Effect of maternal gestational diabetes on the cardiovascular risk factor profile of infants at 1 year of age.

BACKGROUND AND AIM: Offspring of women with gestational diabetes (GDM) exhibit an adverse cardiovascular risk factor profile by as early as age 5 years. Recently, maternal glycemia has been associated with epigenetic modification of genes on the fetal side of the placenta, including those encoding emerging risk factors (adiponectin, leptin), suggesting that vascular differences may emerge even earlier in life. Thus, we sought to evaluate cardiovascular risk factors and determinants thereof in 1-year-old infants of women with and without GDM. METHODS AND RESULTS: Traditional (glucose, lipids) and emerging (C-reactive protein (CRP), adiponectin, leptin) risk factors were assessed in pregnancy in 104 women with (n = 36) and without GDM (n = 68), and at age 1-year in their offspring. In pregnancy, women with GDM had higher triglycerides (2.49 vs 2.10 mmol/L, p = 0.04) and CRP (5.3 vs 3.6 mg/L, p = 0.03), and lower adiponectin (7.3 vs 8.5 µg/mL, p = 0.04) than did their peers. At age 1-year, however, there were no differences in cardiovascular risk factors (including adiponectin) between the infants of women with and without GDM. Of note, maternal and infant adiponectin levels were associated in the non-GDM group (r = 0.39, p = 0.001) but not in the GDM group (r = 0.07, p = 0.67). Furthermore, on multiple linear regression analyses, maternal adiponectin emerged as an independent predictor of infant adiponectin in the non-GDM group only (beta = 776.1, p = 0.0065). CONCLUSION: Infants of women with and without GDM have a similar cardiovascular risk factor profile at age 1-year. However, there are differences in their early-life determinants of adiponectin that may be relevant to the subsequent vascular risk of GDM offspring.

The postpartum cardiovascular risk factor profile of women with isolated hyperglycemia at 1-hour on the oral glucose tolerance test in pregnancy.

BACKGROUND AND AIMS: Women with gestational diabetes mellitus (GDM) have an enhanced cardiovascular risk factor profile at 3-months postpartum and an elevated risk of future cardiovascular disease, as compared to their peers. Recently, it has emerged that even mild dysglycemia on antepartum oral glucose tolerance test (OGTT) predicts an increased risk of future cardiovascular disease, although it is not known whether there exists an identifiable high-risk subgroup within this patient population. Since gestational impaired glucose tolerance (GIGT) due to isolated hyperglycemia at 1-h during the OGTT (1-h GIGT) bears metabolic similarity to GDM, we hypothesized that, like GDM, 1-h GIGT may predict a high-risk postpartum cardiovascular phenotype. METHODS AND RESULTS: In this prospective cohort study, 485 women underwent antepartum OGTT, followed by cardiovascular risk factor assessment at 3-months postpartum. The antepartum OGTT identified 4 gestational glucose tolerance groups: GDM (n = 137); 1-h GIGT (n = 39); GIGT at 2- or 3-h (2/3-h GIGT)(n = 50); and normal glucose tolerance (NGT)(n = 259). After adjustment for age, ethnicity, breastfeeding and waist circumference, mean levels of the following cardiovascular risk factors progressively increased from NGT to 2/3-h GIGT to 1-h GIGT to GDM: LDL cholesterol (p = 0.0026); total cholesterol:HDL (p = 0.0030); apolipoprotein B (p = 0.004); apolipoprotein B:apolipoprotein A1 (p = 0.026); leptin (p = 0.018); and C-reactive protein (p = 0.011). CONCLUSIONS: Amongst women without GDM, 1-h GIGT predicts an enhanced postpartum cardiovascular risk factor profile. It thus emerges, that amongst young women with mild dysglycemia in pregnancy, those with 1-h GIGT may comprise an unrecognized patient population at risk for future cardiovascular disease.

Low adiponectin concentration during pregnancy predicts postpartum insulin resistance, beta cell dysfunction and fasting glycaemia.

