Type 1 diabetes and pregnancy: trends in birth weight over 40 years at a single clinic.

OBJECTIVE: To examine changes in perinatal mortality and birth weight of babies born to mothers with pregestational type 1 diabetes over 40 years in a single teaching hospital clinic. METHODS: This was a retrospective survey of cases from the combined diabetes and obstetrics antenatal clinic at the Royal Infirmary of Edinburgh and Simpson Memorial Maternity Pavilion, Edinburgh, Scotland. Birth weight, standardized birth weight, and perinatal mortality were obtained from 643 singleton babies born after 28 weeks of gestation to mothers with pregestational type 1 diabetes between 1960 and 1999. RESULTS: There was a dramatic improvement in perinatal mortality rate, falling from 225 (per 1,000 total births after 28 weeks of gestation) in the 1960s to 102 in the 1970s, 21 in the 1980s, and 10 in the 1990s (P < .001 for effect of birth year). In contrast, standardized birth weight (adjusted for sex, gestational age, and parity), which was significantly higher than the background population (+1.41 standard deviations above the population norm, P < .001) showed no significant change over time. CONCLUSION: Changes in diabetic management and obstetric practice over the 40 years of our survey have resulted in enormous improvements in the outlook for offspring of mothers with diabetes. Somewhat surprisingly this has not been associated with a reduction in overgrowth of the fetus. LEVEL OF EVIDENCE: II-2.

The relation of insulin, leptin and IGF-1 to birthweight in offspring of women with type 1 diabetes.

OBJECTIVE: Maternal diabetes is associated with excess foetal growth. We have assessed the influence of maternal diabetes on hormones associated with foetal growth and the relationship of these hormones to birthweight. DESIGN: Case-control study. PATIENTS: Singleton offspring of mothers with type 1 diabetes (ODM, n = 140) and control mothers (Control, n = 49). MEASUREMENTS: Birthweight, cord blood insulin, proinsulin, 32-33 split proinsulin, leptin, IGF-1, IGFBP-3, cortisol. RESULTS: Maternal diabetes was associated with higher birthweight (ODM 3.80 +/- 0.69 kg; Control; 3.56 +/- 0.52 kg, P = 0.02) and marked increases in insulin (median [interquartile range]: ODM 110 [60-217] pmol/l; Control 22 [15-37] pmol/l; P < 0.0001) and leptin (ODM 32 [15-60] ng/ml; Control 9 [4-17] ng/ml; P < 0.0001) but no absolute difference in IGF-1 (ODM 7.9 [6.2-9.8] nmol/l, Control 7.5 [6.2-9.8] nmol/l, P = 0.24) or its principle binding protein IGFBP-3 (ODM 1.63 +/- 0.38 micro g/ml, Control 1.63 +/- 0.28 micro g/ml; P = 0.12). Individually, insulin, insulin propeptides, leptin, IGF-1 and IGFBP-3 were significantly (P < 0.05) correlated with birthweight (in ODM and Control). IGF-1 and leptin were positively related to birthweight independently of each other and insulin in both ODM and Control. By contrast, insulin showed independent relationships to birthweight in ODM (P < 0.0001) but not in Control (P = 0.4). CONCLUSIONS: Maternal diabetes is associated with marked elevation of insulin and leptin in cord blood of their offspring. Hormonal correlates of birthweight differ between ODM and Control with an independent relationship of insulin to birthweight observed only in ODM.

Type 1 diabetes-related antibodies in the fetal circulation: prevalence and influence on cord insulin and birth weight in offspring of mothers with type 1 diabetes.

During pregnancy, maternal type 1 diabetes-associated autoantibodies may cross the placenta. It is proposed that insulin antibodies (IA) allow transfer of insulin across the placenta, contributing to fetal hyperinsulinemia and macrosomia. We assessed the prevalence of IA, the tyrosine phosphatase IA-2, and glutamic acid decarboxylase (GADA) in cord blood from offspring of mothers with type 1 diabetes (ODM, n = 138) and control mothers (control, n = 47) and further assessed cross-sectional relationships of antibody titers to birth weight and fetal insulin. In ODM, antibodies were frequently present in cord blood; 124 ODM (95%) were positive for IA, 82 (59%) were positive for GADA antibodies, and 61 (44%) were positive for IA-2 antibodies. In controls, GADA and IA-2 antibodies were absent, whereas seven controls (15%) were positive for IA at low titers (P < 0.0001 ODM vs. controls for all).ODM with IA (IA positive) or without IA (IA negative) had similar birth weights (mean +/- sd: IA positive, 3.8 +/- 0.7 kg; IA negative, 4.0 +/- 0.6 kg; P = 0.31) and cord insulin concentrations (IA positive: median, 112 pmol/liter; interquartile range, 62-219 pmol/liter; IA negative: median, 114 pmol/liter; interquartile range, 59-194 pmol/liter; P = 0.96). Similarly, the presence of GADA and/or IA-2 autoantibodies (n = 103) was not associated with differences in birth weight or insulin concentrations. Antibody titers were not associated with birth weight or insulin as continuous variables in either controls or ODM. Islet autoantibodies and IA are a common finding in cord blood of ODM, but we found no evidence that they influence offspring insulin concentrations or weight at birth.

