Mette Tanvig

Effects of Lifestyle Intervention in Pregnancy and Anthropometrics at Birth on Offspring Metabolic Profile at 2.8 Years: Results From the Lifestyle in Pregnancy and Offspring (LiPO) Study

CONTEXT Maternal obesity and gestational weight gain are linked to offspring adverse metabolic profiles, and lifestyle interventions during pregnancy in obese women may have long-term positive effects on their children. Furthermore, although the association between birth weight and later metabolic outcomes is well established, little is known about the predictive value of abdominal circumference at birth. OBJECTIVES The purpose of this study was to determine (1) the effects of lifestyle interventions during pregnancy in obese women on offspring metabolic risk factors and (2) predictive values of birth weight (BW) and birth abdominal circumference (BAC). DESIGN This was a follow-up of a randomized controlled trial, the Lifestyle in Pregnancy (LiP) study. SETTING The study was conducted in Odense and Aarhus University Hospitals, Denmark. PARTICIPANTS We studied the offspring of LiP study participants (n = 157) and offspring of normal-weight mothers (external reference group, n = 97). INTERVENTION INTERVENTIONs included dietary advice, coaching, and exercise during pregnancy. MAIN OUTCOME MEASURES The outcome measures were body mass index (BMI) Z-score, abdominal circumference, blood pressure, and fasting plasma glucose, insulin, high-density lipoprotein, and triglycerides at the age of 2.8 years. RESULTS No differences were detected in BMI Z-scores or metabolic risk factors between the LiP intervention and control groups or between the LiP and external reference groups. BAC and BW were associated (all P < .05) with BMI Z-score (0.19-0.23), abdominal circumference (0.57-0.70), plasma glucose (0.11-0.09), insulin (4.33-3.13), and triglycerides (0.07-0.07) but not with blood pressure or high-density lipoprotein (regression coefficients per increase in BAC and BW of 1 SD score). CONCLUSIONS Early childhood metabolic risk factors were unaffected by lifestyle interventions in obese pregnant women. Offspring of obese mothers who participated in the LiP study were comparable to offspring of normal-weight mothers, possibly indicating a general beneficial effect of trial participation. BAC and BW were both associated with later metabolic risk factors.

Anthropometrics and Body Composition by Dual Energy X-Ray in Children of Obese Women: A Follow-Up of a Randomized Controlled Trial (the Lifestyle in Pregnancy and Offspring [LiPO] Study)

Objective In obese women, 1) to assess whether lower gestational weight gain (GWG) during pregnancy in the lifestyle intervention group of a randomized controlled trial (RCT) resulted in differences in offspring anthropometrics and body composition, and 2) to compare offspring outcomes to a reference group of children born to women with a normal Body Mass Index (BMI). Research design and methods The LiPO (Lifestyle in Pregnancy and Offspring) study was an offspring follow-up of a RCT with 360 obese pregnant women with a lifestyle intervention during pregnancy including dietary advice, coaching and exercise. The trial was completed by 301 women who were eligible for follow-up. In addition, to the children from the RCT, a group of children born to women with a normal BMI were included as a reference group. At 2.8 (range 2.5–3.2) years, anthropometrics were measured in 157 children of the RCT mothers and in 97 reference group children with Body Mass Index (BMI) Z-score as a primary outcome. Body composition was estimated by Dual Energy X-ray (DEXA) in 123 successful scans out of 147 (84%). Results No differences between randomized groups were seen in mean (95% C.I.) BMI Z-score (intervention group 0.06 [−0.17; 0.29] vs. controls −0.18 [−0.43; 0.05]), in the percentage of overweight or obese children (10.9% vs. 6.7%), in other anthropometrics, or in body composition values by DEXA. Outcomes between children from the RCT and the reference group children were not significantly different. Conclusions The RCT with lifestyle intervention in obese pregnant women did not result in any detectable effect on offspring anthropometrics or body composition by DEXA at 2.8 years of age. This may reflect the limited difference in GWG between intervention and control groups. Offspring of obese mothers from the RCT were comparable to offspring of mothers with a normal BMI. Trial registration clinicaltrials.gov NCT00530439, NCT01918319 and NCT01918423. URL: NCT00530439?term = NCT00530439&rank = 1, NCT01918319?term = NCT00530439&rank = 2 and NCT01918423?term = NCT00530439&rank = 3.

