Diabetes Care Volume 41, August 2018 1821

Rachel T. McGrath,1,2 Sarah J. Glastras,1,2 Large-for-Gestational-Age Samantha L. Hocking,3 and Neonates in Type 1 Diabetes and Gregory R. Fulcher1 Pregnancy: Contribution of Factors Beyond Hyperglycemia Diabetes Care 2018;41:1821–1828 | https://doi.org/10.2337/dc18-0551

Despite significant reductions in serious adverse perinatal outcomes for women with type 1 diabetes in pregnancy, the opposite effect has been observed for fetal overgrowth and associated complications, such as neonatal hypoglycemia, shoulder dystocia, and admission to the neonatal intensive care unit. In addition, infants born large for gestational age (LGA) have an increased lifetime risk of obesity, diabetes, and chronic disease. Although exposure to hyperglycemia plays an im- portant role, women who seemingly achieve adequate glycemic control in preg- nancy continue to experience a greater risk of excess fetal growth, leading to LGA neonates and macrosomia. We review potential contributors to excess fetal growth in pregnancies complicated by type 1 diabetes. In addition to hyperglycemia, we REVIEW explore the role of glycemic variability, prepregnancy overweight and obesity, gestational weight gain, and maternal lipid levels. Greater understanding of the stimuli that drive excess fetal growth could lead to targeted management strategies in pregnant women with type 1 diabetes, potentially reducing the incidence of LGA neonates and the inherent risk of acute and long-term complications.

The relationship between type1 diabetes in pregnancy and adverse perinatal outcomes is universally recognized. Early in pregnancy, women with type 1 diabetes have an increased risk of miscarriage and a greater likelihood of their fetus having congenital 1Department of Diabetes, Endocrinology & Me- malformations, and prepregnancy planning with optimization of glycemic control tabolism and the Northern Clinical School, Fac- ulty of Medicine and Health, The University of reduces these risks (1). Later in pregnancy, women with type 1 diabetes are more likely Sydney, Royal North Shore Hospital, St Leonards, to experience preeclampsia, preterm birth, induction of labor, cesarean section, and Sydney, New South Wales, Australia delivery complications (2). Of note, babies born to women with type 1 diabetes 2Kolling Institute, St Leonards, Sydney, New South have significantly higher rates of being large for gestational age (LGA) (birth weight Wales, Australia 3 .90th percentile for gestational age and sex), macrosomia (birth weight .4,000 g Central Clinical School and The Boden Institute of Obesity, Nutrition, Exercise & Eating Disorders, or 8 lb 13 oz), and neonatal hypoglycemia (3). Faculty of Medicine and Health, Charles Perkins Hyperglycemia is believed to be the underlying cause for many of the adverse fetal, Centre, The University of Sydney, New South Wales, neonatal, and maternal outcomes in pregnancies complicated by type 1 diabetes; however, Australia in women with well-controlled diabetes, an increased incidence of perinatal complications Corresponding author: Rachel T. McGrath, rachel. still is observed (4). In particular, the rates of LGA neonates and macrosomia remain high, [email protected]. experienced by up to 50% of women (5), and suggest that hyperglycemia may not be the Received 12 March 2018 and accepted 7 May only driver of fetal overgrowthforwomenwith type 1 diabetes or that it may act inconcert 2018. with other factors that lead to fetal hyperinsulinemia and excess fetal weight gain. © 2018 by the American Diabetes Association. Knowledge about the clinical implications of LGA or macrosomia has increased over Readers may use this article as long as the work is properly cited, the use is educational and not the past two decades, with a broader appreciation of the effect of fetal programming for profit, and the work is not altered. More infor- on the metabolic health of the offspring. Elevated birth weight may be associated mation is available at http://www.diabetesjournals with a greater risk of obesity, type 2 diabetes, and chronic disease in later life (6). .org/content/license. 1822 LGA Neonates in Type 1 Diabetes and Pregnancy Diabetes Care Volume 41, August 2018

