In the Journals

Maternal cortisol to cortisone ratio may predict preeclampsia, fetal growth restriction

A lower maternal serum cortisol to cortisone ratio, a marker of placental function, precedes the clinical manifestation of preeclampsia and preterm fetal growth restriction by up to 10 weeks in pregnant women, according to findings from a case-control study.

Gordon C. S. Smith

A steroid enzyme highly expressed in the placenta, 11-beta-hydroxysteroid dehydrogenase-type 2 (11-beta-HSD2), metabolizes cortisol to cortisone, thereby protecting the fetus from exposure to excessive maternal cortisol during pregnancy, Gordon C. S. Smith, DSc, FMedSci, head of the department of obstetrics and gynecology at the University of Cambridge, United Kingdom, and colleagues wrote in the study background. Several studies have suggested that preeclampsia and fetal growth restriction are associated with reduced levels of placental 11-beta-HSD2, they wrote, suggesting that reduced 11-beta-HSD2 activity would result in an increased maternal serum cortisol to cortisone ratio.

“A small number of studies previously addressed this question and, paradoxically, reported that women with [preeclampsia] exhibited lower cortisol to cortisone ratios, suggesting increased maternal [11-beta-HSD2] activity,” the researchers wrote. “However, these analyses were limited to samples obtained following diagnosis and consisted of studies that had not included more than 42 cases of confirmed [preeclampsia] and 14 cases of confirmed [fetal growth restriction] per study.”

Researchers analyzed data from pregnant women participating in the Pregnancy Outcome Prediction study, a prospective cohort study that collected blood, ultrasound scan and pregnancy outcome data from more than 4,000 nulliparous women between 2008 and July 2012. The cohort included 194 women experiencing preeclampsia and 185 women experiencing fetal growth restriction, as well as a random sample of 279 healthy pregnant women who did not experience adverse outcomes (controls). Researchers measured steroid levels at 12, 20, 28 and 36 weeks, with cortisol and cortisone levels expressed as multiples of the median. Cortisol to cortisone ratio was generated by dividing the multiples of the median for cortisol by the multiples of the median for cortisone. Researchers used linear regression analyses for cortisone against cortisol in cases and controls to calculate P values for interaction between groups.

In the healthy women, levels of cortisol and cortisone increased as pregnancy progressed, whereas the cortisol to cortisone ratio showed an upward trend between 12 and 20 weeks, plateaued at 28 weeks and fell at 36 weeks, according to researchers. In cases of fetal growth restriction, this maternal pattern was similar; however, in cases of preeclampsia, the cortisol to cortisone ratio started to decline at 28 weeks onward.

The researchers found that there was a higher incidence of preterm preeclampsia and term preeclampsia in women in the lowest decile of cortisol to cortisone ratio when compared with deciles 2 to 10 at both 28 and 36 weeks’ gestation, respectively, noting approximately 2.2% of preterm preeclampsia cases and 11% of term preeclampsia cases were observed in the lowest decile vs. 0.4% of preterm cases and 3% of term preeclampsia cases in deciles 2 to 10.

At 28 weeks’ gestation, each 1 standard deviation higher cortisol to cortisone ratio measurement was negatively associated with preterm preeclampsia (OR = 0.33; 95% CI, 0.19-0.57), term preeclampsia (OR = 0.61; 95% CI, 0.49-0.76), and preterm fetal growth restriction (OR = 0.5; 95% CI, 0.29-0.85). At 36 weeks’ gestation, each 1 standard deviation higher cortisol to cortisone ratio measurement was negatively associated with term preeclampsia (OR = 0.42; 95% CI, 0.32-0.55) but not term fetal growth restriction (OR = 1.07; 95% CI, 0.87-1.31). Adjustments for maternal characteristics did not change the associations, according to researchers.

“Our observations implicate enhanced maternal [11-beta-HSD2] activity in the pathophysiology of [preeclampsia],” the researchers wrote. “However, further investigation into the potential utility of the cortisol to cortisone ratio as a predictive marker of [preeclampsia] would be beneficial, given there is no current accurate predictive test for the condition.” – by Regina Schaffer

Disclosures: Smith reports he has received research support from GE, GlaxoSmithKline, Roche and Sera Prognostics, served on advisory boards for GlaxoSmithKline and Roche, and received consultant fees from GlaxoSmithKline. One other author reports he has received research support from GlaxoSmithKline and Sera Prognostics.

