Maternal Glycemia and Risk of Large for Gestational Age Babies in a Population- Based Screening

Diabetes Care Publish Ahead of Print, published online September 3, 2009

Maternal glycemia and macrosomia

Maternal glycemia and risk of large for gestational age babies in a population- based screening

Running title: Maternal glycemia and macrosomia

Zsuzsa Kerényi, MD, PhD1,2, Gyula Tamás, MD, PhD1,3, Mika Kivimäki, PhD4,5, Andrea Péterfalvi1,2, Eszter Madarász, MD1,2,6, Zsolt Bosnyák, MD, PhD1,7, Adam G. Tabák, MD, PhD1,3,4

1 – National Centre for Diabetes Care, Budapest, Hungary 2 – Csepel Health Service, Department of Diabetology, Budapest, Hungary 3 – Semmelweis University Faculty of Medicine, 1st Department of Medicine, Budapest, Hungary 4 – University College London, Department of Epidemiology and Public Health, London, United Kingdom 5 – Finnish Institute of Occupational Health, Helsinki, Finland 6 – Semmelweis University School of PhD Studies, Budapest, Hungary 7 – Ferencváros Health Service, Budapest, Hungary

Corresponding author: Ádám Gy. Tabák, MD, PhD Email: [email protected]

Additional information for this article can be found in an online appendix at http://care.diabetesjournals.org

Submitted 15 June 2009.and accepted 25 August 2009.

This is an uncopyedited electronic version of an article accepted for publication in Diabetes Care. The American Diabetes Association, publisher of Diabetes Care, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher- authenticated version will be available in a future issue of Diabetes Care in print and online at http://care.diabetesjournals.org.

Objective – Gestational diabetes is a risk factor for large for gestational age (LGA) newborns, but many LGA babies are born to normal glucose tolerant mothers. We aimed to clarify the association of maternal glycemia across the whole distribution with birthweight and risk of LGA births in normal glucose tolerant mothers.

Research Design and Methods – We undertook a population based gestational diabetes screening in an urban area of Hungary in 2002-2005. All singleton pregnancies of mothers ≥18 years of age, without known diabetes or gestational diabetes (WHO criteria) and data on 75g oral glucose tolerance test at 22-30 weeks of gestation were included (n=3787, 78.9% of the target population). LGA was determined as >90th percentile using national sex and gestational age specific charts.

Results – Mean±SD maternal age was 30±4 years, BMI 22.6±4.0 kg/m2, fasting blood glucose 4.5±0.5 mmol/L and postload glucose 5.5±1.0 mmol/L. The mean birthweight was 3450±476 grams at 39.2±1.2 weeks of gestation. There was a U-shaped association of maternal fasting glucose with birthweight (pcurve=0.004) and risk of having a LGA baby (lowest values between 4-4.5 mmol/L, pcurve=0.0004) with little change after adjustments for clinical characteristics. The association of postload glucose with birthweight (p=0.03) and the risk of LGA (p=0.09) was weaker and linear.

Conclusions – Both low and high fasting glucose at 22-30 weeks of gestation are associated with increased risk of LGA newborn. We suggest that the excess risk related to low glucose reflects the increased use of nutrients by LGA fetuses that also affects the mothers’ fasting glucose.