AIMS/HYPOTHESIS: The postpartum phase following gestational diabetes (GDM) is characterised by subtle metabolic defects, including the beta cell dysfunction that is believed to mediate the increased future risk of type 2 diabetes in this patient population. Low circulating levels of adiponectin and increased leptin and C-reactive protein (CRP) have recently emerged as novel diabetic risk factors, although their relevance to GDM and subsequent diabetes has not been characterised. Thus, we sought to determine whether adiponectin, leptin and CRP levels during pregnancy relate to the postpartum metabolic defects linking GDM with type 2 diabetes. METHODS: Metabolic characterisation, including oral glucose tolerance testing, was undertaken in 487 women during pregnancy and at 3 months postpartum. Based on the antepartum OGTT, there were 137 women with GDM, 91 with gestational impaired glucose tolerance and 259 with normal glucose tolerance. RESULTS: Adiponectin levels were lowest (p < 0.0001) and CRP levels highest (p = 0.0008) in women with GDM. Leptin did not differ between the glucose tolerance groups (p = 0.4483). Adiponectin (r = 0.41, p < 0.0001), leptin (r = -0.36, p < 0.0001) and CRP (r = -0.30, p < 0.0001) during pregnancy were all associated with postpartum insulin sensitivity (determined using the insulin sensitivity index of Matsuda and DeFronzo [IS(OGTT)]). Intriguingly, adiponectin levels were also related to postpartum beta cell function (insulinogenic index/HOMA of insulin resistance; r = 0.16, p = 0.0009). Indeed, on multiple linear regression analyses, adiponectin levels during pregnancy independently predicted both postpartum insulin sensitivity (t = 3.97, p < 0.0001) and beta cell function (t = 2.37, p = 0.0181), even after adjustment for GDM. Furthermore, adiponectin emerged as a significant negative independent determinant of postpartum fasting glucose (t = -3.01, p = 0.0027). CONCLUSIONS/INTERPRETATION: Hypoadiponectinaemia during pregnancy predicts postpartum insulin resistance, beta cell dysfunction and fasting glycaemia, and hence may be relevant to the pathophysiology relating GDM with type 2 diabetes.

Differential impact of maternal and paternal ethnicity on the pattern of fat distribution in infants at age 3 months.

BACKGROUND: As ethnicity is typically recorded as a single demographic variable in clinical studies, little is known about the relative impact of maternal vs. paternal ethnicity on fat distribution. OBJECTIVES: The objective of this study was to determine whether there is a differential impact of maternal and paternal ethnicity on infant adiposity. METHODS: Three hundred fifty-five infants underwent anthropometric assessment at age 3 months, including skin-fold thickness (SFT) measurement at subscapular, suprailiac and triceps. Maternal (M) and paternal (P) ethnicity were classified as white (M = 241, P = 252), Asian (M = 50, P = 42) or other (M = 64, P = 61). RESULTS: Infants with either Asian mother (compared with white) or Asian father (compared with white) had increased subscapular, suprailiac and triceps SFT (all P < 0.05). On logistic regression analysis, however, only maternal Asian ethnicity (compared with white) independently predicted the likelihood of an infant being in the highest tertile for SFT at subscapular (odds ratio [OR] = 2.72, 95% confidence interval 1.17-6.34, P = 0.02), suprailiac (OR = 3.56, 1.51-8.42, P = 0.004) and triceps (OR = 3.26, 1.40-7.55, P = 0.005). In contrast, paternal Asian ethnicity was independently associated with sum of SFT only (OR = 2.46, 1.02-5.97, P = 0.04). CONCLUSION: Maternal and paternal Asian ethnicity have differential effects on infant fat distribution. Future clinical studies on obesity and fat composition should consider the distinct contributions of both parents to the ethnic classification of participants.

Prospective multicenter study of pregnancy outcomes in women with heart disease.

BACKGROUND: The maternal and neonatal risks associated with pregnancy in women with heart disease receiving comprehensive prenatal care have not been well defined. METHODS AND RESULTS: We prospectively enrolled 562 consecutive pregnant women with heart disease and determined the outcomes of 599 pregnancies not ending in miscarriage. Pulmonary edema, arrhythmia, stroke, or cardiac death complicated 13% of pregnancies. Prior cardiac events or arrhythmia, poor functional class or cyanosis, left heart obstruction, and left ventricular systolic dysfunction independently predicted maternal cardiac complications; the cardiac event rate can be predicted using a risk index incorporating these predictors. Neonatal complications (20% of pregnancies) were associated with poor functional class or cyanosis, left heart obstruction, anticoagulation, smoking, and multiple gestations. CONCLUSIONS: Pregnancy in women with heart disease is associated with significant cardiac and neonatal complications, despite state-of-the-art obstetric and cardiac care. Maternal cardiac risk can be predicted with the use of a risk index.

