Introduction
Gestational diabetes mellitus (GDM) affects around 10% of all pregnancies and is defined as hyperglycemia or any degree of glucose intolerance that begins, or is first recognized, during pregnancy, excluding pregestational diabetes that is first discovered in pregnancy.1 The incidence of GDM varies with patients’ racial background and by region or country. For example, the United States Centers for Disease Control and Prevention estimates that GDM affects 2%–10% of pregnancies in the US.2 On the other hand, a study by Bashir et al.3 found that it complicates 24% of pregnancies in Qatar. GDM screening recommendations and guidelines differ from one country to another and estimating the cost-benefit analysis of such screening therefore also varies across countries. The International Federation of Gynecology and Obstetrics recommends that all pregnant women undergo testing for hyperglycemia during pregnancy using a one-step procedure. Likewise, the American College of Obstetricians and Gynecologists recommend that all pregnant women undergo a laboratory-based screening test at 24–28 weeks of gestation.5 On the other hand, the UK’s National Institute for Health and Care Excellence recommend screening pregnant women using risk-stratification involving factors such as body mass index (BMI), prior history of GDM, and family history of diabetes.6 The diagnostic criteria for GDM also vary amongst the different guidelines.
GDM is associated with several fetal and maternal complications. Maternal complications include increased risk of pre-eclampsia, gestational hypertension, operative vaginal and cesarean delivery, genital tract trauma, postpartum hemorrhage, progression to type 2 diabetes mellitus after pregnancy, and an eight-fold risk of developing metabolic syndrome later in life.7 Fetal and neonatal complications include congenital malformations, fetal macrosomia defined as birth weight >90th percentile for gestational age, birth trauma including shoulder dystocia, transient hypoglycemia, polycythemia, hyper-bilirubinemia, and stillbirth.8,9 The aims of this review were to explore the interconnected relationship between gestational diabetes, maternal obesity, and fetal macro-somia.
Maternal obesity and gestational diabetes
Globally, the incidence of GDM is increasing in parallel with that of maternal obesity.10 It is now widely recognized that maternal obesity (defined as BMI ≥30 kg/m2) is a strong risk factor for the development of GDM.11 There are several studies demonstrating a significant association between maternal obesity and GDM (Supplemental Table 1, https://links.lww.com/MFM/A12). This strong relationship was apparent in a Pregnancy Risk Assessment Monitoring System database meta-analysis, which showed that obese women had increased odds ratios (OR) of gestational diabetes (adjusted OR: 2.78, 95% confidence interval (CI): 2.6–2.96) independently of weight gain during pregnancy.12 A study by Agudelo-Espitia et al.13 found a significant difference in the rates of GDM amongst women with increased pre-pregnancy weight (31.5%) compared to women with normal pre-pregnancy weight (1.5%). This finding was also reported in women with multiple gestations. The OR for developing GDM was increased among overweight (OR: 3.3, 95% CI: 1.52–7.3) and obese (OR: 3.2, 95% CI: 1.41–7.1) women with twin pregnancies relative to normal-weight women.14 This risk was found to be greater with increasing obesity. Chu et al.15 found that the OR for developing GDM was 8.56 times greater in severely obese compared to normal-weight pregnant women in a meta-analysis involving twenty studies. The OR was 2.14 and 3.56 for overweight and obese women respectively, relative to normal-weight pregnant women.
Maternal obesity and fetal macrosomia
In addition to its association with GDM, maternal obesity is established as a risk factor for the development of fetal macrosomia in many studies (Supplemental Table 2, https://links.lww.com/MFM/A12). A 5-year cohort study based on an Iranian population demonstrated an increased incidence of fetal macrosomia in women with a high BMI compared to normal-weight women, while a Canada-based cohort study showed that women who were either overweight or obese before pregnancy were 60% and 90% more likely to deliver macrosomic neonates, respective-ly.16,17 A large Turkish population study showed that women with elevated pre-pregnancy BMI and higher gestational weight gain were significantly more likely to deliver macrosomic neonates in the absence of gestational diabetes.18 This finding was supported by a 2017 meta-analysis which showed that pre-pregnancy maternal obesity was associated with fetal macrosomia with an adjusted OR of 1.93 (95% CI: 1.65–2.27).19 A similar meta-analysis by Gaudet et al.20 showed that maternal obesity alone was significantly associated with fetal macrosomia.
