Several recent studies have focused on defining which individuals are destined to have a favorable response to progesterone for the prevention of recurrent preterm birth. These investigations have identified several distinct and consistent clinical risk factors for recurrent SPTB despite 17-OHPC therapy, including black race, gonorrhea or chlamydia infection, vaginal bleeding, family history of SPTB, male fetus (Manuck et al., 2016a,c). Pharmacogenomic studies assessing recurrent SPTB among women using 17-OHPC have been pre-clinical in nature, but have also shown promising results, implicating biologically plausible pathways including the nitric oxide pathway and other genetic pathways involved with signal transduction and infection and inflammation (Manuck et al., 2014b; Manuck, 2016). Unfortunately, insufficient sample numbers, difficulties in defining adequate treatment “response” and lack of randomized studies has prevented this work from reaching direct clinical applicability (Manuck, 2016). Studies examining more acute genetic changes (e.g., epigenetic modifications) in response to the environmental stimuli of 17-OHPC are also currently limited but may offer additional avenues of research and eventual clinical application. Finally, it is possible that genotype or methylation changes affect birth outcomes only in the presence of a certain critical threshold or serum level of 17-OHPC. Many drugs taken by women for a variety of indications during pregnancy are metabolized by the cytochrome P450 enzyme system; 17-OHPC is also metabolized by the cytochrome P450 system, primarily CYP3A (Sharma et al., 2010). Interactions with co-administered CYP3A inhibitors or inducers may influence 17-OHPC drug metabolism and clinical efficacy (Sharma et al., 2008). No studies examining the effects of concomitant drug administration with 17-OHPC have been published to date, though in vitro data suggests these other CYP-metabolized drugs may impact 17-OHPC levels (Sharma et al., 2008).

Epigenetic modifications provide a mechanism by which genes interact with the environment; they affect gene expression by inducing structural changes in DNA that are maintained through cell division, respond to environmental changes including drug exposures, yet are potentially reversible and can be targets for disease therapy (Feinberg, 2007). DNA methylation at cytosine-guanine dinucleotides sites, the most commonly studied epigenetic modification in humans, guides temporal, and tissue-specific gene expression during fetal development and tissue differentiation. Even subtle environmental changes may induce epigenetic changes and have effects on phenotype (Golbabapour et al., 2011). Epigenetic biomarkers from blood have been used in a variety of complex conditions in other fields (e.g., depression, addiction/smoking). Moreover, these changes are potentially reversible and reflect dynamic interactions with the environment. For example, studies of women with breast cancer (Antoni et al., 2012; Bower et al., 2014; Stagl et al., 2015), caregivers of family members with dementia (Black et al., 2013), patients with inflammatory bowel disease (Kuo et al., 2015), and even healthy individuals (Qu et al., 2013) have shown that the body's response to chronic stress may be dynamic, mediated by glucocorticoid gene expression, and at least partly reversible at the genomic level when treated with cognitive behavioral therapy or relaxation techniques. Therefore, study of the methylome and transcriptome is a promising and understudied avenue of investigation in prematurity research (Fuchikami et al., 2011; Mikeska et al., 2012; Philibert et al., 2013). Methylation is tissue specific; results from blood, placental, or cervical tissue, for example typically cannot be directly compared. However, methylation studies in blood may be a reliable correlate of physiologic processes in other tissues (Smith et al., 2014). Limited studies of epigenetics in obstetrics have demonstrated identifiable differences among women delivering preterm and those with term deliveries, but more work is needed to evaluate whether these differences may be influenced (positively or negatively) by medication exposure or other known risks factors for SPTB, such as vaginal bleeding or a short cervical length.

Unfortunately, the aforementioned pharmacogenomics associations have been modest. Larger scale genome wide association studies of SPTB in general (without considering treatment response) have also been largely disappointing. It has been hypothesized that suboptimal clinical phenotyping is a major contributing factor to the challenges of reproducibility that have characterized genetic investigations of prematurity. Many genetic studies of SPTB have limited or inconsistent phenotype information; even those that do collect detailed information tend to be based on relatively heterogeneous groups of women. We recently described a phenotype classification system. This tool uses clinical data to group women into nine distinct SPTB phenotypes (e.g., cervical insufficiency, infection/inflammation, decidual hemorrhage), and may provide further insight beyond the heterogenous PTB categorization, improving upon prior classification systems (Manuck et al., 2015).

Determination of individuals most likely to remain pregnant 48 h after indomethacin therapy is a challenge, as placebo-controlled tocolytic studies are limited and retrospective studies are fraught with confounding. The diagnosis of “preterm labor” remains imperfect, and studies have traditionally used varying definitions to determine participant eligibility. Many women initially diagnosed with acute preterm labor will eventually deliver at term. We are unaware of any reported studies of indomethacin pharmacogenetics in the setting of pregnancy, though investigation of maternal and/or fetal genome, epigenome, methylome may shed additional light on variation in response in a similar fashion to pharmacogenomics investigations of 17-OHPC as outlined above.

If women who are most likely to benefit from indomethacin treatment for acute preterm labor can be identified through pharmacogenomic or other investigations, the issue of potential toxicity to the fetus must be resolved in order for this therapy to be administered optimally. Recently, nanomedicine has been investigated as one potential way to overcome this limitation. Nanomedicine provides a mechanism to vector drugs (e.g., through liposomes) preferentially to diseased or target tissues in the body, while limiting exposure (and thus toxicity) to healthy tissues (and in the case of pregnancy, the fetus). Specifically engineered liposomes, encapsulated with indomethacin and with a surface oxytocin receptor antagonist, have been designed for this purpose, to deliver indomethacin directly to the myometrium while limiting fetal exposure. In initial murine studies, these liposomes successfully delivered indomethacin to the uterus and inhibited prostaglandin production—thus maintaining its pharmacologic effects—while reducing fetal exposure by 7.6-fold. (Refuerzo et al., 2015) In subsequent murine models, these specifically engineered liposomes prolonged pregnancy by 31% and reduced the rate of PTB by 15% (Refuerzo et al., 2016). The application of nanotechnology has great promise as a solution to the fetal toxicity appreciated with indomethacin, and refinement of these techniques will expand researcher's abilities to investigate other therapeutics for SPTB prevention and treatment with lower concern for fetal exposure.

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.