The Toronto Tri-Hospital Gestational Diabetes Project. A preliminary review.

In this study, we assessed maternal-fetal outcomes in untreated patients with increasing carbohydrate intolerance not meeting the current criteria for the diagnosis of gestational diabetes mellitus (GDM), examined the relationship between birth weight and mode of delivery among women with untreated borderline GDM, treated overt GDM, and normoglycemia, and established more efficient screening strategies for detection of GDM. This was a prospective analytic cohort study in which nondiabetic women aged > or = 24 years were eligible for enrollment. A 50-g glucose challenge test (GCT) and a 100-g oral glucose tolerance test (OGTT) were administered at 26 and 28 weeks gestational age, respectively. Risk factors for unfavorable maternal-fetal outcomes were recorded. Time since the last meal prior to the screening test was recorded, as well. Caregivers and patients were blinded to glucose values except when test results met the National Diabetes Data Group criteria for GDM. Maternal and fetal outcomes, including the mode of the delivery, were recorded in the postpartum period. Of 4,274 patients screened, 3,836 (90%) continued to the diagnostic oral glucose tolerance test. GDM was seen in 145 women. Increasing carbohydrate intolerance in women without overt gestational diabetes was associated with a significantly increased incidence of cesarean section, preeclampsia, macrosomia, and need for phototherapy, as well as an increased length of maternal and neonatal hospital stay. Multivariate analysis showed that increasing carbohydrate intolerance remained an independent predictor for various unfavorable outcomes, but the strength of the associations was diminished. Compared with normoglycemic control subjects, the untreated borderline GDM group had increased rates of macrosomia (28.7 vs. 13.7%, P < 0.001) and cesarean delivery (29.6 vs. 20.2%, P = 0.03). Usual care of known GDM patients normalized birth weights, but the cesarean delivery rate was about 33%, whether macrosomia was present or absent. An increased risk of cesarean delivery among treated patients compared with normoglycemic control subjects persisted after adjustment for multiple maternal risk factors. As for the screening tests, time since the last meal had a marked effect on mean plasma glucose. Receiver operating characteristic curve analysis allowed the selection of the most efficient cut points for the GCT based on the time since the last meal. These cut points were 8.2, 7.9, and 8.3 mmol/l (1 mmol/l = 18.015 mg/dl) for elapsed postprandial time of < 2, 2-3, and > 3 h, respectively. With this change from the current threshold of 7.8 mmol/l, the number of patients with a positive screening test dropped from 18.5 to 13.7%. There was an increase in positive predictive value from 14.4 to 18.7%. The overall rate of patient misclassification fell from 18.0 to 13.1%. In conclusion, increasing maternal carbohydrate intolerance in pregnant women without GDM is associated with a graded increase in adverse maternal and fetal outcomes. Infant macrosomia is an important factor in high cesarean delivery rates for women with untreated borderline GDM. Although detection and treatment of GDM normalizes birth weights, rates of cesarean delivery remain inexplicably high. Recognition of GDM may lead to a lower threshold for surgical delivery. The efficiency of screening for GDM can be enhanced by adjusting the current GCT threshold of 7.8 mmol/l to new values related to time since the last meal before screening. Further analyses are underway to elucidate whether maternal risk factors can be used to achieve additional efficiency gains in screening.

Omphalocele in Miller-Dieker syndrome: expanding the phenotype.

We report on a patient prenatally diagnosed with omphalocele, mild cerebral ventriculomegaly, nuchal fold thickening, and cystic changes in the umbilical cord who was found postnatally to have lissencephaly type I. Prenatal chromosome analysis showed a normal male karyotype; however, postnatal high resolution banding and FISH analysis, using a probe for locus D17S379 in chromosome region 17p13.3, demonstrated a deletion at 17p13.3 consistent with Miller-Dieker syndrome (MDS). A review documented four more cases with MDS/isolated lissencephaly/17p-, with omphalocele. Because MDS is a contiguous gene disorder, we speculate that a gene or genes in this region have a major role in the closure of the lateral folds or the return of the midgut from the body stalk to the abdomen at 5-11 weeks of gestation. Prenatal diagnosis of omphalocele with mild ventriculomegaly should prompt FISH analysis for a deletion in 17p13.3.