Insulin and insulin propeptides at birth in offspring of diabetic mothers.

Maternal diabetes during pregnancy is associated with excess fetal growth and increased fetal insulin production. We hypothesized that insulin propeptides (proinsulin and 32-33 split proinsulin) might be more robust indicators of chronic fetal overproduction of insulin. We examined insulin-like molecules in cord blood (ILM) (insulin, proinsulin, and 32-33 split proinsulin) in relation to birth weight, maternal glycemia, and cord glucose in 140 offspring of mothers with type 1 diabetes (ODM) and 49 offspring of mothers who did not have diabetes (CONTROL) as well as degradation of ILM in response to sampling conditions at birth. Insulin propeptides were abundant in cord blood, comprising 50% of ILM in CONTROL and 36% in ODM (P < 0.0001) and more resistant to degradation than insulin (P < 0.05). Concentrations of all three ILM were highly intercorrelated with median values 2- to 5-fold higher in ODM than CONTROL [e.g. median (range): insulin ODM 110 (60-217) pmol/liter; CONTROL 22 (15-37) pmol/liter; P < 0.0001]. In ODM, 32-33 split proinsulin and proinsulin were more closely related to birth weight (Spearman r for ILM: r(32-33 split)= 0.54; r(PROINSULIN): r = 0.54; r(INSULIN) = 0.40: r(32-33 split) and r(PROINSULIN) > r(INSULIN)P < 0.05) and fetal leptin (r(32-33 split)= 0.55; r(PROINSULIN); r = 0.54; r(INSULIN) = 0.22: r(32-33 split) and r(PROINSULIN) > r(INSULIN)P < 0.05) than insulin). By contrast, insulin was more closely related to cord glucose (r(32-33 split) = 0.15; r(PROINSULIN): r = 0.10; r(INSULIN) = 0.42: r(INSULIN) > r(32-33 split) and r(PROINSULIN)P < 0.05). In CONTROL, 32-33 split proinsulin was also more closely related to fetal leptin r(32-33 split)= 0.61; r(PROINSULIN): r = 0.29; r(INSULIN) = 0.33: r(32-33 split) > r(INSULIN)P < 0.05). In ODM, 32-33 split proinsulin and proinsulin have closer relationships to fetal growth and leptin concentrations at birth than insulin. Measurement of insulin propeptides may be advantageous in assessment of the influence of maternal hyperglycemia on the newborn.

Factors affecting fetal weight distribution in women with type I diabetes.

OBJECTIVE: To identify factors independently affecting fetal weight in women with type I diabetes. DESIGN: Prospectively recorded data in consecutive women with type I diabetes, between 1975-1992. SETTING: Simpson Memorial Maternity Hospital, Edinburgh. Population Three hundred and two pregnancies with type I diabetes identified before pregnancy, with antenatal care and delivery in the Simpson Memorial Maternity Hospital, a singleton pregnancy, and the same diabetic physician. METHODS: Normal ranges for birthweight were established for the total hospital population. All cases and the total population had pregnancy dating by ultrasound. The relation between standardised birthweight and explanatory variables was investigated using correlation analysis, t tests and chi2 tests as appropriate, and subsequently using multiple linear regression. RESULTS: Standardised birthweight in cases, compared with the reference population, showed a unimodal, approximately normal distribution, markedly shifted to the right (mean + 1.26 SD). The most predictive variable was glycated haemoglobin concentration at 27-33 weeks, which explained 6.3% of the birthweight variance, while smoking explained 2.7% and maternal weight 2.0%. There was a trend towards a negative relationship with glycated haemoglobin concentration at 6-12 weeks. Smoking and glycated haemoglobin concentration were strongly intercorrelated. CONCLUSIONS: Most of the variance in standardised birthweight remains unexplained, but glycated haemoglobin concentration at 27-33 weeks is the most powerful explanatory variable. Possible reasons why there is not a stronger relationship between markers of maternal glycaemia and birthweight are discussed.

