Objective
The purpose of this study was to determine whether mid-trimester insulin resistance is associated with subsequent preeclampsia.
Study Design
This was a secondary analysis of 10,154 nulliparous women who received vitamin C and E or placebo daily from 9-16 weeks gestation until delivery. Of these, 1187 women had fasting plasma glucose and insulin tested between 22 and 26 weeks gestation. Insulin resistance was calculated by the homeostasis model assessment of insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index.
Results
Obese women were twice as likely to have a HOMA-IR result of ≥75th percentile. Hispanic and African American women had a higher percentage at ≥75th percentile for HOMA-IR than white women (42.2%, 27.2%, and 16.9%, respectively; P < .001). A HOMA-IR result of ≥75th percentile was higher among the 85 nulliparous women who subsequently had preeclampsia, compared with women who remained normotensive (40.5% vs 24.8%; adjusted odds ratio, 1.9; 95% confidence interval, 1.1–3.2). Quantitative insulin sensitivity check index results were similar to the HOMA-IR results.
Conclusion
Midtrimester maternal insulin resistance is associated with subsequent preeclampsia.
Insulin resistance was first proposed in 1936 and has been established to play a major role in type II diabetes mellitus and in the pathogenesis of hypertension, dyslipidemias, and coronary artery disease. Virtually all obese women with hypertension have an elevated insulin level ; the highest levels occur in obese women with excessive abdominal adipose tissue. Insulin resistance is a hallmark of obesity; in pregnant women, obesity is a consistent risk factor for preeclampsia.
For Editors’ Commentary, see Table of Contents
Normal pregnancy is characterized by lower fasting, higher postprandial glucose values, and hyperinsulinemia. After an oral glucose meal, pregnant women demonstrate both prolonged hyperglycemia and hyperinsulinemia and a greater suppression of glucagon, which cannot be explained by a decreased metabolism of insulin because its half-life during pregnancy is not changed. Instead, this response is consistent with a pregnancy-induced state of peripheral insulin resistance, the purpose of which is likely to ensure a sustained postprandial supply of glucose to the fetus. Indeed, insulin sensitivity in late normal pregnancy is 45-70% lower than that of nonpregnant women.
Our objective was to determine whether increased maternal midtrimester insulin resistance is associated with subsequent preeclampsia. To test this hypothesis, we performed a secondary analysis of a subgroup of low-risk nulliparous women from a multicenter, randomized trial of daily vitamin C and E supplementation vs placebo for prevention of complications of pregnancy-associated hypertension.
Materials and Methods
This was a secondary analysis of the randomized trial in 10,154 nulliparous women who received vitamin C and E or placebo daily from 9-16 weeks’ gestation until delivery; the trial was conducted at the 16 clinical centers that were members of the Eunice Kennedy Shriver National Institute of Child Health and Human Developmental Maternal-Fetal Medicine Units Network between 2003 and 2008. Full details of the study design and technique of data collection have been described previously. Women who were included in the trial had blood samples that were collected at randomization, at 24 and 32 weeks’ gestation, and at admission for delivery. Information about whether the women fasted for ≥12 hours (even though they were not specifically instructed to fast for any of these visits) was collected. Women were included in this secondary analysis if they had a blood sample that had been collected from 22-26 weeks’ gestation and had fasted for ≥12 hours before the blood collection. The study was approved by the Institutional Review Boards of each clinical site and the data coordinating center.
The diagnosis of hypertension was based on blood-pressure measurements that had been obtained during or after the 20th week of pregnancy, excluding intraoperative blood pressures and intrapartum systolic pressures. Severe pregnancy-associated hypertension was defined as a systolic pressure of ≥160 mm Hg or a diastolic pressure of ≥110 mm Hg on 2 occasions 2-240 hours apart or a single blood-pressure measurement that was severely elevated that led to treatment with an antihypertensive medication. Mild pregnancy-associated hypertension was defined as a systolic pressure of 140-159 mm Hg or a diastolic pressure of 90-109 mm Hg on 2 occasions 2-240 hours apart. Mild preeclampsia was defined as mild pregnancy-associated hypertension with documentation of proteinuria within 72 hours before or after an elevated blood-pressure measurement. Proteinuria was defined as total protein excretion of ≥300 mg in a 24-hour urine sample or ≥2+ on dipstick testing or a protein-to-creatinine ratio of ≥0.35 if a 24-hour urine sample was not available. Severe preeclampsia was defined as preeclampsia with either severe pregnancy-associated hypertension or protein excretion of ≥5 g in a 24-hour urine sample or as mild pregnancy-associated hypertension with oliguria (<500 mL in a 24-hour urine sample), pulmonary edema (confirmed by radiography), or thrombocytopenia (platelet count of <100,000 per cubic millimeter). Preeclampsia included mild and severe preeclampsia, HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, and eclampsia. To determine the diagnosis of preeclampsia, deidentified medical charts of all women with pregnancy-associated hypertension were reviewed centrally by at least 3 reviewers.
Determination of insulin resistance
Insulin resistance was calculated from fasting maternal plasma glucose and insulin concentrations that had been obtained between 22 and 26 weeks’ gestation. Insulin resistance was calculated with the use of the surrogate indices of homeostasis model assessment of insulin resistance (HOMA-IR) and also the quantitative insulin sensitivity check index (QUICKI). Surrogate indirect indices describe glucose-insulin homeostasis by empiric nonlinear equations. The intent of the empiric equations is to accommodate glucose ranges, to ensure reduced suppression of hepatic glucose production, and to allow the use of total insulin assays. The equations for the indirect indices are:
HOMA-IR = fasting insulin ( μU / mL ) × fasting glucose ( mmol / L ) / 22.5
QUICKI = 1 / log ( fasting insulin [ μU / mL ] ) + log ( fasting glucose [ mg/dL ] )
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