Original Research
Effect of Excess Gestational Weight Gain on Pregnancy Outcomes in Women With Type 1 Diabetes Christina M. Scifres, MD, Maisa N. Feghali, and Janet M. Catov, PhD
MD,
OBJECTIVE: To evaluate the prevalence and clinical effects of excess gestational weight gain on birth weight and other pregnancy outcomes in women with type 1 diabetes. METHODS: We performed a retrospective cohort study of women with type 1 diabetes delivered between 2009 and 2012. Patients with excess weight gain were identified using the 2009 Institute of Medicine weight gain recommendations adjusted for gestational age at delivery and prepregnancy body mass index (BMI) category. Demographic and outcome data were abstracted from the medical record, and pregnancy outcomes were compared between women with and without excess gestational weight gain. RESULTS: Excess gestational weight gain occurred in 114 of 175 women (65.1%). Large-for-gestational-age (LGA) birth weight occurred in 48 of 114 (42.1%) of women with excess gestational weight gain and 5 of 61 (8.2%) of women with recommended weight gain (P,.001). The association between excess maternal weight gain and LGA birth weight remained significant after adjustment for prepregnancy BMI, gestational age at delivery, nulliparity, vascular complications, and hemoglobin A1c measurements (adjusted odds ratio 8.9, 95% confidence interval 3.1–26.2, P,.001). Stratified analyses demonstrated that excess maternal weight gain is associated
From the Department of Obstetrics, Gynecology and Reproductive Sciences, Magee Women’s Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Presented at the Society for Maternal-Fetal Medicine Annual Meeting, February 3–8, 2014, New Orleans, Louisiana. Corresponding author: Christina M. Scifres, MD, 300 Halket Street, Pittsburgh, PA 15213; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2014 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/14
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Andrew D. Althouse,
PhD,
Steve N. Caritis,
MD,
with LGA neonates in both normal-weight and overweight or obese women. CONCLUSIONS: Excess maternal weight gain is common and leads to higher rates of LGA neonates in both normal-weight and overweight or obese women with type 1 diabetes. Interventions designed to limit excess gestational weight gain may reduce the risk for fetal overgrowth in women with type 1 diabetes. (Obstet Gynecol 2014;123:1295–302) DOI: 10.1097/AOG.0000000000000271
LEVEL OF EVIDENCE: II
T
he prevalence of obesity is increasing in nonpregnant patients with type 1 diabetes.1,2 However, most studies examining pregnancy outcomes in women with type 1 diabetes were conducted in countries with low obesity rates3 or before the onset of the obesity epidemic.4 Weight gain is a common problem in nonpregnant patients with type 1 diabetes using intensive insulin regimens,5 but the prevalence of excess gestational weight gain in pregnant women with type 1 diabetes is unknown. In 2009 the Institute of Medicine issued revised guidelines for recommended gestational weight gain based on the World Health Organization body mass index (BMI, calculated as weight (kg)/[height (m)]2) categories.6 Excess weight gain is known to aggravate insulin resistance and affect diabetes outcomes in nonpregnant individuals with type 1 diabetes.1 However, the effect of excess weight gain on glycemic control and pregnancy outcomes in women with type 1 diabetes is unknown. Women with type 1 diabetes are at significant risk for pregnancy complications including largefor-gestational-age (LGA) birth weight.3,7,8 Rates of macrosomia remain high despite hemoglobin (Hb)A1c levels close to the normal range,9,10
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demonstrating that factors other than maternal glucose control contribute to the excess morbidity seen in pregnant women with type 1 diabetes. Therefore, we designed this study to examine the prevalence of excess gestational weight gain and to evaluate the effect of maternal weight gain on common pregnancy complications such as LGA birth weight in women with type 1 diabetes. We hypothesized that weight gain in excess of the Institute of Medicine recommendations would be predictive of LGA birth weight.
MATERIALS AND METHODS We conducted a retrospective cohort study of all women with type 1 diabetes and singleton pregnancies who were delivered at Magee-Womens Hospital (University of Pittsburgh, Pittsburgh, Pennsylvania) from January 2009 to October 2012. Women were identified using the International Classification of Diseases, 9th Revision, Clinical Modification codes 648.01 (diabetes-delivered) and 648.81 (abnormal glucose tolerance-delivered). We identified 2,339 women with diabetes delivered over the study period, and charts were reviewed to identify 176 women with type 1 diabetes based on clinical history (7.5% of women with diabetes at delivery). Information on pregnancy weight gain was available for 175 women who were included in the final analysis (one patient presented in labor and delivered at 35 weeks of gestation with no prenatal care). Women received prenatal care in the maternal-fetal medicine office and obstetrics clinics at our hospital, and they were seen by dedicated diabetes dieticians who provided consultation regarding their diet and recommended weight gain based on their prepregnancy BMI. Selfmonitoring of plasma glucose was recommended seven times daily, and targets for plasma glucose included a fasting value less than 95 mg/dL (5.3 mmol/L) and 1-hour postmeal values less than 140 mg/dL (7.8 mmol/L). Women had a serum creatinine and either a urinary protein-to-creatinine ratio or 24hour urine collection performed to assess baseline renal function. Demographic and clinical data on the mother and newborn were obtained from the original medical record. Regulatory approval was obtained from the University of Pittsburgh institutional review board, and informed consent was not required given the retrospective nature of the study. The primary exposure of interest in our study was gestational weight gain, which was calculated as the difference between self-reported weight before pregnancy and the last weight recorded before delivery. For 67 of 175 (38%) of women we were able to verify
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the self-reported prepregnancy weight by review of the patient’s medical records for the 6 months before conception. We found that self-reported maternal prepregnancy weight correlated strongly with both documented pregravid weight (r50.99, P,.001) and measured weight at the first prenatal visit (r50.97, P,.001) so we elected to use the maternal selfreported prepregnancy weight for our analyses. Excessive gestational weight gain was defined as gestational weight gain greater than the upper range of Institute of Medicine 2009 guidelines for each prepregnancy BMI category (underweight, normal weight, overweight, and obese) for women who delivered beyond 37 weeks of gestation6 (Table 1). Because many women (n570/175 [40%]) delivered preterm, we additionally examined the association of excess gestational weight gain and outcomes in patients delivered preterm by estimating the maximal gestational weight gain at the gestational age at which they were delivered. We performed these calculations by multiplying the maximal weekly weight gain in the second and third trimesters times the number of weeks preterm the patient was delivered and subtracting this value from the maximum recommended weight gain for each BMI category. Maternal prepregnancy overweight and obesity was reported as an index of weight for height (BMI) and overweight or obesity was defined using the World Health Organization guidelines for classification of BMI. Only 3 of 175 women (1.6%) of women had a prepregnancy BMI that was considered underweight, so these women were included with the normal-weight women for purposes of this analysis. In addition, only 7 of 175 women (4.0%) had a weight gain that was less than expected based on the Institute of Medicine recommendations, so they were grouped with the recommended weight gain group. Sensitivity analyses were
Table 1. 2009 Institute of Medicine Guidelines for Weight Gain in Pregnancy
Prepregnancy BMI Underweight Normal weight Overweight Obese
BMI (kg/m2) Less than 18.5 18.5–24.9 25–29.9 30.0 or greater
Rate of Weight Total Weight Gain, Second and Third Trimesters Gain (lb/wk) (lb) 28–40
1 (1–1.3)
25–35 15–25 11–20
1 (0.8–1) 0.6 (0.5–0.7) 0.5 (0.4–0.7)
BMI, body mass index. Data are range or mean (range) unless otherwise specified.