Postpartum weight retention and breastfeeding among obese women from the randomized controlled Lifestyle in Pregnancy (LiP) trial

To study the effects of lifestyle intervention in pregnancy on weight retention 6 months postpartum among obese women from the “Lifestyle in Pregnancy” (LiP) study, and to determine associations between breastfeeding with postpartum maternal weight.

Pregestational body mass index is related to neonatal abdominal circumference at birth—a Danish population‐based study

To examine the impact of maternal pregestational body mass index (BMI) and smoking on neonatal abdominal circumference (AC) and weight at birth. To define reference curves for birth AC and weight in offspring of healthy, nonsmoking, normal weight women.

A brain slice culture model for studies of endogenous and exogenous precursor cell migration in the rostral migratory stream

The rostral migratory stream (RMS) is the main pathway by which newly born subventricular zone (SVZ) cells reach the olfactory bulb (OB) in rodents. This migration has been well studied in vivo, but an organotypic in vitro model would facilitate more experimental investigations. Here we introduce a slice culture preparation of the rat forebrain including en suite the rostral part of the lateral ventricle, the RMS and the OB. The preparation was validated with regard to endogenous cell proliferation and migration by tracking bromodeoxyuridine (BrdU)-labelled cells in newly established and 3 and 6 week old cultures. For testing the migratory abilities of exogenous precursor cells, rat SVZ neurospheres and human neural (HNS1 cells) and mesenchymal (hMSC-TERT) stem cell lines were micrografted to the rostral SVZ of 1 and 7 day old cultures. Two weeks later graft derivatives were identified by immunohistochemical staining for human nuclei (HNS1/hMSC-TERT cells) and BrdU (HNS1 cells/neurospheres). Numerous HNS1 cells and BrdU-positive neurosphere cells were found in the RMS. Having reached the OB, subpopulations of the cells expressed the astroglial markers glial fibrillary acidic protein/hAM and the neuronal markers NeuN/tyrosine hydroxylase. Interestingly, the hMSC-TERT cells remained at the implantation site, demonstrating a diversity in migratory capability of different precursor cells. In conclusion, the RMS in rat forebrain slice cultures retains its ability to support migration of endogenous and exogenous neural precursors, making the cultures highly feasible for studies of conditions and factors regulating cell migration.

Reversible Albumin-Binding GH Possesses a Potential Once-Weekly Treatment Profile in Adult Growth Hormone Deficiency

CONTEXT NNC0195-0092 is a reversible, albumin-binding GH derivative, developed for once-weekly administration. OBJECTIVES The objective of the study was to evaluate safety, local tolerability, pharmacodynamics, and pharmacokinetics of multiple, once-weekly doses of NNC0195-0092, compared with daily GH. DESIGN AND SETTING This was a phase 1, randomized, open-label, active-controlled, multiple-dose, dose-escalation trial. PATIENTS Thirty-four GH-treated adult subjects (male, n = 25) with GH deficiency participated in the study. INTERVENTIONS AND MAIN OUTCOME MEASURES Subjects were sequentially assigned into four cohorts of eight subjects, randomized within each cohort (3:1) to once-weekly NNC0195-0092 (n = 6) for 4 weeks (0.02, 0.04, 0.08, and 0.12 mg/kg) or daily injections of Norditropin NordiFlex (n = 2) for 4 weeks with a dose replicating the pretrial dose of somatropin. A safety assessment was performed prior to initiating treatment at the next dose level of NNC0195-0092. Daily GH treatment was discontinued 14 days before the trial start. Blood samples were drawn for assessment of safety, pharmacokinetics, pharmacodynamics (IGF-1 and IGF-binding protein-3) profiles, and immunogenicity studies. RESULTS Numbers of adverse events were similar at the dose levels of 0.02, 0.04, and 0.08 mg/kg NNC0195-0092 vs daily injections of Norditropin NordiFlex, whereas the number of adverse events was greater at the highest dose level of NNC0195-0092 (0.12 mg/kg). NNC0195-0092 (area under the curve[0-168h]) and peak plasma concentration) increased in a dose-dependent manner, and a dose-dependent increase in IGF-1 levels was observed. IGF-1 profiles were elevated for at least 1 week, and for the 0.02-mg/kg and 0.04-mg/kg NNC0195-0092 doses, the observed IGF-1 levels were similar to the levels for the active control group. CONCLUSION Four once-weekly doses of NNC0195-0092 (dose range 0.02-0.12 mg/kg) administered to adult patients with GH deficiency were well tolerated, and IGF-1 profiles were consistent with a once-weekly treatment profile. No clinically significant safety and tolerability signals causally related to NNC0195-0092 were identified, nor were any immunogenicity concerns revealed.