Fleten et al.21 proposed that birth weight increased by 20.3 g foreveryone-unitincreaseinmaternal BMI(1 kg/m2). The aforementioned articles support a causal relationship between maternal obesity and fetal macrosomia. Since maternal obesity independently increases the risk of both GDM and fetal macrosomia, it would be reasonable to suggest that the association between GDM and fetal macrosomia is likely to be indirect. If this is the case, then what role does maternal obesity play in the relationship between GDM and fetal macrosomia?
Maternal obesity, gestational diabetes, and fetal macrosomia
To explore the interaction between all three factors, we reviewed studies presenting a relationship between GDM and fetal macrosomia, especially when the authors made an adjustment for maternal obesity (Supplemental Table 3, https://links.lww.com/MFM/A12).
In a meta-analysis of thirty relevant articles, Tabrizi et al.22 found that the rate of fetal macrosomia in GDM mothers was 13.3%, compared to just 2.9% in non-GDM mothers. However, the authors did not adjust for different obesity rates in the two groups, thus creating a limitation in dismissing a potential major confounder of fetal macrosomia. Therefore, clinicians must exercise caution when interpreting such conclusions.
In contrast, many studies explored the association between GDM and fetal macrosomia while adjusting for maternal obesity. In doing so, they showed the true nature of the relationship between these two factors without including the cofounder of maternal obesity. For example, Wang et al.23 concluded that obese women were 4.17 times more likely to give birth to macrosomic fetuses, and that GDM was not a risk factor after adjusting for confounders including maternal obesity. Although this study showed that GDM is not an independent risk factor for macrosomia, others did indeed demonstrate this link after adjusting for maternal obesity. In a study by Agudelo-Espitia et al.,13 for example, GDM was shown to be an independent risk factor for fetal macrosomia (OR: 2.04, 95% CI:1.51–2.76). A retrospective chart review by Yang et al.24 found that the rate of fetal macrosomia in newborns of GDM mothers was 16.4%, compared to 11.2% in controls. In this study, the OR for maternal GDM in macrocosmic neonates was 1.55 (95% CI: 1.5–1.6). The elevated ratio, though still significant, dropped to 1.25 (95% CI: 1.21–1.29) after adjusting for BMI and taking several other maternal factors into consideration. This demonstrates that, although an independent relationship between the two exists, the risk could be overestimated if maternal obesity is not adjusted for. The effect of maternal obesity on fetal macrosomia in GDM was estimated by Pereda et al.,25 who calculated that the OR for fetal macrosomia in the GDM cohort was 1.60 but decreased to 1.39 after adjusting for confounders including maternal obesity. Catalano et al.26 found that the risk of macrosomia was significantly increased in women with GDM (OR: 2.19, 95% CI: 1.93–2.47) and in women with obesity (OR: 1.73, 95% CI: 1.50–2.00). Importantly, this work showed that the presence of GDM and maternal obesity together increased the risk of fetal macrosomia to a greater degree than the presence of one risk factor alone (OR: 3.62, 95% CI: 3.04–4.32).26
Furthermore, a study on 23,000 women found the risk of fetal macrosomia in obese women to be two-fold greater than in normal-weight women regardless of whether the pregnancy was complicated by GDM or not.27–29 The risk of fetal macrosomia was 1.5 times greater in GDM mothers compared to non-GDM mothers in both obese and non-obese women. Another important aspect of this study was that 26% of macrosomic neonates were born to non-obese mothers with GDM, while 41% of macrosomic neonates were born to obese mothers without GDM. These findings offer an important perspective — that GDM is an independent risk factor for macrosomia, and that maternal obesity constitutes a much bigger, often underestimated, risk factor. We may conclude that maternal obesity is a stronger risk factor for fetal macrosomia, but that more cases of macrosomia can be attributed to obesity rather than to GDM.
