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Online ISSN
1305-3124

Established
1993

Editors-in-Chief
​Cihat Şen, ​Nicola Volpe

Editors
Cecilia Villalain, Daniel Rolnik, M. Mar Gil

Managing Editors
Murat Yayla, Oluş Api

Statistics Editor
Resul Arısoy

Correlation of Glycosylated Haemoglobin and Macrosomia in Infants of Diabetic Mothers

Anwika Kirti Kujur, Krishnaswami Devimeenakshi

Article info

Correlation of Glycosylated Haemoglobin and Macrosomia in Infants of Diabetic Mothers. Perinatal Journal 2022;30(3):- DOI: 10.2399/prn.22.0303004

Author(s) Information

Anwika Kirti Kujur,
Krishnaswami Devimeenakshi

  1. Government Kilpauk medical college Department of Pediatrics Chennai India
Correspondence

Krishnaswami Devimeenakshi, Government Kilpauk medical college Department of Pediatrics Chennai India, [email protected]

Publication History

Manuscript Received: June 27, 2022

Manuscript Accepted: July 24, 2022

Earlyview Date: July 24, 2022

Conflicts of Interest

No conflicts declared.

Objective
Maternal diabetes mellitus has a significant impact on the neonatal outcome. Birth weight is related to the degree of glycemic control. Poor glycemic control in the mother causes somatic overgrowth and results in macrosomia. Maternal obesity is an independent risk factor for macrosomia. The study objective was to evaluate the correlation between glycosylated haemoglobin level(HbA1c) in diabetic mothers and macrosomia in their neonates.
Methods

A cross sectional observational study was done on diabetic mothers and their neonates.  Maternal body mass index, weight gain, duration of diabetes and type of treatment was recorded. Maternal HbA1c levels were measured within one hour of delivery and birth order, mode of delivery, gestational age and birth weight were recorded. The discrete variables were analysed by chi square test and continuous variables by independent t test. Receiver operating characteristic (ROC) analysis was used to determine the optimum cut off for predicting macrosomia with HbA1c.  A p value of <0.05 was considered significant.
Results
A total of 228  diabetic mothers and their neonates were studied and  18 neonates were macrosomic. Diabetes was pre gestational in 56.6 % of mothers and gestational in 43.4 % of mothers. There was a significant difference in BMI, weight gain, and HbA1c in mothers of macrosomic and non macrosomic neonates. There was no significant difference in mean values of maternal age, duration of diabetes and gestational age in the two groups
Conclusion


This study suggests diabetic women with elevated HbA1c >5.6% measured after delivery were likely to have  macrosomic neonates.
Keywords

Gestational diabetes , Macrosomia,glycosylated haemoglobin A

Introduction

Maternal diabetes mellitus both pre-gestational and gestational have a significant impact on the neonatal outcome.  Outcome of pregnancy is related to the degree of glycaemic control and poor glycaemic control in the mother causes somatic overgrowth and results in macrosomia. The term macrosomia denotes birth weight more than the 90th percentile or baby weighing >4000gm.[1]  These infants have excess fat deposition on shoulders and trunk which predisposes to primary caesarean section and birth trauma. Factors like increased insulin like growth factor-1, fibroblast growth factor, epidermal growth factor, platelet derived growth factor, leptin and also adiponectin  are implicated in macrosomia.[2, 3, 4]   Maternal obesity is an independent risk factor for macrosomia.  Prevalence of gestational diabetes mellitus increases with increase in body mass index.[ 5] Excess weight gain during pregnancy is an additional risk factor for macrosomia. Excessive gestational weight gain was considered when it exceeded the total weight gain recommendations from the Institute of Medicine(IOM).  As per the revised guidelines,the upper limit of recommended weight gain in pregnant women ranges from 9 kg to  11.5 kg  for obese and overweight women, and 16 kg to 18 kg for  normal and underweight women. [6,7]  
   This study was planned to find a correlation between glycosylated haemoglobin level in the mother and macrosomia in the infant of diabetic mother. Emerging evidence indicates that abnormal fetal growth can occur before the routine biochemical diagnosis of gestational diabetes at 24–28 weeks of gestation.[8]  This warrants measures to improve glycemic control early, more so  in high risk obese  population.[9]
 
The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study  compared diabetic mothers with normal mothers and observed a strong association of higher maternal glucose levels with increased birth weight above the 90th percentile for gestational age.[10] Adverse pregnancy outcomes were higher in diabetic mothers if ideal glucose levels were not maintained.[11]
The cause of macrosomia in infants of diabetic mother is considered to be the poor glycemic control. However, there are other studies where no significant correlation was found between the fetal body weight and the level of glycosylated haemoglobin in the mother. This study was planned to get a better understanding of the cause of macrosomia and plan ways to reduce its occurrence.  
Methods


