Drug dosing during pregnancy—opportunities for physiologically based pharmacokinetic models

Drugs can have harmful effects on the embryo or the fetus at any point during pregnancy. Not all the damaging effects of intrauterine exposure to drugs are obvious at birth, some may only manifest later in life. Thus, drugs should be prescribed in pregnancy only if the expected benefit to the mother is thought to be greater than the risk to the fetus. Dosing of drugs during pregnancy is often empirically determined and based upon evidence from studies of non-pregnant subjects, which may lead to suboptimal dosing, particularly during the third trimester. This review collates examples of drugs with known recommendations for dose adjustment during pregnancy, in addition to providing an example of the potential use of PBPK models in dose adjustment recommendation during pregnancy within the context of drug-drug interactions. For many drugs, such as antidepressants and antiretroviral drugs, dose adjustment has been recommended based on pharmacokinetic studies demonstrating a reduction in drug concentrations. However, there is relatively limited (and sometimes inconsistent) information regarding the clinical impact of these pharmacokinetic changes during pregnancy and the effect of subsequent dose adjustments. Examples of using pregnancy PBPK models to predict feto-maternal drug exposures and their applications to facilitate and guide dose assessment throughout gestation are discussed

Effects on birthweight of alcohol and caffeine consumption in smoking women

STUDY OBJECTIVE--Previous work found no effect on birthweight of alcohol and caffeine consumption in non-smokers but such an effect was found in smokers. This report investigates further the effects on birthweight of alcohol and caffeine at three stages of pregnancy in smoking women. DESIGN--This was a prospective population study. SETTING--District general hospital in inner London. PARTICIPANTS--Out of 1309 women who completed all pregnancy interviews, 895 were excluded because they did not smoke, leaving a sample of 414 smokers. MEASUREMENTS AND MAIN RESULTS--Number and brand of cigarettes smoked, and quantity of alcohol and caffeine consumed were obtained by interview at booking, 28, and 36 weeks gestation. Birthweight was corrected for gestation and adjusted for maternal height, sex of infant and parity. The effect on birthweight of alcohol consumption was not explained by the amount smoked in terms of quantity and yield. Similarly the effect of caffeine was independent of smoking. When alcohol, caffeine, and smoking were analysed together, alcohol and caffeine were both associated with reductions in birthweight. Alcohol was associated with a reduction of up to 8% after adjusting for tobacco and caffeine intake, and caffeine was associated with a reduction of up to 6.5% after adjusting for tobacco and alcohol intake. Women who at booking were heavy smokers (greater than or equal to 13 cigarettes/day or greater than or equal to 15 mg carbon monoxide/cigarette), heavy drinkers (greater than or equal to 100 g/week alcohol), and had high caffeine intake (greater than or equal to 2801 mg/week) had a predicted reduction in mean birthweight of 18% (95% CI 11% to 24%). CONCLUSIONS--It is well known that women who smoke in pregnancy have smaller babies than non-smokers. Our study suggests that if these women also drink alcohol and high quantities of caffeine then the risk of poor fetal growth is increased even further

Caffeine intake and pregnancy outcomes: a meta-analytic review Consumo de cafeína na gravidez e desfechos perinatais

Epidemiological publications on the relationship of caffeine to birth weight and duration of human pregnancy, from 1966 to 1995, were searched through Medline. Each study was treated as the stratification variable, and its weight in the weighted average was proportional to the inverse of its variance. Twenty-six studies were located. Among the twenty-two studies on birth weight, eleven were on mean birth weight, nine on low birth weight (LBW), and four on intrauterine growth retardation (IUGR). Combined analysis of mean birth weigh study results showed a significant decrease in birth weight of nearly 43g among newborns of the heaviest caffeine-consuming mothers. LBW, IUGR, and preterm delivery displayed significant homogeneity in the test results, indicating that a pooled estimate should not be taken as an adequate measure. The high heterogeneity of the available literature on the effects of caffeine on LBW, IUGR, and preterm delivery prevents estimation of reliable pooled estimates through meta-analysis. Further assessment of caffeine intake during pregnancy is needed in future research.<br>Foram rastreadas as publicações epidemiológicas de 1966 a 1995 sobre a associação entre cafeína e peso ao nascer e duração da gestação humana através de pesquisa em Medline. Cada estudo foi tratado como uma categoria de uma variável e seu peso foi proporcional ao inverso de sua variância. Foram localizados vinte e seis estudos. Entre os vinte e dois estudos sobre peso ao nascer, onze foram sobre peso médio ao nascer, nove sobre baixo peso ao nascer (BPN) e quatro sobre retardo do crescimento intra-uterino (RCIU). O efeito agregado sobre o peso médio ao nascer mostrou uma redução estatisticamente significativa de 43 gramas entre os recém-nascidos de mães que consumiam maiores quantidades de cafeína. A análise agregada do efeito sobre BPN, RCIU e nascimentos pré-termos apresentou teste de homegeneidade estatisticamente significativo, indicando que uma estimativa combinada não seria confiável. A grande heterogeneidade da literatura disponível quanto ao efeito da cafeína sobre o BPN, RCIU e partos pré-termo não permite o cálculo confiável de estimativas agrupadas através de meta-análise. Torna-se necessária uma avaliação mais cuidadosa do consumo de cafeína durante a gestação em estudos futuros