Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 18  |  Issue : 2  |  Page : 73-78

Severe maternal insulin resistance in pregnancy: An independent predictor of fetal macrosomia


1 Department of Chemical Pathology, Jos University Teaching Hospital, Jos, Nigeria
2 Department of Chemical Pathology, University of Abuja, Abuja, Nigeria
3 Department of Paediatrics, Jos University Teaching Hospital, Jos, Nigeria
4 Department of Obstetrics and Gynaecology, Jos University Teaching Hospital, Jos, Nigeria

Date of Web Publication13-Oct-2016

Correspondence Address:
Lucius Chidiebere Imoh
Department of Chemical Pathology, Jos University Teaching Hospital, P.M.B 2076, Jos, Plateau
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2276-7096.188531

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  Abstract 

Objective: Macrosomia is associated with increased maternal and fetal complications in obstetric practice. Gestational diabetes mellitus (GDM), maternal obesity, insulin resistance (IR), and other variables such as maternal age and gestational age at delivery may influence neonatal birth weight. It is not clear if a severe degree of IR in pregnancy is an independent risk factor for macrosomia. We therefore investigated the association between IR and macrosomia independent of GDM and other confounding factors.
Materials and Methods: We measured the insulin sensitivity index (Matsuda index) in 118 pregnant women during a 75-g oral glucose tolerance test at 24-32 weeks of gestation. The birth weights of their neonates were measured at delivery. Multiple logistic regression was use to assess the association between IR and macrosomia after controlling for confounders GDM and other confounding factors.
Results: Twenty-four women (20.3%) were classified under IR, 20 women (16.9%) and 62 women (52.5%) had GDM and obesity, respectively. Eleven women (9.3%) had macrosomic babies. Although the fasting insulin and 2-h insulin were higher in women with macrosomic babies compared to the normal weight babies, the observed difference was not significant (P > 0.05). The Matsuda index was significantly lower among women with macrosomic babies. Severe IR (odds ratio [OR] [95% confidence interval (CI)] = 9.3 [2.4-35.1]) and GDM (OR [95% CI] = 12.7 [3.3-49.2]) were significantly associated with macrosomia. After adjusting for the confounding variables, IR remained significantly associated with macrosomia (adjusted OR [95% CI] = 10.0 [1.6-64.4]).
Conclusion: IR is an independent risk factor for macrosomia, and its assessment during pregnancy should form a basis for categorizing women at risk of macrosomia.

Keywords: Birth weight, diabetes mellitus, gestational insulin resistance, macrosomia, obesity


How to cite this article:
Imoh LC, Ogunkeye OO, Isichei CO, Gadzama AA, John C, Ocheke AN. Severe maternal insulin resistance in pregnancy: An independent predictor of fetal macrosomia. J Med Trop 2016;18:73-8

How to cite this URL:
Imoh LC, Ogunkeye OO, Isichei CO, Gadzama AA, John C, Ocheke AN. Severe maternal insulin resistance in pregnancy: An independent predictor of fetal macrosomia. J Med Trop [serial online] 2016 [cited 2017 Sep 20];18:73-8. Available from: http://www.jmedtropics.org/text.asp?2016/18/2/73/188531


  Introduction Top


Macrosomia, defined as birth weight of 4000 g or more, is a relatively common phenomenon in obstetric practice. [1],[2] The global incidence of macrosomia varies considerably across racial and geographical divide. Recent studies in Nigeria reports that macrosomic newborns constitute 3.0-8.1% of all deliveries and evidence points to a consistent trend of increasing average birth weight and the incidence of birth of macrosomic babies. [3],[4],[5],[6]

Macrosomia has adverse implications for obstetric practice because it predisposes to labor complications that may result in maternal and fetal adverse outcomes. Associated maternal complications include prolonged labor, labor augmentation with oxytocin, increased cesarean delivery rate, 3 rd and 4 th degree perineal tear, and postpartum hemorrhage. [2],[6],[7] Neonatal concerns in macrosomic deliveries include increased risk of morbidity and mortality attributable to birth asphyxia, shoulder dystocia, birth injury, metabolic disorders, for example, hypoglycemia, and meconium aspiration syndrome. [6],[7],[8],[9],[10]

