Pre-pregnancy overweight or obesity and gestational diabetes as predictors of body composition in offspring twenty years later: evidence from two birth cohort studies.

BACKGROUND: Global prevalence of overweight/obesity and gestational diabetes (GDM) is increasing. In pregnant women both conditions affect offspring's later health. Overweight/obesity is a risk factor of GDM; to what extent maternal overweight/obesity explains long-term effects of GDM in offspring is unknown. OBJECTIVE: To evaluate effects of maternal pre-pregnancy overweight/obesity (body mass index (BMI) ⩾25 kg m-2) and GDM, occurring together or separately, on body composition among adult offspring. METHODS: Participants include 891 individuals aged 24.1 years (s.d. 1.4) from two longitudinal cohort studies (ESTER and AYLS). Adult offspring of normoglycemic mothers with overweight/obesity (ONOO, n=153), offspring of mothers with GDM (OGDM; n=191) and controls (n=547) underwent anthropometric measurements and bioimpedance analysis. Gestational diabetes mellitus was diagnosed by oral glucose tolerance test. Data were analyzed by linear regression models adjusted for confounders. RESULTS: Compared with controls, ONOO-participants showed higher BMI (men 1.64 kg m-2 (95% confidence interval 0.57, 2.72); women 1.41 kg m-2 (0.20, 2.63)) and fat percentage (men 2.70% (0.99, 4.41); women 2.98% (0.87, 5.09)) with larger waist circumferences (men 3.34 cm (0.68, 5.99); women 3.09 cm (0.35, 5.83)). Likewise, OGDM-participants showed higher fat percentage (men 1.97% (0.32, 3.61); women 2.32% (0.24, 4.41)). Body mass index was non-significantly different between OGDM-participants and controls (men 0.88 kg m-2 (-0.17, 1.92); women 0.82 kg m-2 (-0.39, 2.04)). Also waist circumferences were larger (men 2.63 cm (-0.01, 5.28); women 3.39 cm (0.60, 6.18)); this difference was statistically significant in OGDM-women only. Differences in body composition measures were stronger among offspring of women with both GDM and overweight/obesity. For instance, fat mass was higher among OGDM-participants of overweight mothers (men 4.24 kg (1.36, 7.11) vs controls; women 5.22 kg (1.33, 9.11)) than OGDM participants of normal weight mothers (men 1.50 kg (-2.11, 5.11) higher vs controls; women 1.57 kg (-3.27, 6.42)). CONCLUSIONS: Maternal pre-pregnancy overweight and GDM are associated with unhealthy body size and composition in offspring over 20 years later. Effects of maternal pre-pregnancy overweight appear more pronounced.

A follow-up of a randomised study of metformin and insulin in gestational diabetes mellitus: growth and development of the children at the age of 18 months.

OBJECTIVE: To compare the growth and development of children born to mothers with gestational diabetes mellitus (GDM) requiring pharmacological treatment, and randomised to treatment with metformin or insulin. DESIGN: Follow-up of a randomised controlled trial (RCT) comparing metformin and insulin treatment of GDM. SETTING: Data were gathered during routine visits to child welfare clinics at the ages of 6, 12, and 18 months, including weight and height measurements, and assessment of motor, social, and linguistic development. SAMPLE: The children of mothers with GDM randomised to metformin (n = 47) or insulin (n = 50) treatment during pregnancy. METHODS: Data were collected from the structured questionnaire filled in at the child welfare clinics. MAIN OUTCOME MEASURES: The growth and development of the children until the age of 18 months. RESULTS: Children exposed to metformin were significantly heavier (10.47 versus 9.85 kg, 95% CI 0.04-1.20) at the age of 12 months and taller and heavier (83.9 vs 82.2 cm, 95% CI 0.23-3.03, 12.05 vs 11.32 kg, 95% CI 0.04-1.43) at the age of 18 months. The mean ponderal index (PI) did not differ significantly. The motor, social, or linguistic development evaluated at the age of 18 months did not differ between the groups. CONCLUSIONS: Children prenatally exposed to metformin were heavier at the 12 months measurements and taller and heavier at the 18 months measurements than those exposed to insulin, but their body composition defined by PI did not differ. Over the short term, metformin does not seem to be harmful with regards to early motor, linguistic, or social development.

