Indian Journal of Obstetrics and Gynecology Research 2022;9(2):147–152

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Indian Journal of Obstetrics and Gynecology Research

Journal homepage: www.ijogr.org

Review Article
A clinical update on the molecular pathogenesis of gestational diabetes mellitus
and its consequences
Balaji Vijayam1, *, Taarika Balaji2 , Madhuri S Balaji1 , Seshiah Veerasamy1 ,
Vinothkumar Ganesan 3
1 Dept. of Diabetology, Dr. V Balaji Diabetes Care and Research Institute, Chennai, Tamil Nadu, India
2 Dept. of Medicine, Saveetha Institute of Technical and Medical Sciences, Chennai, Tamil Nadu, India
3 Dept. of Medical Research, Dr. V Balaji Diabetes Care and Research Institute, Chennai, Tamil Nadu, India

ARTICLE INFO ABSTRACT

Article history: Gestational diabetes mellitus (GDM) is becoming more common all over the world, mainly to an increase in
Received 31-1-2022 maternal obesity. There have been a number of approaches to screening for and diagnosing GDM described,
Accepted 25-02-2022 however there is no consensus on which methods are the most effective. For the mother, developing
Available online 20-05-2022 fetus, and children born to mothers with GDM, GDM poses severe short and long-term health hazards.
Macrosomia, shoulder dystocia, delivery trauma, and hypoglycemia in the immediate postpartum period are
all short-term dangers for the fetus. Increased rates of childhood and adulthood obesity, as well as a higher
Keywords:
cardio metabolic risk, are long-term hazards for offspring born to women with GDM. More investigations
Diabetes mellitus
on the aetiology and underlying mechanisms of gestational diabetes and its complications on the long-term
Insulin resistance health of offspring are needed to offer a foundation for creating effective therapies during this important
Gestational diabetes mellitus period with the goal of promoting lifelong health and well-being.
Macrosomia
This is an Open Access (OA) journal, and articles are distributed under the terms of the Creative Commons
Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon
the work non-commercially, as long as appropriate credit is given and the new creations are licensed under
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1. Introduction ranging from 14% in urban regions to 13.2% in rural areas.

In India, T2DM affects an estimated 62 million people, with
India has long been known as the world’s diabetic capital, that number expected to climb to 79.4 million by 2025. It is
and gestational diabetes mellitus (GDM) is a much worse unsurprising that the incidence of GDM is increasing at the
problem in India than it is elsewhere. It is commonly same time as the prevalence of diabetes. 4 In the year 2013,
accepted that diabetic women, especially pregnant and 6 million pregnant women in India were diagnosed with
lactating women, are among the most vulnerable. 1 India hyperglycemia, with GDM accounting for 90% of the cases.
is the world’s most populous democratic country, with GDM is usually asymptomatic and is most often discovered
16 percent of the world’s population. Unfortunately, with by standard screening during pregnancy. The guidelines
45,000 maternal deaths in 2015, India has the highest developed by the International Association of Diabetes and
maternal mortality rate in the world. It is one of six countries Pregnancy Study Group (IADPSG) were implemented in
responsible for half of all maternal deaths worldwide. 2 In 2010 and have subsequently gained universal recognition.
comparison to other Asian nations; the prevalence of GDM However, other studies suggest that it may raise the risk of
is significantly higher in the Indian population. 3 Diabetes GDM. 5 GDM affects about 5 million women in India each
is a major health problem in India, with prevalence rates year. According to the literature, pre-diabetes and diabetes
* Corresponding author.
impact nearly six million newborns in India alone, with
E-mail address: [email protected] (B. Vijayam). GDM accounting for 90% of cases. 6

https://doi.org/10.18231/j.ijogr.2022.031
2394-2746/© 2022 Innovative Publication, All rights reserved. 147
148 Vijayam et al. / Indian Journal of Obstetrics and Gynecology Research 2022;9(2):147–152