The determinants of neonatal weight include maternal weight, maternal age, parity, ethnicity, and gestational age at delivery although there are inconsistent reports on the extent of influence of these factors on birth weight. [2],[11] There is growing evidence that pregnancy complicated by gestational diabetes mellitus (GDM) or other forms of diabetes in pregnancy are more at risk for large for gestational age (LGA) or macrosomic babies. [12],[13],[14],[15]

Insulin resistance (IR) refers to a condition, in which the body tissues' response to the action of insulin is reduced. [16] It is a phenomenon underlying many disease conditions including obesity, DM, and GDM. [16],[17] In normal pregnancy, there is a decrease in insulin sensitivity as a physiologic adaptation to facilitate glucose diffusion from mother to fetus. The degree of this IR however varies from one pregnant woman to another.

Although some studies have suggested that IR may be associated with adverse pregnancy outcomes including increased risk of macrosomic deliveries, [16],[18],[19],[20] it is not clear if a severe degree of IR in pregnancy, independent of GDM, and other confounding factors is a risk factor for macrosomia. The aim of this study therefore was to investigate the association of IR and fetal macrosomia independent of GDM and other confounding factors.


  Materials and Methods Top


This was a prospective study involving 118 pregnant women at 24-32 weeks gestation. The women were referred from the antenatal clinic of the Jos University Teaching Hospital (JUTH) to the Chemical Pathology Metabolic Research Unit (JUTH) for oral glucose tolerance test (OGTT) between June 2012 and July 2013. Blood samples were collected from the subjects during a standard 75 g-OGTT after an overnight fast of between 8 and 12 h (for analysis of glucose and insulin in serum). The fasting and 2-h glucose and insulin were used to measure the composite insulin sensitivity described by Matsuda and DeFronzo; thus, [21],[22]

Composite (total) insulin sensitivity = 10,000/√([FG × FI] × [G × I]).

where 10,000 is a constant that allows for numbers ranging from 1 to 12 to be obtained.

FG = Fasting glucose

FI = Fasting insulin

G = Mean OGTT glucose concentration

I = Mean OGTT insulin concentration.

Women with the lowest 20% of insulin sensitivity index in the study population had the most severe form of impaired insulin sensitivity and were classified as severe IR. [23] For our study population, this corresponds to a Matsuda index of ≤3.4. Subjects were also classified as gestational diabetic if they met the 1999 WHO criteria for diagnosis of GDM (which is met when fasting glucose is ≥7.0 mmol/L and/or 2-h glucose ≥7.8 mmol/L following a 75 g-glucose load OGTT). [24] Maternal obesity was classified as having weight of 90 kg or more between 24 and 32 weeks of gestation. [25],[26]

The subjects were followed up to delivery. At delivery, the weights of the neonate were measured. Babies with birth weight ≥4.0 kg were classified as "macrosomic." Only subjects with singleton pregnancy who delivered babies with weight ≥2.5 kg between 29 and 41 weeks were included in the study. We excluded women with medical conditions such as thyroid disorders, human immunodeficiency virus/acquired immune deficiency syndrome, and sickle cell anemia.

Glucose in serum was assayed within 4 h of sampling. Serum for insulin assay was stored at –20°C and insulin assayed within 30 days of collection. Blood samples were analyzed for glucose by hexokinase method using commercial kits on the Roche/Hitachi 902 automatic analyzer. Insulin was assayed using DRG® human insulin ELISA kits (DRG International, Inc., USA), noncompetitive binding principle. The within-assay coefficient of variation (CV) for glucose and insulin assays was 2.4% and 1.9%, respectively while the between-batch CVs for both assays were 4.3% and 5.4%, respectively.

The collected data were compiled, tabulated, and analyzed using Statistical Package for Social Sciences (Version 15.0, SPSS Incorporated, Chicago, IL, USA) software. The association between IR and macrosomia was tested by bivariate analysis (Fisher's exact test), and multiple logistic regression analysis was used to adjust for confounding variables including GDM, hypertensive disorder, maternal age, maternal obesity, family history of DM, estimated gestational age (EGA) at OGTT, gestational age at delivery, previous macrosomia, and parity. A P < 0.05 was considered statistically significant.