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undertaken excluding women with an underweight BMI and suboptimal weight gain, and the overall findings of the study were unchanged so they remained in final analysis. Maternal demographics and clinical characteristics were extracted from the chart. Diabetic nephropathy was defined as greater than 0.3 g protein on 24-hour urine collection and retinopathy assessed by patient report and review of ophthalmology records. Hemoglobin A1c values were recorded by the trimester in which they were measured. When more than one measurement per trimester was available the values were averaged, and the mean HbA1c across pregnancy was also calculated. We also abstracted the type of therapy used in each trimester and at delivery, and these were grouped based on the basal insulin therapy including either neutral protamine Hagedorn insulin, insulin glargine, or insulin pump therapy. Chronic hypertension was defined as blood pressure 140/90 mmHg or greater diagnosed before pregnancy before 20 weeks of gestation. Pregnancy outcomes were compared between women with standard and excess gestational weight gain including gestational age at delivery, preterm delivery less than 37 weeks of gestation, LGA (greater than the 90th percentile for gestational age) or small for gestational age (less than the 10th percentile for gestational age) status based on U.S. national birth weight data,11 macrosomia (defined as a birth weight greater than 4,000 g), ponderal index, placental weight, cesarean delivery, shoulder dystocia, and stillbirth. Gestational hypertension was defined as newonset resting blood pressure greater than 140/90 mmHg on two or more occasions 6 hours apart in the second half of pregnancy with absence of significant proteinuria. Mild preeclampsia was defined as a systolic blood pressure of 140 mmHg or greater or a diastolic blood pressure of 90 mmHg or greater on two occasions at least 6 hours apart occurring after 20 weeks of gestation accompanied by detectable urinary protein (1+ or greater by dipstick or 0.3 g or greater/24 hours). Severe preeclampsia was defined as a blood pressure 160/110 mmHg or greater with either a urine dipstick demonstrating 3+ or 4+ protein in a random urine sample or greater than 5.0 g of proteinuria over 24 hours. Other criteria for severe disease included eclampsia, pulmonary edema, oliguria (less than 500 mL/24 hours), fetal growth restriction, oligohydramnios, and symptoms suggestive of significant end-organ involvement (headache, visual disturbance, or epigastric or right upper quadrant pain). Superimposed preeclampsia was diagnosed in the setting of blood pressure exacerbations along with
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new-onset proteinuria (0.3 g or greater/24 hours). Neonatal outcomes included neonatal intensive care unit admission, hypoglycemia (defined as a glucose value less than 35 mg/dL within the first 24 hours of life), hyperbilirubinemia requiring phototherapy, respiratory distress syndrome, congenital anomalies, and neonatal death. Statistical analyses were completed using Stata 10 Special Edition and SAS 9.4. Distributions of variables were tested for normality using visual inspection of histograms and the Shapiro–Wilk W-test. Women with and without excess gestational weight gain were compared using x2 statistic, Fisher’s exact test, or t tests as appropriate. Effect modification by prepregnancy BMI (as a continuous variable) was assessed using the likelihood ratio test. Multivariable logistic regression analysis was used to analyze whether excess gestational gain was associated with the aforementioned pregnancy outcomes when controlling for potential confounders, including age, parity, maternal education, glycemic control, the presence of vascular complications, and prepregnancy BMI. Repeatedmeasures analysis was undertaken to examine differences in gestational weight gain per trimester between women who delivered LGA neonates compared with those that delivered appropriate-for-gestational-age neonates; this was performed only in the 137 women who had complete data on weight gain in each trimester in addition to prepregnancy and delivery weight. Mean weights in each group were plotted for each trimester, and an interaction between LGA delivery and trimester was tested to determine whether there was a difference in the pattern of weight gain across trimesters between women that delivered LGA neonates compared with those who delivered appropriate-for-gestational-age neonates. P values ,.05 were considered significant in all analyses.
RESULTS The mean weight gain was 34.1614.1 pounds (range 0–83 pounds) for the entire cohort. Excess weight gain was a common occurrence, affecting 114 of 175 (65.1%) of the overall cohort. Notably, women with excess gestational weight gain gained significantly more than the upper limits of recommended weight gain (14.8610.7 pounds). Table 2 shows the clinical characteristics of women with appropriate compared with excess gestational weight gain. As expected, women in the excess gestational weight gain group gained almost twice as much weight as those women in the appropriate weight gain group. Women with excess gestational weight gain were more likely to be overweight or obese before pregnancy, and they
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Table 2. Maternal Characteristics Associated With Gestational Weight Gain Characteristic Age (y) White race Some college education Private insurance Nulliparity Prepregnancy BMI (kg/m2) Overweight or obese Total weight gain (lb) Tobacco use Vascular complications Years disease Mean HbA1c (%) HbA1c (%) 1st trimester 3rd trimester Therapy Neutral protamine Hagedorn insulin Insulin glargine Pump therapy 1st-trimester SBP (mmHg) 1st-trimester DBP (mmHg) Chronic hypertension Hypothyroid Serum creatinine (mg/dL)
Weight Gain Within IOM Guidelines (n561)
Weight Gain Greater Than IOM Guidelines (n5114)
P
28.866.3 54 (88.5) 36 (59.0) 35 (57.4) 24 (39.3) 26.866.1 30 (49.1) 21.268.1 12 (19.7) 17 (27.9) 16.468.8 7.561.4
27.965.4 107 (94.0) 83 (72.8) 76 (66.7) 48 (42.1) 27.665.4 77 (67.5) 41.2611.5 14 (12.3) 14 (12.3) 15.267.2 7.261.2
.36 .26 .06 .22 .72 .36 .02 ,.001 .19 .01 .32 .08
8.462.1 6.961.1
7.661.7 6.761.2
.01 .35
10 (16.4)
24 (21.2)
17 (27.9) 34 (55.7) 114.8614.3 69.567.2 9 (14.8) 15 (24.6) 0.7660.57
20 (17.5) 70 (61.4) 115.6611.6 70.167.8 9 (7.9) 29 (25.4) 0.6760.14
.26 .68 .66 .16 .90 .22
IOM, Institute of Medicine; BMI, body mass index; HbA1c, hemoglobin A1c; SBP, systolic blood pressure; DBP, diastolic blood pressure. Data are mean6standard deviation or n (%) unless otherwise specified.