2. The Molecular Pathophysiology of GDM human placentas from both GDM and PGDM mothers
corresponded with foetal birth weight, suggesting the
The biology of GDM isn’t completely understood. Insulin involvement of GLUT proteins in intrauterine foetal growth
resistance is a major feature of the underlying pathology; facilitation. 20
in general, pregnancy triggers a number of maternal
adaptation processes that help the embryo develop and grow
2.1. Insulin and fetal growth
in a metabolically healthy way. Reversible expansion of
maternal insulin secretion and increasing insulin resistance Insulin regulates foetal growth as an anabolic hormone. 21
are two key pregnancy adaptation processes that happen as Foetal hyperglycemia and hyperinsulinemia are caused
a result of functional changes and increased β cell mass. 7 by maternal hyperglycemia, which activates the foetal
The placenta is important in the development of temporary mitogenic and anabolic pathways in growing muscles,
insulin resistance during pregnancy, which returns to normal connective tissues, and adipose tissue. 22 Overgrowth is
immediately after delivery. Insulin resistance is caused by caused by foetal hyperinsulinemia, whereas intrauterine
the placenta’s release of hormones, cytokines, adipokines, growth retardation (IUGR) is caused by foetal insulin
and other chemicals into the maternal circulation. 8 Human insufficiency. 23 The amniotic fluid of foetuses from mothers
chorionic gonadotropin (hCG), human placental lactogen with PGDM or GDM had high insulin levels. 24 Carpenter
(hPL), and human placental growth hormone (hPGH) are et al. found a link between high amniotic fluid insulin
all secreted by the placenta and bypass the regular hormonal levels in the second trimester and foetal macrosomia
regulation circuits. 9 Hepatic gluconeogenesis and lipolysis in 247 hyperglycemic pregnant women. 25 As a result,
are boosted by placental lactogen and growth hormone, and maternal glucose intolerance during pregnancy may have
maternal insulin-like growth factor I (IGF-1) levels rise in an impact on foetal insulin production as early as the
response to higher growth hormone levels. Placental growth second trimester. Indeed, diabetes women’s foetuses have
hormone (PGH) is a key regulator of maternal insulin like pronounced β-cell mass within the pancreatic islets in
growth factor I (IGF-I). 10 Increased levels of IGF-I, IGF- the second trimester, compared to nondiabetic women’s
II, IGF-IR, and IGF-IIR mRNA in the placenta are linked foetuses, and release more insulin after acute glucose
to foetal macrosomia. 11 The maternal circulation has an exposure with increasing gestational age, the difference in
increase in pregnancy related hormones such as estrogen, pancreatic β-cell mass between diabetic and nondiabetic
progesterone, cortisol, and placental lactogen, 12 increased foetuses becomes increasingly prominent. 26
insulin resistance is also present. This normally occurs The insulin-secretory activity of pancreatic β-cell has
between the 20th and 24th week of pregnancy. been found to be reflected in plasma C-peptide, which could
In addition, adipocytokines, such as leptin, adiponectin, be employed as a diagnostic for foetal hyperinsulinemia. 27
tumour necrosis factor- (TNF-), interleukin-6, resistin, Total insulin, C-peptide, and free insulin levels in umbilical
visfatin, and apelin, are produced by adipose tissue. 13 vein plasma have all been found to be elevated in diabetic
These play a role in glucose homeostasis, which can pregnancies. Two months after delivery, DubÉ et al.
lead to insulin resistance in a pregnant woman. 14 GDM discovered a link between cord blood C-peptide levels and
affected pregnant women have higher glucose levels maternal insulin, C-peptide, and insulin sensitivity indices
and lower levels of various amino acids, creatinine, values. 27 The levels of C-peptide in the cord blood of
and glycerophosphocholine. 15 Changes in glucose, amino 18 pregnant women with GDM and 23 pregnant women
acids, glutathione, fatty acids, sphingolipids, and bile with normal glucose tolerance (NGT) were measured.
acid metabolites in the amniotic fluid of GDM compared When GDM mothers offspring were compared to control
to non GDM foetuses were also described in mid- nondiabetic mothers’ offspring, higher cord blood glucose
gestation in the amniotic fluid of GDM fetuses. 16 levels were found. In general, maternal insulin, fasting C-
Maternal hyperglycemia is linked to structural abnormalities peptide, insulin sensitivity, interleukin-6, body mass index,
in the placenta, including increased placental weight, and newborn weight were all linked with cord blood C-
increased angiogenesis (chorangiosis), and delayed villous peptide levels in both groups. 27
maturation. 17 The placenta secretes glucose, proteins, and
lipoproteins into the umbilical cord plasma. Some of 2.2. Factors affecting fetal growth in diabetic
these compounds aid in the development and growth of pregnancies
the foetus. 18 As a result, foetal macrosomia may be
caused by abnormal function and expression of glucose The factors that affect foetal growth in diabetes mothers
transporter proteins (Glut proteins) in the placenta, which are depicted in Figure 1. Insulin resistance is mediated by
results in excessive maternal to foetal glucose transfer. 19 pregnancy related hormones such as estrogen, progesterone,
Glucose levels were found to be higher in foetal amniotic cortisol, and cytokines, as well as additional growth
fluid samples taken from GDM mothers. 15 The increased hormones released by the placenta and circulating in
expression of GLUT-1, GLUT-4, and GLUT-9 in term the maternal circulation, such as hPGH and placental
 Vijayam et al. / Indian Journal of Obstetrics and Gynecology Research 2022;9(2):147–152 149