Consent and Ethical Approval

Written informed consent and ethical approval were obtained from the subjects and the ethics committee of the JUTH. Written permission was also obtained from the department of obstetrics and gynecology, JUTH.


  Results Top


One hundred and eighteen subjects were recruited for this study. The maternal characteristics, biochemical indices at OGTT, and neonatal birth weight are summarized in [Table 1]. The mean maternal age was 31.2 ± 4.9 years. The mean EGA at OGTT and delivery was 28.2 ± 1.7 weeks and 38.7 ± 1.6 weeks, respectively. The mean Matsuda index was 6.6 ± 3.4 and the 20 th percentile was 3.4. The neonatal weight ranges from 2.5 kg to 5.5 kg, with a mean of 3.4 ± 0.5 kg.
Table 1: Clinical and biochemical indices of study population

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Twenty-four women (20.3%) were classified as severely IR. The mean maternal weight and neonatal birth weight were significantly higher in IR women compared to less non-IR women (P < 0.05). Furthermore, all the biochemical results during the 75-g OGTT, i.e., fasting glucose (FG), 2-h glucose, fasting Insulin (FI), and 2-h insulin were significantly higher among the IR women (P < 0.01) [Table 2].
Table 2: Clinical and biochemical indices of severe insulin resistant and noninsulin resistant women using independent t-test

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Twenty women (16.9%) and 62 women (52.5%) had GDM and obesity, respectively. IR was significantly associated with gestational diabetes but not with maternal obesity [Table 3].
Table 3: Association of insulin resistance with gestational diabetes mellitus and maternal obesity using Fisher's exact test and odds ratio

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Eleven women (9.3%) had macrosomic babies. We compared maternal characteristics and biochemical parameters in women with macrosomic and normal weight deliveries [Table 4]. The FG, 2-hr glucose, were significantly higher in the macrosomic group (P =.001). Although the FI and 2-hr Insulin were higher in women with macrosomic babies compared to the normal weight babies, the observed difference was not significant (P = 0.066 and 0.056 respectively). The Matsuda Index was significantly lower among women with macrosomic babies, (P = 0.004).
Table 4: Clinical and biochemical indices of women with macrosomic and normal weight deliveries using independent t-test

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We assessed the association of IR, GDM, and obesity and other variables with macrosomia. Only severe IR (odds ratio [OR] [95% confidence interval (CI)] =9.3 {2.4-35.1}), GDM (P < 0.001; OR [95% CI] =12.7 {3.3-49.2}), and hypertension (OR [95% CI] =11.7 {1.5-92.9}) were significantly associated with macrosomia [Table 5]. Multiple logistic regression analysis was used to adjust for confounding variables such as GDM, hypertensive disorder, maternal age, maternal obesity, family history of DM, EGA at OGTT, gestational age at delivery, previous macrosomia, and parity of the subjects. The association was statistically significant only for severe IR and GDM, adjusted OR (95% CI) =10.0 (1.6-64.4) and 8.2 (1.5-44.7), respectively [Table 5].
Table 5: Multiple logistic regression analysis of the association of macrosomia with severe insulin resistance, gestational diabetes mellitus, maternal obesity and other variables

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  Discussion Top


This study demonstrates that pregnant women with the most severe degree of IR were more likely to have higher weight, FG, and 2-h glucose levels. With respect to fetal birth weight, the results of this study show that the average birth weight is significantly higher in pregnant women with the more severe IR compared to those with mild IR.

Many studies have suggested that maternal obesity predisposes to fetal overgrowth independent of maternal hyperglycemia. [15],[16] In our study, maternal obesity was not significantly associated with macrosomic deliveries. Plausible explanation could be that in many of the studies where a significant relationship was observed, prepregnancy weight and/or weight gained in pregnancy were used to categorize the women. [15],[16] Due to late booking of women and the general lack of awareness of prepregnancy weight of women in our environment, an absolute booking weight of >90 kg as reported in some articles was employed in our study. [25],[26] This finding would suggest that obese pregnant women with greater risk of having macrosomic babies are likely to be the ones with higher pregnancy weight or those who gained the most weight in pregnancy.