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he presence of a large fetus (either distribution, but cannot detect any true effect defined by a weight cut-off or as large of low glucose levels on the risk of T for gestational age, LGA) is associated macrosomia. with multiple risks for both the mother and To clarify the association between the newborn. Short-term risks include a 2-3 maternal glucose and newborn size, we set fold increase in intrauterine death rate, a out to investigate in detail the association of higher probability of operative delivery and fasting and 2-hour postload glucose with several neonatal morbidities (e.g. shoulder birthweight and the risk of LGA newborns in dystocia and brachial plexus injuries), and normal glucose tolerant women drawn from a increased risk of maternal injuries (i.e. general population. perineal laceration). There are also long-term risks for the newborn, such as diabetes RESEARCH DESIGN AND METHODS mellitus later in life, obesity, and the Subjects and design. In 1999 a development of metabolic syndrome. (1) universal, population-based screening Maternal uncontrolled pregestational and program for gestational diabetes was launched gestational diabetes mellitus are important at the Szent Imre Teaching Hospital in risk factors for macrosomia and LGA Budapest, Hungary. Screening was carried out newborns (1,2) and evidence from using a 75g Oral Glucose Tolerance Test randomized controlled trials on the treatment (OGTT) according to WHO criteria. (16) The of gestational diabetes supports a causal link program was approved by the Szent Imre between maternal hyperglycemia and risk of Hospital Ethics Committee. The institute is macrosomia. (3,4) located in Budapest and serves an urbanized Recently, some reports have raised the population of about 200,000. After the first 2 possibility that the association of fasting years of the screening program, ascertainment glucose and 2-hour postload glucose with rate was over 99% of all pregnant women birthweight and risk of macrosomia may delivered in the hospital. (17,18) actually be U-shaped such that both high and The screening database captured 5335 low levels of maternal glucose are related to pregnancies between January 1, 2002 and elevated risk of having large babies. (5-7) To April 30, 2005. Our target population did not date, however, evidence to support this include women less than 18 years of age at curvilinear association is weak. The largest the time of delivery (n=8), twin pregnancies observational study addressing this question, (n=115) or women with known pregestational the HAPO study, was unable to prove any or gestational diabetes mellitus (n=411), significant deviation from linearity in the leaving a total of 4801 pregnancies for further association between fasting and postload analysis. We excluded 641 women with an glucose and the risk of LGA babies. However, early or late OGTT (<22 or >30 weeks of this multicenter study had to correct the level gestation at the time of analysis), 45 due to of significance for multiple testing potentially missing birthweight data or delivery before 24 increasing risk of false null findings. (8) Most weeks of gestation, 266 due to missing or other population-based studies did not incomplete blood glucose data, and 62 due to formally tested non-linearity in the blood missing data on covariates. Thus, the final glucose - macrosomia association. (5-7,9-15) analytic sample consisted of 3787 pregnancies Moreover, many studies were based on non- (78.9% of the pregnancies in the target fasting maternal glucose measurements which population). allow analysis of the high end of the glucose

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Measurements. All 75g OGTTs were smoking status during pregnancy (yes/no), carried out in the morning hours (before 10 ethnicity (Caucasian/other), and parity (0, 1, a.m.) between 22-30 weeks of gestation. ≥2) were recorded. Women were instructed to follow an Statistical analysis. Descriptive unrestricted diet for at least 3 days before the statistics are given as mean ± standard test and to come for the investigation after at deviation (SD) for continuous variables and least 8 hours of fasting. After the collection of percentages for categorical variables. After fasting blood sample, women were asked to investigation of crude frequencies of LGA drink 75 grams of anhydrous glucose in 250– babies according to fasting and 2-hour 300 ml water. Blood samples, also taken 2 postload glucose categories, we computed hours after the glucose load, were collected binary logistic regression models with LGA into fluoride containing tubes. Venous plasma as the outcome and glucose categories as glucose was measured in the central dummy variables (fasting glucose: ≤3.5, 3.51- laboratory of the hospital using a glucose- 4.0, 4.01-4.5, 4.51-5.0, 5.01-5.5, ≥5.51 oxidase based method. Gestational diabetes mmol/L, 2-hour postload glucose: ≤4.0, 4.01- mellitus was diagnosed if either the fasting 4.8, 4.81-5.6, 5.61-6.4, 6.41-7.2, ≥7.21 venous plasma glucose was ≥7.0 mmol/l or mmol/L) the third category being the the 2-hour post-load venous plasma glucose reference category in both analyses. Odds was ≥7.8 mmol/l. ratios and 95% confidence intervals were Data on birthweight and sex of the adjusted for ethnicity, parity of the mother newborn were extracted from the discharge and the sex of the newborn (model 1), and documentation. LGA was determined as a then further adjusted for maternal age, BMI, birthweight above the 90th percentile on sex smoking, family history of diabetes, and gestational age specific national charts. gestational age at the OGTT, mean arterial (19) blood pressure, and height (model 2). Similar Gestational age was primarily based generalized linear models using logit link on the date of the last menstrual period and were computed using continuous fasting and was substituted by the result of a first postload blood glucose and their squared trimester ultrasound examination (about 8-12 terms (to test for non-linearity) as weeks of gestation) if information on the last independent variables instead of glucose menstrual period was missing or there was a categories and to estimate probabilities and more than 2 week discrepancy between the 2 their confidence intervals on continuous estimates. glucose scales. At the time of the OGTT, Further analyses applying general anthropometric measurements (height and linear modeling examined associations of weight) were performed and body mass index maternal glucose with birthweight describing (BMI) was calculated. Systolic and diastolic crude and adjusted birthweights (and standard blood pressure (SBP and DBP) was errors) in the above glucose categories. Then determined by a trained nurse using a we applied similar models to test for linear standard mercury sphygmomanometer. The and curvilinear trends in these associations mean arterial pressure (MAP) was calculated with linear and quadratic glucose terms (as as (2xDBP+SBP)/3. After delivery a detailed required). We estimated birthweights from questionnaire was completed during a face-to- these models after adjusting for covariates face interview by a trained researcher (A.P.). (model 1 and model 2) as described above. Family history of diabetes mellitus among All statistical analyses were done using SPSS first degree relatives, age of the mother,