were also more likely to have at least some college education. Women with standard weight gain were more likely have vascular complications (either retinopathy or nephropathy). In the overall cohort the mean HbA1c values decreased from the first trimester to the third trimester (7.861.8% compared with 6.761.1%, P,.01). Women with excess maternal weight gain demonstrated lower mean HbA1c values in the first trimester, although by the third trimester, mean HbA1c values were similar between groups (Table 2). Gestational age at delivery and rates of preterm delivery were similar between women with excess gestational weight gain and those without. However, women with excess gestational weight gain had larger mean birth weights, placental weights, and their neonates had higher ponderal indices. They also experienced much higher rates of LGA birth weight and macrosomia, whereas rates of small-forgestational-age birth weight were similar between groups (Table 3). There were no significant interactions between prepregnancy BMI and gestational weight gain with regard to LGA birth weight. We performed a stratified
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analysis to assess the magnitude of the effect of excess weight gain on LGA birth weight separately in normal-weight and overweight or obese women. Excess weight gain was associated with LGA birth weight in both normal-weight (15/22 [40.5%] compared with 2 of 31 [6.5%], P5.001, odds ratio [OR] 9.9, 95% confidence interval [CI] 1.9–95.0) and overweight or obese women (33/77 [42.9] compared with 3 of 30 [10%], P5.001, OR 6.8, 95% CI 1.8–37.1, Mantel-Haenszel test for homogeneity P,.01). We next performed a multivariable logistic regression analysis to further characterize the relationship between excess maternal weight gain and LGA birth weight. Excess maternal weight gain remained independently associated with LGA birth weight after adjustment for prepregnancy BMI, vascular complications, mean HbA1c across gestation, gestational age at delivery, nulliparity, and maternal education (48/114 [42.1%] compared with 5 of 61 [8.2%], P,.001, adjusted OR 8.9, 95% CI 3.1–26.2, P,.001) (Table 4). The risk of having an LGA neonate was the same in women who achieved a mean HbA1c value 6.5% or less and those who had a mean HbA1c value greater than 6.5% (30.1 compared with 30.7%, P5.94), and
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Table 3. Obstetric and Neonatal Outcomes Outcome Gestational age at delivery (wk) Preterm birth (less than 37 wk of gestation) Birth weight (g) Placental weight (g) Ponderal index (weight/length3)3 100 LGA birth weight SGA birth weight Macrosomia Gestational hypertension Mild preeclampsia Severe preeclampsia Superimposed preeclampsia Cesarean delivery Stillbirth Shoulder dystocia NICU admission Hypoglycemia Respiratory distress syndrome Hyperbilirubinemia Congenital anomaly Neonatal death
Weight Gain Within IOM Guidelines (n561)
Weight Gain Greater than IOM Guidelines (n5114)
P
36.262.4 24 (39.3)
36.662.1 46 (40.3)
.43 .90
2,8986789 4376121 2.5260.32
3,4656833 5016141 2.6460.34
,.001 .004 .05
5 5 4 5 5 7 7 33 1 4 27 11 13 16 5 0
(8.2) (8.2) (6.6) (8.2) (8.2) (11.5) (11.5) (54.1) (1.6) (6.6) (45) (18.3) (21.7) (26.7) (8.2) (0)
48 6 31 5 10 18 21 78 1 4 44 23 18 17 6 1
(42.1) (5.3) (27.2) (4.4) (8.8) (15.8) (18.4) (68.4) (0.9) (3.5) (38.9) (29.4) (15.9) (15.0) (6.2) (0.9)
,.001 .45 .004
.53 .06 .58 .45 .44 .75 .35 .06 .45 1.0
IOM, Institute of Medicine; LGA, large for gestational age; SGA, small for gestational age; NICU, neonatal intensive care unit. Data are mean6standard deviation or n (%) unless otherwise specified.
the type of treatment used did not alter the risk for having an LGA neonate. Because of the possibility that pregnancy complications leading to preterm birth could also affect risk for LGA birth weight, we performed a sensitivity analysis including only the 126 women who delivered at or beyond 36 0/7 weeks of gestation. We found that excess maternal weight gain was associated with LGA birth weight in women who were delivered at or near term (42/83 [50.6%] compared with 5/43 [11.6%], P,.001, OR 7.8, 95% CI 2.8–21.7, P,.001), similar to our findings in the overall cohort. We also noted the strong relationship
between vascular complications and LGA birth weight. We therefore analyzed the association between gestational weight gain and LGA birth weight after excluding the 31 women with vascular complications and found that excess gestational weight gain remained significantly associated with LGA birth weight (47/100 [47%] compared with 5/44 [11.4%], P,.001, OR 6.9, 95% CI 2.5–19.0, P,.001). We then proceeded to examined weight gain patterns during each trimester for women with appropriate-for-gestational-age and LGA neonates in the 137 women with a recorded weight at all four time
Table 4. Logistic Regression Model Identifying Factors Independently Associated With Large-forGestational-Age Birth Weight Variable Weight gain greater than IOM guidelines Prepregnancy BMI Maternal education Nulliparity Vascular complications Gestational age at delivery
Unadjusted OR 8.1 1.0 1.5 0.30 0.06 1.3
(3.0–21.9) (0.98–1.10) (0.71–3.0) (0.15–0.63) (0.01–0.44) (1.1–1.6)
P ,.001 .18 .30 .001 .01 .007
Adjusted OR* 8.9 1.1 0.92 0.23 0.05 1.3
(3.1–25.6) (0.98–1.1) (0.35–2.4) (0.10–0.53) (0.01–0.46) (1.0–1.7)
P ,.001 .13 .88 .001 .008 .02
OR, odds ratio; IOM, Institute of Medicine; BMI, body mass index. * Adjusted OR represents the OR for each variable when adjusting for all other variables in the multivariable logistic regression model.
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points. Women that delivered LGA neonates were moderately heavier prepregnancy (P5.06) and significantly heavier at the first trimester, second trimester, and delivery (P,.05 for all; Fig. 1). Women who delivered LGA neonates had significantly greater first-trimester weight gain than those who delivered appropriate-for-gestational-age neonates (8.2 pounds compared with 5.3 pounds, P5.01), similar secondtrimester weight gain (14.6 pounds compared with 12.9 pounds, P5.11), and significantly greater thirdtrimester weight gain (16.8 pounds compared with 12.7 pounds, P5.002). There was a statistically significant interaction between delivery of an LGA neonate and time (P5.01), indicating that women who ultimately delivered LGA neonates were not only heavier at study entry but that they also gained more weight than their counterparts who delivered appropriate-forgestational-age neonates. As a result of the modest sample size, we lacked statistical power to compare infrequent outcomes between those with expected and excess gestational weight gain, but there was a trend toward higher rates of cesarean delivery in women with excess gestational weight gain. However, this relationship was not significant after adjustment for LGA birth weight, gestational age at delivery, overweight or obese status, and pregnancy-induced hypertension (78/114 [68.4%] compared with 33/61 [54.1%], P5.06, adjusted OR 1.3, 95% CI 0.6–2.6, P5.34). Shoulder dystocia rates were similar between groups. There were two stillbirths in the study participants, both complicated by multiple fetal anomalies (Table 3) Neonatal outcomes were similar between women with expected and excessive maternal weight gain, and there were no other significant relationships between excess gestational weight gain and other pregnancy outcomes.
DISCUSSION Excess gestational weight gain is a common occurrence in women with type 1 diabetes. This excess gestational weight gain leads to increased risk for LGA birth weight and macrosomia as well as higher ponderal indices, suggesting that the observed increase in birth weight may result from increased aiposity. The association between excess gestational weight gain and LGA birth weight was robust in both normal-weight and overweight or obese women Notably, excess weight gain as early as the first trimester results in an increased risk for LGA birth weight. We hypothesize that interventions to limit excess gestational weight gain may need to occur preconception or early in pregnancy to reduce the prevalence of LGA neonates. Macrosomic neonates of diabetic mothers have higher body fat compared with nondiabetic control neonates of similar weight and length,12 and this increased adiposity may predispose to obesity, diabetes, and cardiovascular disease later in life.13–16 Therefore, effective strategies to reduce the risk for LGA birth weight may have beneficial longterm effects on the offspring of women with type 1 diabetes. Our findings are consistent with prior studies, which have shown that excess gestational weight gain is associated with an increased risk for LGA birth weight in women with gestational diabetes17 or type 2 diabetes.18 However, the mechanisms linking excess gestational weight gain to LGA birth weight are incompletely understood. Increased body fat in patients with type 2 diabetes is associated with higher levels of proinflammatory adipocytokines, ectopic fat stores, dyslipidemia, insulin resistance, oxidative stress, and hypofibrinolysis or procoagulation,1 but additional studies are needed to understand the
Fig. 1. Trends in gestational weight gain for women who delivered largefor-gestational-age (LGA) neonates compared with appropriate-for-gestational-age (AGA) neonates. Scifres. Gestational Weight Gain and Type 1 Diabetes. Obstet Gynecol 2014.
