Pre-embryonic stage (weeks 0–2 post-conception)

The first two weeks post-conception are regarded as the pre-embryonic stage and describe the period up to implantation of the fertilised ovum. Teratogenic exposure during the pre-embryonic stage is thought to elicit an ‘all-or-nothing’ response, leading either to death of the embryo or complete recovery and normal development of the fetus. Fetal malformations following drug exposure during this period are therefore thought to be unlikely, except where the half-life of the drug is sufficient to extend exposure into the embryonic stage. A good example of the latter is isotretinoin and related vitamin A derivatives which have half-lives up to a week, and which when used systemically, for example, for the treatment of acne and psoriasis, are recognised teratogens (Nulman et al., 1998).

Embryonic stage (weeks 3-8 post-conception)

Organogenesis occurs predominantly during the embryonic stage and, with the exception of the central nervous system, eyes, teeth, external genitalia and ears, is complete by the end of the 10th week of pregnancy. Exposure to drugs during this critical period therefore represents the greatest risk of major birth defects. For this reason, women are often advised to avoid or minimise all drug use in the first trimester whenever possible. It is important to bear in mind however, that very few drugs are in fact proven teratogens and that exposure in the second and third trimesters may still result in fetal harm.

Fetal stage (weeks 9–38 post-conception)

During the fetal stage, the fetus continues to develop, grow and mature and, importantly, remains susceptible to some drug effects. This is especially true for the central nervous system, which can be damaged by exposure to certain drugs, for example, ethanol, at any stage of pregnancy. The external genitalia also continue to form from the seventh week until term, and consequently, danazol, which has weak androgenic properties, can cause virilisation of a female fetus if given in any trimester after the eighth week of pregnancy when the androgen receptors begin to form (Rosa, 1984).

Further examples include the angiotensin-converting enzyme (ACE) inhibitors, which if given in the second and third trimesters can result in fetal renal dysfunction and subsequent oligohydramnios, that is, reduced amniotic fluid volume (Sedman et al., 1995). The non-steroidal anti-inflammatory drugs (NSAIDs) are another important group of drugs that may cause problems specifically in the third trimester. These drugs inhibit prostaglandin synthesis in a dose-related fashion and, when given late in pregnancy, may result in premature closure of the fetal ductus arteriosus and fetal renal impairment (Koren et al., 2006). NSAIDs should therefore be avoided during the third trimester.

Timing of exposure

The stage of pregnancy at which a drug exposure occurs is key to determining the likelihood, severity or nature of any adverse effect on the fetus. Risk both between and within trimesters may be variable. For example, folic acid antagonists, for example, trimethoprim, are associated with an increased risk of neural tube defects if exposure occurs before neural tube closure (third to fourth week post-conception), but not after this period (Hernandez-Diaz et al., 2001). It has also been suggested that trimethoprim should be avoided after 32 weeks’ gestation in view of the theoretical risk of severe jaundice in the neonate as a result of bilirubin displacement from protein binding, although clinical evidence to support this is lacking (Dunn, 1964). Unfortunately, the precise period of teratogenic risk is known for very few substances. One drug for which this period has been established is thalidomide, where exposure between days 20 and 36 post-conception is associated with a high risk of congenital malformation (Lenz, 1988; Newman, 1986).

Drug dose

A threshold dose above which drug-induced malformations are more likely to occur has now been demonstrated for certain teratogenic compounds, although for most a ‘safe dose’ has not been conclusively determined. The likelihood of a dose relationship underlies the recommendation to use the lowest effective dose in pregnancy. For this reason, more frequent monitoring of drug levels may be recommended for certain drugs during pregnancy.

Species

Teratogenicity of a drug may be species dependent. Interestingly, preclinical thalidomide studies in mice and rats did not result in congenital malformation in the offspring (Breitkreutz and Anderson, 2008; Miller et al., 2009; Vorhees et al., 2001). Birth defects or other adverse reproductive outcomes observed in animal studies cannot therefore be simply extrapolated to the human situation. Further, the drug dose and route of administration used in early animal studies may not be comparable to clinical use in humans.

