Personalised medicine—the potential yet realised

The complex interactions between genes and the environment yield multiple pathophysiologies for the great obstetric diseases such as preterm birth (Romero et al. Science 2014;345:760–5). Our current, limited capacity to define when and to what extent any number of these pathophysiologies are in effect in individual pregnant women has resulted in therapeutic strategies being aimed preferentially toward populations defined by risk factors, particularly obstetric history. However, strategies such as prophylactic progestogen administration indicated for a previous preterm birth necessarily overtreat pregnant women, exposing them and their children to potential, possibly unforeseen, harm (O'Brien BJOG 2015;122:610–14). Defining populations for intervention primarily based upon biomarkers has the potential to better inform obstetricians when a treatment is more likely to be effective, when a therapy should be avoided, or optimise intervention once initiated. The application of therapeutics based on variations in the human genome, pharmacogenomics, is presently perceived as the ultimate expression of a more personalised strategy employing biomarkers to define a treatment approach. Against this backdrop, Manuck et al. (BJOG 2018;344–50) interrogated the human exome in a cohort of women with a history of preterm birth who also received 17-hydroxyprogesterone caproate (17-OHPC) prophylaxis. Their goal was to identify women with particular genotypes who experienced a varied outcome potentially related to this intervention. Remarkably, over 50% of these unselected women experienced a recurrent preterm birth; again begging the question whether a prophylactic progestogen is sufficiently effective in an unselected population who experienced one or more of several potential pathophysiologies in a previous pregnancy to justify this strategy. These investigators used a longstanding definition of an adverse outcome, delivery before 37 weeks of gestation; and a novel definition, prolongation of pregnancy by 3 weeks or more from the gestational age of a previous preterm birth. Despite a concern for effectiveness, these investigators explore the application of pharmacogenomics for guiding therapeutics in women with a history of preterm birth. Multiple reports have demonstrated that clinical preterm birth phenotypes including intact preterm labour, prelabour rupture of membranes, and cervical incompetence are associated with particular maternal genotypes and pathophysiological pathways. As suggested by the data of Manuck et al., several pathways leading to preterm birth may be modifiable by a progestogen. However, results from available small investigations have varied by study and by outcome designation. Additional larger data sets are needed, most pressingly in subpopulations where other biomarkers suggest specific pathophysiological pathways. Finally, pharmacogenomic studies such as the present investigation hold promise to define when treatment should be avoided, but it is premature to suggest that women with a history of preterm birth with a particular genotype should avoid prophylactic exposure to 17-OHPC. Ultimately, to improve confidence in our treatments and because safety is so important to our patients, the field of obstetrics must put greater emphasis on the constructs of a personalised approach to interventions despite future challenges regarding cost and translation. Manuck et al. demonstrate that pharmacogenomics will likely be a very useful tool in our armamentarium to better understand our patients and improve their outcomes. Full disclosure of interests available to view online as supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.