Rønnaug Ødegård

Risk factors and clinical manifestations of pre‐eclampsia

Objective To study associations between established risk factors for pre‐eclampsia and different clinical manifestations of the disease.

Relationship of insulin-like growth factor-I and insulin-like growth factor binding proteins in umbilical cord plasma to preeclampsia and infant birth weight

OBJECTIVE To determine whether preeclampsia influences insulin‐like growth factor‐I (IGF‐I), insulin‐like growth factor binding protein‐1 (IGFBP‐1), and insulin‐like growth factor binding protein‐3 (IGFBP‐3), independent of its effect on birth weight. METHODS Cord blood was collected in 12,804 consecutive deliveries. We identified 258 preeclamptic pregnancies that were subclassified as mild or severe and early or late. For comparison, 609 control pregnancies were selected. Fetal growth was expressed as the ratio between observed and expected birth weight, with adjustment for gestational age at birth. IGF‐I, IGFBP‐1, and IGFBP‐3 were measured in umbilical plasma. The contribution of preeclampsia and birth weight to each measured factor was assessed by multiple linear regression analyses. RESULTS Between mild preeclampsia and controls, there were no differences in IGF‐I, IGFBP‐1, and IGFBP‐3. In severe and early onset preeclampsia, umbilical cord plasma IGF‐I was approximately 50% lower, and IGFBP‐1 was more than twice as high as in controls (both P < .01). At each birth weight level, IGF‐I was lower and IGFBP‐1 was higher in severe or early preeclampsia than among controls of similar weight. Birth weight and preeclampsia were, independent of each other, associated with IGF‐I, whereas birth weight, but not preeclampsia, was associated with IGFBP‐1, after adjustment for gestational age. CONCLUSION Fetal growth restriction caused by severe or early preeclampsia is associated with lower umbilical levels of IGF‐I than low birth weight caused by other conditions. Preeclampsia may contribute to the observed IGF‐I reduction, either as part of the underlying causes of preeclampsia, or as a consequence of the disease.

Maternal and Fetal Variants of Genetic Thrombophilias and the Risk of Preeclampsia

Background: A womans thrombophilic genes may increase her risk of preeclampsia in pregnancy. Vascular conditions of the placenta related to thrombophilic genes of the fetus could also be relevant for preeclampsia. The case–parent triad study design provides separate estimation of maternal and fetal genes. Methods: We recruited 92 mother–father–child triads of preeclamptic pregnancies from a birth clinic in Stavanger, Norway. All parents were of Norwegian origin. Maternal, paternal, and fetal DNA were genotyped for the methylenetetrahydrofolate reductase (MTHFR) C677T and Factor V Leiden (FVL) G1691A SNPs. Estimation of the relative risk (RR) associated with fetal and maternal genetic variants was performed by log-linear models. Results: There was no indication of an effect of the childs FVL alleles on preeclampsia risk. For case babies with 2 copies of the variant allele, the association with the MTHFR variant was inconclusive (RR = 1.6; 95% confidence interval [CI] = 0.6–4.3). Case mothers who were homozygous for the MTHFR variant had a relative risk of 2.0 (CI = 1.0–4.1) assuming a recessive gene effect. A 2.5-fold risk (CI = 1.1–5.7) of preeclampsia was estimated when the mother carried one copy of the FVL. Among mothers homozygous for the MTHFR variant, the relative risk of the FVL variant was 4.6-fold (CI = 1.0–21). Conclusions: We found little evidence of an effect of the childs MTHFR or FVL alleles on the risk of preeclampsia. Our estimates of effects of maternal MTHFR and FVL alleles were consistent with estimates from case-control studies. The case–parent triad design may be a useful tool for studies of pregnancy complications such as preeclampsia.

Umbilical cord plasma interleukin-6 and fetal growth restriction in preeclampsia: a prospective study in Norway.

OBJECTIVE To study the association between umbilical plasma levels of interleukin‐6 (IL‐6) in relation to fetal growth in subgroups of preeclampsia, and in control pregnancies. METHODS Umbilical cord plasma was collected from 12,804 consecutive births. A total of 271 singleton cases of preeclampsia were identified, and classified as mild or severe, and as disease with early or late onset. As controls, 611 singleton pregnancies without preeclampsia were selected, and the ratio between observed and expected birth weight was used as a measure of fetal growth. In the analysis, we also included maternal smoking during pregnancy. Umbilical cord plasma IL‐6 concentration was measured with an IL‐6 bioassay. Comparing controls with subgroups of preeclampsia (severe and early onset), this study had a statistical power of 90% to detect a difference in cord IL‐6 of 10 pg/mL. RESULTS In severe preeclampsia, cord plasma IL‐6 concentration was lower than among controls (P < .001), and there was a sharp decrease in cord plasma IL‐6 with decreasing birth weight ratio (P trend <.001). By further dividing the preeclampsia group into early or late onset, the strong association between low IL‐6 levels and low birth weight ratio appeared to be present mainly in early‐onset disease. These results were not confounded by maternal smoking. CONCLUSION Restricted fetal growth related to preeclampsia is associated with reduced umbilical cord plasma IL‐6 concentration in cases with early‐onset disease. In these cases, fetal growth restriction could be mediated by impaired trophoblast function.