Anti-Mullerian hormone and risk of invasive serous ovarian cancer.

PURPOSE: Epithelial ovarian cancers either arise directly from Mullerian-type epithelium or acquire Mullerian characteristics in the course of neoplastic transformation. The anti-Mullerian hormone (AMH) causes regression of Mullerian structures during fetal development in males and has been shown to inhibit the growth of epithelial ovarian cancer. Therefore, we hypothesized that pre-diagnostic serum concentrations of AMH are inversely associated with risk of invasive serous ovarian cancer. METHODS: A case-control study (107 cases, 208 controls) was nested within the population-based Finnish Maternity Cohort (1986-2007). The sample donated during the first trimester of the last pregnancy preceding cancer diagnosis of the case subjects was selected for the study. For each case, two controls, matched on age and date at sampling, as well as parity at sampling and at cancer diagnosis were selected. AMH was measured by a second-generation AMH ELISA. Conditional logistic regression was used to compute odds ratios (OR) and 95 % confidence intervals (CI) for invasive serous ovarian cancer associated with AMH concentrations. RESULTS: Overall AMH concentrations were not associated with risk of invasive serous ovarian cancer (OR 0.93; 95 % CI 0.49-1.77 for top vs. bottom tertile, P trend=0.83). In women older than the median age at sampling (32.7 years), a doubling of AMH was associated with decreased risk (OR 0.69; 95 % CI 0.49-0.96), whereas an increased risk (OR 1.64; 95 % CI 1.06-2.54) was observed in younger women, P homogeneity = 0.002. CONCLUSIONS: In this first prospective investigation, risk of invasive serous ovarian cancer was not associated with pre-diagnostic AMH concentrations overall; however, the association may depend on age at AMH measurement.

The impact of self-reported oligo-amenorrhea and hirsutism on fertility and lifetime reproductive success: results from the Northern Finland Birth Cohort 1966.

