Gestational diabetes:metformin treatment, maternal overweight and long-term outcome

Abstract Gestational diabetes mellitus (GDM) is defined as disturbed glucose metabolism first recognized during pregnancy. Untreated GDM increases the risk of obstetric and neonatal complications, such as fetal overgrowth (macrosomia). The first-line treatment of GDM includes diet therapy and the self-monitoring of blood glucose concentrations and, if needed, pharmacotherapy, which is most commonly accomplished with insulin. Oral anti-diabetic agents such as metformin have recently been under investigation. GDM increases the risk of developing overt diabetes, metabolic syndrome and cardiovascular diseases. The aim of the present study was to investigate the effect of metformin vs. insulin therapy on pregnancy and neonatal outcome as well as on later growth and development of the infant and to investigate the independent and concomitant effects of GDM and maternal overweight/obesity on pregnancy outcome and maternal long-term risks. In a randomized study of 100 women, metformin therapy was not associated with an increased risk of pregnancy or neonatal complications when compared with insulin treatment. However, 32% of the women treated with metformin needed additional insulin in the achievement of normoglycaemia. The need of additional insulin was associated with maternal obesity, an earlier need of pharmacotherapy and fasting hyperglycaemia in OGTT. Infants exposed to metformin were taller and heavier at the age of 18 months compared with infants exposed to insulin. There was no difference in the motor, social or linguistic development between these children when assessed at the age of 18 months. In an epidemiological study of 24,565 pregnancies, normal-weight women with GDM did not have an increased risk of macrosomia or Caesarean delivery when compared with normal-weight women without GDM. GDM was an independent risk factor of neonatal morbidity, especially hypoglycaemia. Maternal overweight and obesity were independent risk factors of macrosomia and obesity was also an independent risk factor of Caesarean delivery and neonatal morbidity. In a follow-up study (n = 116), women with a history of insulin-treated GDM had an increased risk of metabolic syndrome when compared with women without GDM 19 years after index pregnancy. However, maternal pre-pregnancy overweight as such was a stronger risk factor as regards the development of metabolic syndrome than previous GDM.Tiivistelmä Raskausdiabetes on ensimmäisen kerran raskauden aikana ilmaantuva glukoosiaineenvaihdunnan häiriö. Hoitamattomana raskausdiabetes lisää raskaana olevan ja vastasyntyneen komplikaatioriskiä, erityisesti sikiön liiallista kasvua (makrosomiaa). Raskausdiabetestä hoidetaan ruokavaliolla, veren glukoosipitoisuuksien omaseurannalla sekä tarvittaessa lääkehoidolla, joka on useimmiten insuliinihoitoa. Muita diabeteslääkkeitä, kuten metformiinia, on tutkittu viime vuosina paljon. Raskausdiabetes lisää myöhemmällä iällä riskiä sairastua diabetekseen, metaboliseen oireyhtymään sekä sydän- ja verisuonisairauksiin. Tämän tutkimuksen tarkoituksena oli selvittää metformiinihoidon tehoa ja turvallisuutta verrattuna insuliiniin raskausdiabeteksen hoidossa. Lisäksi selvitettiin raskausdiabeteksen ja ylipainon itsenäistä vaikutusta raskauskomplikaatioiden esiintyvyyteen sekä naisen myöhempään sairastuvuuteen. Satunnaistetussa tutkimuksessa (n = 100) metformiini ei lisännyt vastasyntyneen makrosomian eikä vastasyntyneen tai raskauskomplikaatioiden riskiä verrattuna insuliiniin. Metformiinilla hoidetuista naisista 32% tarvitsi lisäksi insuliinia normaalin glukoositasapainon saavuttamiseksi. Lisäinsuliinin tarvetta ennustivat äidin lihavuus, varhainen lääkehoidon tarve sekä kohollaan olevat glukoosin paastoarvot sokerirasituksessa. Metformiinille altistuneet lapset olivat sekä pidempiä että painavampia 18 kuukauden iässä kuin insuliinille altistuneet lapset, mutta heidän motorisessa, sosiaalisessa tai kielellisessä kehityksessään ei ollut eroja. Epidemiologisessa tutkimuksessa (n = 24,565) normaalipainoisen naisen raskausdiabetes ei lisännyt keisarileikkauksen tai sikiön makrosomian riskiä verrattuna normaalipainoisiin naisiin, joiden sokeriaineenvaihdunta oli normaali. Raskausdiabetes lisäsi itsenäisesti vastasyntyneen sairastavuuden ja hypoglykemian riskiä. Äidin ylipaino ja lihavuus lisäsivät itsenäisesti makrosomian riskiä ja lihavuus myös keisarileikkauksen ja vastasyntyneen sairastuvuuden riskiä. Seurantatutkimuksessa (n = 116) insuliinihoidettujen raskausdiabeetikoiden riski sairastua 19 vuotta raskauden jälkeen myöhempään metaboliseen oireyhtymään oli lisääntynyt verrattuna terveisiin verrokkeihin. Raskautta edeltävä ylipaino oli vahvempi riskitekijä metabolisen oireyhtymän kehittymiselle kuin aiempi raskausdiabetes

Pregnancy risk factors as predictors of offspring cerebrovascular disease:the Northern Finland Birth Cohort Study 1966