Alpha-foetoprotein in umbilical cord in relation to severe pre-eclampsia, birth weight and future breast cancer risk.

Women born after pre-eclamptic pregnancies have been reported to be at reduced risk of breast cancer as adults, because of reduced intrauterine oestrogen influence on breast tissue; high levels of α-foetoprotein (a glycoprotein with anti-oestrogenic properties), however, could also be important. In severe pre-eclampsia, placental function and foetal growth are reduced, and umbilical cord plasma levels of α-foetoprotein could reflect the underlying processes. Umbilical cord blood was collected in 12 804 consecutive deliveries. Among 307 pregnancies with clinical pre-eclampsia, 66 singleton pregnancies were identified as clinically severe, and 610 singleton pregnancies were selected as controls. Oestradiol and α-foetoprotein were measured from umbilical plasma, and birth weight was standardized as the ratio between the observed and expected birth weight, adjusted for differences in gestation length and offspring sex. Cord plasma levels of α-foetoprotein were significantly higher in severe pre-eclampsia than controls (P<0.01) after adjustment for gestational age and birth weight. For oestradiol, there was no difference in cord plasma levels between the severe pre-eclampsia group and controls, after adjustment for length of gestation and birth weight. These results suggest that an anti-oestrogenic effect associated with pre-eclampsia may be mediated through high levels of α-foetoprotein rather than low levels of oestradiol.

Metformin Use in PCOS Pregnancies Increases the Risk of Offspring Overweight at 4 Years of Age: Follow-Up of Two RCTs

Context Metformin is used in pregnancy in women with gestational diabetes mellitus, polycystic ovary syndrome (PCOS), and obesity. Metformin passes the placenta. Objective To explore the effects of metformin use in PCOS pregnancies on offspring growth to 4 years of age. Design Follow-up study of two randomized, double-blind, placebo-controlled trials. Setting Secondary care centers. Eleven public hospitals in Norway. Participants One hundred eighty-two children of mothers with PCOS who participated in two randomized controlled trials. Intervention Metformin 1700 or 2000 mg/d or placebo from first trimester to delivery in the original studies. No intervention in the current study. Main Outcome Measures Height, weight, body mass index (BMI), and overweight/obesity at 4 years of age and head circumference at 1 year of age, converted to z scores. Results The difference in height z score means between the groups at 4 years of age was nonsignificant (0.07 [95% confidence interval (CI): -0.22 to 0.36]; P = 0.651). At 4 years of age, the metformin group had higher weight z score than the placebo group [difference in means: 0.38 (0.07 to 0.69); P = 0.017] and higher BMI z score [difference in means: 0.45 (0.11 to 0.78); P = 0.010]. There were more overweight/obese children in the metformin group [26 (32%)] than in the placebo group [14 (18%)] at 4 years of age [odds ratio: 2.17 (1.04 to 4.61); P = 0.038]. The difference in mean head circumference z score at 1 year of age was 0.27 (-0.04 to 0.58; P = 0.093). Conclusion Metformin-exposed children had higher BMI and increased prevalence of overweight/obesity at 4 years of age.

Change in body fat during a family-based treatment of obesity in children: the relative importance of energy intake and physical activity.

Objective: The aim of the current study was to examine to what extent changes in reported energy intake and physical activity predict changes in body fat during a family-based outpatient treatment of obesity in children. Methods: Total body fat (DXA), reported energy intake (4-day diet record), and physical activity (accelerometer) was measured in 99 children (age 7–12 years, mean BMI SDS = 2.99) at baseline as well as after 6 months 2 years of treatment. Repeated measures (GLM), growth modeling, and structural equation modeling (SEM) were applied in the data analyses. Results: There was significant decrease in body fat, reported energy intake, and physical activity at both follow-ups (p < 0.001) compared to baseline. Changes in reported energy intake from baseline to 6 months predicted a decrease in body fat from baseline to 6 months (β = 0.68, p < 0.001). In addition, changes in reported energy intake had a strong indirect effect on body fat at 2-year follow-up, mediated by changes in body fat from baseline to 6 months (indirect β = 0.50, p < 0.001). Changes in physical activity did not predict changes in body fat during treatment. Conclusions: Changes in reported energy intake significantly affected body fat at 6 months and indirectly predicted the amount of body fat at 2-year follow-up. The indirect effect was mediated by a decrease in body fat obtained during the first phase of treatment.