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for Windows 16.0. A two-tailed p<0.05 was crude birthweight showed a U-shaped considered statistically significant. association with the predefined fasting RESULTS glucose categories with the lowest values in Characteristics of the mothers and the third group (4.01-5.0 mmol/L) and higher newborns and pregnancy outcomes are values at both ends of the glucose distribution summarized in Table 1. The mean age of the (Table 3). The association between subjects was 29.7 year, and the mean fasting continuous maternal fasting glucose levels and 2-hour postload glucose levels were 4.5 and birthweight followed a quadratic and 5.5 mmol/L. There were 12 stillbirths and function; the lowest birthweight values were no maternal deaths in the target population. between 4 and 4.5 mmol/L (pcurve<0.0001 for Risk of LGA newborns according to model 1) (Figure 1B). This association was the fasting and 2-hour postload glucose robust to adjustments covariates (, pcurve=0.01 levels. The frequency of LGA newborns for model 2, detailed data not shown). across the predefined fasting and postload There was a linear association glucose categories is shown in Table 2. between 2-hour postload glucose and Fasting blood glucose showed a non-linear birthweight (p=0.03 for model 1) with no relationship with the risk of LGA: compared evidence of curvilinearity (Table 3, Figure to the reference group (4.01-4.5 mmol/L) both 1C). Again, further adjustment had little lower and higher maternal fasting glucose effect on the models (p=0.002 for model 2, levels were associated with increased risk detailed data not shown). (Table 2). The curvilinear association was statistically significant in a model CONCLUSIONS simultaneously including continuous fasting Short summary. In this population- glucose and its square irrespective of based screening program of gestational adjustments (pcurve=0.004 for model 1, diabetes mellitus using a 75g OGTT, the risk pcurve=0.04 for model 2) (Figure 1A). of large for gestational age newborns was Postload glucose showed a weaker non-linearly related to fasting glucose levels association with the risk of LGA and only the among predominantly Caucasian women highest maternal glucose category was related residing in an urban area of Hungary. to elevated risk in a model adjusted for sex, Increased risk was found at both ends of the ethnicity, and parity. However, this maternal fasting glucose distribution. The association was attenuated and became non- association between fasting glucose and significant after further adjustments (Table birthweight of the newborns was similarly U- 2). In the logistic regression analysis using shaped with the lowest values found between continuous glucose values as predictors, the 4 and 4.5 mmol/L. In contrast, 2-hour squared term was non-significant (pcurve=0.46) postload glucose showed only a borderline and the linear association between postload relationship with the risk of LGA and the glucose and the risk of LGA was weak and association with birthweight was linear and only borderline significant (odds ratio [OR] weaker than that for fasting glucose. 1.08, 95% CI 0.99-1.17, per 1 mmol/L increase in postload glucose, p=0.08 for Comparison with other studies. model 1; OR 1.07, 95% CI 0.98-1.17, per 1 Although there are several population-based mmol/L increase in postload glucose, p=0.13 screening studies for gestational diabetes, for model 2). only a few report fasting glucose values at the Birthweight according to the fasting time of the screening. (5,7-11,13,14,20) This and 2-hour postload glucose levels. The is not surprising in the light of the fact that the