It is well documented that macrosomia is associated with pregnancies complicated by GDM. This was also the finding in this study where GDM was independently associated with macrosomia. The maternal hyperglycemia in women with GDM increases the gradient of glucose flux into fetus leading to fetal hyperglycemia. This, with the accompanying hyperinsulinemia, results in fetal overgrowth. This explains the increased glucose levels found in women with macrosomic babies compared to those with normal babies. In the same vein a higher insulin levels in women with macrosomic babies would be expected. However in our study this was not statistically significant. Perhaps this could be due to a small sample size.

The degree of increase of the physiologic IR in pregnancy may be related to maternal glucose levels. [18] Indeed, IR in pregnancy usually becomes severe in the context of GDM. [17],[18] This has prompted the question as to the causal role of IR in adverse pregnancy outcome such as fetal macrosomia.

Previous researchers have reported that IR does not independently cause fetal macrosomia in women with or without GDM after taking consideration of the maternal weight. [27],[28] It is noteworthy that in this study, IR remained significantly associated with fetal macrosomia after controlling for GDM and other variables such as hypertensive disorder, maternal age, maternal obesity, family history of DM, EGA at OGTT, gestational age at delivery, previous macrosomia, and parity of the subjects. This agrees with the findings of a recent study in Japanese women by Yamashita et al. [29] They found that homeostasis model assessment of IR (HOMA-IR) was a significant independent risk factor of giving birth to an LGA infant after controlling for maternal obesity and plasma glucose levels in normal pregnancy. Compared to their study, we controlled for more confounding variables as documented in literature. We used Matsuda index described by Matsuda and Defronzo [21] rather than HOMA-IR to assess for IR. The Matsuda index measures the total body insulin sensitivity unlike the HOMA-IR which assesses predominantly hepatic insulin sensitivity. Besides, compared with HOMA-IR, Matsuda Index has been shown to correlate better with the gold standard hyperinsulinemic-euglycemic clamp method for assessing IR. [21] This correlation has been demonstrated in pregnancy. [30],[31]

In this study, about two-third of the women with IR did not manifest as GDM. This may be attributable to varying capacity for compensatory secretion of insulin by the islet beta cell in the pregnant women. IR also affects other metabolic pathways that could lead to fetal overgrowth. Increased fatty acid mobilization and efflux into the fetus is encouraged in the setting of IR. [18] In addition, the anabolic effects of the hyperinsulinemia that characterizes IR may also account for increased fetal growth. [32]

Women diagnosed with GDM in this study were not prevented from receiving necessary treatment for ethical reasons. Treatment options such as exercise or dietary therapy may improve maternal IR or reduce fetal birth weight. Although we do not know the effect of GDM treatment on the women in this study, even if we assume reduction in IR and fetal birth weight, we still found the fetal birth weight to be higher in women with GDM. Moreover, severe IR was observed to be associated with macrosomia in spite of GDM, maternal obesity, and other confounders, thus making severe IR an independent risk factor for macrosomia. This finding, not previously documented in our environment, suggests that besides the conventional screening for GDM by OGTT to determine women at risk for adverse pregnancy outcome, assessment of IR should form another basis for categorizing women at risk of macrosomia and other adverse pregnancy outcomes. However, a larger randomized study would be needed to validate this proposition.





The finding of severe insulin resistance as an independent risk factor for macrosomia has not been previously documented in our environment. We suggest that besides the conventional screening for GDM by OGTT to determine women at risk for adverse pregnancy outcome, assessment of insulin resistance should form another basis for categorising women at risk of macrosomia and other adverse pregnancy outcomes. However, a larger randomized study would be needed to validate this proposition.

Acknowledgments

We are grateful to Dr. Alexander Abu, Dr. Noel Amadu, Dr. Solomon Asorose, and the members of staff of Chemical Pathology Department for their assistance during the OGTT of the subject. We also appreciate Mrs. Joy Abiola Imoh for helping with statistical analysis.

Financial Support and Sponsorship

Nil.

Conflicts of Interest

There are no conflicts of interest.

 
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