Other studies, however, had a contradictory conclusion with regards to this relationship: GDM may not be an independent risk factor by itself, but rather a factor that strengthens a preexisting relationship between obesity and macrosomia. In attempting to separate the specific contributions of maternal obesity and GDM to the development of macrosomia, Ricart et al.30 found that maternal obesity had a greater impact on macrosomia compared to GDM. In this cohort, normal-weight women with GDM did not a have a significantly higher risk of delivering a macrosomic neonate (OR: 1.32, 95% CI: 0.83–2.01), while women who were overweight had a significantly higher risk (OR: 1.82, 95% Cl: 1.47–2.25), but especially so when they were overweight and diabetic (OR: 2.16, 95% CI: 1.43–3.26). This study supports the hypothesis that GDM potentiates a pre-existing relationship between maternal obesity and fetal macrosomia but does not act as an independent risk factor for the macrosomia. Ijäs et al.31 similarly analyzed data from nearly 25,000 patients and demonstrated that the risk of macrosomia in normal-weight women with GDM was not significantly increased relative to normal weight women without GDM (OR: 1.17, 95% Cl: 0.85–1.62). Obese women without GDM had an increased risk of fetal macrosomia compared to normal-weight women without GDM (OR: 1.50, 95% CI: 1.19–1.88).31
These different studies offer varying conclusions about GDM: GDM may or may not be an independent risk factor, GDM may be compounded by maternal obesity, and GDM may amplify the preexisting relationship between maternal obesity and fetal macrosomia. Simply put some uncertainty remains in the literature with regards to the relationship between GDM, maternal obesity and fetal macrosomia.
A potential relationship defined on pathophysiological basis
A question worth asking here is: Does pathophysiology underlie the association between obesity and gestational diabetes? It has been shown that adipose tissue and the adipokines it produces play a role in increasing resistance to insulin. Such adipokines include the adipocytokines leptin, adiponectin, tumor necrosis factor-a, and interleu-kin-6. These add to a natural resistance to insulin that occurs in normal pregnancy.32 Furthermore, local hypoxia in adipose tissue of obese patients increases adipocyte death and production of pro-inflammatory cytokines which also contribute to insulin resistance and thus a tendency towards hyperglycemia.33 These changes can explain, at least partially, the increased risk of gestational diabetes in obese women.
The complex interplay between gestational diabetes, maternal obesity, and fetal macrosomia can be examined by taking a closer look at some of the mechanisms that underlie this relationship. Some theories propose a direct relationship between GDM and fetal macrosomia while others support different conclusions. For example, maternal hyperglycemia, the hallmark of GDM, leads to increase in-utero transport of glucose and a subsequent anabolic state that predisposes to fetal macrosomia. Similarly, adiponectin seems to support a more direct role in the relationship between gestational diabetes and fetal macro-somia. Adiponectin impairs transport of amino acids across the placenta, limiting fetal growth and reducing the risk of fetal macrosomia. The production of this adipokine is reduced in mothers with gestational diabetes through gene methylation. This reduction more strongly correlates with insulin resistance than with measures of adiposity.34 This demonstrates a perspective that favors a direct correlation between gestational diabetes and fetal macro-somia. Furthermore, a microarray analysis study that compared placentas of GDM and non-GDM women found that microRNA changes in GDM may contribute to fetal macrosomia through enhancing epidermal growth factor receptor signaling which promotes fetal growth.35
At the same time, changes in leptin could reinforce the role of maternal obesity in macrosomia, more so than GDM. Augmented production of leptin leads to enhanced transport of amino acids across the placenta, contributing to fetal macrosomia.36 Interestingly, maternal obesity may be the main determinant of leptin levels (P < 0.0001) rather than gestational diabetes (P = 0.34),37 supporting the proposition that perhaps maternal obesity is a greater risk factor for fetal macrosomia than gestational diabetes is.