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widely accepted ADA Position Statement glucose levels and suggests no deviation from generally recommends a prescreening with a linearity. (5) glucose challenge test that is performed The literature is not much more irrespective of fasting status. An OGTT is detailed on the relationship between fasting recommended only in the case of an abnormal glucose and birthweight. There are at least 4 result. (21) studies reporting positive correlations with However, at least six previous studies various strengths between birthweight and had data on maternal fasting glucose. Two of fasting glucose without testing for non- the medium sized studies did not report tests linearity. (11,13,14,20) One of these for non-linearity or risk for categorical investigated the shape of the fasting glucose- glucose groups thus being uninformative birth weight relationship and found that the regarding the U-shaped association between linear association between fasting glucose and fasting glucose and the risk of LGA. (9,20) birthweight holds only for the middle ranges Two other studies reported formal tests of of the glucose distribution. (7) non-linearity for fasting glucose-LGA We did not observe a U-shaped relationship: One found no clear inflection association between postload glucose and size point for these associations, but observed an of newborn and the linear trend found was elevated risk in the lowest glucose category. only suggestive. In previous studies, a linear (7) The HAPO study found no significant relationship between 2-hour postload glucose deviation from linearity. (8) Despite of its and the risk of LGA or macrosomia is a very large sample size, some circumstances frequent observation before adjustment for should be mentioned that might have reduced covariates. (5,7-10,12,15) While some studies sensitivity to observe elevated LGA at the low report strong linear relationship after several end of maternal fasting glucose. First, the adjustments (8,9), others, similarly to us, HAPO study involved a multinational, found weak or non-significant relationships multiethnic population leading to several tests between postload glucose and the risk of LGA for interactions in the analysis limiting the or macrosomia. (5,10) In our study, this power for showing a relationship that might observation was related to normal glucose only hold for certain ethnicities. Second, due tolerant mothers, that is, those with the low to the excessive number of outcomes and moderate, but not the high-end of the 2- investigated, the HAPO investigators had to hour postload glucose distribution (glucose correct their p-values for multiple testing levels < 7.8 mmol/L). In general, the 2-hour which may have increased the risk of a type I postload glucose seems to be a weaker error (rejecting a null hypothesis when it is predictor of birthweight than fasting glucose true). Third, in the categorical analysis of similarly to our findings with or without fasting glucose, their lowest group was further adjustments. (7,14,15) defined as glucose levels < 4.2 mmol/L which Possible mechanisms. Elevated risk does not differentiate the three lowest of an LGA newborn and an increased categories used in the present analysis. (8) birthweight at the high end of the maternal Furthermore, when we combined the first 3 glucose distribution supports the Pedersen groups into one category in our data, the hypothesis that suggests that maternal relationship between fasting glucose hyperglycemia (even within the normal range) categories and LGA seems to be linear (data increases the levels of fetal insulin leading to available on request). There is a further study accelerated growth and macrosomia in the that reports on macrosomia (birthweight over fetus. (22) We propose fetal hyperinsulinemia a certain cutoff value) as a function of fasting as a plausible mechanism underlying the

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association between low fasting glucose and unlikely to have selectively removed the risk of LGA newborns. Fetal insulin is smaller babies from the lowest categories or probably the most important growth hormone the larger babies from the middle ranges, so during the intrauterine development and we think that our findings of a nonlinear increases in fetal insulin levels are related to association of fasting glucose with accelerated growth. (1,2) Fetal birthweight and macrosomia are valid. We hyperinsulinemia may lead to lower maternal used the latest published percentile charts for glucose levels by increasing feto-placental the definition of the large for gestational age siphoning of maternal glucose in newborns however it is obviously does not normoglycaemic mothers. (2,23) In line with correspond to our target population given the this reasoning, there is some evidence to show 16.5% rate of LGA in this study.(19) This is a decrease in glucose levels as gestation in agreement with an overall increase in the progresses in women with hyperinsulinemic prevalence of large babies worldwide. (1) We newborns while glucose levels are increasing believe that a general increase in birthweight in mothers with normoinsulinemic newborns. would not invalidate our findings on the risk (24) All the above together suggests a of LGA and definitely would not effect the common mechanism (fetal hyperinsulinemia) associations found for birthweight. However, linking lower fasting glucose levels and the we investigated a surrogate pregnancy risk of LGA or increased birthweight. Further outcome, and thus it remains unclear whether studies are warranted to test this hypothesis. the LGA babies of mothers with decreased Study strengths and limitations. Our fasting glucose have an otherwise poor study benefits from the universal use of the obstetric outcome compared to normal weight 75g OGTT in an ethnically homogeneous babies. population as this allowed us to reliably Implications. In a large-scale study explore the low-end of the glucose we found that the prediction of a large for distribution. A similar shape of the gestational age newborn and birthweight may association was confirmed both for be improved by adding the square of fasting categorical and continuous glucose levels as glucose value to the known predictors. predictors and we were able to adjust for a Further research is needed to determine wide range of known confounders of whether our findings are generalizable to macrosomia in our analysis. The women who other populations and to examine fetal were excluded based on missing data were hyperinsulinemia and other potential more likely to be from ethnic minorities and underlying mechanisms for the excess risk of to be smokers, but their general characteristics LGA babies among mothers with low fasting were very similar to the investigated glucose. population; thus it is unlikely that this had a large effect on our findings (see online ACKNOWLEDGEMENTS appendix which is available at The research was supported by the http://care.diabetesjournals.org). Although Hungarian Scientific Medical Council (ETT the exclusion of women meeting the WHO 254/2000). The authors report no other criteria for gestational diabetes reduced the potential conflict of interest to disclose. high end of the glucose distribution, this is