Pregnancy following surgical correction for transposition of the great arteries.

OBJECTIVE: To determine the maternal and fetal outcomes in pregnant patients with prior surgical correction of dextro-transposition of the great arteries. METHODS: A retrospective review was conducted of seven pregnancies managed from 1986-1992 in four women who had surgical correction for dextro-transposition of the great arteries. RESULTS: Three of the four patients had had the Mustard operation and the other had had the Rastelli operation. There were no maternal deaths. One patient who received the Mustard operation experienced functional deterioration in the last of three pregnancies, so it was terminated. Three of the remaining six pregnancies resulted in preterm deliveries, but there was no perinatal mortality and no infants had congenital heart disease. CONCLUSION: Maternal outcome can be satisfactory and the perinatal outcome good in patients with surgically corrected dextro-transposition of the great arteries.

Ventriculoperitoneal shunt malfunction during pregnancy.

Many women with cerebrospinal fluid shunts are now reaching reproductive age. Shunt malfunction may occur during pregnancy, and management requires a well-planned, combined neurosurgical and obstetrical approach. We present a case of ventriculoperitoneal shunt obstruction manifesting during the third trimester managed successfully in a conservative fashion. The literature on ventriculoperitoneal shunt malfunction during pregnancy is reviewed.

Systemic lupus erythematosus and pulmonary hypertension during pregnancy: report of a case fatality.

The case of a 25-year-old pregnant woman with systemic lupus erythematosus and severe pulmonary hypertension is presented. The pregnancy was complicated by worsening right heart failure and pre-eclampsia, requiring a caesarian section at 29 weeks' gestation. On the fourth day postpartum, the patient's respiratory status worsened and she was transferred to the coronary care unit where she soon died from combined right heart failure and respiratory arrest. The presumed pathogenesis and etiology of lupus-related pulmonary hypertension are discussed, in addition to noninvasive tests and proposed management. Given that the mortality rate is very high during pregnancy and therapy is of limited value, women with lupus-associated pulmonary hypertension should avoid conceiving. Those who choose to become pregnant must be carefully managed by a multidisciplinary team.

Congenital heart disease in pregnancy.

Care of pregnant patients with congenital heart disease requires understanding of the specific congenital defect, the nature of previous surgical correction, and the residua and sequelae. General risks and principles can be adduced in management decisions. In addition, lesion- and patient-specific details are important. There are only a few conditions that place patients at a high enough risk to advise that pregnancy be avoided under all circumstances (pulmonary vascular obstructive disease, Marfan syndrome with dilated aortic root, severe aortic stenosis, and severe systemic ventricular dysfunction). Preconception counseling, optimization of status, and meticulous multidisciplinary management during pregnancy and the postpartum period will improve outcomes.

Pregnancy after the fontan procedure for tricuspid atresia. A case report.

BACKGROUND: Pregnancy is contraindicated in uncorrected tricuspid atresia. Even following palliative surgery with the Fontan procedure, only four pregnancies have been reported. CASE: A 32-year-old female presented at 8 weeks' gestation in her first pregnancy with a history of the Fontan procedure performed seven years earlier for cardiac decompensation despite two previous palliative procedures for tricuspid atresia. She remained class I with no deterioration and required no medication throughout the pregnancy. Amniocentesis for positive maternal alpha-fetoprotein screening was normal. The pregnancy was complicated by antepartum hemorrhage at 29 weeks and premature rupture of membranes at 33 weeks, resulting in preterm labor and delivery of a 2.5-kg infant five days later. Apart from postpartum hemorrhage, the puerperium was uneventful, and the patient was well 20 weeks after delivery. CONCLUSION: Five similar pregnancies, including this one, have been reported. Although all were successful, three infants were preterm and two growth retarded. This observation suggests that for these patients, pregnancy must be monitored closely even though the mothers may be hemodynamically stable.

