Materials and Methods
From 1978, pregnant women with type 1 diabetes were enrolled prospectively in a program at the University of Cincinnati. The institutional review board approved the study, and patient informed consent was obtained before enrollment. The current study is a secondary analysis of that prospective interdisciplinary study of diabetes in pregnancy. We included pregnant women who enrolled before 14 weeks' gestation, had type 1 diabetes, White classification of B-RF, and at least two ophthalmologic examinations (one before 20 weeks and one in late pregnancy or up to 12 weeks postpartum).
Treatment of women in our program has been described.9 Each subject was supplied with a blood glucose reflectance meter and instructed to check blood glucose concentrations 4–8 times a day. Long-term glucose control was assessed by measurement of glycohemoglobin A1 concentrations at enrollment and each trimester. Management and goals of glycemic control were fasting and preprandial capillary blood glucose concentration below 100 mg/dL and a 90-minute post prandial capillary blood glucose concentration below 140 mg/dL. Daily insulin dosages were divided into three or four injections of short-acting and intermediate-acting insulin, and adjustments were made as needed. At enrollment, nephropathy was evaluated with 24-hour urine collection for quantitative estimations of proteinuria. Nephropathy was defined by proteinuria at least 500 mg/24-hour urine collection before 16 weeks' gestation.
Women were instructed to have ophthalmologic evaluations by one of two ophthalmologists at enrollment, every trimester, and at 6–12 weeks postpartum. For this analysis, an examination in early pregnancy (before 20 weeks) and during the third trimester or postpartum up to 12 weeks was required. Without a third-trimester evaluation (because of early delivery or noncompliance), a postpartum evaluation that showed progression of retinopathy beyond that of the initial evaluation was considered indicative of progression during pregnancy. The ophthalmologic examination included documentation with color photographs and fluorescein angiography (during nonpregnant state). Retinopathy was graded according to a predefined scale (grades 0–6).10 Progression of retinopathy was defined as its development in one or both eyes de novo, or upgrade from first or second trimester to third trimester or postpartum. Women with grade 6 retinopathy and previous photocoagulation who had changes that required repeat photocoagulation were classified as progressed in their retinopathy. The definitions for chronic hypertension and preeclampsia have been published.11
Neonatal outcome data included a ponderal index defined as the cubed root of body weight times 100 divided by height. To compare birth weights between groups, gestational age at delivery and chronic hypertension status were included in the model and an adjusted birth weights were compared.
Data were analyzed with SAS (SAS Institute, Inc., Cary, NC). χ2 test was used for categorical variables. t test or Wilcoxon rank-sum was used to compare ordinal and continuous variables depending on normality assumption. A logistic regression model was used for multivariable associations with reduced fetal growth. Independent variables significant at P < .15 were considered for initial inclusion in the logistic model. A general linear modeling procedure was used to analyze the effect of retinal change on growth alteration. P < .05 was considered statistically significant.
There were 522 pregnancies in women with type 1 diabetes. One hundred forty women were excluded because the pregnancy did not extend beyond 20 weeks' gestation, 82 were excluded because they did not enroll before 14 weeks' gestation, and 95 were excluded because they did not have at least two ophthalmologic examinations. Two hundred five pregnancies met inclusion criteria, and development or progression of retinopathy occurred in 59 (29%). Advanced White classification was associated with increased progression (P = .001). Rates of progression in women with class B, C, D, and F-RF were 3 (5%), 14 (23%), 24 (41%), and 18 (30%), respectively. The eighteen subjects in the progression group with White classification F-RF included 12 women with nephropathy (alone or with proliferative retinopathy). Among 12 with retinopathy, two had infants that were small for gestational age (SGA) and seven had infants with low birth weight. Maternal characteristics for the two groups are presented in Table 1. Women in the progression group were more likely to be younger at diagnosis of diabetes (P = .01) and have preeclampsia (P = .01). There was no difference between groups in cesarean or preterm birth rates before 34 and 37 weeks' gestation. Entry and first-trimester blood glycohemoglobin A1 concentrations were higher, and magnitude of their decrease from first to second trimester was greater in women with progression of retinopathy (Table 2). A summary of changes in retinopathy in our population is given in Table 3. The median week for the early ophthalmologic examination was the 11th week with an interquartile range of the eighth to 15th weeks. The median week for the late examination was the 32nd week with an interquartile range of the 27th to 36th weeks. The median week for the postpartum eye examination was the sixth week with an interquartile range of 3–8 weeks. There were 70 subjects who did not have postpartum ophthalmologic examinations.