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15. Little RR, McKenzie EM, Shyken JM, Winkelmann SE, Ramsey LM, Madsen RW, Goldstein DE: Lack of relationship between glucose tolerance and complications of pregnancy in nondiabetic women. Diabetes Care 1990;13:483-487 16. Alberti KG, Zimmet PZ: Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998;15:539-553 17. Kerényi Z, Péterfalvi A, Bosnyák Z, Madarász E, Tabák ÁG, Szánthó J, Rákóczi I, Tamás G. Incidence of gestational diabetes mellitus: results of a validated universal screening (Abstract). Diabetologia 2004;47:A104 18. Tabák Á, Tamás G, Péterfalvi A, Bosnyák Z, Madarász E, Rákóczi I, Kerényi Z: The effect of paternal and maternal history of diabetes mellitus on the development of gestational diabetes mellitus. J Endocrinol Invest DOI: 10.3275/6293 19. Joubert K: Magyar születéskori testtömeg- és testhossz-standardok az 1990-96. évi országos élveszületési adatok alapján. Magy Noorv Lapja 2000;63:155-163 20. Ong KK, Diderholm B, Salzano G, Wingate D, Hughes IA, MacDougall J, Acerini CL, Dunger DB: Pregnancy insulin, glucose, and BMI contribute to birth outcomes in nondiabetic mothers. Diabetes Care 2008;31:2193-2197 21. American Diabetes Association: Standards of medical care in diabetes--2008. Diabetes Care 2008;31:S12-S54 22. Pedersen J: Weight and length at birth of infants of diabetic mothers. Acta Endocrinol (Copenh) 1954;16:330-342 23. Nolan CJ, Proietto J: The feto-placental glucose steal phenomenon is a major cause of maternal metabolic adaptation during late pregnancy in the rat. Diabetologia 1994;37:976- 984 24. Weiss PA, Scholz HS, Haas J, Tamussino KF: Effect of fetal hyperinsulinism on oral glucose tolerance test results in patients with gestational diabetes mellitus. Am J Obstet Gynecol 2001;184:470-475

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Table 1. Characteristics of study subjects and their newborns (n=3787)

Interquartile Characteristic Percent Mean ± SD range Maternal characteristics Age (yrs) 29.7 ± 4.2 27.1 – 32.3 Body mass index (kg/m2)* 25.2 ± 4.0 22.4 – 27.0 Caucasian (%) 98.4% Mean arterial pressure (mmHg)* 81.4 ± 9.1 73.3 – 86.7 Blood glucose (mmol/L)* Fasting 4.5 ± 0.5 4.2 – 4.8 2-hour 5.5 ± 1.0 4.8 – 6.2 Length of gestation at the time of OGTT (wks) 25.5 ± 1.8 24 – 27 Any smoking during pregnancy (%) 4.4% Diabetes among first degree relatives (%) 12.8% Nulliparous (%) 56.9% Newborn characteristics Gestational age at delivery (wk) 39.2 ± 1.2 39-40 Birthweight (g) 3450 ± 476 3150 – 3750 Male sex (%) 51.6% Large for gestational age (%)† 16.5% * Age, body mass index, and mean arterial pressure were obtained at the OGTT (22-30 weeks of gestation). † Large for gestational age was determined as a birthweight above the 90th percentile on sex and gestational age specific national chart

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Table 2. Risk of large for gestational age newborns by fasting and 2-hour postload glucose categories in 3787 singleton pregnancies.