Intrauterine Extremity Gangrene and Cerebral Infarction at Term: A Case Report

Intrauterine extremity gangrene in combination with cerebral infarction is a serious and rare event. We present a case with a healthy mother who gave birth to a child with this condition. At term, the mother presented at the antenatal clinic with decreased fetal movements. Cardiotocography (CTG) showed signs of fetal distress and a caesarean section was performed. The left arm of the newborn was found gangrenous. Amputation of the arm was necessary and the child was subsequently treated with anticoagulant therapy due to thrombosis and cerebral infarction in the left hemisphere found by magnetic resonance imaging (MRI). At one year of age the boy was doing well and had prosthesis as a left arm. He had no signs of further complications. Despite thorough examination of the parents and the child, the reason for the thrombosis is still unknown.

Risk factors for hyperglycemia in pregnancy in the DALI study differ by period of pregnancy and OGTT time point

OBJECTIVE Risk factors are widely used to identify women at risk for gestational diabetes mellitus (GDM) without clear distinction by pregnancy period or oral glucose tolerance test (OGTT) time points. We aimed to assess the clinical risk factors for Hyperglycemia in pregnancy (HiP) differentiating by these two aspects. DESIGN AND METHODS Nine hundred seventy-one overweight/obese pregnant women, enrolled in the DALI study for preventing GDM. OGTTs were performed at ≤19 + 6, 24-28 and 35-37 weeks (IADPSG/WHO2013 criteria). Women with GDM or overt diabetes at one time point did not proceed to further OGTTs. Potential independent variables included baseline maternal and current pregnancy characteristics. STATISTICAL ANALYSIS Multivariate logistic regression. RESULTS Clinical characteristics independently associated with GDM/overt diabetes were at ≤19 + 6 weeks, previous abnormal glucose tolerance (odds ratio (OR): 3.11; 95% CI: 1.41-6.85), previous GDM (OR: 2.22; 95% CI: 1.20-4.11), neck circumference (NC) (OR: 1.58; 95% CI: 1.06-2.36 for the upper tertile), resting heart rate (RHR, OR: 1.99; 95% CI: 1.31-3.00 for the upper tertile) and recruitment site; at 24-28 weeks, previous stillbirth (OR: 2.92; 95% CI: 1.18-7.22), RHR (OR: 3.32; 95% CI: 1.70-6.49 for the upper tertile) and recruitment site; at 35-37 weeks, maternal height (OR: 0.41; 95% CI: 0.20-0.87 for upper tertile). Clinical characteristics independently associated with GDM/overt diabetes differed by OGTT time point (e.g. at ≤19 + 6 weeks, NC was associated with abnormal fasting but not postchallenge glucose). CONCLUSION In this population, most clinical characteristics associated with GDM/overt diabetes were non-modifiable and differed by pregnancy period and OGTT time point. The identified risk factors can help define the target population for future intervention trials.

