Diabetes Mellitus in Pregnancy: Updates on Impact and Management

The prevalence of diabetes mellitus (DM) complicating pregnancy continues to increase worldwide, currently affecting more than 21 million births per year.1 Prevalence varies depending on the demographics of the population evaluated. For example, pregnant people of diverse racial and ethnic backgrounds have a disproportionate risk of gestational DM (GDM) and prepregnancy DM.2

The incidence of type 1 diabetes mellitus (DM-1) has increased to 3% to 4% over the past 30 years, with environmental factors playing a major role.3 Rates are higher in areas with decreased access to green spaces and less walkability.4 Among women who gave birth to a live-born baby in the United States between 2012 and 2016, 0.9% were diagnosed with pregestational DM (PGDM) and 6% were diagnosed with GDM.5

For GDM, the incidence can vary from 5% to 16% depending on the diagnostic test used.6 The body mass index (BMI) of the population also significantly affects the reported incidence; Populations with a high BMI have a much higher risk of GDM (15%) compared to those with a normal BMI (4%).7,8

As part of the normal physiological changes that accompany any pregnancy, insulin sensitivity increases early during gestation to allow for an increase in maternal fat storage.9 This is mediated primarily by human placental lactogen, but also by estrogen, progesterone and cortisol.

As pregnancy progresses, there is a 2- to 3-fold increase in peripheral insulin resistance, leading to a state of relative decreased insulin sensitivity, accompanied by a corresponding increase in insulin production. All of these physiological changes are designed to provide an energy substrate in the form of glucose that crosses the placenta and supplies the developing fetus.9,10,11

> Gestational diabetes

GDM, defined as DM diagnosed during pregnancy, was not recognized as a unique condition until the 1960s.12 GDM essentially results from an inadequate insulin secretory response in combination with peripheral insulin resistance that occurs naturally in pregnancy. Approaches to diagnosing GDM vary widely, although in pregnancies routine testing is usually performed between 24 and 28 weeks of gestation.

In 2013, the World Health Organization (WHO) adopted the 2010 International Association of Diabetes in Pregnancy (IADPSG) GDM criteria.13,14 The IADPSG criteria use a 2-hour oral glucose tolerance (OGTT) by administering a single dose of 75 g of glucose. This is in contrast to Carpenter and Coustan’s traditional 2-step approach of performing an OGTT with 50 g of glucose in the first hour, followed by a 3-hour diagnostic OGTT with 100 g, which the American College of Obstetricians and Gynecologists (CAOG) recommended based on a consensus summary from the National Institutes of Health.15,16

Table 1 summarizes these 2 types of screening approaches and the corresponding diagnostic criteria.15,16,17 The 2-step diagnostic approach has not been validated against the IADPSG diagnostic approach. Although the CAOG supports the use of the 2-step approach, it recognizes that the 1-step approach may be appropriate for certain populations. The American Diabetes Association (ADA) supports the 1- and 2-step approaches outlined in Table 1 for the diagnosis of GDM.17 Regardless of which approach is used, GDM is separated into 2 types: GDM1 , which is managed with modifications in diet and physical activity, and DMGA2, which requires medication.

It is controversial whether GDM is solely a disease of late pregnancy and needs to be investigated further.18 Some experts advocate testing before 24 weeks of gestation for those with risk factors such as high BMI or history of GDM. , although no consensus has been established on diagnostic criteria in early pregnancy. If DM is diagnosed early in pregnancy according to the criteria in Table 1, affected patients are designated as having overt DM (according to the IADPSG) or are simply labeled as having gestational DM (according to the WHO).

> Pregestational DM (DM-1 and DM-2)

The diagnosis of pregestational DM is based on the ADA criteria as follows:

• Hemoglobin A1C (HbA1C) ≥ 6.5% or fasting blood glucose ≥ 126 mg/dl (7 mmol/l) or
• Blood glucose 2 hours after ingestion ≥ 200 mg/dl (11.1 mmol/l) or
• Diabetic ketoacidosis (DKA) or symptoms of DKA with random blood glucose ≥ 200 mg/dL (11.1 mmol/L)19,20

Patients with DM-1 cannot increase their insulin secretion, which is a necessary response during pregnancy.

Patients with DM-2 face insulin resistance before pregnancy, which worsens during pregnancy.