What do pregnant women think about the HIV test? A qualitative study.

Before any new antenatal screening test is introduced, the opinions of pregnant women should be considered. This is particularly relevant with HIV testing. This qualitative study reports the views of 29 women attending an antenatal clinic in a large maternity hospital in Scotland where a trial of different ways of offering HIV testing on a universal, voluntary basis occurred. Women were in favour of a test offer, although they did not necessarily wish to accept testing for themselves. Generally they were more worried about having an unhealthy baby. There was a commonly held view that routine testing would cause less anxiety because it would eliminate the stigma of saying yes to testing. A move towards the HIV test being recommended to pregnant women as opposed to merely offered is likely to be acceptable, would probably increase uptake rates and should therefore be assessed.

Uptake and acceptability of antenatal HIV testing: randomised controlled trial of different methods of offering the test.

OBJECTIVE: To determine the uptake and acceptability of different methods of a universal offer of voluntary HIV testing to pregnant women. DESIGN: Randomised controlled trial involving four combinations of written and verbal communication, followed by the direct offer of a test. The control group received no information and no direct offer of a test, although testing was available on request. SETTING: Hospital antenatal clinic covering most of the population of the city of Edinburgh. SUBJECTS: 3024 pregnant women booking at the clinic over a 10 month period. MAIN OUTCOME MEASURES: Uptake of HIV testing and women's knowledge, satisfaction, and anxiety. RESULTS: Uptake rates were 6% for those in the control group and 35% for those directly offered the test. Neither the style of leaflet nor the length of discussion had an effect on uptake. Significant independent predictors of uptake were a direct test offer; the midwife seen; and being unmarried, previously tested, and younger age. Knowledge of the specific benefits of testing increased with the amount of information given, but neither satisfaction nor anxiety was affected by the type of offer. CONCLUSIONS: The universal offer of HIV testing is not intrusive and is acceptable to pregnant women. A policy of offering the HIV test to all women resulted in higher uptake and did not increase anxiety or dissatisfaction. Uptake depends more on the midwife than the method of offering the test. Low uptake rates and inadequate detection of HIV infection point to the need to assess a more routine approach to testing.

Effect of absent end diastolic flow velocity in the fetal umbilical artery on subsequent outcome.

Sixty babies, delivered over a six and a half year period, who had absent end diastolic frequency (AEDF) in the umbilical artery, were studied. Individually matched control pregnancies for gestational age, birth-weight, maternal clinical condition and date of delivery, in whom umbilical artery recordings showed end diastolic frequency, were also studied. Matching was achieved in 36 cases. Neonates from case pregnancies showed no increase in necrotising enterocolitis, intraventricular haemorrhage, pneumothorax, neonatal death or bronchopulmonary dysplasia. However, they were significantly less likely to require ventilation for respiratory distress syndrome (P = 0.02). Although AEDF indicates a fetus under vascular stress, this finding alone will include a spectrum of response in the baby, from the well compensated to the irreversibly damaged. Delivery at different points in the deteriorating fetal environment may explain discrepant study results. This intrauterine stress, by increasing fetal corticosteroid and thyroid hormones, may account for enhanced lung maturity. Predictions of neonatal course need to be based on more comprehensive awareness of fetal status.

Contraception for HIV-infected women.

AIDS: Decisions regarding the use of contraception for HIV-infected women are complicated by changing opinions regarding prevention and treatment. In addition, there is also interplay between the two risks involved: vertical HIV transmission in the event of pregnancy, and horizontal transmission to an uninfected partner. Unfortunately, the methods of contraception that have historically best protected against HIV transmission, such as condoms, have also been least effective in preventing pregnancy. Moreover, studies have shown that HIV-positive women who use a more effective method of contraception are less likely to also use a condom, even with an uninfected partner. While two different methods of contraception are advisable to deal with the two separate risk factors, it is still unclear which methods are safest and most effective.^ieng

The effect of human immunodeficiency virus infection and drug use on birth characteristics.