Furthermore, LGA neonates still experi- production enhances glucose utilization during pregnancy and maintained ence higher rates of acute perinatal com- in insulin-sensitive tissues, such as liver, at ,6% (42 mmol/mol), if possible, plications than their appropriate-weight heart, skeletal muscle, and adipose tissue, avoiding hypoglycemia. Although the tar- counterparts, including neonatal hypogly- and fetal hyperinsulinemia leads to the get HbA1c of 6% (42 mmol/mol) is con- cemia, shoulder dystocia, and admission expansion of adipocytes and increased sidered tight glycemic control for type 1 to the neonatal intensive care unit (7). fat tissue deposition. Early maternal hy- diabetes, the average HbA1c in pregnant The St. Vincent declaration of 1989 set perglycemia, such as that experienced by women without diabetes is 5% (31 mmol/ a 5-year target to reduce the risk of ad- women with type 1 diabetes in the late mol) in late pregnancy (16). The differ- verse perinatal outcomes for women with first trimester and beginning of the sec- ence between 5% (31 mmol/mol) and 6% type 1 diabetes to the level of women with- ond trimester, may prime the fetus to- (42 mmol/mol) (1% [11 mmol/mol]) cor- out diabetes (8). Despite many advances ward elevated insulin production, and responds to a higher average circulating in diabetes management and therapy, this this coincides with the gestational age at glucose of ;1.6 mmol/L (;29 mg/dL) in target has not been attained. In light of which fetal fat accretion begins (10,11). type1diabetes.Moreover,19%ofwomen the continuing high incidence of LGA and A continuous relationship exists be- with type 1 diabetes who maintain their , macrosomic infants and their greater risk of tween maternal fasting plasma glucose HbA1c 5.5% (37 mmol/mol) in the third acute and chronic complications, we eval- and birth weight, with a similar associ- trimester have LGA neonates compared uated the factors beyond hyperglycemia with 52% of women with HbA1c .6.4% ation seen for HbA1c (12,13). In addition, associated with the risk of fetal overgrowth (46 mmol/mol) (17). we recently observed that HbA1c in type 1 in type 1 diabetes and pregnancy, with a diabetes and pregnancy is significantly Although maternal hyperglycemia fi particular focus on the possible roles of and positively correlated with fetal leads to a signi cant risk of excess fetal glycemic variability, prepregnancy BMI, ges- abdominal circumference in the second growth, several studies have found no tational weight gain, and maternal lipid association between maternal glycemic and third trimesters and that HbA .6% levels (Fig. 1). This review describes perti- 1c control and fetal overgrowth or that a (42 mmol/mol) later in pregnancy is nent studies on the topic of fetal growth in reduction in hyperglycemia completely associated with an increased risk of neo- pregnancy complicated by type 1 diabetes ameliorates the risk of infants being born nates being born LGA (14), similar to the but does not intend to include an exhaustive LGA. For example, use of real-time con- findings of Maresh et al. (3). As well as list of all literature on this subject. First, we tinuous glucose monitoring (CGM) was fastingplasmaglucoseandoverallhyper- briefly review the role of maternal hyper- associated with improved glycemic cont- glycemia, elevated glucose levels during glycemia in excess fetal growth. rol and reduced the incidence of fetal specific periods of the day (late morning overgrowth and neonatal hypoglycemia, and afternoon in the second trimester yet the proportion of neonates who were MATERNAL GLYCEMIA and evening in the third trimester) are born LGA remained high at 53% (18). Glycemic Control and Hyperglycemia associated with LGA neonates in women Likewise, closed-loop insulin pump tech- Initially described by Pedersen (9), ma- with type 1 diabetes (15). Thus, the lat- nology improved glycemic control with ternal hyperglycemia in the second and est American Diabetes Association guide- less time spent in hyperglycemia; how- third trimesters of pregnancy can promote lines recommend that to reduce the risk ever, LGA births occurred in 81% of off- excess fetal weight gain through stimula- of LGA neonates, HbA1c should be tar- spring (19). Fetal hyperinsulinemia is tion of fetal hyperinsulinemia. Fetal insulin getedto6–6.5% (42–48 mmol/mol) recognized as the main causal factor for excess fetal growth, yet the association between fetal insulin levels and mater- nal glucose levels generally is not strong enough to explain all of the variation seen (20). Thus, abnormal maternal glycemia may account for some but not all of the risk of LGA neonates in type 1 diabetes and pregnancy. In other instances, either small perturbations in glycemic control leading to mild maternal hyperglycemia throughout pregnancy sufficiently stimu- late excess fetal growth in type 1 diabetic pregnancy or elements outside hyper- glycemia play a causative or contributory role.