STUDY QUESTION: To what extent do self-reported oligo-amenorrhea and hirsutism affect reproductive performance (childlessness, age at first delivery, family size and miscarriage rates)? SUMMARY ANSWER: At the age of 44, among women with both self-reported oligo-amenorrhea and hirsutism the prevalence of childlessness was not significantly different from non-symptomatic women but they had a smaller family size than non-symptomatic women. WHAT IS KNOWN ALREADY: Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by oligo-amenorrhea or amenorrhea, hyperandrogenism and hirsutism and it is the most frequent cause of anovulatory infertility, but there are few studies on the reproductive capacity of women with PCOS. In our previous population-based cohort study the women with self-reported oligo-amenorrhea and hirsutism were found to have more infertility problems and smaller family size than non-symptomatic women at the age of 31. STUDY DESIGN, SIZE, DURATION: A prospective population-based cohort study. The population of the study is derived from the prospective Northern Finland Birth Cohort 1966 (NFBC1966), comprising all expected births from the year 1966 in the two northernmost provinces of Finland (n = 12 058). Of them, 5889 were females. Enrollment in this database begun at the 24th gestational week and so far data have been collected from the subjects at the ages of 1, 14 and 31 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: A postal questionnaire including questions about oligo-amenorrhea and hirsutism was sent to all women at the age of 31 (n = 5608, response rate 81%, n = 4535) and a clinical examination was performed (attendance rate 76.5%). Those who reported both hirsutism and oligo-amenorrhea were defined as women with both symptoms (n = 153). Data on pregnancies/deliveries were obtained from the Finnish Medical Birth Register (FMBR) in 2010 when the women were 44 years old. MAIN RESULTS AND THE ROLE OF CHANCE: Women with both symptoms had delivered at least one child as often as non-symptomatic women [75.2 versus 79.0%, adjusted odds ratio (OR) 0.86, 95% confidence intervals (CI) 0.57-1.30], were of similar age [mean (SD)] at first delivery [27.7 (4.81) versus 27.3 (4.71)] and had similar incidence of miscarriages. However, non-symptomatic women had more often ≥2 deliveries (61.6 versus 52.9%, adjusted OR 0.70, 95% CI 0.49-1.00, P = 0.048) and had larger family size [mean (SD)] [2.4 (1.4) versus 1.9 (0.8), P < 0.001]. Women with both symptoms had been treated more often for infertility than non-symptomatic women (6.1 versus 2.4%, adjusted OR 2.74, 95% CI 1.14-6.60, P = 0.024). LIMITATIONS, REASONS FOR CAUTION: The diagnosis of oligo-amenorrhea and hirsutism was based on a questionnaire, suggesting a risk of information bias in reporting the symptoms. However, we have previously shown that self-reported oligo-amenorrhea and hirsutism can distinguish most women with the typical profile of PCOS. Only the women who had delivered at least once were recorded in the FMBR, thus excluding from the study those who had experienced miscarriages and/or infertility treatments but did not have a live birth. This feature could potentially decrease the differences in incidence of miscarriages and/or infertility treatment between symptomatic and non-symptomatic subjects. WIDER IMPLICATIONS OF THE FINDINGS: This is one of the few studies, in which the impact of self-reported oligo-amenorrhea and hirsutism on lifetime reproductive success can be measured. Our results suggest that even at more advanced age, women with both symptoms do not quite match the parity of healthy non-symptomatic women, and that infertility treatment does not always restore normal reproductive capacity in these women. Obese women with both symptoms had the worst prognostic as regards reproduction, which emphasizes the importance of life intervention and preventive politics against obesity in this group of women. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from the Finnish Medical Society Duodecim, the North Ostrobothnia Regional Fund, the Academy of Finland, University Hospital Oulu, Biocenter, University of Oulu, Finland, the European Commission and the Medical Research Council, UK, the National Institute for Health Research (NIHR). None of the authors has any conflict of interest to declare.

Pre-pregnancy overweight overtakes gestational diabetes as a risk factor for subsequent metabolic syndrome.

OBJECTIVE: Gestational diabetes mellitus (GDM) is associated with an increased risk of subsequent diabetes and metabolic syndrome (MS). The independent significance of overweight, often associated with GDM, is controversial. This study was aimed to investigate the prevalence of MS and carotid intima-media thickness (CIMT) values in normal and overweight women with previous insulin-treated GDM and control without GDM 19 years after the index pregnancy. METHODS: The study group consisted of 61 women with prior GDM and 55 controls who gave birth in Oulu University Hospital between 1988 and 1993. These women were further divided into subgroups according to pre-pregnancy BMI (<25 or ≥25 kg/m(2)). In 2008-2010, anthropometrics and blood pressure were measured, blood samples were taken, and an oral glucose tolerance test was performed to investigate the components of MS. CIMT was measured by Doppler ultrasound. RESULTS: Total prevalence of MS was 62% in the GDM group and 31% in the control group (P=0.001); it was highest (86%) in GDM women with pre-pregnancy overweight. CIMT was significantly thicker (0.67 vs 0.56 mm, P=0.007) and more often abnormal (71.7 vs 45.3%, P=0.004) in the GDM group compared with the controls. In logistic regression analysis, the strongest factor predicting MS in the whole study population was pre-pregnancy overweight. CONCLUSIONS: Pre-pregnancy overweight was the strongest predictive factor for later MS, whereas GDM indicated increased risk of subsequent diabetes and subclinical atherosclerosis. The risk of MS was highest when both of these factors were present.

