Clinical Pharmacology and Therapeutics. Группа авторов
Therefore, higher doses may be required as the pregnancy progresses.
Drug treatment of common medical problems during pregnancy
Infection
Urinary tract infections are common during pregnancy. Penicillins and cephalosporins are the preferred treatment (subject to appropriate sensitivity testing), because these drugs have never been implicated in teratogenesis and are generally well tolerated. Nitrofurantoin is not harmful to the foetus but frequently causes nausea. Tetracyclines are contraindicated. Trimethoprim should be avoided in early pregnancy since it can possibly cause limb reduction and cleft palate.
Severe infections in pregnancy are rare. Aminoglycosides cause foetal eighth nerve damage, and the benefits of their use must be seen in this context. The risk is smallest with gentamicin and if indicated, the levels should be monitored closely. In the case of viral infection, including primary herpes simplex and varicella zoster, acyclovir is thought to be safe to administer in pregnancy. With regards to tuberculosis, present data suggest that the most commonly used agents including isoniazid, rifampicin, pyrazinamide and ethambutol are safe to use in pregnancy and the benefits of treatment of active tuberculosis outweigh any concerns of drug toxicity. Vitamin K should be given with isoniazid and rifampicin from 36 weeks to reduce the incidence of postpartum haemorrhage and haemorrhagic disease of the newborn. Due to concerns of hepatotoxicity in pregnancy with isoniazid, liver function should be monitored prior to treatment and at monthly intervals. Vitamin B6 should be given with isoniazid to reduce the risk of neuropathy. Streptomycin causes auditory damage in the foetus and is contraindicated in pregnancy.
Nausea and vomiting
Nausea affects about 90% of pregnant women and nausea and vomiting around 50%. Non‐drug treatments include dietary modification, hypnotherapy, acupressure and ginger. Antiemetics considered safe to use in pregnancy include antihistamines (e.g. cyclizine), phenothiazines (e.g. prochlorperazine), metoclopramide and the 5HT3 antagonist ondansetron (although as there is less evidence regarding foetal effects, this should be reserved as a second‐line agent). In severe cases, intravenous fluid and electrolyte replacement with thiamine supplementation may be required.
Diabetes
Diabetes in pregnancy is divided primarily into pre‐existing diabetes (type 1 and type 2) and gestational diabetes. Diabetes is associated with increased risk for both the mother and the foetus and the most important goal of treatment is to achieve as near to normoglycaemia in the mother as possible to reduce these risks. For type 1 and type 2 diabetes, tight diabetic control is achieved ideally pre‐pregnancy to reduce the risk of congenital malformations. For type 1 diabetes, insulin pump with variable basal background insulin rate and ability to deliver boluses with meals and many will be on as standard, a four times daily basal bolus regimen such as an intermediate acting insulin to be taken at night and three pre‐meal injections of fast‐acting insulin allow maximum flexibility. As pregnancy progresses, there will be increased insulin requirements which rapidly returns to pre‐pregnancy levels post‐delivery. The short‐acting insulin analogues, insulin aspart and insulin lispro, are not known to be harmful, and may be used during pregnancy and lactation. The safety of long‐acting insulin analogues in pregnancy has not been established, therefore isophane insulin is recommended where longer‐acting insulins are needed. Insulin is adjusted based mainly on post‐prandial blood glucose monitoring (1 hour < 7.8 mmol/L) and fasting levels (3.5–5.9 mmol/L).
Women with type 2 diabetes are usually converted to insulin either pre‐pregnancy or in early pregnancy, with the aim of optimising glycaemic control. The sulphonylureas are generally avoided in pregnancy as they cross the placenta and theoretically cause neonatal hypoglycaemia. The thiazolidinediones are contraindicated due to teratogenesis in animal studies. Metformin can be used either alone or in combination with insulin in type 2 and gestational diabetics. However, at present the long‐term effects of metformin on the foetus are not known.
Asthma
Poorly controlled asthma is associated with increased perinatal mortality. Maternal hypoxia and respiratory alkalosis are the major determinants of foetal distress in asthmatic pregnancies. Inhaled short‐acting β2‐agonists, inhaled anticholinergics, theophyllines and steroids have good safety records at all stages of pregnancy. There has been limited human data with long‐acting β2‐agonists but they are still felt to be safe when administered by inhalation.
Pregnancy should not alter the general approach to asthma as described in Chapter 6. It is important to control bronchospasm and avoid prolonged abnormalities of blood gases or acid–base balance. Although asthma management is largely unchanged in pregnancy, the leukotriene antagonists should be avoided as there is extremely limited safety data in human pregnancy.
Epilepsy
Epilepsy is the commonest neurological disorder encountered in pregnancy affecting 0.5% of pregnant women. The main issues are possible teratogenicity associated with anticonvulsants and adjustment of doses of drug to control fits. The incidence of congenital malformations in children of mothers with epilepsy is about 3–5% which is three times higher than in the general population. In part, this could reflect a genetic predisposition, but anticonvulsants seem largely to be responsible. Most evidence exists for the older drugs: carbamazepine, phenytoin and valproate, with cleft palate, neural tube defects and congenital heart disease being the most common findings. Sodium valproate is associated with a 40% risk of persistent neurodevelopmental disorders and 10% risk of birth defects during pregnancy. It should be avoided in women of childbearing age unless there are compelling indications. There is much less evidence for the newer anticonvulsant drugs but preliminary data suggest low rates of malformations (Table 1.9), particularly with lamotrigine and oxcarbazepine. There is a dose–response relationship for valproate (>1 g/day) and lamotrigine (>400 mg/day). Co‐administration of anticonvulsants produces a greater risk than when either drug is used alone (Table 1.10). To increase our knowledge of the effects of epilepsy and its drug treatment on pregnancy, all women should be added to the UK epilepsy and pregnancy register. The key points to managing pregnant women with epilepsy are shown in the Key point box in this section.
The pharmacokinetic changes associated with pregnancy are clinically important in the treatment of epilepsy. There are several factors in pregnancy which influence drug levels including altered protein binding, changes in absorption, increased plasma volume, and increased metabolism and excretion. Non‐compliance is also an issue in mothers concerned about the effects of the drugs. Therapy should be monitored by the clinical response and seizure activity and the lowest effective dose should be used. Generally, dose increases are required in pregnancy particularly for drugs with little protein binding such as lamotrigine which may need to be increased two‐ to threefold. After delivery, if drugs were increased during pregnancy, they should be reduced to preconception levels by around 1 week post‐partum. Breastfeeding should be encouraged as most anticonvulsants are secreted in very small amounts in breast milk. Neonates should be monitored for sedation. Higher doses of oestrogen in the combined oral contraceptive pill and progesterone in progesterone‐only contraception are required in women on hepatic enzyme‐inducing drugs.
Table 1.9 Data from UK epilepsy and pregnancy register 2005.
| Anticonvulsant | Major malformation rate (%) |
|---|---|
| Carbamazepine | 2.2 |
| Sodium valproate | 6.2 |