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physiologic adaptations in pregnancies complicated by type 1 diabetes and obesity or excess gestational weight gain. Hypertriglyceridemia is an established risk factor for LGA birth weight in pregnancies complicated by gestational diabetes,19 but the effect of dyslipidemia on fetal growth in pregnancies with type 1 diabetes is unknown. There are some similarities in placental gene expression relating to fatty acid transport and activation between women with gestational diabetes and type 1 diabetes,20 suggesting that there may be common pathways to fetal overgrowth in pregnancies complicated by type 1 diabetes and other forms of diabetes. Pregnant women are counseled regarding the importance of good glycemic control, and the observed reduction in HbA1c levels across gestation suggests that this counseling was effective. More troubling is that rates of LGA were similar between women who achieved a mean HbA1c less than 6.5% and those who did not, indicating that mechanisms other than suboptimal glucose control contribute to fetal overgrowth in women with type 1 diabetes. Weight gain is a common problem with intensive insulin regimens, and this weight gain has significant metabolic effects outside of pregnancy including elevations in serum lipids, blood pressure, and abdominal obesity.5,21 This constellation of lipid abnormalities, abdominal obesity, and hypertension is similar to the central obesity–insulin resistance syndrome that is characteristic of type 2 diabetes and highlights the possibility of metabolic deterioration associated with excess weight gain in pregnant patients with type 1 diabetes. Gestational weight gain also has long-term effects on women with type 1 diabetes. Cyganek et al22 observed that women with type 1 diabetes who experienced a pregnancy weighed 2.5 kg more than their prepregnancy baseline after a median of 20 months postpartum. This long-term weight retention may have significant effects on both glycemic control and risk for cardiovascular disease, particularly for women affected by both obesity and type 1 diabetes. The retrospective nature of this cohort study and the relatively modest sample size lacked statistical power to adequately examine the association between excess gestational weight gain and rare outcomes such as shoulder dystocia or birth trauma. Our cohort included a small number of patients with underweight BMI or inadequate weight gain, so we were unable to assess the relationship between these factors and adverse pregnancy outcomes. Women in our study were mostly white and there were few women with significant vascular disease; therefore, our results may
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not be generalizable to all pregnancies complicated by type 1 diabetes. Maintaining maternal weight gain within the Institute of Medicine guidelines based on prepregnancy BMI may reduce the risk of LGA birth weight in women with type 1 diabetes. Although there are few data demonstrating how to manage weight gain in this population, intensive patient education regarding weight gain goals may be most effective if it starts preconceptionally and continues early in gestation with regular reinforcement throughout pregnancy.23,24 Future studies into the metabolic adaptations associated with excess weight gain will also identify the optimal dietary and medical targets to reduce the risk for fetal overgrowth, which may have long-term benefits for women with type 1 diabetes and their offspring. REFERENCES 1. Cleland SJ. Cardiovascular risk in double diabetes mellitus— when two worlds collide. Nat Rev Endocrinol 2012;8:476–85. 2. Conway B, Miller RG, Costacou T, Fried L, Kelsey S, Evans RW, et al. Temporal patterns in overweight and obesity in Type 1 diabetes. Diabet Med 2010;27:398–404. 3. Persson M, Norman M, Hanson U. Obstetric and perinatal outcomes in type 1 diabetic pregnancies: a large, populationbased study. Diabetes Care 2009;32:2005–9. 4. Feghali MN, Khoury JC, Timofeev J, Shveiky D, Driggers RW, Miodovnik M. Asymmetric large for gestational age newborns in pregnancies complicated by diabetes mellitus: is maternal obesity a culprit? J Matern Fetal Neonatal Med 2012;25:32–5. 5. Weight gain associated with intensive therapy in the diabetes control and complications trial. The DCCT Research Group. Diabetes Care 1988;11:567–73. 6. Rasmussen KM, Catalano PM, Yaktine AL. New guidelines for weight gain during pregnancy: what obstetrician/gynecologists should know. Curr Opin Obstet Gynecol 2009;21:521–6. 7. Jensen DM, Damm P, Moelsted-Pedersen L, Ovesen P, Westergaard JG, Moeller M, et al. Outcomes in type 1 diabetic pregnancies: a nationwide, population-based study. Diabetes Care 2004;27:2819–23. 8. Persson M, Pasupathy D, Hanson U, Norman M. Birth size distribution in 3,705 infants born to mothers with type 1 diabetes: a population-based study. Diabetes Care 2011;34:1145–9. 9. Evers IM, de Valk HW, Mol BW, ter Braak EW, Visser GH. Macrosomia despite good glycaemic control in Type I diabetic pregnancy: results of a nationwide study in The Netherlands. Diabetologia 2002;45:1484–9. 10. Persson B, Hanson U. Fetal size at birth in relation to quality of blood glucose control in pregnancies complicated by pregestational diabetes mellitus. Br J Obstet Gynaecol 1996;103:427–33. 11. Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M. A United States national reference for fetal growth. Obstet Gynecol 1996;87:163–8. 12. McFarland MB, Trylovich CG, Langer O. Anthropometric differences in macrosomic infants of diabetic and nondiabetic mothers. J Matern Fetal Med 1998;7:292–5. 13. Rijpert M, Evers IM, de Vroede MA, de Valk HW, Heijnen CJ, Visser GH. Risk factors for childhood overweight in offspring
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of type 1 diabetic women with adequate glycemic control during pregnancy: Nationwide follow-up study in the Netherlands. Diabetes Care 2009;32:2099–104. 14. Buinauskiene J, Baliutaviciene D, Zalinkevicius R. Glucose tolerance of 2- to 5-yr-old offspring of diabetic mothers. Pediatr Diabetes 2004;5:143–6. 15. Manderson JG, Mullan B, Patterson CC, Hadden DR, Traub AI, McCance DR. Cardiovascular and metabolic abnormalities in the offspring of diabetic pregnancy. Diabetologia 2002;45:991–6. 16. Kelstrup L, Damm P, Mathiesen ER, Hansen T, Vaag AA, Pedersen O, et al. Insulin resistance and impaired pancreatic b-cell function in adult offspring of women with diabetes in pregnancy. J Clin Endocrinol Metab 2013;98:3793–801. 17. Cheng YW, Chung JH, Kurbisch-Block I, Inturrisi M, Shafer S, Caughey AB. Gestational weight gain and gestational diabetes mellitus: perinatal outcomes. Obstet Gynecol 2008;112:1015–22. 18. Yee LM, Cheng YW, Inturrisi M, Caughey AB. Effect of gestational weight gain on perinatal outcomes in women with type 2 diabetes mellitus using the 2009 Institute of Medicine guidelines. Am J Obstet Gynecol 2011;205:257. e1–6. 19. Schaefer-Graf UM, Graf K, Kulbacka I, Kjos SL, Dudenhausen J, Vetter K, et al. Maternal lipids as strong determinants of fetal environment and growth in pregnancies
with gestational diabetes mellitus. Diabetes Care 2008;31: 1858–63. 20. Radaelli T, Lepercq J, Varastehpour A, Basu S, Catalano PM, Hauguel-De Mouzon S. Differential regulation of genes for fetoplacental lipid pathways in pregnancy with gestational and type 1 diabetes mellitus. Am J Obstet Gynecol 2009;201:209. e1–10. 21. Purnell JQ, Hokanson JE, Marcovina SM, Steffes MW, Cleary PA, Brunzell JD. Effect of excessive weight gain with intensive therapy of type 1 diabetes on lipid levels and blood pressure: results from the DCCT. Diabetes Control and Complications Trial. JAMA 1998;280:140–6. 22. Cyganek K, Hebda-Szydlo A, Skupien J, Janas I, Walczyk J, Lipowska A, et al. Postpregnancy glycemic control and weight changes in type 1 diabetic women. Diabetes Care 2013;36: 1083–7. 23. Phelan S, Phipps MG, Abrams B, Darroch F, Schaffner A, Wing RR. Randomized trial of a behavioral intervention to prevent excessive gestational weight gain: the Fit for Delivery Study. Am J Clin Nutr 2011;93:772–9. 24. Vinter CA, Jensen DM, Ovesen P, Beck-Nielsen H, Jørgensen JS. The LiP (Lifestyle in Pregnancy) study: a randomized controlled trial of lifestyle intervention in 360 obese pregnant women. Diabetes Care 2011;34:2502–7.