OBJECTIVE: To explore the effect of human immunodeficiency virus (HIV) infection and drug use on birth weight, length, and gestational duration at delivery. METHODS: Subjects had a history of injection drug use or a sexual partner who was an injection drug user, were Scottish, and their HIV serostatus during pregnancy was known. Control pregnancies were matched for age, parity, ethnic group, year of delivery, and postal code sector of home address. In addition, some were matched for smoking and housing deprivation score. Birth weights were standardized for gestational age by expressing them as z scores with a mean of zero and a standard deviation of unity. Statistical analysis was by univariate and multiple regression with multilevel modeling. RESULTS: Regression analysis for birth weight, gestational age, and gestation-adjusted birth weights (z score) included 789 pregnancies in 693 women. Human immunodeficiency virus seropositivity was associated with a z score that was 0.27 lower (P = .03), but there was no significant difference in gestational duration at delivery. Current oral or injection drug use were associated with a reduction in standardized birth weight (z score -0.27, P = .06, and z score -0.28, P = .04, respectively), and injection drug use with a reduction in occipitofrontal circumference only (1.8 cm reduction, P = .05). Injection drug use, but not the other factors, had an effect on gestational age at delivery (1.54 weeks earlier, P < .001). CONCLUSION: Although HIV seropositivity is associated with a small reduction in standardized birth weight, this effect is less than that attributable to smoking and may not be of clinical significance. The effect seems to be associated with placental size. Opiate use, regardless of route, had a small association with reduced birth weight, suggesting a specific drug effect. However, only injection drug use had a strong association with early delivery, and this effect was likely to be clinically significant at the population level.

Clinical and ultrasound prediction of macrosomia in diabetic pregnancy.

OBJECTIVE: To study prospectively the prediction power, at different gestations, of clinical and ultrasound measurements for fetal size in diabetic pregnancy. SETTING: A large combined obstetric diabetic clinic in a teaching hospital. PARTICIPANTS: One hundred and eighty-one pregnancies in which women had scans at least two of three specific time points and who were delivered of singletons after 34 weeks: 73% were pre-gestational insulin-dependent diabetics, the others were pre-gestational White class A or gestational diabetics. INTERVENTIONS: Clinical estimates of fundal height and fetal size and ultrasound estimates of abdominal circumference and head circumference were routinely carried out at gestational ages of 28, 34 and 38 weeks or before delivery. MAIN OUTCOME MEASURES: Standardised birthweight, corrected for gestation and parity. The relation with clinical and ultrasound measurements was investigated using multiple linear regression and the capability of the measurements to predict macrosomic births (> 95th centile of normals) using receiver-operator characteristic curves. RESULTS: All measurements are poor predictors of eventual standardised birthweight. Prediction improves with closeness to delivery. Prediction is significantly improved by adding ultrasound to clinical information, but at 34 weeks or later this only contributes 8% of the variance. There is no difference in the prediction power for macrosomia between clinical and ultrasound measurements. CONCLUSIONS: Even regular serial scanning and clinical examination will not always diagnose the macrosomic fetus in diabetic pregnancy. In our hands, clinical examination is as predictive as ultrasound measurements. Ultrasound does add to clinical prediction power but only to a small extent. Ultrasound should be used in a selected way, as defined by clinical findings, and with recognition and understanding of the errors and biases involved.

Smoking during pregnancy: the dose dependence of birthweight deficits.

OBJECTIVE: To assess whether a simple urine based estimate of relative daily nicotine intake could predict smoking related birthweight deficits more accurately than self-reported cigarette consumption. DESIGN: Active smokers were identified by a simple qualitative colorimetric urine test procedure and their relative nicotine intakes assessed by determining the ratios of the urinary concentrations of nicotine plus its metabolites to creatinine using automated colorimetric methods. SETTING: A large teaching hospital. PARTICIPANTS: Three thousand and thirty-eight mothers from whom smoking histories had been elicited and who gave birth to live singleton babies after 28 weeks of gestation. MAIN OUTCOME MEASURES: Birthweights (adjusted for maternal weight, maternal age, baby's sex, parity and length of gestation), maternal weight gains during pregnancy and placental weights. RESULTS: The adjusted birthweight deficits of babies born to proven active smokers averaged 226 g (95% confidence interval 194 g to 258 g), but dose dependent effects were only apparent when nicotine intake was based on urinary nicotine metabolites/creatinine ratios. Among the smokers, adjusted birthweights fell linearly with increasing nicotine intakes but gave a predicted mean birthweight for nonsmokers that was 102 g (95% CI 50 g to 154 g) lighter than that actually found (P < 0.0001). Maternal weight gains during pregnancy were substantially reduced in smokers and correlated more closely with urinary nicotine metabolite excretions than with reported daily cigarette consumptions. Placental weights were unaffected by smoking. CONCLUSION: There was a closer dose-effect relationship between birthweight deficits and urinary nicotine metabolites/creatinine ratios than with self-reported daily cigarette consumptions. The influence of nicotine exposure on birthweight appears to be biphasic, with one mechanism operating at very low levels of tobacco smoke intake and the other causing seemingly linearly related effects over the whole range of nicotine intakes of active smokers. These findings support recent evidence that passive smoking can cause substantial birthweight deficits.