Maternal weight gain during the first half of pregnancy and offspring obesity at 16 years: a prospective cohort study.

OBJECTIVE: To assess the association between maternal gestational weight gain (GWG) during the first 20 weeks of gestation and overweight/obesity and abdominal obesity of offspring at the age of 16 years. DESIGN: A prospective cohort study. SETTING: The two northernmost provinces of Finland. POPULATION: Mothers and their adolescent offspring born from singleton pregnancies (3265 boys; 3372 girls) in the Northern Finland Birth Cohort 1986. METHODS: Maternal weight at 20 weeks of gestation was measured in municipal maternity clinics. Maternal GWG was based on the difference between the measured weight and self-reported pre-pregnancy weight, and was classified into quartiles. Offspring weight, height and waist circumference were measured by study nurses during a clinical examination. Logistic regression analyses [with and without adjustment for maternal pre-pregnancy body mass index (BMI), glucose metabolism, education level, haemoglobin, smoking status, parity, and gender of offspring] were performed. MAIN OUTCOME MEASURE: Offspring overweight/obesity, based on BMI and abdominal obesity at 16 years. RESULTS: The highest quartile of maternal weight gain (>7.0 kg during the first 20 weeks of gestation) was independently associated with BMI-based overweight/obesity and abdominal obesity in the 16-year-old offspring (OR 1.46, 95% CI 1.16-1.83, and OR 1.37, 95% CI 1.10-1.72, respectively). Among all covariates, maternal pregravid obesity showed the highest odds for both overweight/obesity and abdominal obesity (OR 4.57, 95% CI 3.18-6.57, and OR 4.43, 95% CI 3.10-6.34, respectively). CONCLUSIONS: Maternal overnutrition during the first half of gestation predicts offspring overweight/obesity and abdominal obesity in adolescence, yet a high pregravid BMI appears to be a more important determinant of both outcomes.

Metformin should be considered in the treatment of gestational diabetes: a prospective randomised study.

OBJECTIVE: To examine if oral metformin is as effective as insulin in the prevention of fetal macrosomy in pregnancies complicated with gestational diabetes mellitus (GDM). DESIGN: Open-label prospective randomised controlled study. SETTING: Maternity outpatient clinics in a secondary and tertiary level hospital in Finland. SAMPLE: One hundred women with GDM who did not attain euglycaemia with diet. METHODS: Women were randomised to therapy with insulin (n = 50) or oral metformin (n = 50). MAIN OUTCOME MEASURES: Incidence of large-for-gestational-age (LGA) infants and neonatal morbidity. RESULTS: There were no statistically significant differences in the incidence of LGA (8.5 versus 10.0%, P = 0.97), mean birthweight, mean cord artery pH or neonatal morbidity between the insulin and metformin groups. Fifteen (31.9%) of the 47 women randomised to metformin needed supplemental insulin. They were more obese (with a body mass index of 36 versus 30 kg/m(2), P = 0.002), had higher fasting blood glucose levels in an oral glucose tolerance test (6.1 versus 5.0 mmol/l, P = 0.001) and needed medical treatment for GDM earlier (26 versus 31 gestational weeks, P = 0.002) than women who were normoglycemic with metformin. There was a tendency to a higher rate of caesarean sections in the metformin group than in the insulin group (RR 1.9; 95% CI 0.99-3.71). CONCLUSIONS: Metformin seems to be suitable for the prevention of fetal macrosomy, especially in lean or moderately overweight women developing GDM in late gestation. Women with considerable obesity, high fasting blood glucose and an early need for pharmacological treatment may be more suitable for insulin therapy.

Prevalence of metabolic syndrome at age 16 using the International Diabetes Federation paediatric definition.