Glycemic Variability Glycemic variability (GV), or acute fluc- tuations in blood glucose levels, occurs Figure 1—Contribution of maternal factors to fetal overgrowth in type 1 diabetes in pregnancy and possible mechanisms of action. Additional cross talk between pathways may occur through frequently in individuals with type 1 diabe- as-yet unidentified mechanisms. TG, triglyceride. tes, despite acceptable glycemic control reflected by HbA1c. The optimal method of care.diabetesjournals.org McGrath and Associates 1823

detection of GV is through the analysis of because higher indices of GV in the se- low, moderate, and high levels of mean CGM data, and CGM is an accurate tech- cond and third trimesters have been as- glucose and GV (27). nique for assessing glucose levels in preg- sociated with LGA neonates for women Of note, reductions in hyperglycemia nancy complicated by type 1 diabetes with type 1 diabetes (15). Furthermore, and GV, specifically the SD of glucose and (21). Of note, women with type 1 dia- increased GV was predictive of asym- mean amplitude of glycemic excursions betes in pregnancy experience greater metrical fetal growth and associated for women with type 1 diabetes who GV than those with gestational diabetes with an increased risk of macrosomia, used real-time CGM, have led to a lower mellitus (GDM) (22), with both significant which was attributed to fluctuations in risk of LGA neonates (18). However, the intra- and interday variability in glucose glucose rather than to time spent in absolute reductions in HbA1c, SD of glu- (23). Furthermore, CGM is a more robust hyperglycemia per se (26). In our center, cose, and mean amplitude of glycemic indicator of the time spent in hypergly- we have observed that the combina- excursions from baseline to 34 weeks of cemia in pregnancy than HbA1c (24). A tion of elevated GV and HbA1c .6% gestation for women in the real-time small study of women with and without (42 mmol/mol) in the late second tri- CGM group were 6.83% to 6.35% (51 preexisting diabetes found that average mester of type 1 diabetic pregnancy was to 46 mmol/mol), 3.1 to 2.2 (55.8 to 3-day maternal glucose levels were not associated with LGA neonates (27). In 36.9 mg/dL), and 6.0 to 4.2 mmol/L (108 to associated with birth weight, but a sig- addition, women who had LGA neonates 75.6 mg/dL), respectively. Although clini- nificant positive correlation between hy- had a significantly greater J-index (a mea- cally significant, this may not have been perglycemic excursions and birth weight sure of GV that incorporates both the a sufficient decrease in overall glucose centile was observed (25). mean and the SD of glucose to describe levels or GV to mitigate fetal overgrowth In addition to identifying transient pe- overall glycemia and variability) between because 53% of neonates in the real-time riods of hyperglycemia, CGM data can 24 and 28 weeks of gestation. Examples CGM group were, nonetheless, born LGA. be used to derive summary measures of CGM traces for women with type 1 The use of short-term glycemic markers of GV, which is relevant in pregnancy diabetes are provided in Fig. 2, showing in pregnancy rather than HbA1c has been

Figure 2—Examples of CGM traces carried out between 24 and 28 weeks of gestation in women with type 1 diabetes in pregnancy (27). A: Low mean glucose with low GV. B: Moderate mean glucose with moderate GV. C: High mean glucose with high GV. GV indicated by SD of glucose and J-index. 1824 LGA Neonates in Type 1 Diabetes and Pregnancy Diabetes Care Volume 41, August 2018