Guidelines for the management of insulin-dependent diabetes mellitus in pregnancy.

The infant of an insulin-dependent diabetic mother is at increased risk of perinatal death, neonatal problems and major congenital malformations: Many of these problems are preventable. All young women with diabetes should receive contraceptive advice and information about pregnancy. The objects of pre-pregnancy care are to assess suit-ability for pregnancy, to optimise control in early pregnancy and to improve pregnancy outcome through the provision of individualised education and information. Pre-pregnancy care can reduce the congenital malformation rate to approximately that of the nondiabetic. In each area there should be one designated diabetologist and one designated obstetrician who, together with their team, should see all pregnant women in a combined clinic in a hospital with an intensive care baby unit. All pregnant women with diabetes should have 24-hour access to the specialist team. Tight glycaemic control during pregnancy can reduce complications of pregnancy greatly, improving infant mortality and morbidity. Insulin requirements usually change during pregnancy. Education about hypoglycaemia and avoidance of ketoacidosis is essential. Women should have regular examination of the fundi and renal function. They should have ultrasound scanning to assess gestation, to look for abnormalities and to assess fetal growth. Fetal monitoring should be used, particularly for those at high risk. Women with good diabetic control and no complications of diabetes or pregnancy may be delivered at 39 to 40 weeks but those at high risk earlier. During labour or caesarean section blood glucose should be normalised using intravenous glucose and insulin supervised by a specialist team. An experienced paediatrician should be available. Breast feeding should be encouraged.

Maternal HIV and drug use: effect on health and social morbidity.

A retrospective analysis of routine child health surveillance information was performed on health visitor records of 459 children, to examine the independent effects of maternal HIV infection and drug use during pregnancy on morbidity in the first 3 years of life. No significant differences were observed in the developmental progress of children born to HIV infected or drug using women when compared to community controls. The pattern of medical consultations in the first 18 months of life was significantly different, maternal drug use exerting a negative influence on outpatient visits (odds ratio 0.6, 95% confidence interval 0.4 to 1.0). At 6 weeks, the majority of children lived with their birth parent(s), and no differences were observed between the groups. By 10 months of age, only 81% of children born to HIV infected drug using women lived with their parent(s). While maternal drug use and HIV did not have adverse effects on child health and development, these findings highlight the social implications for children affected by the heterosexual spread of HIV.

Maternal HIV infection, drug use, and growth of uninfected children in their first 3 years.

OBJECTIVE: To determine the separate effects of maternal HIV infection and drug use during pregnancy on growth of uninfected children in their first 3 years. DESIGN: Retrospective analysis of measurements from health visitor records made during routine child health surveillance at 6 weeks, 10 months, and 3 years of age. Multilevel analysis allowed for between-infant variation in fitted growth lines, and adjustment for other factors. Growth was described in terms of an intercept (z score at term) and growth slopes (change in z score per year) up to, and from, 4 months. SUBJECTS: 290 case babies delivered in Edinburgh hospitals to women who reported injection drug use by either themselves or their HIV infected partner, and 186 community controls. A total of 131 (45%) of the case babies were born to women who used drugs, predominantly opiates, during pregnancy and 93 (32%) to HIV infected women. The eight infected children were excluded from analysis. MAIN OUTCOME MEASURES: Age and sex standardised z scores for height, weight, and body mass index. RESULTS: 459 (96%) of the 476 records for cases and controls were traced, yielding 1432 weight and 939 height measurements. Maternal HIV infection was not found to affect growth; at 3 years the estimated effect on weight z score was 0.16 with 95% confidence interval (-0.25 to 0.57) and for height 0.18 (-0.19 to 0.55). Drug use during pregnancy was associated with lighter babies at 40 weeks followed by depressed growth in the first four months, these infants remaining just slightly smaller at 3 years with an estimated effect on z scores of -0.5 for weight with 95% confidence interval (-0.89 to -0.11) and -0.37 (-0.72 to -0.02) for height. CONCLUSIONS: Maternal HIV infection does not adversely affect growth in uninfected infants, and the effect of drug use during pregnancy is limited to small decrease in size at 3 years.