Re: Vitamin D and gestational diabetes mellitus: a systematic review based on data free of Hawthorne effect

Sir, We have read with utmost interest the recently published systematic review and meta-analysis of Zhang et al. on the relationship between vitamin D and gestational diabetes mellitus (GDM). The authors have performed a comprehensive review including 87 observational studies and 25 randomised controlled trials addressing the relationship between vitamin D and glucose homeostasis during pregnancy. The meta-analysis on observational studies confirmed that gravidas with low blood vitamin D have a higher risk of GDM (odds ratio 1.85) linked to higher fasting plasma glucose and Homeostatic Model Assessment of Insulin Resistance index (HOMA-IR). The crucial point in clinical practice is to know if vitamin D supplementation in addition to recommended dietary allowances is able to prevent GDM. The authors have performed a meta-analysis on randomised controlled trials showing that vitamin D supplementation elevates the concentrations of 25-OHD in blood, and reduces fasting insulin, fasting plasma glucose and HOMA-IR, as well as having favourable effects on glutathione, C-reactive protein and total and high-density lipoprotein cholesterol. However, after pooling the data from four trials including 968 pregnant women, it was unclear whether vitamin D supplementationwas effective inGDM prevention (relative risk 0.718, 95% CI 0.392–1.314, I = 0% [I is in fact 37]). The authors identified that omitting the study of Hossain et al. rendered the comparison significant (Table 1 in Zhang et al, P = 0.008). In the study of Hossain et al. the outcome reported was not incident GDM but an abnormal glucose challenge test. Although it is intriguing that the rate of abnormal glucose challenge tests was higher albeit not significantly in the intervention group, our point is that this study should not be pooled together with studies where the outcome is GDM. We have performed the meta-analysis of the remaining three studies including 793 pregnant women and the result is relative risk 0.53, 95% CI 0.33–0.85, I = 0%, P = 0.009 (Figure 1). Common features of these three studies are that the participants’ average vitamin D concentration at baseline was < 50 nmol/l and that vitamin D doses in the intervention arm were high ( 3500 iu/day, 5000 iu/ day, up to 3400 iu/day), including doses higher than the Institute of Medicine’s tolerable upper intake level. Hence, as to external validity, these results would only apply to pregnant women with low vitamin D receiving high daily doses of the vitamin. Furthermore, in one of the trials, women in the control arm did not receive any supplement. Notably, the magnitude of the risk of GDM with low vitamin D (odds ratio 1.85) and the protection afforded by supplementation (relative risk 0.53) are of a similar magnitude and opposite direction. On the basis of these additional considerations, we conclude that ‘highdose vitamin D supplementation during pregnancy halves the rate of GDM in pregnant women with baseline vitamin D for less than 50 nmol/l’.&

Lifestyle Intervention in Danish Obese Pregnant Women With Early Gestational Diabetes Mellitus According to WHO 2013 Criteria Does Not Change Pregnancy Outcomes: Results From the LiP (Lifestyle in Pregnancy) Study

OBJECTIVE To study effects of lifestyle intervention on metabolic and clinical outcomes in obese women fulfilling the World Health Organization (WHO) 2013 diagnostic criteria for gestational diabetes mellitus (GDM) in early gestation. RESEARCH DESIGN AND METHODS Secondary analysis of data from the Lifestyle in Pregnancy (LiP) study, a lifestyle randomized controlled trial in 304 pregnant women with BMI ≥30 kg/m2. Early GDM (week 12–15) was diagnosed according to modified WHO 2013 GDM criteria: fasting venous plasma glucose ≥5.1 mmol/L and/or 2-h capillary blood glucose (CBG) ≥8.5 mmol/L (75-g oral glucose tolerance test [OGTT]). Women with treated GDM fulfilling local Danish GDM criteria (2-h CBG ≥9.0 mmol/L) (n = 16) and women with normal OGTT (n = 198) were excluded. RESULTS Of 90 women with early GDM, 36 received lifestyle intervention and 54 standard care. All were Caucasian, and median age was 29 years (interquartile range 27–33) and BMI 34.5 kg/m2 (32.3–38.1). All baseline characteristics were similar in the lifestyle intervention and standard care groups. At gestational week 28–30, the women in the lifestyle intervention group had significantly higher fasting total cholesterol and fasting LDL. All other metabolic parameters including measurements of glucose, insulin, and HOMA of insulin resistance were similar. There were more planned cesarean sections in the lifestyle intervention group (22.2 vs. 5.6%), but all other obstetric outcomes were similar. CONCLUSIONS Lifestyle intervention in obese women fulfilling WHO 2013 GDM criteria in early pregnancy was not effective in improving obstetric or metabolic outcomes. Future studies should focus on interventions starting prepregnancy.