The multifaceted impact of maternal obesity and GDM on fetal macrosomia makes it difficult to characterize the true relationship. For clinicians, the optimal management approach for these two (usually coexisting) risks factors is still fraught with difficulties. A commonly used approach is to directly address maternal obesity as a way of reducing risk of GDM. In fact, studies have shown that lifestyle changes reduce the risk of GDM in obese women. For example, a randomized control study by Koivusalo et al.38 found that individualized counseling on diet, physical activity, and weight control reduced GDM rates in obese women from 21.6% in the control group to 13.9% in the treatment group. Another randomized controlled study by Wang et al.39 found that exercising three times per week for at least 30 minutes per session reduced the risk of GDM in obese women (GDM incidence rate of 22.0% vs. 40.6%, P < 0.001). Although preventing GDM is associated with overall improved outcomes, strategies implemented in the study did not correlate with a significant risk reduction in macrosomia (6.3% vs. 9.6%; OR: 0.624, 95% CI: 0.233–1.673, P = 0.3).39 On the other hand, a meta-analysis by Horvath et al.40 showed that treating gestational diabetes (with diet or insulin) was associated with a lower risk of macrosomia. These conclusions must be considered when attempting to target the risk of macrosomia with lifestyle modifications.
Conclusions
All in all, GDM is becoming an increasingly prevalent complication of pregnancy due to the worldwide surge in maternal obesity. Given its association with fetal macro-somia and several other maternal and neonatal comorbidities, it would be helpful to understand the respective contribution of GDM and maternal obesity. Several studies have shown GDM to be an independent risk factor for fetal macrosomia, while many others found it to be a potentiating factor that functions only to magnify the effect of maternal obesity. Both relationships are supported by specific pathophysiological explanations with alteration in adiponectin levels and microRNA expression supporting the role of GDM, while changes in leptin levels supporting the effect of obesity.
In conclusion this review unfortunately failed to find conclusive evidence that neither maternal obesity nor GDM individually are the predominant factor that is associated with fetal macrosomia. What is certain is that the combination has a multiplier effect most likely mechanistically. There is the need for more well-designed studies to further unravel these complex relationships.
Funding
None.
Conflicts of Interest
None.
References
1. Behboudi-Gandevani S., Amiri M., Bidhendi Yarandi R., et al. The impact of diagnostic criteria for gestational diabetes on its prevalence: a systematic review and meta-analysis. Diabetol Metab Syndr 2019;11:11. doi: 10.1186/s13098-019-0406-1.
2. Man B., Turyk M.E., Kominiarek M.A., et al. Diabetes screening in US women with a history of gestational diabetes, national health and nutrition examination survey, 2007-2012. Prev Chronic Dis 2016;13:E124. doi: 10.5888/pcd13.160106.
3. Bashir M.E., Abdel-Rahman M., Aboulfotouh M., et al. Prevalence of newly detected diabetes in pregnancy in Qatar, using universal screening. PLoS One 2018;13(8):e0201247. doi: 10.1371/journal.pone.0201247.
4. Hod M., Kapur A., Sacks D.A., et al. The International Federation of Gynecology and Obstetrics (FIGO) initiative on gestational diabetes mellitus: a pragmatic guide for diagnosis, management, and care. Int J Gynaecol Obstet 2015;131(Suppl 3):S173–S211. doi: 10.1016/S0020-7292(15)30033-3.
5. Caughey A., Turrentine M. ACOG practice bulletin no. 190: Gestational diabetes mellitus. Obstet Gynecol 2018;131(2):e49–49e64. doi: 10.1097/AOG.0000000000002501.
6. Bhatia M., Mackillop L.H., Bartlett K., et al. Clinical implications of the NICE 2015 criteria for gestational diabetes mellitus. J Clin Med 2018;7(10):376. doi: 10.3390/jcm7100376.
7. Damm P. Future risk of diabetes in mother and child after gestational diabetes mellitus. Int J Gynaecol Obstet 2009;104(Suppl 1):S25–S26. doi: 10.1016/j.ijgo.2008.11.025.
8. Lepercq J., Timsit J., Hauguel-de Mouzon S. Etiopathogeny of fetal macrosomia (in French). J Gynecol Obstet Biol Reprod (Paris) 2000;29(1 Suppl):6–12.
9. Girz B.A., Divon M.Y., Merkatz I.R. Sudden fetal death in women with well-controlled, intensively monitored gestational diabetes. J Perinatol 1992;12(3):229–233.