Neonatal outcome data are shown in Table 4. Birth weight (P = .02) and adjusted birth weight (adjusted for gestational age and chronic hypertension, P = .01) were lower in the progression group. Reduced fetal growth (below tenth percentile, P = .02) and low birth weight (below 2500 g, P = .02) occurred at higher rates in the progression group, whereas the rate of large-for-gestational-age infants was significantly lower (P = .04) in that group. The birth weight percentile distributions are illustrated in Figure 1, showing a shift of the curve to the left for the progression group (P = .03). There was no difference between groups with regard to macrosomia (weight above 4000 g) or ponderal index (above 90th percentile). More polycythemia (P = .01) was noted for infants in the progression group. In the no-progression group, there was one stillbirth and one neonatal death, each with congenital malformations (transposition of the great vessels and anencephaly, respectively) and low birth weight.
Nine infants were SGA, six born to women in the progression group. Two of six infants had mothers with retinopathy progression and nephropathy. Twenty-seven infants had low birth weights, 13 in the progression group. Seven of 13 infants had mothers with retinopathy progression and nephropathy.
In the no-progression group, three infants were SGA, two of whose mothers had proliferative retinopathy (grade 6) at their first-trimester ophthalmologic examination and chronic hypertension. The third infant had a congenital malformation and was born to a mother with benign retinopathy (grade 3) and no hypertension. Six infants whose mothers were in the progression group were SGA, and none had congenital malformations. The first-trimester ophthalmologic examinations of those six mothers showed three with proliferative retinopathy (grade 4), two with benign retinopathy (grade 2), and one with no retinopathy. Three of those mothers had chronic hypertension, one with superimposed preeclampsia.
Logistic regression analysis was done to evaluate the independent effect of retinopathy progression on reduced fetal growth (Tables 5 and 6). Independent variables analyzed were progression of retinopathy (change in grade), gestational age at delivery, initial glycohemoglobin A1, change in glycohemoglobin A1 from first to second trimester, chronic hypertension, preeclampsia, and nephropathy. Progression of retinopathy (odds ratio [OR] 4.7; 95% confidence interval [CI] 1.2, 23.8) was significantly and independently associated with reduced fetal growth after accounting for chronic hypertension (OR 6.4; 95% CI 1.5, 27.9).
We evaluated risk of reduced fetal growth in women who developed or had progression of diabetic retinopathy during pregnancy because retinal deterioration might indicate worsening microvascular disease not specific to the retina. We hypothesized that the mechanism leading to progression of retinopathy also might lead to reduced fetal growth by compromising utero-placental blood flow. In a study on adverse pregnancy outcomes in women with type 1 diabetes and proliferative retinopathy at initial ophthalmologic examinations, we found that without nephropathy, proliferative retinopathy was not a risk for adverse pregnancy outcomes. However, there was a 325-g lower overall birth weight and an 18% incidence of low birth weight in the group with retinopathy compared with 8% incidence of low birth weight in the group without retinopathy. Those findings prompted further investigation of the association between fetal birth weight and progression of retinopathy during pregnancy.
In the current study, we showed reduced fetal growth with a twofold increase in low birth weight, fivefold more SGA infants, and fewer large-for-gestational-age infants in the progression group. There also was a 268-g reduction in overall birth weight in the progression group. Not only were the extremes (small and large for gestational age) affected, but the entire distribution of growth (Figure 1) was shifted to the left. Small-for-gestational-age infants are at increased risk of adverse outcomes, and women with progressive retinopathy should have fetal growth monitored closely.
Most reports on diabetic retinopathy in pregnancy did not address neonatal outcomes. Among those that studied neonatal outcomes, most focused on the most advanced stage, proliferative diabetic retinopathy, without defining whether subjects had stable or progressive disease. Reece et al12 reported neonatal outcomes in 20 pregnant women with proliferative retinopathy (at least half progressed during pregnancy): 15% of those pregnancies ended in abortion or stillbirth and the perinatal survival rate was 94%. They concluded that most pregnancies resulted in live births of appropriate-for-gestational-age infants. Nine of 17 (53%) births had no neonatal complications and three (18%) had congenital anomalies. Klein et al13 reported pregnancy outcomes in 179 women with diabetes. Among maternal factors, severity of diabetic retinopathy was the most significant predictor of adverse pregnancy outcome, defined as abortion, perinatal death, and severe congenital malformations. Those studies did not differentiate stable from progressive retinal disease, so we were unable to compare them with our current findings. A weakness in our study was lack of smoking history in the logistic regression model. Data on smoking history were not collected after 1988; however, incidence of smoking in women enrolled before 1988 was 30%.
Logistic regression supported an independent association between progression of retinopathy and reduced fetal growth. We found an association of reduced fetal growth with chronic hypertension and change in blood glycohemoglobin A1 concentration (from first to second trimester). Previous studies8,14,15 showed an association of chronic hypertension and change in blood glycohemoglobin A1 concentration with progression of retinopathy. The association of chronic hypertension with SGA infants is well established16; however, association between change in glycohemoglobin A1 concentration and SGA is not. This investigation found that the mechanism in which rapid normalization of glucose control leads to progression of retinopathy might also lead to reduced fetal growth. The association of retinopathy progression with advanced White classification was consistent with other studies.17
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