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Effect of Excess Gestational Weight Gain on Pregnancy Outcomes in Women With Type 1 Diabetes Christina M. Scifres, MD, Maisa N. Feghali, and Janet M. Catov, PhD
MD,
OBJECTIVE: To evaluate the prevalence and clinical effects of excess gestational weight gain on birth weight and other pregnancy outcomes in women with type 1 diabetes. METHODS: We performed a retrospective cohort study of women with type 1 diabetes delivered between 2009 and 2012. Patients with excess weight gain were identified using the 2009 Institute of Medicine weight gain recommendations adjusted for gestational age at delivery and prepregnancy body mass index (BMI) category. Demographic and outcome data were abstracted from the medical record, and pregnancy outcomes were compared between women with and without excess gestational weight gain. RESULTS: Excess gestational weight gain occurred in 114 of 175 women (65.1%). Large-for-gestational-age (LGA) birth weight occurred in 48 of 114 (42.1%) of women with excess gestational weight gain and 5 of 61 (8.2%) of women with recommended weight gain (P,.001). The association between excess maternal weight gain and LGA birth weight remained significant after adjustment for prepregnancy BMI, gestational age at delivery, nulliparity, vascular complications, and hemoglobin A1c measurements (adjusted odds ratio 8.9, 95% confidence interval 3.1–26.2, P,.001). Stratified analyses demonstrated that excess maternal weight gain is associated
From the Department of Obstetrics, Gynecology and Reproductive Sciences, Magee Women’s Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Presented at the Society for Maternal-Fetal Medicine Annual Meeting, February 3–8, 2014, New Orleans, Louisiana. Corresponding author: Christina M. Scifres, MD, 300 Halket Street, Pittsburgh, PA 15213; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2014 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/14
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Andrew D. Althouse,
PhD,
Steve N. Caritis,
MD,
with LGA neonates in both normal-weight and overweight or obese women. CONCLUSIONS: Excess maternal weight gain is common and leads to higher rates of LGA neonates in both normal-weight and overweight or obese women with type 1 diabetes. Interventions designed to limit excess gestational weight gain may reduce the risk for fetal overgrowth in women with type 1 diabetes. (Obstet Gynecol 2014;123:1295–302) DOI: 10.1097/AOG.0000000000000271
LEVEL OF EVIDENCE: II
T
he prevalence of obesity is increasing in nonpregnant patients with type 1 diabetes.1,2 However, most studies examining pregnancy outcomes in women with type 1 diabetes were conducted in countries with low obesity rates3 or before the onset of the obesity epidemic.4 Weight gain is a common problem in nonpregnant patients with type 1 diabetes using intensive insulin regimens,5 but the prevalence of excess gestational weight gain in pregnant women with type 1 diabetes is unknown. In 2009 the Institute of Medicine issued revised guidelines for recommended gestational weight gain based on the World Health Organization body mass index (BMI, calculated as weight (kg)/[height (m)]2) categories.6 Excess weight gain is known to aggravate insulin resistance and affect diabetes outcomes in nonpregnant individuals with type 1 diabetes.1 However, the effect of excess weight gain on glycemic control and pregnancy outcomes in women with type 1 diabetes is unknown. Women with type 1 diabetes are at significant risk for pregnancy complications including largefor-gestational-age (LGA) birth weight.3,7,8 Rates of macrosomia remain high despite hemoglobin (Hb)A1c levels close to the normal range,9,10
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demonstrating that factors other than maternal glucose control contribute to the excess morbidity seen in pregnant women with type 1 diabetes. Therefore, we designed this study to examine the prevalence of excess gestational weight gain and to evaluate the effect of maternal weight gain on common pregnancy complications such as LGA birth weight in women with type 1 diabetes. We hypothesized that weight gain in excess of the Institute of Medicine recommendations would be predictive of LGA birth weight.
MATERIALS AND METHODS We conducted a retrospective cohort study of all women with type 1 diabetes and singleton pregnancies who were delivered at Magee-Womens Hospital (University of Pittsburgh, Pittsburgh, Pennsylvania) from January 2009 to October 2012. Women were identified using the International Classification of Diseases, 9th Revision, Clinical Modification codes 648.01 (diabetes-delivered) and 648.81 (abnormal glucose tolerance-delivered). We identified 2,339 women with diabetes delivered over the study period, and charts were reviewed to identify 176 women with type 1 diabetes based on clinical history (7.5% of women with diabetes at delivery). Information on pregnancy weight gain was available for 175 women who were included in the final analysis (one patient presented in labor and delivered at 35 weeks of gestation with no prenatal care). Women received prenatal care in the maternal-fetal medicine office and obstetrics clinics at our hospital, and they were seen by dedicated diabetes dieticians who provided consultation regarding their diet and recommended weight gain based on their prepregnancy BMI. Selfmonitoring of plasma glucose was recommended seven times daily, and targets for plasma glucose included a fasting value less than 95 mg/dL (5.3 mmol/L) and 1-hour postmeal values less than 140 mg/dL (7.8 mmol/L). Women had a serum creatinine and either a urinary protein-to-creatinine ratio or 24hour urine collection performed to assess baseline renal function. Demographic and clinical data on the mother and newborn were obtained from the original medical record. Regulatory approval was obtained from the University of Pittsburgh institutional review board, and informed consent was not required given the retrospective nature of the study. The primary exposure of interest in our study was gestational weight gain, which was calculated as the difference between self-reported weight before pregnancy and the last weight recorded before delivery. For 67 of 175 (38%) of women we were able to verify
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the self-reported prepregnancy weight by review of the patient’s medical records for the 6 months before conception. We found that self-reported maternal prepregnancy weight correlated strongly with both documented pregravid weight (r50.99, P,.001) and measured weight at the first prenatal visit (r50.97, P,.001) so we elected to use the maternal selfreported prepregnancy weight for our analyses. Excessive gestational weight gain was defined as gestational weight gain greater than the upper range of Institute of Medicine 2009 guidelines for each prepregnancy BMI category (underweight, normal weight, overweight, and obese) for women who delivered beyond 37 weeks of gestation6 (Table 1). Because many women (n570/175 [40%]) delivered preterm, we additionally examined the association of excess gestational weight gain and outcomes in patients delivered preterm by estimating the maximal gestational weight gain at the gestational age at which they were delivered. We performed these calculations by multiplying the maximal weekly weight gain in the second and third trimesters times the number of weeks preterm the patient was delivered and subtracting this value from the maximum recommended weight gain for each BMI category. Maternal prepregnancy overweight and obesity was reported as an index of weight for height (BMI) and overweight or obesity was defined using the World Health Organization guidelines for classification of BMI. Only 3 of 175 women (1.6%) of women had a prepregnancy BMI that was considered underweight, so these women were included with the normal-weight women for purposes of this analysis. In addition, only 7 of 175 women (4.0%) had a weight gain that was less than expected based on the Institute of Medicine recommendations, so they were grouped with the recommended weight gain group. Sensitivity analyses were
Table 1. 2009 Institute of Medicine Guidelines for Weight Gain in Pregnancy
Prepregnancy BMI Underweight Normal weight Overweight Obese
BMI (kg/m2) Less than 18.5 18.5–24.9 25–29.9 30.0 or greater
Rate of Weight Total Weight Gain, Second and Third Trimesters Gain (lb/wk) (lb) 28–40
1 (1–1.3)
25–35 15–25 11–20
1 (0.8–1) 0.6 (0.5–0.7) 0.5 (0.4–0.7)
BMI, body mass index. Data are range or mean (range) unless otherwise specified.