Pregnancy and functional deterioration in a woman with a univentricular heart. A case report.

A patient who had undergone Pott's procedure and a right Blalock-Taussig shunt in childhood for complex cyanotic congenital heart disease with a single ventricle presented with a planned pregnancy at age 22. Although asymptomatic prior to pregnancy, she experienced functional deterioration from the first trimester and had preterm labor with a footling breech presentation at 29 weeks following prelabor rupture of the membranes. A normal, 900-g female infant was delivered by cesarean section. Despite delivery the patient continued to experience progressive functional deterioration and returned to her prepregnancy cardiac status only after a Fontan operation, performed 14 months postpartum.

Bladder pheochromocytoma in pregnancy without hypertension. A case report.

A 33-year-old nullipara presented at 20 weeks' gestation with episodes of nonsustained ventricular tachycardia, which were controlled with amiodarone. No hypertension was recorded except once after an attack of ventricular tachycardia. Pheochromocytoma was suspected when repeat 24-hour urine catecholamine levels were markedly elevated. Neither computed tomography nor postpartum metaiodobenzylguanidine scan could locate the tumor. Finally it was identified in the bladder by ultrasound after selective venous sampling localized it to the pelvis. It was excised four months postpartum.

Lower dietary vitamin E intake during the second trimester is associated with insulin resistance and hyperglycemia later in pregnancy.

BACKGROUND/OBJECTIVES: Beneficial effects of vitamin E on insulin sensitivity have been reported in observational and short-term intervention studies in non-pregnant populations. We aimed to investigate whether dietary vitamin E intake during the second trimester would be associated with glucose metabolism later in pregnancy and whether this association would be influenced by an insulin-sensitizing hormone adiponectin. SUBJECTS/METHODS: Women with singleton pregnancies (n=205) underwent a 3-h oral glucose tolerance test at 30 weeks gestation and were asked to recall second trimester dietary intake. RESULTS: Higher dietary vitamin E intake was associated with lower fasting glucose, lower HOMA insulin resistance, and higher Matsuda insulin sensitivity index after covariate adjustment including serum adiponectin among women consuming daily multivitamin supplements (all P≤0.03). CONCLUSIONS: Lower dietary vitamin E intake during the second trimester is associated with hyperglycemia and insulin resistance later in pregnancy among women consuming daily multivitamin supplementations. Further, these associations are not influenced by adiponectin.

Maternal pregravid weight is the primary determinant of serum leptin and its metabolic associations in pregnancy, irrespective of gestational glucose tolerance status.

CONTEXT: Several previous studies have investigated circulating levels of the adipokine leptin in relation to gestational diabetes mellitus (GDM). However, these studies have yielded markedly conflicting results, including increased, decreased, and unchanged leptin levels in women with GDM as compared with their peers. OBJECTIVE: We sought to evaluate the metabolic determinants of serum leptin in a well-characterized cohort reflecting the full spectrum of glucose intolerance in pregnancy. DESIGN, SETTING, AND PARTICIPANTS: Metabolic characterization, including oral glucose tolerance test (OGTT) and measurement of serum leptin, insulin, lipids, adiponectin, and C-reactive protein, was performed in 817 pregnant women. The OGTT identified 198 women with GDM, 142 with gestational impaired glucose tolerance, and 477 with normal glucose tolerance. RESULTS: Median leptin (ng/ml) did not differ between the normal glucose tolerance (33.7), gestational impaired glucose tolerance (36.3), and GDM (36.4) groups (P = 0.085). On univariate correlation analysis, leptin was most strongly associated with prepregnancy body mass index (BMI) (r = 0.54, P < 0.0001), fasting insulin (r = 0.60, P < 0.0001), and C-reactive protein (r = 0.38, P < 0.0001) but only weakly associated with area under the glucose curve (AUC(glucose)) on the OGTT (r = 0.10, P = 0.0066). On multiple linear regression analysis, the strongest independent determinant of leptin was prepregnancy BMI (t = 11.55, P < 0.0001), whereas AUC(glucose) was not a significant predictor (t = -0.95, P = 0.34). Furthermore, although its respective associations with fasting insulin, triglycerides, and adiponectin varied across tertiles of prepregnancy BMI, leptin was not significantly associated with AUC(glucose) in any BMI tertile. CONCLUSIONS: Pregravid BMI, rather than gestational glucose tolerance, is the primary determinant of serum leptin concentration in pregnancy.