OBJECTIVE: We estimated the prevalence of metabolic syndrome (MS) in adolescents, using the new International Diabetes Federation (IDF) paediatric definition and compared this with prevalence estimated using the IDF adult definition and five other previously published definitions. DESIGN: Cross-sectional survey in the prospective general population-based Northern Finland Birth Cohort 1986 (NFBC 1986) at age 16 years. SETTING: Birth cohort in Finland. PARTICIPANTS: 5665 adolescents (2862 males and 2803 females) clinically examined in 2001-2002. MAIN OUTCOME MEASURES: The prevalence of MS using different definitions. RESULTS: The overall prevalence of MS using the IDF paediatric definition was 2.4% (95% CI 2.0 to 2.8%) at the age of 16 years. Using the IDF adult definition the overall prevalence was lower, 1.7% (CI 1.3 to 2.0%, European cut-offs for waist circumference) and 1.0% (CI 0.7 to 1.3%, North American cut-offs). CONCLUSION: In 16-year-old adolescents, the paediatric IDF definition rendered a higher prevalence estimate than the adult definition.

A comparison of intrapartum automated fetal electrocardiography and conventional cardiotocography--a randomised controlled study.

OBJECTIVE: To examine whether intrapartum monitoring by means of automatic ST analysis (STAN) of fetal electrocardiography could reduce the rate of neonatal acidemia and the rate of operative intervention during labour, compared with monitoring by means of cardiotocography (CTG). DESIGN: Randomised controlled trial. SETTING: Labour ward in tertiary-level university hospital. SAMPLE: A total of 1483 women in active labour with singleton term fetus in cephalic presentation. METHODS: Women were randomly assigned to be monitored either by STAN or by CTG. Fetal blood sampling (FBS) was optional in both groups. MAIN OUTCOME MEASURES: Neonatal acidemia (umbilical artery pH <7.10), neonatal metabolic acidosis (umbilical artery pH <7.05 and base excess <-12 mmol/l) and operative interventions: caesarean section rate, vacuum outlet (VO) rate and FBS rate. RESULTS: There were no statistically significant differences between the STAN group and CTG group in the incidence of neonatal acidemia (5.8 versus 4.7%) or metabolic acidosis (1.7 versus 0.7%). The caesarean section rate (6.4 versus 4.7%) and the VO rate (9.5 versus 10.7%) were also similar in the STAN and CTG groups. The incidence of FBS was lower (P < 0.001) in the STAN group (7.0%) than in the CTG group (15.6%). CONCLUSIONS: Intrapartum fetal monitoring by means of automatic STAN did not improve the neonatal outcome or decrease the caesarean section rate. However, the need for FBS during labour was lower in the STAN group.

Congenital anomalies and first life year surveillance in Type 1 diabetic births.

AIMS: To evaluate the rate of congenital anomalies (CA) and the reasons for mortality from 22 weeks of gestation until 1 year of age in births by Type 1 diabetic mothers. METHODS: Population-based cohort study using combined data from four national health registers in Finland during 1991-1995, including 954 singleton pregnancies complicated by Type 1 diabetes. RESULTS: Sixty births (629/10 000) involved registered major CA, of which 68% (n = 41) were isolated and 22% (n = 13) multiple anomalies, and in six cases, a syndrome was diagnosed (10%). After the exclusion of syndromes, the total number of anomalies was 73. Of the malformed infants, 63% were boys. The total rate of deaths among births until 1 year of age was higher in diabetic than in non-diabetic mothers (19.9/1000 vs. 8.1/1000): especially the rates of stillborns (odds ratio 2.4; 95% confidence interval 1.2-4.7) and post-neonatal deaths (3.8; 1.6-9.2) were higher. Of perinatal mortality (PNM) from the 22nd gestational week to the age of 7 days (13.6/1000), 23% were due to CA, 23% to prematurity, and the rest were intrauterine, mostly unexplained, deaths. Respiratory distress syndrome was the main cause of death among infants. CONCLUSIONS: The rate of CAs in Type 1 diabetic pregnancies is still high, but their proportion as a cause of PNM has decreased. Though PNM rate was low, post-neonatal mortality was significantly increased, reflecting the shift of deaths from the perinatal period to a later age.