LGA / Total number % LGA* Model 1† Model 2‡ OR 95%CI OR 95%CI Fasting glucose categories

(mmol/L) ≤3.5 23 / 137 16.8% 1.28 0.79-2.06 1.33 0.81-2.19 3.51-4.0 84 / 489 17.2% 1.33 1.003-1.77 1.38 1.03-1.86 4.01-4.5 178 / 1300 13.7% 1 (ref.) 1 (ref.) 4.51-5.0 230 / 1357 16.9% 1.27 1.03-1.57 1.25 1.00-1.56 5.01-5.5 84 / 417 20.1% 1.53 1.15-2.05 1.36 1.00-1.83 ≥5.51 25 / 87 28.7% 2.45 1.50-4.03 1.84 1.08-3.15 2-hour postload glucose categories (mmol/L) ≤4.0 42 / 275 15.3% 1.00 0.69-1.45 1.02 0.69-1.50 4.01-4.8 120 / 710 16.9% 1.15 0.89-1.49 1.16 0.88-1.51 4.81-5.6 164 / 1106 14.8% 1 (ref.) 1 (ref.) 5.61-6.4 165 / 957 17.2% 1.19 0.94-1.51 1.21 0.95-1.55 6.41-7.2 94 / 550 17.1% 1.18 0.90-1.56 1.19 0.89-1.59 ≥7.21 39 / 189 20.6% 1.50 1.02-2.23 1.43 0.95-2.17

* Large for gestational age was determined as a birthweight above the 90th percentile on sex and gestational age specific national charts. † Model 1 is adjusted for ethnicity, parity of the mother and the sex of the newborn. ‡ Model 2 is adjusted for ethnicity, parity of the mother, the sex of the newborn, maternal age, BMI, smoking, family history of diabetes, gestational age at the OGTT, mean arterial blood pressure, and height. Maternal glycemia and macrosomia

Table 3. Birthweight by fasting and 2-hour postload glucose categories in 3787 singleton pregnancies.

Crude birthweight (g) Model 1* Model 2† mean 95% CI mean 95%CI mean 95%CI Fasting glucose categories

(mmol/L) ≤3.5 3496 3417-3576 3525 3447-3604 3529 3451-3606 3.51-4.0 3447 3405-3489 3477 3435-3520 3491 3449-3532 4.01-4.5 3397 3371-3423 3423 3396-3450 3437 3410-3464 4.51-5.0 3466 3440-3491 3492 3465-3518 3496 3470-3522 5.01-5.5 3535 3490-3581 3553 3508-3599 3528 3483-3572 ≥5.51 3537 3437-3637 3559 3461-3657 3549 3452-3646 2-hour postload glucose categories (mmol/L) ≤4.0 3440 3383-3496 3459 3403-3515 3453 3398-3508 4.01-4.8 3427 3392-3462 3451 3416-3487 3443 3409-3478 4.81-5.6 3450 3422-3478 3479 3449-3508 3486 3458-3515 5.61-6.4 3454 3424-3485 3479 3448-3511 3488 3458-3519 6.41-7.2 3466 3426-3506 3498 3457-3538 3511 3471-3550 ≥7.21 3484 3416-3552 3521 3453-3588 3530 3465-3595

* Model 1 is adjusted for ethnicity, parity of the mother and the sex of the newborn. † Model 2 is adjusted for ethnicity, parity of the mother, the sex of the newborn, maternal age, BMI, smoking, family history of diabetes, gestational age at the OGTT, mean arterial blood pressure, and height.

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Figure 1. Estimated probability of a large for gestational age newborn by continuous fasting blood glucose (A) and estimated birthweight according to continuous fasting (B) and 2-hour postload (C) glucose levels adjusted for ethnicity, parity of the mother and the sex of the newborn.

Error bars show 95% confidence interval around the estimates.