Pregnancy may interact with drugs in a number of different ways. Firstly, the pregnant state confers alterations in both pharmacokinetics and pharmacodynamics; secondly, the fetus may be affected by drugs administered to the mother, and in many cases this may restrict the use of certain drugs; and thirdly, there may be further passage of certain drugs to the neonate in breast milk (see Chapter 162, Drugs and breastfeeding). Because of these considerations, special licensing requirements exist for drugs to be used in pregnancy, which have not been met by many drugs in current use.
Pharmacokinetics
Each of the traditional components of pharmacokinetics may be altered in the pregnant, as opposed to the non-pregnant, state.
• Absorption of drug. This depends on the route of administration and, in general, is little affected by pregnancy. However, absorption of enterally administered drugs may be affected by pregnancy-associated gastrointestinal upsets including vomiting and delayed gastrointestinal motility. However, a higher cardiac output increases intestinal blood flow, which may counter these effects, and there is little evidence to suggest altered bioavailability of drugs sufficient to alter dosage. Enterally administered drug absorption may be delayed in labour, particularly after administration of opioids. Drugs administered intramuscularly are often absorbed more rapidly due to increased tissue perfusion. Owing to the increased minute ventilation and cardiac output, absorption of inhalational agents is more rapid.
• Distribution of drug. This is affected by the increased blood volume and body fluids, and altered plasma protein profile, which vary as gestation progresses. The first two result in a greater volume of distribution. Decreased plasma protein binding can lead to increased availability of free drug, resulting in an increased risk of toxicity, particularly of highly protein-bound drugs such as phenytoin and local anaesthetics. In addition, the fetus represents an additional compartment to which drugs will distribute, depending on their lipid solubility, pKa and protein binding. The increased cardiac output will tend to redistribute drugs more quickly unless they are extensively bound to the tissues. During labour, acute changes in plasma pH (e.g. acidosis associated with maternal exhaustion or alkalosis associated with pain-induced hyperventilation) may affect both protein binding and degree of dissociation of drug.
• Metabolism of drugs. Drugs broken down by the major organs (usually the liver) may be handled in the same way as in the non-pregnant state, unless there is hepatic impairment, e.g. in HELLP (haemolysis, elevated liver enzymes and low platelet count) syndrome. Changes in the activity of enzymes involved in phase I and phase II metabolism, such as the cytochrome P450 family and uridine 5'-diphosphate glucuronosyltransferases (UGTs), may affect drug metabolism, and have been shown to alter concentrations of drugs such as nifedipine and lamotrigine. For drugs with a narrow therapeutic window, dosage alterations may be required in pregnancy to maintain disease control or avoid toxicity. Some drugs are metabolised by plasma cholinesterases, which are reduced in pregnancy and may lead to a longer duration of drug action; the clinical duration of suxamethonium may be prolonged.
• Elimination. Since glomerular filtration rate (GFR) is increased in pregnancy, clearance of many drugs is increased unless renal function is impaired, e.g. in pre-eclampsia.
Variation in renally eliminated drugs in pregnancy does not merely reflect changes in GFR, suggesting changes in renal tubular transport also. Another route of elimination is in breast milk, although this represents a relatively small amount of total drug elimination. Inhalational agents are excreted via the lungs more rapidly in the pregnant than the non-pregnant state.
Pharmacodynamics
The effects of most drugs are unchanged in pregnancy. However, notable and important exceptions are anaesthetic agents. Thus the minimum alveolar concentration (MAC) of inhala- tional agents is reduced, as is the minimal blocking concentration of local anaesthetics. While the volume of distribution of thiopental is increased during pregnancy, it is clinically more effective, resulting in a similar dose requirement in the pregnant state. The cause of this decrease in anaesthetic requirement is thought to be progesterone and/or a metabolite thereof. In addition, a given amount of epidural local anaesthetic solution produces a more extensive block than in non-pregnant subjects, possibly related to the reduction in epidural space caused by epidural venous engorgement, although progesterone has also been suggested as a cause.
Fetal effects of drugs
Drugs may affect the fetus at any stage of pregnancy. During the first trimester, the developing organ systems and overall body structure are especially at risk, particularly between the third and tenth weeks; administration of certain drugs during this period may result in congenital malformations. During the second and third trimesters, the growth and development of fetal tissues may be affected. Finally, drugs given before delivery may affect fetal oxygenation indirectly (e.g. by causing maternal hypotension or respiratory depression), may affect labour (e.g. ^-agonists), or may have neonatal effects after birth (e.g. opioids and non-steroidal anti-inflammatory drugs).
Many drugs are known to be harmful when given during pregnancy, but for many others, precise information is not always available. Thus, in general, drugs are not prescribed unless the benefits are felt to outweigh any possible risk, especially during the first trimester. Where possible, older drugs of which clinicians have greater experience are preferred over newer ones, and this is also true of anaesthetic agents.
Licensing of drugs in pregnancy
Many drugs, including anaesthetic agents, are not licensed for use in pregnancy, mainly because of the prohibitive costs to the manufacturer of performing the appropriate studies required and the relatively limited addition such licensing would make to the market. For example, the data sheets of many drugs, including fentanyl, contain the sentence ‘safety in human pregnancy has not been established’ or words to that effect, while that of propofol specifically warns against its use in obstetrics. Even in the case of thiopental, the data sheet merely states that there is ‘epidemiological and clinical evidence’ of its safety in pregnancy, whereas those of atracurium, vecuronium and suxamethonium state that they should only be used in pregnancy ‘if the potential benefits outweigh any potential risks’. In 2015 the US Food and Drug Administration (FDA) created a pregnancy exposure registry, which may result in more data surrounding drug use in pregnancy.
Key points
• Pharmacokinetics and pharmacodynamics in pregnancy may be altered from those in the non-pregnant state.
• Most drugs administered to the mother will pass to the fetus to a degree.
• Many drugs pass into breast milk.
• Most anaesthetic drugs are not licensed for use in pregnancy.
Further reading
Henderson E, Mackillop L. Prescribing in pregnancy and during breast feeding: using principles in clinical practice. Postgrad Med J 2011; 87: 349-54.
Howell PR, Madej T. Administration of drugs outside of product licence: awareness and current practice. Int J Obstet Anesth 1999; 8: 30-6.
World Health Organization. Breastfeeding and Maternal Medication: Recommendations for Drugs in the Eleventh WHO Model List of Essential Drugs. Geneva: WHO, 2002. http://whqlibdoc.who.int/ hq/2002/55732.pdf (accessed December 2018).