A lower maternal serum cortisol to cortisone ratio, a marker of placental function, precedes the clinical manifestation of preeclampsia and preterm fetal growth restriction by up to 10 weeks in pregnant women, according to findings from a case-control study.

Gordon C. S. Smith

A steroid enzyme highly expressed in the placenta, 11-beta-hydroxysteroid dehydrogenase-type 2 (11-beta-HSD2), metabolizes cortisol to cortisone, thereby protecting the fetus from exposure to excessive maternal cortisol during pregnancy, Gordon C. S. Smith, DSc, FMedSci, head of the department of obstetrics and gynecology at the University of Cambridge, United Kingdom, and colleagues wrote in the study background. Several studies have suggested that preeclampsia and fetal growth restriction are associated with reduced levels of placental 11-beta-HSD2, they wrote, suggesting that reduced 11-beta-HSD2 activity would result in an increased maternal serum cortisol to cortisone ratio.

“A small number of studies previously addressed this question and, paradoxically, reported that women with [preeclampsia] exhibited lower cortisol to cortisone ratios, suggesting increased maternal [11-beta-HSD2] activity,” the researchers wrote. “However, these analyses were limited to samples obtained following diagnosis and consisted of studies that had not included more than 42 cases of confirmed [preeclampsia] and 14 cases of confirmed [fetal growth restriction] per study.”

Researchers analyzed data from pregnant women participating in the Pregnancy Outcome Prediction study, a prospective cohort study that collected blood, ultrasound scan and pregnancy outcome data from more than 4,000 nulliparous women between 2008 and July 2012. The cohort included 194 women experiencing preeclampsia and 185 women experiencing fetal growth restriction, as well as a random sample of 279 healthy pregnant women who did not experience adverse outcomes (controls). Researchers measured steroid levels at 12, 20, 28 and 36 weeks, with cortisol and cortisone levels expressed as multiples of the median. Cortisol to cortisone ratio was generated by dividing the multiples of the median for cortisol by the multiples of the median for cortisone. Researchers used linear regression analyses for cortisone against cortisol in cases and controls to calculate P values for interaction between groups.

In the healthy women, levels of cortisol and cortisone increased as pregnancy progressed, whereas the cortisol to cortisone ratio showed an upward trend between 12 and 20 weeks, plateaued at 28 weeks and fell at 36 weeks, according to researchers. In cases of fetal growth restriction, this maternal pattern was similar; however, in cases of preeclampsia, the cortisol to cortisone ratio started to decline at 28 weeks onward.

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The researchers found that there was a higher incidence of preterm preeclampsia and term preeclampsia in women in the lowest decile of cortisol to cortisone ratio when compared with deciles 2 to 10 at both 28 and 36 weeks’ gestation, respectively, noting approximately 2.2% of preterm preeclampsia cases and 11% of term preeclampsia cases were observed in the lowest decile vs. 0.4% of preterm cases and 3% of term preeclampsia cases in deciles 2 to 10.

At 28 weeks’ gestation, each 1 standard deviation higher cortisol to cortisone ratio measurement was negatively associated with preterm preeclampsia (OR = 0.33; 95% CI, 0.19-0.57), term preeclampsia (OR = 0.61; 95% CI, 0.49-0.76), and preterm fetal growth restriction (OR = 0.5; 95% CI, 0.29-0.85). At 36 weeks’ gestation, each 1 standard deviation higher cortisol to cortisone ratio measurement was negatively associated with term preeclampsia (OR = 0.42; 95% CI, 0.32-0.55) but not term fetal growth restriction (OR = 1.07; 95% CI, 0.87-1.31). Adjustments for maternal characteristics did not change the associations, according to researchers.

“Our observations implicate enhanced maternal [11-beta-HSD2] activity in the pathophysiology of [preeclampsia],” the researchers wrote. “However, further investigation into the potential utility of the cortisol to cortisone ratio as a predictive marker of [preeclampsia] would be beneficial, given there is no current accurate predictive test for the condition.” – by Regina Schaffer

Disclosures: Smith reports he has received research support from GE, GlaxoSmithKline, Roche and Sera Prognostics, served on advisory boards for GlaxoSmithKline and Roche, and received consultant fees from GlaxoSmithKline. One other author reports he has received research support from GlaxoSmithKline and Sera Prognostics.