suggested because they can more accu- the contribution of GV to oxidative stress (46). The relationship between maternal rately reflect glucose excursions that occur and/or endothelial dysfunction in type 1 body weight and fetal overgrowth appears over weeks rather than months (28), which diabetes in pregnancy and the possible to be linear because the likelihood of neo- could be more relevant during gestation. effects on fetal growth in experimental nates being born with a ponderal index Third trimester 1,5-anhydroglucitol, a short- models or clinical studies would be of (birth weight in grams per length in cubic term marker of glycemic control that is benefit. Moreover, future studies should centimeters) .90th percentile was higher significantly correlated with measures of determine whether reducing glycemic ex- for obese than for overweight women with GV, was a better predictor of LGA neonates cursions in type 1 diabetes in pregnancy type 1 diabetes (42). Similarly, higher pre- than HbA1c measured at the same time contribute to lower rates of LGA neonates. pregnancy BMI compounded poor mater- point in pregnancy in women with type 1 nal glycemic control to increase the risk of diabetes (29). Furthermore, a study of dia- neonatal LGA, yet the interaction among betes complicating 85 pregnancies (includ- PREPREGNANCY BMI AND maternal BMI, hyperglycemia, and fetal ing 37 women with type 1 diabetes) showed GESTATIONAL WEIGHT GAIN overgrowth is restricted to women with 2 that 1,5-anhydroglucitol is inversely cor- Prepregnancy BMI and Maternal aBMI.23 kg/m (47). related with birth weight and may be a Obesity useful adjunct to HbA1c in the assessment The rise in obesity worldwide has led to Gestational Weight Gain of women with diabetes at risk for fetal a higher incidence of elevated prepreg- In addition to the trend toward over- overgrowth (30). Another marker of recent nancy BMI in women of reproductive weight and obesity, gestational weight glucose exposure (2–4 weeks) is glycated age. Of note, even in the absence of di- gain is increasing in women with type 1 albumin, and higher levels of glycated abetes, prepregnancy obesity increases diabetes (1). The Institute of Medicine albumin and HbA1c 1 month before birth the likelihood of fetal overgrowth (37,38). gestational weight gain guidelines rec- have been associated with LGA neonates Furthermore, the increased birth weight ommend the optimal targets for weight in GDM and preexisting diabetes in preg- observed in neonates born to obese gain in pregnancy on the basis of pre- nancy (31). Additional studies are required mothers is attributable to greater fat pregnancy BMI and further categorize to determine the utility of glycated albu- mass than lean mass because the higher weight gain as insufficient, appropriate, mincomparedwithHbA1c in type 1 dia- supply of nutrients promotes fetal hyper- or excessive (48). As is the case in preg- betes and pregnancy. insulinemia, leading to increased neonatal nancies not complicated by diabetes, ex- Exposure to short-term periods of adiposity (39,40). cessive gestational weight gain in type 1 hyperglycemia, in addition to chronic Traditionally, type 1 diabetes has been diabetes heightens the risk of macrosomia hyperglycemia, may contribute to fetal associated with a lean body type; how- (49). Although women with type 1 diabetes hyperinsulinemia, leading to a weight- ever, the number of pregnant women who become pregnant at a greater body promoting environment in utero. This is with type 1 diabetes who have a BMI in weight or gain excessive weight in preg- 2 supported by evidence that glucose ex- the overweight (.25 kg/m ) or obese nancy tend to have a higher HbA (47,50), 2 1c cursions are more predictive of macro- (.30 kg/m ) range has been increasing the relationship between accelerated fe- somia than HbA1c (32), and third trimester (41). For example, a study in Sweden tal growth and excess gestational weight peaks in glucose predict excess fetal found that the rate of overweight and gain in type 1 diabetes remains significant growth (17). In addition, animal models obesity among pregnant women with after controlling for glycemia (51) and have demonstrated that pulsatile glucose type 1 diabetes is ;45% greater than adjustment for prepregnancy BMI in pre- rather than chronic hyperglycemia leads for pregnant women without type 1 di- GDM (51,52). In addition, no difference to higher fetal insulin production (33). abetes (42). These results have been in prepregnancy BMI has been found Short-term measures of glucose fluctua- mirrored in Ireland (43), Australia (41), between