10. Hunt K.J., Schuller K.L. The increasing prevalence of diabetes in pregnancy. Obstet Gynecol Clin North Am 2007;34(2):173–199. doi: 10.1016/j.ogc.2007.03.002.
11. Catalano P.M. The impact of gestational diabetes and maternal obesity on the mother and her offspring. J Dev Orig Health Dis 2010;1(4):208–215. doi: 10.1017/S2040174410000115.
12. Shin D., Song W.O. Prepregnancy body mass index is an independent risk factor for gestational hypertension, gestational diabetes, preterm labor, and small- and large-for-gestational-age infants. J Matern Fetal Neonatal Med 2015;28(14):1679–1686. doi: 10.3109/14767058.2014.964675.
13. Agudelo-Espitia V., Parra-Sosa B.E., Restrepo-Mesa S.L. Factors associated with fetal macrosomia. Rev Saude Publica 2019;53:100. doi: 10.11606/s1518-8787.2019053001269.
14. Al-Obaidly S., Parrish J., Murphy K.E., et al. Maternal pre-gravid body mass index and obstetric outcomes in twin gestations. J Perinatol 2014;34(6):425–428. doi: 10.1038/jp.2014.29.
15. Chu S.Y., Callaghan W.M., Kim S.Y., et al. Maternal obesity and risk of gestational diabetes mellitus. Diabetes Care 2007;30(8):2070–2076. doi: 10.2337/dc06-2559a.
16. Najafian M., Cheraghi M. Occurrence of fetal macrosomia rate and its maternal and neonatal complications: a 5-year cohort study. ISRN Obstet Gynecol 2012;2012:353791. doi: 10.5402/2012/353791.
17. Vinturache A.E., Chaput K.H., Tough S.C. Pre-pregnancy body mass index (BMI) and macrosomia in a Canadian birth cohort. J Matern Fetal Neonatal Med 2017;30(1):109–116. doi: 10.3109/14767058.2016.1163679.
18. Usta A., Usta C.S., Yildiz A., et al. Frequency of fetal macrosomia and the associated risk factors in pregnancies without gestational diabetes mellitus. Pan Afr Med J 2017;26:62. doi: 10.11604/pamj.2017.26.62.11440.
19. Dai R.X., He X.J., Hu C.L. Maternal pre-pregnancy obesity and the risk of macrosomia: a meta-analysis. Arch Gynecol Obstet 2018;297(1):139–145. doi: 10.1007/s00404-017-4573-8.
20. Gaudet L, Ferraro ZM, Wen SW, et al. Maternal obesity and occurrence of fetal macrosomia: a systematic review and metaanalysis. Biomed Res Int 2014;2014:640291. doi: 10.1155/2014/640291.
21. Fleten C., Stigum H., Magnus P., et al. Exercise during pregnancy, maternal prepregnancy body mass index, and birth weight. Obstet Gynecol 2010;115(2 Pt 1):331–337. doi: 10.1097/AOG.0-b013e3181ca4414.
22. Tabrizi R., Asemi Z., Lankarani K.B., et al. Gestational diabetes mellitus in association with macrosomia in Iran: a meta-analysis. J Diabetes Metab Disord 2019;18(1):41–50. doi: 10.1007/s40200-019-00388-0.
23. Wang L.F., Wang H.J., Ao D., et al. Influence of pre-pregnancy obesity on the development of macrosomia and large for gestational age in women with or without gestational diabetes mellitus in Chinese population. J Perinatol 2015;35(12):985–990. doi: 10.1038/jp.2015.119.
24. Yang G.R., Dye T.D., Li D. Effects of pre-gestational diabetes mellitus and gestational diabetes mellitus on macrosomia and birth defects in Upstate New York. Diabetes Res Clin Pract 2019;155:107811. doi: 10.1016/j.diabres.2019.107811.
25. Pereda J., Bove I., Pineyro M.M. Excessive maternal weight and diabetes are risk factors for macrosomia: a cross-sectional study of 42,663 pregnancies in Uruguay. Front Endocrinol (Lausanne) 2020;11:588443. doi: 10.3389/fendo.2020.588443.