Genotype and environmental interaction

Not all fetuses exposed to known teratogenic drugs show evidence of having been affected in utero. It remains undetermined as to whether this variable susceptibility to teratogenic drugs is a result of genetic differences in the exposed mothers, the fetal genotype, modifying environmental factors or a combination of all three. Malformations are reported to occur in only 20–50% of infants born to mothers exposed to thalidomide during the period of greatest risk for embryopathy, that is, days 20–36 post-fertilisation (Lenz, 1966; Newman, 1985). Similarly, maternal treatment with systemic isotretinoin during the first trimester results in fetal malformation in only 18–35% of the live born infants, with a further 30% of children exhibiting developmental delay in the absence of physical deformity (Benke, 1984; Braun et al., 1984; Hill, 1984).

Absorption

Gastric and intestinal emptying time increases by 30–40% in the second and third trimesters (Pavek et al., 2009) and could be important in delaying absorption and time to onset of action for some drugs (Loebstein et al., 1997). There is also a reduction in gastric acid secretion in the first and second trimesters and an increase in mucus secretion. As a consequence of the increase in gastric pH, the ionisation, and hence absorption, of weak acids and bases can be affected.

Cardiac output and respiratory volume increase during pregnancy leading to hyperventilation and increased pulmonary blood perfusion. These changes cause higher pulmonary absorption of anaesthetics, bronchodilators, pollutants, cigarette smoke and other volatile drugs.

Protein binding

Albumin is the main plasma protein responsible for binding acidic drugs such as phenytoin and salicylates, whilst α₁-acid glycoprotein predominantly binds basic drugs, including β-blockers and opioid analgesics. As pregnancy progresses, the plasma volume increases at a greater rate than the increase in albumin which results in hypoalbuminaemia. In addition, steroid and placental hormones occupy the protein-binding sites. This leads to an increase in the fraction of unbound drug. Clinical effect is related to the concentration of unbound drug, which usually remains unchanged even though the total (bound plus unbound) plasma concentration is decreased. Thus, a fall in the total plasma concentration does not usually require an increase in dose. The α₁-acid glycoprotein concentrations remain the same as those in non-pregnancy.

Phenytoin is bound to albumin and exhibits the effects described earlier, but the situation is further complicated by increased hepatic metabolism that may necessitate a dose increase. Consequently, therapy can only be reliably guided by clinical assessment or measurement of unbound rather than total plasma concentration.

Metabolism

The metabolic activity of cytochrome P450 isoenzymes CYP3A4, CYP2D6, CYP 2A6 and CYP 2C9 and uridine 5′-diphosphate glucuronosyltransferase (UGT) isoenzymes (UGT1a1, UGT1A4 and UGT2B7) is increased during pregnancy. Drugs metabolised by these isoenzymes may therefore require dose adjustment. This may decrease the amount of the drug available for transfer across the placenta and thereby influence fetal exposure. In contrast, the metabolic activity of CYP1A2 and CYP2C19 is decreased during pregnancy and drugs metabolised by these isoenzymes may need dose reduction to minimise toxicity (see Table 47.3).

Table 47.3 Summary of pregnancy-induced effects on hepatic metabolism of some drugs

In general, the effects on individual drugs are inconsistent and difficult to predict, but knowledge of the effect of pregnancy on isoenzymes may inform decisions about possible monitoring and/or dose alterations.

Excretion

Within the first few weeks of pregnancy, the glomerular filtration rate (GFR) increases by approximately 50%. Consequently, those drugs which are excreted primarily unchanged by the kidneys, for example, lithium, digoxin and penicillin, show enhanced elimination and lower steady-state concentrations. The following drugs have shown pregnancy-induced increases of 20–65% on their renal elimination (Anderson, 2005):