women with type 1 diabetes tions, such as GV indices calculated from and Finland (44), where maternal BMI whodidordidnothaveLGAneonates,yet CGM data, 1,5-anhydroglucitol, and gly- has been independently associated with excessive gestational weight gain and cated albumin, may be more sensitive a higher likelihood of macrosomia to- HbA in the first and third trimesters fi 1c indicators of glucose patterns suf cient to gether with third trimester HbA1c (44). In were independent predictors of LGA (53). increase fetal weight gain. Another hy- fact, the combination of elevated BMI Excessive gestational weight gain also pothesis is that increased GV enhances and type 1 diabetes in pregnancy has a may be a risk factor for asymmetrical oxidative stress and endothelial dysfunc- synergistic effect, and the presence of fetalgrowthinwomenwithtype1di- tion (34). Oxidative stress is greater in both factors is estimated to increase the abetes because for every 1-lb increase pregnancies complicated by type 1 diabe- risk of LGA neonates by 13-fold (42). in maternal weight during gestation, the tes than by GDM, yet levels of breakdown Maternal obesity may compound hy- likelihood of having an asymmetrically products associated with oxidative stress perglycemia in type 1 diabetes to augment LGA infant (birth weight .90th percentile are higher in both forms of diabetes in the fetal nutrient supply, yet elevated for gestational age, race, and sex) in- pregnancy than in nondiabetic pregnancy fetal abdominal circumference as early creases by 4% (54). (35).Furthermore,arelationshipbetween as 18 weeks of gestation is associated with endothelial dysfunction in women with higher maternal BMI rather than glycemic Possible Mechanisms type 1 and type 2 diabetesdspecifically control (45). Furthermore, a prepregnancy The mechanisms underpinning the con- elevated soluble E-selectindand fetal BMI .30 kg/m2 was an independent risk tribution of maternal obesity and gesta- overgrowth has been demonstrated factor for LGA neonates in women with tional weight gain to fetal overgrowth in (36). Additional research to elucidate either type 1 or type 2 diabetes in pregnancy type 1 diabetes in pregnancy have not care.diabetesjournals.org McGrath and Associates 1825

been fully determined. Excess maternal appetite. Paradoxically, leptin levels planning in type 1 diabetes could com- weight either before or during pregnancy are increased in obese individuals who prisemanagementofglycemiaandweight could compound hyperglycemia through are thus considered to be leptin resistant, before pregnancy (1,68), with an ongo- increased insulin resistance. However, and similarly, obese pregnant women ing focus on these parameters during weight gain itself is a known significant have higher levels of leptin than their gestation. Our review of the evidence for risk factor for LGA in nondiabetic preg- lean counterparts (63). Leptin may be such management strategies is shown in nancy (55), and this association persists a surrogate marker that mirrors an un- Table 1. in type 1 diabetes in pregnancy, even derlying metabolic process responsible when tight glycemic control is achieved. for excess fetal growth. In addition, In addition, maternal obesity induces in women with type 1 diabetes, type 2 MATERNAL LIPID LEVELS insulin resistance in the fetus (56), which diabetes, and without diabetes, mater- Fatty acids are an important source of has been postulated to contribute to- nal BMI significantly correlates with fe- fuel for the growing fetus, particularly in ward greater neonatal fat mass (9,55). tal leptin levels, as has third trimester later gestation, and are vital for normal Additional nutrients (separate from HbA1c (in women with pre-GDM alone) retinal and neural development (69). Con- glucose) crossing the placenta may con- (64).Cord bloodleptin levelsare higher in sequently, maternal circulating lipid levels tribute to excess fetal growth. Fetal neonates of women with type 1 diabetes increase throughout pregnancy, and the hyperinsulinemia has long been recog- than in women with GDM or