3.1. Type 2 diabetes mellitus (T2DM

Women who have had previous GDM have been
demonstrated to have a significantly higher chance
of developing T2DM.28 When compared to non-GDM
pregnancies, GDM patients have a 7-fold increased risk of
T2DM, according to a systematic evaluation of 20 research
papers. 28 According to a population-based study, 18.9% of
women with previous GDM got T2DM within 9 years of the
index pregnancy, while only 2% of women without GDM
had T2DM (2.0 percent). The rate of T2DM development
increased in the first nine months after delivery, with
3.7 percent of patients acquiring T2DM during that time
frame. 29

3.2. Cardiovascular disease

Fig. 1: The pathophysiology of GDM
GDM increases the risk of metabolic syndrome and
cardiovascular disease after childbirth. Central obesity,
hypertension, insulin resistance, and dyslipidemia are all
lactogen. Adipocytokines, such as leptin, adiponectin, risk factors for metabolic syndrome. 29 Several studies
and TNF-α, are also produced by adipose tissue and have found a link between GDM and the incidence
may play a role in insulin resistance. Insulin resistance of maternal cardiovascular morbidity. 30 Women with a
causes glucose intolerance and hyperglycemia in most history of GDM are more likely to develop cardiovascular
people. As a result, the placenta alters and the fetus risk factors as hypertension, dyslipidemia, obesity, and
accumulates too much glucose, amino acids, and lipids. metabolic syndrome. Specifically, GDM was revealed to
Hyperinsulinemia is produced by the fetus in response be an independent risk factor for noninvasive diagnostic
to maternal hyperglycemia, which lowers foetal blood procedures, uncomplicated cardiovascular events, and
glucose levels while increasing foetal fat tissue and cardiovascular hospitalizations in long-term mothers. 31
promoting development. Furthermore, PGH promotes foetal Women with GDM showed considerably greater levels of
gluconeogenesis and lipogenesis, resulting in increased vascular endothelial dysfunction indicators than women
foetal growth. who had normal pregnancies; according to Bo et al. GDM
mothers have a higher risk of developing cardiovascular
disorders than normoglycemic mothers, according to the
3. Long-term Complications to the Mother
authors. 32 Furthermore, another study found a dose
response effect between glucose levels during pregnancy
and postpartum atherosclerotic morbidity when there is
modest glucose intolerance. 33

3.3. Obesity
A comprehensive metaanalysis looked at the link between
childhoods elevated BMI and maternal diabetes, and
showed a robust link between prenatal mother diabetes
exposure and increased childhood BMI. 34 Obesity rates
after in utero exposure to GDM were as high as 4.9 percent
in diet controlled GDM and 7.8 percent in diet-uncontrolled
GDM, according to Abokaf et al. Obesity rates in non-GDM
women’s offspring were as low as 1.8 percent. 35 In other
cohorts, a link between GDM and offspring obesity has been
found. 36