Fetal Growth and Birth Anthropometrics in Metformin-Exposed Offspring Born to Mothers With PCOS

Context Metformin is used in an attempt to reduce pregnancy complications associated with polycystic ovary syndrome (PCOS). Little is known about the effect of metformin on fetal development and growth. Objectives To compare the effect of metformin versus placebo on fetal growth and birth anthropometrics in PCOS offspring compared with a reference population in relation to maternal body mass index (BMI). Design Post hoc analysis of a randomized controlled trial. Setting Double-blind, placebo-controlled, multicenter study. Patients 258 offspring born to mothers with PCOS. Intervention 2000 mg metformin (n = 131) or placebo (n = 121) from first trimester to delivery. Main Outcome Measures Mean abdominal diameter and biparietal diameter (BPD) at gestational weeks 19 and 32. Head circumference (HC), birth length, and weight related to a reference population of healthy offspring, expressed as gestational age- and sex-adjusted z-scores. Results Metformin- versus placebo-exposed offspring had larger heads at gestational week 32 (BPD, 86.1 mm versus 85.2 mm; P = 0.03) and at birth (HC, 35.6 cm versus 35.1 cm; P < 0.01). Analyses stratified by maternal prepregnancy BMI, larger heads were observed only among offspring of overweight/obese mothers. Among normal-weight mothers, the effect of metformin compared with placebo was reduced length (z-score = -0.96 versus -0.42, P = 0.04) and weight (z-score = -0.44 versus 0.02; P = 0.03). Compared with the reference population, offspring born to PCOS mothers (placebo group) had reduced length (z-score = -0.40; 95% confidence interval, -0.60 to -0.40), but similar birth weight and HC. Conclusions Metformin exposure resulted in larger head size in offspring of overweight mothers, traceable already in utero. Maternal prepregnancy BMI modified the effect of metformin on offspring anthropometrics. Anthropometrics of offspring born to PCOS mothers differed from those of the reference population.

Camp-based family treatment of childhood obesity: randomised controlled trial

Objective To compare the effectiveness of a 2-year camp-based family treatment programme and an outpatient programme on obesity in two generations. Design Pragmatic randomised controlled trial. Setting Rehabilitation clinic, tertiary care hospital and primary care. Patients Families with at least one child (7–12 years) and one parent with obesity. Interventions Summer camp for 2 weeks and 4 repetition weekends or lifestyle school including 4 days family education. Behavioural techniques motivating participants to healthier lifestyle. Main outcome measures Children: 2-year changes in body mass index (BMI) SD score (SDS). Parents: 2-year change in BMI. Main analyses: linear mixed models. Results Ninety children (50% girls) were included. Baseline mean (SD) age was 9.7 (1.2) years, BMI 28.7 (3.9) kg/m2 and BMI SDS 3.46 (0.75). The summer-camp children had a lower adjusted estimated mean (95% CI) increase in BMI (−0.8 (−3.5 to −0.2) kg/m2), but the BMI SDS reductions did not differ significantly (−0.11 (−0.49 to 0.05)). The 2-year baseline adjusted BMI and BMI SDS did not differ significantly between summer-camp and lifestyle-school completers, BMI 29.8 (29.1 to 30.6) vs 30.7 (29.8 to 31.6) kg/m2 and BMI SDS 2.96 (2.85 to 3.08) vs 3.11 (2.97 to 3.24), respectively. The summer-camp parents had a small reduction in BMI (−0.9 (−1.8 to −0.03) vs −0.8 (−2.1 to 0.4) in the lifestyle-school group), but the within-group changes did not differ significantly (0.3 (−1.7 to 2.2)). Conclusions A 2-year family camp-based obesity treatment programme had no significant effect on BMI SDS in children with severe obesity compared with an outpatient family-based treatment programme. Trial registration number NCT01110096.

Metformin in pregnancy – safe or sorry?

Given the increasing incidence of overweight and obesity among young women and the subsequent high prevalence of type 2 diabetes mellitus and gestational diabetes mellitus, metformin treatment during pregnancy is increasing worldwide. A new study reports that metformin exposure in the first trimester of pregnancy does not increase the risk of congenital anomalies.