Gestational Weight Gain and Type 1 Diabetes
OBSTETRICS & GYNECOLOGY
undertaken excluding women with an underweight BMI and suboptimal weight gain, and the overall findings of the study were unchanged so they remained in final analysis. Maternal demographics and clinical characteristics were extracted from the chart. Diabetic nephropathy was defined as greater than 0.3 g protein on 24-hour urine collection and retinopathy assessed by patient report and review of ophthalmology records. Hemoglobin A1c values were recorded by the trimester in which they were measured. When more than one measurement per trimester was available the values were averaged, and the mean HbA1c across pregnancy was also calculated. We also abstracted the type of therapy used in each trimester and at delivery, and these were grouped based on the basal insulin therapy including either neutral protamine Hagedorn insulin, insulin glargine, or insulin pump therapy. Chronic hypertension was defined as blood pressure 140/90 mmHg or greater diagnosed before pregnancy before 20 weeks of gestation. Pregnancy outcomes were compared between women with standard and excess gestational weight gain including gestational age at delivery, preterm delivery less than 37 weeks of gestation, LGA (greater than the 90th percentile for gestational age) or small for gestational age (less than the 10th percentile for gestational age) status based on U.S. national birth weight data,11 macrosomia (defined as a birth weight greater than 4,000 g), ponderal index, placental weight, cesarean delivery, shoulder dystocia, and stillbirth. Gestational hypertension was defined as newonset resting blood pressure greater than 140/90 mmHg on two or more occasions 6 hours apart in the second half of pregnancy with absence of significant proteinuria. Mild preeclampsia was defined as a systolic blood pressure of 140 mmHg or greater or a diastolic blood pressure of 90 mmHg or greater on two occasions at least 6 hours apart occurring after 20 weeks of gestation accompanied by detectable urinary protein (1+ or greater by dipstick or 0.3 g or greater/24 hours). Severe preeclampsia was defined as a blood pressure 160/110 mmHg or greater with either a urine dipstick demonstrating 3+ or 4+ protein in a random urine sample or greater than 5.0 g of proteinuria over 24 hours. Other criteria for severe disease included eclampsia, pulmonary edema, oliguria (less than 500 mL/24 hours), fetal growth restriction, oligohydramnios, and symptoms suggestive of significant end-organ involvement (headache, visual disturbance, or epigastric or right upper quadrant pain). Superimposed preeclampsia was diagnosed in the setting of blood pressure exacerbations along with
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new-onset proteinuria (0.3 g or greater/24 hours). Neonatal outcomes included neonatal intensive care unit admission, hypoglycemia (defined as a glucose value less than 35 mg/dL within the first 24 hours of life), hyperbilirubinemia requiring phototherapy, respiratory distress syndrome, congenital anomalies, and neonatal death. Statistical analyses were completed using Stata 10 Special Edition and SAS 9.4. Distributions of variables were tested for normality using visual inspection of histograms and the Shapiro–Wilk W-test. Women with and without excess gestational weight gain were compared using x2 statistic, Fisher’s exact test, or t tests as appropriate. Effect modification by prepregnancy BMI (as a continuous variable) was assessed using the likelihood ratio test. Multivariable logistic regression analysis was used to analyze whether excess gestational gain was associated with the aforementioned pregnancy outcomes when controlling for potential confounders, including age, parity, maternal education, glycemic control, the presence of vascular complications, and prepregnancy BMI. Repeatedmeasures analysis was undertaken to examine differences in gestational weight gain per trimester between women who delivered LGA neonates compared with those that delivered appropriate-for-gestational-age neonates; this was performed only in the 137 women who had complete data on weight gain in each trimester in addition to prepregnancy and delivery weight. Mean weights in each group were plotted for each trimester, and an interaction between LGA delivery and trimester was tested to determine whether there was a difference in the pattern of weight gain across trimesters between women that delivered LGA neonates compared with those who delivered appropriate-for-gestational-age neonates. P values ,.05 were considered significant in all analyses.
RESULTS The mean weight gain was 34.1614.1 pounds (range 0–83 pounds) for the entire cohort. Excess weight gain was a common occurrence, affecting 114 of 175 (65.1%) of the overall cohort. Notably, women with excess gestational weight gain gained significantly more than the upper limits of recommended weight gain (14.8610.7 pounds). Table 2 shows the clinical characteristics of women with appropriate compared with excess gestational weight gain. As expected, women in the excess gestational weight gain group gained almost twice as much weight as those women in the appropriate weight gain group. Women with excess gestational weight gain were more likely to be overweight or obese before pregnancy, and they
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Table 2. Maternal Characteristics Associated With Gestational Weight Gain Characteristic Age (y) White race Some college education Private insurance Nulliparity Prepregnancy BMI (kg/m2) Overweight or obese Total weight gain (lb) Tobacco use Vascular complications Years disease Mean HbA1c (%) HbA1c (%) 1st trimester 3rd trimester Therapy Neutral protamine Hagedorn insulin Insulin glargine Pump therapy 1st-trimester SBP (mmHg) 1st-trimester DBP (mmHg) Chronic hypertension Hypothyroid Serum creatinine (mg/dL)
Weight Gain Within IOM Guidelines (n561)
Weight Gain Greater Than IOM Guidelines (n5114)
P
28.866.3 54 (88.5) 36 (59.0) 35 (57.4) 24 (39.3) 26.866.1 30 (49.1) 21.268.1 12 (19.7) 17 (27.9) 16.468.8 7.561.4
27.965.4 107 (94.0) 83 (72.8) 76 (66.7) 48 (42.1) 27.665.4 77 (67.5) 41.2611.5 14 (12.3) 14 (12.3) 15.267.2 7.261.2
.36 .26 .06 .22 .72 .36 .02 ,.001 .19 .01 .32 .08
8.462.1 6.961.1
7.661.7 6.761.2
.01 .35
10 (16.4)
24 (21.2)
17 (27.9) 34 (55.7) 114.8614.3 69.567.2 9 (14.8) 15 (24.6) 0.7660.57
20 (17.5) 70 (61.4) 115.6611.6 70.167.8 9 (7.9) 29 (25.4) 0.6760.14
.26 .68 .66 .16 .90 .22
IOM, Institute of Medicine; BMI, body mass index; HbA1c, hemoglobin A1c; SBP, systolic blood pressure; DBP, diastolic blood pressure. Data are mean6standard deviation or n (%) unless otherwise specified.