Anesthetic management of a consecutive cohort of women with heart disease for labor and delivery.

BACKGROUND: The cardiovascular changes of pregnancy may place additional stress upon women with pre-existing heart disease, increasing peripartum morbidity and mortality. The purpose of this descriptive study was to report the anesthetic management of a large cohort of pregnant women with heart disease. METHODS: The medical records of 522 consecutive parturients (657 pregnancies) with heart disease who delivered at Toronto General Hospital or Mount Sinai Hospital in Toronto, Ontario, Canada between 1986 and 2004 were reviewed. Obstetric, medical and anesthetic management data were collected and the women were stratified by New York Heart Association (NYHA) functional status at delivery. The main outcome of interest was the method of analgesia or anesthesia administered during labor and delivery. Univariate and multivariate analysis was performed to identify risk factors associated with the administration of general anesthesia. RESULTS: Of 657 pregnant women, 602 were NYHA 1/2 and 55 were NYHA 3/4 at time of delivery. Epidural analgesia was administered to 84% of NYH 1/2 women and 83% of NYH 3/4. The cesarean section rates were 29% and 31% respectively. The rate of general anesthesia for the entire cohort was 9%. Factors associated with the use of general anesthesia for operative delivery included cesarean delivery (adjusted O.R. 74; 95% CI 9.5, 573), delivering at Toronto General Hospital site (adjusted O.R. 5.5; 95% CI 2.3, 13.3), presence of complex congenital heart lesion (adjusted O.R. 2.3; 95% CI 1.0, 5.4) and each week of premature delivery (adjusted O.R. 1.3; 95% CI 1.1, 1.5). Three percent suffered intrapartum cardiac complications; there was one death. CONCLUSIONS: Pregnant women with heart disease managed within an organized program may undergo labor and delivery with acceptable rates of complications. Cesarean section, epidural analgesia/anesthesia and general anesthesia rates are similar to those in the general obstetric population.

Decreased high-molecular-weight adiponectin in gestational diabetes: implications for the pathophysiology of Type 2 diabetes.

AIMS: Low serum concentrations of the insulin-sensitizing protein adiponectin predict the development of incident Type 2 diabetes (T2DM). It has recently emerged that the anti-diabetic activity of adiponectin may be mediated by its high-molecular-weight (HMW) isoform, circulating levels of which are decreased in T2DM. The relevance of decreased HMW adiponectin to incident T2DM, however, has not been assessed. Since gestational diabetes (GDM) identifies a population of young women at high risk of future T2DM (i.e. representing an early stage in the natural history of the disease), we sought to determine if decreased HMW adiponectin is a feature of GDM. METHODS: HMW and total adiponectin were measured in 121 women at the time of oral glucose tolerance testing (OGTT) in late pregnancy, following an abnormal glucose challenge test. Based on the OGTT, there were 41 women with and 80 without GDM. RESULTS: Median HMW adiponectin concentration was lower in women with GDM (3.5 microg/ml) than in those without GDM (5.5 microg/ml) (P < 0.0001). After full adjustment for covariates, mean HMW adiponectin remained significantly lower in women with GDM compared with their peers (3.6 vs. 5.3 microg/ml, P = 0.0035). HMW adiponectin was positively associated with insulin sensitivity (IS(OGTT)) (r = 0.38, P < 0.0001) and pancreatic B-cell function [insulin secretion-sensitivity index (ISSI)] (r = 0.33, P = 0.0002) and inversely related to blood glucose levels, including area-under-the-glucose-curve during the OGTT (AUC(glucose)) (r = -0.31, P = 0.0007). On separate multiple linear regression analyses, HMW adiponectin emerged as an independent determinant of AUC(glucose), IS(OGTT) and ISSI, respectively, mirroring the relationships of total adiponectin. CONCLUSIONS: HMW adiponectin is significantly decreased in women with GDM. Deficiency of HMW adiponectin may be an early event in the natural history of T2DM.