors are contraindicated in pregnancy. The use of ACE inhibitors is associated with an increased risk of major congenital malformations after first trimester exposure and causes oligohydramnios, renal dysplasia and pulmonary hypoplasia if administered in the second or third trimester of pregnancy. Ideally they should be discontinued pre‐pregnancy.
Statins are also contraindicated due to reported teratogenesis associated with their use which may be secondary to interference with cholesterol biosynthesis in the foetus.
Hyperthyroidism
Propylthiouracil tends to be used more often than carbimazole during pregnancy. Propylthiouracil is less lipid‐soluble and more protein‐bound and crosses less well into the foetus and breast milk. The dose should be titrated against maternal thyroid function and adjusted to maintain free T4 in the upper non‐pregnant range. Requirements tend to decrease in pregnancy. Propranolol may be used to treat symptoms and there are no known teratogenic effects. Radioactive iodine should not be given to any women who is or may be pregnant.
Thrombosis
Pregnancy is associated with a 10‐fold increased risk of developing venous thromboembolic disease (VTE) and is the major direct cause of maternal mortality in the UK. Treatment and prophylaxis of VTE requires anticoagulants which have special considerations in pregnancy. Warfarin is teratogenic when given between the sixth and twelfth week of pregnancy – a 5% risk of major abnormality and 0.6% risk of warfarin embryopathy. It is also associated with bleeding during pregnancy and at delivery, and is generally avoided except in very high risk cases. Low molecular weight heparin is usually the treatment of choice and has a much lower incidence of side effects (e.g. such as heparin‐induced thrombocytopaenia, allergic reactions and osteoporosis) than unfractionated heparin.
Depression
There are several factors to take into consideration when prescribing antidepressant medication in pregnancy. All antidepressants will cross freely across the placenta and the foetus and neonate are susceptible to side effects. A balance of the risk of treatment against the risk of serious mental illness should be made, and there should be consideration of efficacious non‐pharmacological treatments. The older drugs such as tricyclic antidepressants have been used for many years and there are no known teratogenic effects. Therefore, they are the drug of choice in pregnancy. They can cause withdrawal symptoms or anticholinergic side effects in the neonate, and reducing the dose in the third trimester wherever possible, may minimise this risk. They are safe in breastfeeding. The newer SSRIs (selective serotonin reuptake inhibitors) are commonly used as first‐line agents outside pregnancy and will often be taken by women around the time of conception. It is not wise to abruptly stop these drugs as this may cause withdrawal in the mother. There appears to be a modest increased risk of congenital malformations and in particular cardiac defects with first trimester exposure. Paroxetine in particular is associated with an increased risk of foetal abnormalities and should be substituted by another antidepressant in pregnancy. SSRIs are also associated with a neonatal withdrawal syndrome if taken in late pregnancy.
Connective tissue disease
This group of disorders includes conditions such as systemic lupus erythematosus and rheumatoid arthritis. Special considerations are made when prescribing in pregnancy (Table 1.11).
Drug use in breastfeeding
A 40‐year‐old woman attends her doctor for advice. She was diagnosed with diabetes during pregnancy and treated with insulin. After pregnancy she continues on metformin alone. Her doctor is keen to start her on simvastatin for primary cardiac prevention. She is concerned that her baby might be exposed to the metformin and any other drugs the doctor is recommending because she is breastfeeding and plans to continue to do so. Is her baby at risk and how should her doctor deal with this enquiry?
Most commonly used drugs can be safely used in women who are