3.4. Ophthalmic disease

Fig. 2: The gestational diabetes mellitus and its complications
GDM has also been linked to an increased risk of long-
term ophthalmic morbidity. When compared to controls,
150 Vijayam et al. / Indian Journal of Obstetrics and Gynecology Research 2022;9(2):147–152

women with a history of GDM had a considerably greater 4.3. Cesarean delivery and surgical complication
prevalence of ophthalmic morbidity. 37 Up to 20% of women
with GDM will develop T2DM years after giving birth, The most common complication of a caesarean section is
resulting in retinopathy. 38 haemorrhage, which can occur during or after the procedure.
However, there is no consensus on the true incidence; it is
3.5. Renal disease estimated that about 75% of obstetric haemorrhages occur
following caesarean section. Obstetric haemorrhage and
GDM appears to be a major risk factor for long term renal preeclampsia alternate first and second position as causes
morbidity. Hypertensive renal illness without renal failure, of maternal death in developing countries, with the World
hypertensive renal disease with renal failure, chronic renal Health Organization adopting a rate of 10% worldwide in
failure, and end-stage renal disease were the four most all births with a viable foetus. 44
common future renal diagnoses. 39

3.6. Malignancies 5. Long-term Complications to the Offspring

Women having a history of GDM may be at a higher long 5.1. Glucose intolerance
term risk of malignancy development: hospitalizations for
malignancies years after delivery were higher in women The offspring’s development of T2DM is highly linked
with GDM. The risk of ovarian, endometrial, and/or breast to the mother’s diabetic intrauterine environment. In a
cancer has been linked to GDM. 40 Other research has found multiethnic group, 30.4% with T2DM had been exposed to
a link between GDM and higher glucose levels during maternal diabetes, compared to 6.3 percent of nondiabetic
pregnancy and an increased risk of breast cancer.Perrin et al. children. 45 Over the course of a relatively short time,
observed five instances of pancreatic cancer in women with 31.1% of obese adolescents with normal glucose tolerance
GDM history over the course of a 28–40-year follow-up who were exposed to GDM developed impaired glucose
period, with an adjusted relative risk of 7.1. 41 GDM women tolerance/diabetes. The findings show that offspring of
were also more likely to be diagnosed with pancreatic mothers who have had prenatal diabetes are at least 5 times
cancer, according to another study. 42 more likely to acquire impaired glucose tolerance than those
who have not had GDM. 46 Similarly, 21% of young with
4. Short-term Complications to the Mother T2DM or prediabetes were offspring of women who had
GDM treated with diet, compared to 4% of women in the
4.1. Preeclampsia and eclampsia
general population. 47 Obesity and T2DM are extremely
Preeclampsia and eclampsia caused by pregnancy are still common among Pima people. T2DM is up to 6 times more
a big problem in developed countries. Increased knowledge common in Pima children who have diabetic or prediabetic
and antenatal visits, along with good antenatal care, may mothers; T2DM occurs nearly exclusively in childhood and
assist to reduce the frequency of maternal and fetal adolescence in the offspring of diabetic and prediabetic
problems. Increased illiteracy and poor socioeconomic level mothers. 48 There is evidence that the greater prevalence
create a target group for medical interventions and public of diabetes and obesity in the offspring of diabetic Pima
health programmes. Early detection of instances is aided women is attributable to a combination of hereditary and
by frequent blood pressure monitoring at every visit, a environmental factors. Studies involving sibling pairs with
history of previous preeclampsia, and diabetes mellitus. one sibling born before and one after the beginning of
Proper institutional management minimises maternal and mother diabetes have yielded interesting results: Offspring
fetal mortality due to preeclampsia and eclampsia. 43 who were born after their mother got diabetes had a much
greater risk of developing diabetes themselves. 49
4.2. Prolonged labour or dystocia
Prolonged labour is a complex disorder that has a 5.2. Neuropsychiatric morbidity and
detrimental impact on obstetric outcomes as well neurodevelopmental outcome
as women’s experiences. Consensus is required in
the classification and treatment of prolonged labour. Previous research reveals that offspring of diabetic
Interventions must be carefully managed in order to mothers are at risk for poor neurodevelopment. Long-
maintain normal births and avoid abuse. Increased clinical term neuropsychiatric morbidities in offspring exposed
skill and thorough documentation of labour progress in to GDM was studied in a population based study done
birth records are critical for identifying and classifying in southern Israel. Autism spectrum disorder, eating
protracted labour and improving care for all women and disorders, cerebral palsy, obstructive sleep apnea, epilepsy,
their delivering experiences, regardless of whether they and infantile spasms were among the neuropsychiatric
have experienced prolonged labour or not. 28 conditions investigated in this study. 50
 Vijayam et al. / Indian Journal of Obstetrics and Gynecology Research 2022;9(2):147–152 151

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