without gestational rise in lipids observed for nized to be stimulated by amino acids in diabetes, and higher leptin levels have womenwithtype1diabetesissimilarto addition to glucose and leads to in- been associated with increased birth that seen in nondiabetic pregnancy (70). creased fetal adiposity and birth weight weight and LGA neonates (65). Further- Recently, low HDL levels throughout (57,58). Moreover, some macrosomic more, despite no difference in maternal type 1 diabetic pregnancy were associ- infants born to mothers without diabetes HbA1c during pregnancy, these infants are ated with LGA neonates, as were higher are hyperinsulinemic (55). Excessive ges- more likely to be overweight or obese at triglycerides in the first and third trimes- tational weight gain is associated with 7 years of age (66). Fetal leptin levels also ters (71). Of note, these relationships higher levels of circulating fatty acids are correlated with fetal IGF-1, a key were independent of maternal prepreg- (59), and in lean women with type 1 diab- regulator of fetal growth, and a signifi- nancy BMI, gestational weight gain, and etes, fetal weight correlates with plasma cant positive association exists between HbA1c, suggesting a separate role for amino acid levels (58). Furthermore, a cord blood IGF-1 and neonatal adiposity lipids in modulating fetal growth. Simi- positive relationship between maternal in pregnant women without diabetes larly, Gobl¨ et al. (72) observed that BMI and cord blood amino acid levels (67). elevated triglycerides and low HDL levels has been observed independent of ma- In summary, in addition to hypergly- in the third trimester are predictive of ternal fasting plasma glucose (60). With cemia, weight gain above the recom- LGA neonates in women with pre-GDM. the increase in obesity in pregnant wo- mended rates in pregnancy contributes to Furthermore, type 1 diabetes has been menwithtype1diabetes,aminoacid excess fetal weight gain and macrosomia, showntoleadtoincreasedplacental transfer across the placenta may be possibly through fetal overnutrition and triglyceride concentrations and a greater greater (61), and fatty acid transfer may hyperinsulinemia, together with altera- fetal-to-maternal triglyceride ratio, indi- be upregulated (as evidenced in obese tions in adipokine levels. These data sug- cating an augmented transfer of lipids women with type 2 diabetes [62]) (Fig. 1). gest that interventions targeting both across the placenta (73). This finding has Another potential mediator of fetal maternal blood glucose levels and body been confirmed by microarray analyses weight gain is leptin, a hormone se- weightmayresultinthebestenvironment demonstrating an upregulation of genes creted from adipocytes that suppresses for the growing fetus, and prepregnancy related to lipid pathways in the placentas

Table 1—Modifiable maternal factors and possible management strategies to target individual factors Modifiable factor Management strategy Evidence*

Hyperglycemia Maintaining HbA1c ,6.5% (48 mmol/mol) or ,6% Strong (3,18). Many studies have demonstrated that lower (42 mmol/mol), where possible, before and HbA1c in type 1 diabetes in pregnancy can reduce the throughout gestation incidence of LGA neonates. GV Reducing frequent excursions in blood glucose levels Minimal (18,26,27). Additional prospective clinical studies are required. Maternal obesity Losing weight before pregnancy to achieve a Moderate (42,44). Studies are yet to be carried out in type 1 BMI ,25 kg/m2 diabetes in pregnancy. Gestational weight gain Minimizing weight gain throughout pregnancy to keep Moderate (47,49). Studies are yet to be carried out in type 1 in line with Institute of Medicine guidelines (48) diabetes in pregnancy. Maternal lipid levels Lowering maternal triglyceride levels through dietary Minimal (72,73). Further prospective clinical studies are manipulation required. The aim of reducing the incidence of LGA neonates in type 1 diabetes in pregnancy are outlined. *The evidence is graded as minimal, moderate, or strong, where minimal indicates that supporting literature includes mechanistic or associative studies only, moderate indicates minimal evidence along with evidence in studies outside type 1 diabetes in pregnancy, and strong indicates minimal and moderate evidence as well as direct evidence from studies in type 1 diabetes in pregnancy. 1826 LGA Neonates in Type 1 Diabetes and Pregnancy Diabetes Care Volume 41, August 2018