were also more likely to have at least some college education. Women with standard weight gain were more likely have vascular complications (either retinopathy or nephropathy). In the overall cohort the mean HbA1c values decreased from the first trimester to the third trimester (7.861.8% compared with 6.761.1%, P,.01). Women with excess maternal weight gain demonstrated lower mean HbA1c values in the first trimester, although by the third trimester, mean HbA1c values were similar between groups (Table 2). Gestational age at delivery and rates of preterm delivery were similar between women with excess gestational weight gain and those without. However, women with excess gestational weight gain had larger mean birth weights, placental weights, and their neonates had higher ponderal indices. They also experienced much higher rates of LGA birth weight and macrosomia, whereas rates of small-forgestational-age birth weight were similar between groups (Table 3). There were no significant interactions between prepregnancy BMI and gestational weight gain with regard to LGA birth weight. We performed a stratified
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analysis to assess the magnitude of the effect of excess weight gain on LGA birth weight separately in normal-weight and overweight or obese women. Excess weight gain was associated with LGA birth weight in both normal-weight (15/22 [40.5%] compared with 2 of 31 [6.5%], P5.001, odds ratio [OR] 9.9, 95% confidence interval [CI] 1.9–95.0) and overweight or obese women (33/77 [42.9] compared with 3 of 30 [10%], P5.001, OR 6.8, 95% CI 1.8–37.1, Mantel-Haenszel test for homogeneity P,.01). We next performed a multivariable logistic regression analysis to further characterize the relationship between excess maternal weight gain and LGA birth weight. Excess maternal weight gain remained independently associated with LGA birth weight after adjustment for prepregnancy BMI, vascular complications, mean HbA1c across gestation, gestational age at delivery, nulliparity, and maternal education (48/114 [42.1%] compared with 5 of 61 [8.2%], P,.001, adjusted OR 8.9, 95% CI 3.1–26.2, P,.001) (Table 4). The risk of having an LGA neonate was the same in women who achieved a mean HbA1c value 6.5% or less and those who had a mean HbA1c value greater than 6.5% (30.1 compared with 30.7%, P5.94), and
Gestational Weight Gain and Type 1 Diabetes
OBSTETRICS & GYNECOLOGY
Table 3. Obstetric and Neonatal Outcomes Outcome Gestational age at delivery (wk) Preterm birth (less than 37 wk of gestation) Birth weight (g) Placental weight (g) Ponderal index (weight/length3)3 100 LGA birth weight SGA birth weight Macrosomia Gestational hypertension Mild preeclampsia Severe preeclampsia Superimposed preeclampsia Cesarean delivery Stillbirth Shoulder dystocia NICU admission Hypoglycemia Respiratory distress syndrome Hyperbilirubinemia Congenital anomaly Neonatal death
Weight Gain Within IOM Guidelines (n561)
Weight Gain Greater than IOM Guidelines (n5114)
P
36.262.4 24 (39.3)
36.662.1 46 (40.3)
.43 .90
2,8986789 4376121 2.5260.32
3,4656833 5016141 2.6460.34
,.001 .004 .05
5 5 4 5 5 7 7 33 1 4 27 11 13 16 5 0
(8.2) (8.2) (6.6) (8.2) (8.2) (11.5) (11.5) (54.1) (1.6) (6.6) (45) (18.3) (21.7) (26.7) (8.2) (0)
48 6 31 5 10 18 21 78 1 4 44 23 18 17 6 1
(42.1) (5.3) (27.2) (4.4) (8.8) (15.8) (18.4) (68.4) (0.9) (3.5) (38.9) (29.4) (15.9) (15.0) (6.2) (0.9)
,.001 .45 .004
.53 .06 .58 .45 .44 .75 .35 .06 .45 1.0
IOM, Institute of Medicine; LGA, large for gestational age; SGA, small for gestational age; NICU, neonatal intensive care unit. Data are mean6standard deviation or n (%) unless otherwise specified.
the type of treatment used did not alter the risk for having an LGA neonate. Because of the possibility that pregnancy complications leading to preterm birth could also affect risk for LGA birth weight, we performed a sensitivity analysis including only the 126 women who delivered at or beyond 36 0/7 weeks of gestation. We found that excess maternal weight gain was associated with LGA birth weight in women who were delivered at or near term (42/83 [50.6%] compared with 5/43 [11.6%], P,.001, OR 7.8, 95% CI 2.8–21.7, P,.001), similar to our findings in the overall cohort. We also noted the strong relationship
between vascular complications and LGA birth weight. We therefore analyzed the association between gestational weight gain and LGA birth weight after excluding the 31 women with vascular complications and found that excess gestational weight gain remained significantly associated with LGA birth weight (47/100 [47%] compared with 5/44 [11.4%], P,.001, OR 6.9, 95% CI 2.5–19.0, P,.001). We then proceeded to examined weight gain patterns during each trimester for women with appropriate-for-gestational-age and LGA neonates in the 137 women with a recorded weight at all four time
Table 4. Logistic Regression Model Identifying Factors Independently Associated With Large-forGestational-Age Birth Weight Variable Weight gain greater than IOM guidelines Prepregnancy BMI Maternal education Nulliparity Vascular complications Gestational age at delivery
Unadjusted OR 8.1 1.0 1.5 0.30 0.06 1.3
(3.0–21.9) (0.98–1.10) (0.71–3.0) (0.15–0.63) (0.01–0.44) (1.1–1.6)
P ,.001 .18 .30 .001 .01 .007
Adjusted OR* 8.9 1.1 0.92 0.23 0.05 1.3
(3.1–25.6) (0.98–1.1) (0.35–2.4) (0.10–0.53) (0.01–0.46) (1.0–1.7)
P ,.001 .13 .88 .001 .008 .02
OR, odds ratio; IOM, Institute of Medicine; BMI, body mass index. * Adjusted OR represents the OR for each variable when adjusting for all other variables in the multivariable logistic regression model.
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points. Women that delivered LGA neonates were moderately heavier prepregnancy (P5.06) and significantly heavier at the first trimester, second trimester, and delivery (P,.05 for all; Fig. 1). Women who delivered LGA neonates had significantly greater first-trimester weight gain than those who delivered appropriate-for-gestational-age neonates (8.2 pounds compared with 5.3 pounds, P5.01), similar secondtrimester weight gain (14.6 pounds compared with 12.9 pounds, P5.11), and significantly greater thirdtrimester weight gain (16.8 pounds compared with 12.7 pounds, P5.002). There was a statistically significant interaction between delivery of an LGA neonate and time (P5.01), indicating that women who ultimately delivered LGA neonates were not only heavier at study entry but that they also gained more weight than their counterparts who delivered appropriate-forgestational-age neonates. As a result of the modest sample size, we lacked statistical power to compare infrequent outcomes between those with expected and excess gestational weight gain, but there was a trend toward higher rates of cesarean delivery in women with excess gestational weight gain. However, this relationship was not significant after adjustment for LGA birth weight, gestational age at delivery, overweight or obese status, and pregnancy-induced hypertension (78/114 [68.4%] compared with 33/61 [54.1%], P5.06, adjusted OR 1.3, 95% CI 0.6–2.6, P5.34). Shoulder dystocia rates were similar between groups. There were two stillbirths in the study participants, both complicated by multiple fetal anomalies (Table 3) Neonatal outcomes were similar between women with expected and excessive maternal weight gain, and there were no other significant relationships between excess gestational weight gain and other pregnancy outcomes.
DISCUSSION Excess gestational weight gain is a common occurrence in women with type 1 diabetes. This excess gestational weight gain leads to increased risk for LGA birth weight and macrosomia as well as higher ponderal indices, suggesting that the observed increase in birth weight may result from increased aiposity. The association between excess gestational weight gain and LGA birth weight was robust in both normal-weight and overweight or obese women Notably, excess weight gain as early as the first trimester results in an increased risk for LGA birth weight. We hypothesize that interventions to limit excess gestational weight gain may need to occur preconception or early in pregnancy to reduce the prevalence of LGA neonates. Macrosomic neonates of diabetic mothers have higher body fat compared with nondiabetic control neonates of similar weight and length,12 and this increased adiposity may predispose to obesity, diabetes, and cardiovascular disease later in life.13–16 Therefore, effective strategies to reduce the risk for LGA birth weight may have beneficial longterm effects on the offspring of women with type 1 diabetes. Our findings are consistent with prior studies, which have shown that excess gestational weight gain is associated with an increased risk for LGA birth weight in women with gestational diabetes17 or type 2 diabetes.18 However, the mechanisms linking excess gestational weight gain to LGA birth weight are incompletely understood. Increased body fat in patients with type 2 diabetes is associated with higher levels of proinflammatory adipocytokines, ectopic fat stores, dyslipidemia, insulin resistance, oxidative stress, and hypofibrinolysis or procoagulation,1 but additional studies are needed to understand the
Fig. 1. Trends in gestational weight gain for women who delivered largefor-gestational-age (LGA) neonates compared with appropriate-for-gestational-age (AGA) neonates. Scifres. Gestational Weight Gain and Type 1 Diabetes. Obstet Gynecol 2014.