A uniform regimen enables decentralized care of diabetic pregnancies.

AIMS: A nationwide recommendation to standardize the care of diabetic pregnancies in different hospitals was given in Finland in 1993. The Medical Birth Register (MBR) was used to investigate whether these recommendations have been accepted and how they have affected the outcome of newborns. METHODS: Data on 1442 singleton pregnancies complicated by insulin-treated diabetes in 1991-1995 were obtained from the MBR. RESULTS: The incidence of insulin treatment during pregnancy was 4.5 per 1000 births. Sixty-six per cent (n = 954) of all women had Type 1 diabetes. During the study period, the number of deliveries managed in tertiary centres decreased from 59% to 47% (95% confidence interval [CI] 39-58%) and care was more often carried out on an out-patient basis. The perinatal mortality rate (>or= 28 weeks of gestation) declined from 19.3 to 8.2/1000, being 12.6/1000 in the whole diabetic population and 5.5/1000 in the general population (95% CI 3.4-8.8/1000). The risk was especially increased in insulin-treated gestational diabetic (GDM) pregnancies (14.3/1000). The proportion of macrosomic newborns (31.7%) in diabetic women was significantly higher than among the general population (3.2%) (95% CI 27.0-33.9%). CONCLUSIONS: The decentralization and change-over to a mainly out-patient basis of management does not appear to have increased the number of cases of adverse outcome of diabetic pregnancy when patients have been selected to the appropriate level of care. The risks in insulin-treated GDM pregnancies were almost similar to Type 1 diabetes. To succeed, there must be a standardized care programme, continuous education and motivated personnel.

Factors predicting peri- and neonatal outcome in diabetic pregnancy.

A population-based birth cohort including 296 consecutive type 1 diabetic births in a geographically defined catchment area was used to evaluate factors predicting poor perinatal and neonatal outcome. Though perinatal mortality has decreased (17.1/1000 births at 28 or more weeks of gestation), the neonatal morbidity rate still remains high despite improved maternal metabolic control and developed antepartum surveillance. Poor glycemic control during the first weeks of pregnancy was the most important risk factor (relative risk (RR) 2.91; 95% confidence interval (CI) 1.29-6.55) predicting adverse neonatal events such as long (>10 days) stay in the neonatal unit, malformation or perinatal death. The risk was further increased in cases of severe diabetes (White class F-R; RR 2.75; 95% CI 1.59-4.76) and primiparity (RR 1.64; 95% CI 1.02-2.65). By evaluating these risk factors at the first antenatal visit, a subgroup with a particular need of counselling and intensive feto-maternal monitoring can be identified.

Out-patient management does not impair outcome of pregnancy in women with type 1 diabetes.

In recent years, out-patient protocols have mainly displaced historical obstetric management of diabetic pregnancy. The impact of the change from centralized in-patient to decentralized out-patient treatment on glycaemic control and its effects on the outcome of newborns in diabetic pregnancies was therefore studied using the population-based data on 296 pregnancies in 224 women with type 1 diabetes over 10 years (1986-1995) in the two northernmost provinces of Finland. The area comprises one tertiary level and four other central hospitals. The change of policy was effected in 1990 and to determine the impact of this change, the study period was divided in two (period 1, 1986-1990, n = 135; period 2, 1991-1995, n = 161). At the first antenatal contact (mean 9.9 weeks of gestation) 73% of women had unsatisfactory glycaemic control, but it improved rapidly with pregnancy and was significantly better (P < 0.05) in the second study period. The incidence of congenital malformations was somewhat greater (NS) in period 2 but perinatal mortality did not change. Out-patient management does not impair outcome in type 1 diabetic pregnancy.