of type 1 diabetic pregnancies, specifically contribute to fetal hyperinsulinemia and ac- 4. Evers IM, de Valk HW, Mol BW, ter Braak EW, fatty acid uptake and transport (74). celerated fetal growth; thus, reducing GV Visser GH. Macrosomia despite good glycaemic Moreover, venous cord blood levels of could prevent excess fetal weight gain, control in Type I diabetic pregnancy; results of a nationwide study in The Netherlands. Diabeto- fatty acids are significantly increased in but large prospective studies are required logia 2002;45:1484–1489 pregnancies complicated by type 1 di- to confirm this. Moreover, the utility of 5. Mackin ST, Nelson SM, Kerssens JJ, et al.; abetes compared with nondiabetic preg- HbA1c in type 1 diabetes and pregnancy SDRN Epidemiology Group. Diabetes and preg- nancies (75). is unclear, and the use of short-term gly- nancy: national trends over a 15 year period. – We hypothesize that an enhanced cemic markers may play a role in identifying Diabetologia 2018;61:1081 1088 6. Oken E, Gillman MW. Fetal origins of obesity. supply of fatty acids to the fetus, in con- women with type 1 diabetes at risk for Obes Res 2003;11:496–506 junction with fetal hyperinsulinemia, delivering LGA neonates. Prepregnancy ma- 7. Yamamoto JM, Kallas-Koeman MM, Butalia S, accelerates the incorporation of fatty ternal obesity and gestational weight gain Lodha AK, Donovan LE. Large-for-gestational-age acids into adipocytes, leading to greater in type 1 diabetes exacerbate the effects (LGA) neonate predicts a 2.5-fold increased odds fetal adiposity. Szabo and Szabo (76) of maternal hyperglycemia on fetal over- of neonatal hypoglycaemia in women with type 1 fi diabetes. Diabetes Metab Res Rev 2017;33:e2824 were the rst to suggest that maternal growth, and more interventional studies 8. Colstrup M, Mathiesen ER, Damm P, Jensen DM, free fatty acids cross the placenta to the are needed to determine whether strate- Ringholm L. Pregnancy in women with type 1 fetal circulation where they are taken gies to reduce weight before pregnancy diabetes: have the goals of St. Vincent declaration up by developing adipocytes, and fatty or minimize gestational weight gain ame- been met concerning foetal and neonatal compli- acids, rather than glucose, are the pri- liorates the risk of LGA neonates. Further- cations? J Matern Fetal Neonatal Med 2013;26: 1682–1686 mary cause of fetal adiposity. In addition, more, decreasing maternal triglyceride 9. Pedersen J. Weight and length at birth of women with an elevated prepregnancy levels in both early and late pregnancy infants of diabetic mothers. 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Analysis weight loss before pregnancy or a diet G.R.F. were involved in the design of the review, of continuous glucose monitoring in pregnant contributed to and edited the manuscript, and women with diabetes: distinct temporal patterns lower in triglycerides on fetal overgrowth approved the final version before submission. maybewarranted. of glucose associated with large-for-gestational- R.T.M. is the guarantor of this work and, as such, age infants. Diabetes Care 2015;38:1319–1325 had full access to all the data in the study and 16. Nielsen LR, Ekbom P, Damm P, et al. HbA1c takes responsibility for the integrity of the data levels are significantly lower in early and late CONCLUSIONS and the accuracy of the data analysis. pregnancy. Diabetes Care 2004;27:1200–1201 The management of type 1 diabetes in 17. Damm P, Mersebach H, Rastam˚ J, et al. Poor References pregnancy centers on insulin therapy to pregnancy outcome in women with type 1 di- 1. Owens LA, Egan AM, Carmody L, Dunne F. 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