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physiologic adaptations in pregnancies complicated by type 1 diabetes and obesity or excess gestational weight gain. Hypertriglyceridemia is an established risk factor for LGA birth weight in pregnancies complicated by gestational diabetes,19 but the effect of dyslipidemia on fetal growth in pregnancies with type 1 diabetes is unknown. There are some similarities in placental gene expression relating to fatty acid transport and activation between women with gestational diabetes and type 1 diabetes,20 suggesting that there may be common pathways to fetal overgrowth in pregnancies complicated by type 1 diabetes and other forms of diabetes. Pregnant women are counseled regarding the importance of good glycemic control, and the observed reduction in HbA1c levels across gestation suggests that this counseling was effective. More troubling is that rates of LGA were similar between women who achieved a mean HbA1c less than 6.5% and those who did not, indicating that mechanisms other than suboptimal glucose control contribute to fetal overgrowth in women with type 1 diabetes. Weight gain is a common problem with intensive insulin regimens, and this weight gain has significant metabolic effects outside of pregnancy including elevations in serum lipids, blood pressure, and abdominal obesity.5,21 This constellation of lipid abnormalities, abdominal obesity, and hypertension is similar to the central obesity–insulin resistance syndrome that is characteristic of type 2 diabetes and highlights the possibility of metabolic deterioration associated with excess weight gain in pregnant patients with type 1 diabetes. Gestational weight gain also has long-term effects on women with type 1 diabetes. Cyganek et al22 observed that women with type 1 diabetes who experienced a pregnancy weighed 2.5 kg more than their prepregnancy baseline after a median of 20 months postpartum. This long-term weight retention may have significant effects on both glycemic control and risk for cardiovascular disease, particularly for women affected by both obesity and type 1 diabetes. The retrospective nature of this cohort study and the relatively modest sample size lacked statistical power to adequately examine the association between excess gestational weight gain and rare outcomes such as shoulder dystocia or birth trauma. Our cohort included a small number of patients with underweight BMI or inadequate weight gain, so we were unable to assess the relationship between these factors and adverse pregnancy outcomes. Women in our study were mostly white and there were few women with significant vascular disease; therefore, our results may
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not be generalizable to all pregnancies complicated by type 1 diabetes. Maintaining maternal weight gain within the Institute of Medicine guidelines based on prepregnancy BMI may reduce the risk of LGA birth weight in women with type 1 diabetes. Although there are few data demonstrating how to manage weight gain in this population, intensive patient education regarding weight gain goals may be most effective if it starts preconceptionally and continues early in gestation with regular reinforcement throughout pregnancy.23,24 Future studies into the metabolic adaptations associated with excess weight gain will also identify the optimal dietary and medical targets to reduce the risk for fetal overgrowth, which may have long-term benefits for women with type 1 diabetes and their offspring. REFERENCES 1. Cleland SJ. Cardiovascular risk in double diabetes mellitus— when two worlds collide. Nat Rev Endocrinol 2012;8:476–85. 2. Conway B, Miller RG, Costacou T, Fried L, Kelsey S, Evans RW, et al. Temporal patterns in overweight and obesity in Type 1 diabetes. Diabet Med 2010;27:398–404. 3. Persson M, Norman M, Hanson U. Obstetric and perinatal outcomes in type 1 diabetic pregnancies: a large, populationbased study. Diabetes Care 2009;32:2005–9. 4. Feghali MN, Khoury JC, Timofeev J, Shveiky D, Driggers RW, Miodovnik M. Asymmetric large for gestational age newborns in pregnancies complicated by diabetes mellitus: is maternal obesity a culprit? J Matern Fetal Neonatal Med 2012;25:32–5. 5. Weight gain associated with intensive therapy in the diabetes control and complications trial. The DCCT Research Group. Diabetes Care 1988;11:567–73. 6. Rasmussen KM, Catalano PM, Yaktine AL. New guidelines for weight gain during pregnancy: what obstetrician/gynecologists should know. Curr Opin Obstet Gynecol 2009;21:521–6. 7. Jensen DM, Damm P, Moelsted-Pedersen L, Ovesen P, Westergaard JG, Moeller M, et al. Outcomes in type 1 diabetic pregnancies: a nationwide, population-based study. Diabetes Care 2004;27:2819–23. 8. Persson M, Pasupathy D, Hanson U, Norman M. Birth size distribution in 3,705 infants born to mothers with type 1 diabetes: a population-based study. Diabetes Care 2011;34:1145–9. 9. Evers IM, de Valk HW, Mol BW, ter Braak EW, Visser GH. Macrosomia despite good glycaemic control in Type I diabetic pregnancy: results of a nationwide study in The Netherlands. Diabetologia 2002;45:1484–9. 10. Persson B, Hanson U. Fetal size at birth in relation to quality of blood glucose control in pregnancies complicated by pregestational diabetes mellitus. Br J Obstet Gynaecol 1996;103:427–33. 11. Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M. A United States national reference for fetal growth. Obstet Gynecol 1996;87:163–8. 12. McFarland MB, Trylovich CG, Langer O. Anthropometric differences in macrosomic infants of diabetic and nondiabetic mothers. J Matern Fetal Med 1998;7:292–5. 13. Rijpert M, Evers IM, de Vroede MA, de Valk HW, Heijnen CJ, Visser GH. Risk factors for childhood overweight in offspring
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of type 1 diabetic women with adequate glycemic control during pregnancy: Nationwide follow-up study in the Netherlands. Diabetes Care 2009;32:2099–104. 14. Buinauskiene J, Baliutaviciene D, Zalinkevicius R. Glucose tolerance of 2- to 5-yr-old offspring of diabetic mothers. Pediatr Diabetes 2004;5:143–6. 15. Manderson JG, Mullan B, Patterson CC, Hadden DR, Traub AI, McCance DR. Cardiovascular and metabolic abnormalities in the offspring of diabetic pregnancy. Diabetologia 2002;45:991–6. 16. Kelstrup L, Damm P, Mathiesen ER, Hansen T, Vaag AA, Pedersen O, et al. Insulin resistance and impaired pancreatic b-cell function in adult offspring of women with diabetes in pregnancy. J Clin Endocrinol Metab 2013;98:3793–801. 17. Cheng YW, Chung JH, Kurbisch-Block I, Inturrisi M, Shafer S, Caughey AB. Gestational weight gain and gestational diabetes mellitus: perinatal outcomes. Obstet Gynecol 2008;112:1015–22. 18. Yee LM, Cheng YW, Inturrisi M, Caughey AB. Effect of gestational weight gain on perinatal outcomes in women with type 2 diabetes mellitus using the 2009 Institute of Medicine guidelines. Am J Obstet Gynecol 2011;205:257. e1–6. 19. Schaefer-Graf UM, Graf K, Kulbacka I, Kjos SL, Dudenhausen J, Vetter K, et al. Maternal lipids as strong determinants of fetal environment and growth in pregnancies
with gestational diabetes mellitus. Diabetes Care 2008;31: 1858–63. 20. Radaelli T, Lepercq J, Varastehpour A, Basu S, Catalano PM, Hauguel-De Mouzon S. Differential regulation of genes for fetoplacental lipid pathways in pregnancy with gestational and type 1 diabetes mellitus. Am J Obstet Gynecol 2009;201:209. e1–10. 21. Purnell JQ, Hokanson JE, Marcovina SM, Steffes MW, Cleary PA, Brunzell JD. Effect of excessive weight gain with intensive therapy of type 1 diabetes on lipid levels and blood pressure: results from the DCCT. Diabetes Control and Complications Trial. JAMA 1998;280:140–6. 22. Cyganek K, Hebda-Szydlo A, Skupien J, Janas I, Walczyk J, Lipowska A, et al. Postpregnancy glycemic control and weight changes in type 1 diabetic women. Diabetes Care 2013;36: 1083–7. 23. Phelan S, Phipps MG, Abrams B, Darroch F, Schaffner A, Wing RR. Randomized trial of a behavioral intervention to prevent excessive gestational weight gain: the Fit for Delivery Study. Am J Clin Nutr 2011;93:772–9. 24. Vinter CA, Jensen DM, Ovesen P, Beck-Nielsen H, Jørgensen JS. The LiP (Lifestyle in Pregnancy) study: a randomized controlled trial of lifestyle intervention in 360 obese pregnant women. Diabetes Care 2011;34:2502–7.
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