The study objective was to evaluate the correlation between HbA1c and macrosomia in infants of diabetic mothers. This was a cross sectional study done between February 2016- July 2016 at Department of Pediatrics of a tertiary care Medical College Hospital. The study protocol was approved by Institutional ethics committee (protocol ID no 13/2016 meeting held on 4-4-2016). The study population included neonates born to diabetic mothers who delivered in a tertiary care Medical College hospital. Sample size was calculated using single population proportion formula by using the following statistical assumptions :65% proportion( based on previous studies) , 95% confidence interval ,5% marginal error(alpha) and expected  response rate of 90%. For estimating the expected proportion with a 10% precision relative to the expected proportion which was 6.5%. The final sample size was 230.
                                                              
 Pregnant women who were diagnosed as having pre gestational diabetes or gestational diabetes fulfilling the inclusion criteria were enrolled into the study after written informed consent (Figure-1). Maternal blood samples were taken to measure HbA1c levels within one hour of delivery of baby. HemoCue HbA1c 501 Analyser was used to estimate HbA1c. The women were classified into two categories as having pre-gestational and gestational diabetes mellitus. Their body mass index, weight gain during pregnancy, duration of diabetes mellitus and type of treatment for diabetes were recorded. Neonates with congenital anomalies and neonates of mothers having any other co-morbid conditions apart from diabetes mellitus were excluded. Electronic weighing scale was used to measure birth weight. The newborn’s birth order, mode of delivery, gestational age and birth weight were recorded. The discrete variables were analysed by chi square test and continuous variables by t test. The analysis was done by SPSS 17 software. The variables like maternal BMI, type of diabetes and treatment plan adopted were analysed by chi square test. The variables like maternal age,duration of diabetes,weight gain during pregnancy,HbA1c at the time of delivery and gestational age were analysed by independent t test. Receiver operating characteristic (ROC) analysis was used to determine the optimum cut off for predicting  macrosomia using the HbA1c levels at the time of delivery. A p value <0.05 was taken as significant.
Results

A total of 230 diabetic pregnant women and their neonates were enrolled for the study. As 2 patients had missing data and a total of 228 diabetic pregnant women and their neonates were analysed.
We observed that majority of the macrosomic neonates were born to mothers less than 25  years of age, and this constituted 55.6 % of the macrosomic neonates.  The prevalence of macrosomia in  mothers above 31 yrs of age was only 11.1%.  We observed that as maternal age increases the occurrence of macrosomia decreased. However this was not statistically significant. Maternal anthropometric parameters had a significant impact on the birth weight of the babies and the BMI of the mother was significantly associated with macrosomia.  In women with BMI  > 25 majority of the babies (50%) were macrosomic. With increasing BMI the occurrence of macrosomia increased and this was statistically significant(p value 0.000).  There was no difference in macrosomia between gestational diabetes mellitus and pre-gestational diabetes mellitus but this was not statistically significant. Macrosomia was more common in mothers who were on insulin (61.1%) as compared to those on meal plan but this was not statistically significant. The information about duration of insulin therapy was not obtained in our study and the impact of the duration of treatment on the outcome of macrosomia was not evaluated.   Macrosomia was more common (38.9%)when the birth order was first or second.  It was observed that all macrosomic babies were delivered by caesarean section.  (Table-1).
 