Abstract Background and Purpose: For prevention of cerebrovascular diseases, it is important to understand the risk factors occurring early in life. The aim was to investigate the relationship of maternal and offspring anthropometrics and pregnancy complications with offspring’s risk of ischemic and hemorrhagic stroke and transient ischemic attack in adulthood. Methods: Within the population-based prospective Northern Finland Birth Cohort 1966, 11 991 persons were followed from early pregnancy to 52 years of age. Information on pregnancy and birth complications were collected starting between 24th and 28th gestational week and at birth. Ischemic and hemorrhagic strokes of the offspring were identified from national registers in Finland. Cox proportional hazard models were used to estimate the association of pregnancy and birth complications with incidence of cerebrovascular disease in the offspring, with adjustments for sex, family socioeconomic status, mother’s age, and smoking during pregnancy. Results: During 568 821 person-years of follow-up, 453 (3.8%) of the offspring had a stroke or transient ischemic attack. Small and large gestational weight gain among normal weight mothers were associated with increased ischemic stroke risk in offspring (adjusted hazard ratio [aHR], 1.93 [95% CI, 1.28–2.90] and aHR, 1.54 [95% CI, 1.02–2.31], respectively). Small birth weight for gestational age and small ponderal index were associated with increased risk for ischemic stroke (aHR, 1.95 [CI, 1.21–3.13] and aHR, 1.36 [CI, 1.04–1.77], respectively). Threatening miscarriage was also associated with increased risk of any stroke (aHR, 1.64 [CI 1.14–2.37]). Maternal smoking, hypertension, or birth complications were not associated with increased risk of cerebrovascular disease in the offspring. Conclusions: The results of this study suggest that disturbances in maternal and fetal growth during pregnancy may predispose offspring to developing cerebrovascular diseases in adulthood

Polycystic ovary syndrome and risk factors forngestational diabetes

Abstract Objective: To study the roles of self-reported symptoms and/or prior diagnosis of polycystic ovary syndrome (PCOS) and other potential risk factors for gestational diabetes mellitus (GDM) and to clarify whether the screening of GDM in early pregnancy is beneficial for all women with PCOS. Design: The FinnGeDi multicentre case-control study including 1146 women with singleton pregnancies diagnosed with GDM and 1066 non-diabetic pregnant women. There were 174 women with PCOS (symptoms and/or diagnosis self-reported by a questionnaire) and 1767 women without PCOS (data missing for 271). Methods: The study population (N = 1941) was divided into four subgroups: GDM + PCOS (N = 105), GDM + non-PCOS (N = 909), non-GDM + PCOS (N = 69), and controls (N = 858). The participants’ characteristics and their parents’ medical histories were compared. Results: The prevalence of PCOS was 10.4% among GDM women and 7.4% among nondiabetics (odds ratios (OR) 1.44, 95% CI: 1.05–1.97), but PCOS was not an independent risk for GDM after adjustments for participants’ age and pre-pregnancy BMI (OR 1.07, 95% CI: 0.74–1.54). In a multivariate logistic regression analysis, the most significant parameters associated with GDM were overweight, obesity, age ≥35 years, participant’s mother’s history of GDM, either parent’s history of type 2 diabetes (T2D) and participant’s own preterm birth. Conclusions: The increased risk of GDM in women with PCOS was related to obesity and increased maternal age rather than to PCOS itself, suggesting that routine early screening of GDM in PCOS women without other risk factors should be reconsidered. Instead, family history of GDM/T2D and own preterm birth were independent risk factors for GDM

Long-term effects of oral antidiabetic drugs during pregnancy on offspring:a systematic review and meta-analysis of follow-up studies of RCTs

Abstract Introduction: Antidiabetic drugs (OADs) are increasingly prescribed to treat hyperglycaemia during pregnancy in women with gestational diabetes mellitus (GDM) or polycystic ovary syndrome (PCOS), even though long-term effects on offspring are unknown. This systematic review summarises the evidence of follow-up studies of randomised controlled trials (RCTs) reporting on long-term effects of prenatal exposure to OADs on offspring. Methods: The MEDLINE, EMBASE and CENTRAL databases were searched from inception to April 2018 for the concepts antidiabetic agents and prenatal exposure (or pregnancy and offspring/child) in combination with an RCT search filter. RCTs evaluating post-neonatal health effects in offspring and comparing maternal treatment with an OAD with no treatment, placebo, an alternative OAD or insulin during pregnancy were eligible for inclusion. Two independent researchers selected, extracted and assessed the data. Meta-analyses were performed using a random effects model and the Cochrane Collaboration’s risk of bias tool was used for quality assessment. Results: Ten studies were included, with a maximal follow-up duration of 9 years, comprising 778 children of mothers with GDM or PCOS who were randomised to either metformin or insulin/placebo during pregnancy. Meta-analysis showed that children prenatally exposed to metformin were heavier compared to controls (standardised mean difference (SMD) 0.26 [95% CI 0.11–0.41]), but not taller (SMD 0.10 [95% CI −0.14–0.33]). Additionally, offspring body mass index (BMI) z scores did not differ according to metformin exposure (mean difference 0.30 [95% CI −0.01–0.61]). Individual small studies reported that prenatal exposure to metformin was associated with greater mid-upper arm, head and waist circumferences, biceps skinfolds, waist-to-height ratio, more arm fat, higher fasting glucose, ferritin and lower LDL cholesterol in offspring. Conclusion: Prenatal exposure to metformin is associated with increased offspring weight, but not with height or BMI. Larger follow-up studies are needed to confirm and look into the implications of these findings. Plain language summary: Plain language summary available for this article