26. Catalano PM, McIntyre HD, Cruickshank JK, et al. The hyperglycemia and adverse pregnancy outcome study: associations of GDM and obesity with pregnancy outcomes. Diabetes Care 2012;35(4):780–786. doi: 10.2337/dc11-1790.
27. Metzger B.E., Lowe L.P., et al. HAPO Study Cooperative Research GroupHyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008;358(19):1991–2002. doi: 10.1056/NEJMoa0707943.
28. Kc K., Shakya S., Zhang H. Gestational diabetes mellitus and macrosomia: a literature review. Ann Nutr Metab 2015;66(Suppl 2):14–20. doi: 10.1159/000371628.
29. Metzger B.E. Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study: associations of higher levels of maternal glucose and BMI with macrosomia: an example of diabesity. ADA 70th Scientific Session, 2010. Abstract No. 154-OR. Available from:
https://professional.diabetes.org/abstract/hyperglycemia-amp-adverse-pregnancy-outcome-hapo-study-associations-higher-levels-maternal. Date accessed: 10 April, 2021.
30. Ricart W., Lopez J., Mozas J., et al. Body mass index has a greater impact on pregnancy outcomes than gestational hyperglycaemia. Diabetologia 2005;48(9):1736–1742. doi: 10.1007/s00125-005-1877-1.
31. Ijäs H., Koivunen S., Raudaskoski T., et al. Independent and concomitant associations of gestational diabetes and maternal obesity to perinatal outcome: a register-based study. PLoS One 2019;14(8):e0221549. doi: 10.1371/journal.pone.0221549.
32. Hotamisligil G.S., Peraldi P., Budavari A., et al. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 1996;271(5249): 665–668. doi: 10.1126/science.271.5249.665.
33. Šimják P., Cmkajzlová A., Anderlová K., et al. The role of obesity and adipose tissue dysfunction in gestational diabetes mellitus. J Endocrinol 2018;238(2):R63–R163. doi: 10.1530/JOE-18-0032.
34. Retnakaran R., Hanley A.J., Raif N., et al. Reduced adiponectin concentration in women with gestational diabetes: a potential factor in progression to type 2 diabetes. Diabetes Care 2004;27(3):799–800. doi: 10.2337/diacare.27.3.799.
35. Li J., Song L., Zhou L., et al. A microRNA signature in gestational diabetes mellitus associated with risk of macrosomia. Cell Physiol Biochem 2015;37(1):243–252. doi: 10.1159/000430349.
36. Pérez-Pérez A., Maymó J.L., Gambino Y.P., et al. Activated translation signaling in placenta from pregnant women with gestational diabetes mellitus: possible role of leptin. Horm Metab Res 2013;45(6):436–442. doi: 10.1055/s-0032-1333276.
37. Maple-Brown L., Ye C., Hanley A.J., et al. Maternal pregravid weight is the primary determinant of serum leptin and its metabolic associations in pregnancy, irrespective of gestational glucose tolerance status. J Clin Endocrinol Metab 2012;97(11):4148–4155. doi: 10.1210/jc.2012-2290.
38. Koivusalo S.B., Rönö K., Klemetti M.M., et al. Gestational diabetes mellitus can be prevented by lifestyle intervention: the Finnish Gestational Diabetes Prevention Study (RADIEL): a randomized controlled trial [published correction appears in diabetes care. 2017 Jun 14]. Diabetes Care 2016;39(1):24–30. doi: 10.2337/dc15-0511.
39. Wang C., Wei Y., Zhang X., et al. A randomized clinical trial of exercise during pregnancy to prevent gestational diabetes mellitus and improve pregnancy outcome in overweight and obese pregnant women. AmJ Obstet Gynecol 2017;216(4):340–351. doi: 10.1016/j. ajog.2017.01.037.
40. Horvath K., Koch K., Jeitler K., et al. Effects of treatment in women with gestational diabetes mellitus: systematic review and metaanalysis. BMJ 2010;340:c1395. doi: 10.1136/bmj.c1395.