 
The mean maternal age of mothers who had macrosomic neonates was 25.56 years( SD= 3.382) and was similar to  non macrosomic neonates with  no statistically significant difference.  The mean BMI was higher 24.72 (SD= 2.461) in mothers who had macrosomic neonates than in non macrosomic neonates and this was found to be statistically significant.  Mothers of macrosomic neonates had a mean weight gain of 13.72 kg (SD= 0.895) which was higher than in those of non macrosomic neonates and this was found to be statistically significant. Mean duration of diabetes was lower 14.89months ( SD= 14.768 )among mothers who had macrosomic neonates and in mothers who had non macrosomic babies  it was  21.81 months (SD=25.463)and this was not statistically significant. Details about the duration of different types of treatment (insulin and meal plan)was not obtained in the study and hence not compared between the groups. The mean HbA1C at delivery was higher 5.978 % ( SD= 0.2365) in mothers who had macrosomic neonates while in those  who had non macrosomic neonates the mean HbA1C at delivery was 4.853% (SD=0.4825) and was statistically significant.  Mothers who had macrosomic neonates had HbA1c values above 5.6 % than those who had non-macrosomic babies. There was no statistically significant difference between mean gestational age of macrosomic neonates (37.67weeks)  and non-macrosomic neonates  (37.69 weeks).(Table-2).
Receiver operating characteristic (ROC) analysis was used to determine the optimum cut off for predicting the occurrence of macrosomia using the HbA1c levels at the time of delivery The area under the ROC curve = 0.984656 which signifies that it is an excellent tool to predict macrosomia with a HbA1c value >5.6% (Table-3).
Discussion
In our study it was found that majority of of macrosomic neonates (55.6% ) were born to young mothers below 25yrs of age. The mean age of women having macrosomic neonates was 25.56 yrs (S.D.=3.382). This is in contrast to the study published by N.E. Stotland et al[12]where they observed that macrosomia was more common in advanced maternal age between 30 to 40 years.  We found that although 61.1% of the macrosomic neonates were born in the group of women who were taking insulin implying that women requiring insulin to maintain a stable glucose control have a more deranged carbohydrate metabolism in the body with poor glycemic control which ultimately leads to fetal overgrowth. Women on meal plan offer a better intra-uterine environment so as not to lead to fetal growth alterations. This is in confirmation of the study done by L Suhonen et al[13]in which they found that macrosomia occurred more often in women treated with insulin which supports the fact that the requirement for insulin is probably in those mothers with poor glycemic control.
In the present study, there was no difference in incidence of macrosomia in different types of diabetes mellitus. In our study macrosomia occurred with equal frequency in women with gestational diabetes mellitus(50%)  and pre-gestational diabetes mellitus(50%). However Hayfaa Wahabi et al[14]  in their study found that women with gestational diabetes mellitus had increased odds of having a macrosomic baby (Odds Ratio : 1.65, 95% Confidence Interval : 1.32 – 2.07).
In our study, there was a statistically significant correlation between glycosylated haemoglobin (HbA1c) at delivery and occurrence of macrosomia in infants of diabetic mothers. Diabetic mothers with HbA1c > 5.6 %were more likely to have  macrosomic babies. This had a sensitivity of 94.4 and specificity of 96.7. Glycosylated haemoglobin value measured at the time of delivery was a good indicator of macrosomia.  As the major weight gain in the fetus occurs in the last trimester of pregnancy, it is the period during which high glucose level in the maternal blood favours fetal overgrowth.[15] This was similar to the findings by MR Mikkelsen et al [16] in their study that median HbA1c value=5.9 %before delivery, had a 3-fold increased risk of having large for gestational age babies. R .A Gandhi et al [17] in their study evaluated the impact of HbA1c levels and glycemic variability (assessed by mean home blood glucose levels)on the birth weight of neonates born to diabetic mothers and observed that the birth weight increased with HbA1c >6.5 %. Balaji Bhavadharini et al [18]  found that in those patients who had HbA1c>5.0%, the adjusted Odds Ratio for macrosomia was 1.92( CI : 1.24 – 2.97, P=0.003). Those patients with HbA1c >5.0% were also significantly older, had higher body mass index, history of previous gestational diabetes mellitus and increased incidence of macrosomia. Balaji Bhavadharini et al[18] found that pregnant women who had a HbA1c of ≥5.0% had higher risk of macrosomia, majority of whom did not have gestational diabetes mellitus(GDM). This finding is of particular interest because it shows that HbA1c may be used as a marker for macrosomia, independent of the diagnosis of gestational diabetes mellitus.

However, studies by other researchers contradict this theory. Taylor et al[19] in their study found no relationship between mean glycosylated haemoglobin values and birth weight.( R=0.02, p>0.1). A Weissman – Brenner [20]conducted a study on non-diabetic pregnant women and observed that  the mean +/- SD HbA1c level in women who delivered macrosomic neonates was 5.3+/-0.7% and those who had non-macrosomic neonates was 5.2+/- 0.5% (p=0.27). The area under ROC curve for prediction of macrosomia by HbA1c levels was 0.53 (p=0.27) and ROC was a poor screening tool to predict macrosomia. GC Penny et al[21] in their study observed that there was no statistically significant correlation between third trimester HbA1c levels and birth weight of the newborn. Birol Binbir et al[22] found that maternal HbA1c levels and macrosomia did not show any statistically significant relationship (p=0.701). 


This study has its own limitations.  Measuring the blood glucose level at the time of delivery gives us no time for interventions to modify pregnancy outcome. The timing of the test should be such that we can intervene to alter the perinatal outcome in the infants of diabetic mother. The impact of time of initiation of insulin treatment on the outcome of macrosomia was not studied. The study was done in a single centre with limited sample size.
However the study was useful to understand the association between glycemic control and macrosomia.
 
Conclusion

Overall, this study suggests that glycosylated haemoglobin (HbA1c) at delivery > 5.6 % is statistically significantly related to the women giving birth to macrosomic neonates. Diabetic pregnant women who have a higher value of HbA1 c are more likely to have macrosomic neonates.  Other maternal characteristics related significantly to macrosomia are BMI, weight gain during pregnancy and delivery by caesarean section. Diabetic women who had poor glycemic control and warranted treatment with insulin were at higher risk having macrosomia in their babies. Rest of the parameters i.e. age of the mother, type of diabetes mellitus, duration of diabetes mellitus, gestational age were not associated with macrosomia. Adequate control of blood sugar is important to normalise the internal mileu and improve perinatal outcome in the infants of diabetic mothers.
 
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File/Dsecription
Table-1
Maternal factors and macrosomia
Table-2
Comparison of mean values of risk factors in macrosomic and non macrosomic babies
Table-3
ROC curve’s results
Figure-1
Flow diagram of the study enrollment
Figure-2
ROC curve
Correlation of Glycosylated Haemoglobin and Macrosomia in Infants of Diabetic Mothers
ethics approval letter
Correlation of Glycosylated Haemoglobin and Macrosomia in Infants of Diabetic Mothers
reply to reviewers comments