Tamara van Donge

Physiological changes during pregnancy and neonatal life 27 2 of their combination antiretroviral therapy. The following example elegantly shows the practical utility of PBPK modeling in the pregnant population to ensure an optimal and practical dose. A recently developed PBPK model predicted a decrease in darunavir/ ritonavir exposure, and therefore efficacy, during pregnancy when taking 800/100 mg once daily. When the dosing regimen was adjusted to 600/100 mg twice daily, the lack in exposure was compensated. 10,11 In addition to acquire valuable insights in the pharmacokinetics and pharmacodynamics of drugs during pregnancy, it is of equal importance to understand the physiology of pregnancy- related diseases, for example with the aid of biomarkers. New biomarkers can help to understand the cause, diagnosis, progression and treatment of a disease. 12 Hypertensive disorders such as pre-eclampsia are a major contributor to maternal mortality worldwide. 13,14 A lot of research has been done in the field of translational biomarkers which consequently has improved our understanding of pre-eclampsia and helped us better define the diagnosis of this pregnancy-related disease. 15 Pre-eclampsia is diagnosed when there is a combination of increased proteinuria (≥ 300 mg in 24h) and pregnancy-induced hypertension (diastolic blood pressure ≥ 90 mmHg). 14,16 Various placental anti-angiogenic markers have been investigated, such as soluble endoglin (sEng) and soluble fms-like tyrosine kinase 1 (sFlt-1) that both can cause endothelial dysfunction. 17,18 Levels of sEng are correlated with disease severity in pre- eclamptic pregnant women, together with an increase in sFlt-1 levels. 18 Furthermore, women suffering from pre-eclampsia showed decreased levels of free (unbound) serum placental growth factor (PIGF) and free vascular endothelial growth factor (VEGF) before developing clinical signs. 19 Maternal serum neutrophil gelatinase-associated lipocalin (NGAL) levels are significantly increased in preeclamptic women and the renal marker cystatin C measured at the end of the third trimester is a predictor of pre-eclampsia. 20,21 In a longitudinal prospective study, it was found that neurofilament light (NfL) concentrations were higher in women with pre-eclampsia as compared to women who do not develop pre-eclampsia. Elevated levels of NfL are increasingly recognized as a measure of acute or chronic neuroaxonal damage and NfL can be used as a predictive value for pre-eclampsia, especially in women older than 36 years. 16 New attempts aim at combining biochemical with biophysical markers for a more precise diagnosis of pre-eclampsia. 22 Despite the numerous results it is important to note that the biomarkers that are listed are not specific for pre-eclampsia, and are also used outside of pregnancy. It is therefore still necessary to search for specific markers and interventions. 23 Drug exposure in the fetus: does the placenta act as a barrier? Contrary to what was assumed decades ago, the placenta does unfortunately not serve as a barrier that prevents drugs from reaching the fetus. 24 Drug exposure of the pregnant woman can have an impact on the unborn child. Therapeutic drugs are prescribed to