DM-1 is due to the destruction of pancreatic islet B cells through an immune-mediated response. Autoantibodies against pancreatic islet B cells can be found up to 20 years before the clinical onset of the disease.21 However, the etiology of DM-1 is heterogeneous.

Genetic predisposition and response to inflammatory mediators, as well as environmental factors such as infection, poor nutrition, stressed gut microbiome, toxic response to medication, or some combination thereof, contribute to the development of the disease. One or a combination of such factors affects the developing immune system, resulting in an abnormal response to inflammatory mediators.21

A synergistic response to genetic and epigenetic environmental risk factors results in DM-1.22

The history of a father with DM-1 imposes a greater risk of his offspring inheriting the clinical picture than if the mother is affected.23

Similar to DM-1, DM-2 results from a synergistic response to genetic and epigenetic exposures and environmental risk factors. However, patients with DM-2 have adequate insulin secretion with increased insulin resistance.22 Ultimately, in response to this increased insulin resistance, there is a progressive loss of insulin secretion.

There really is no standard for diagnosing DM-2 during pregnancy and patients are traditionally not labeled as such until postpartum confirmation. Bengtson et al. developed a model that has a sensitivity of 80% to predict which patients diagnosed with DM during pregnancy are more likely to be diagnosed with DM-2 after delivery.

This model is based on a combination of clinical indicators such as HbA1C levels, BMI, family history of diabetes, and an early diagnosis of GDM (<24 weeks gestation).24 If validated, this approach may aid prevention efforts of diabetes among people with GDM.

Comorbidities such as obesity and hypertension play a role in the impact of DM during pregnancy.

Furthermore, the impact is transgenerational as will be discussed later. DM is a risk factor for complications of gestational hypertension, and chronic hypertension exacerbates that risk. DM is associated with a higher risk of infections and poor wound healing during pregnancy as occurs in non-pregnant women.

Glucose levels in patients with DM are also more erratic during pregnancy, with traditionally higher peak glucose levels and lower trough glucose levels, respectively. Lower glucose trough levels pose a higher risk of DKA with a lower glucose threshold to trigger this complication.

Public health problems associated with DM during pregnancy include worse outcomes in affected patients who are socially disadvantaged.25 Additionally, DM in pregnancy correlates with risk of long-term cardiovascular and metabolic disease in pregnant women and their offspring. .26 Good glucose control should reduce this effect, although the impact of treatment during pregnancy on the long-term metabolic health of the offspring is currently unknown.18

Overall, DM during pregnancy is associated with a 2- to 5-fold increased risk of fetal anomalies, stillbirth, and neonatal death, with 50% of babies experiencing complications such as NICU admission, prematurity, and/or macrosomia.1 ,25,27 There is an increased risk of spontaneous abortion and structural anomalies in pregnancies complicated by pregestational diabetes.

Poor glycemic control (as reflected by elevated HbA1C levels at conception and early in the first trimester) is associated with an increased risk of miscarriage and major abnormalities.28 Risks for abnormalities are complex and multifactorial. Growth abnormalities can also affect pregnancies complicated by either GDM or pregestational DM.

Animal studies have identified the molecular mechanisms of hyperglycemia-induced birth defects, including a negative impact on lipid metabolism, excess free radical generation, and aberrant cell death.29 Fetal anomalies and Growth disturbances are the result of epigenetic alterations (with changes in gene expression) as well as oxidative stress.6 The risk of abnormalities increases in general, but in particular for heart and neural tube defects.6

In a cohort study of pregnant patients with DM-1, an HbA1C of 8.5% or higher carried a 33% risk of miscarriage or abnormalities.28 An HbA1C higher than 10.4%, regardless of type 1 DM or 2, has been associated with a risk of abnormalities greater than 10%.6,29 Patients with GDM are not immune to the increased risk of abnormalities if they have high fasting blood glucose values, high BMI and/or an early diagnosis of pregnancy .9 If the patient’s HbA1C is less than 6.9%, the risk level approaches that of the general population.6

Growth abnormalities are also more common in pregnancies complicated by DM, particularly when glycemic control is poor, but this is not always true. Causal understanding of the determinants and assessment of growth and development in pregnancies complicated by DM remain limited. For example, first trimester HbA1C is a good predictor of fetal macrosomia, as is dietary glycemic index (calculated based on carbohydrate intake) and glycemic load in early pregnancy, but it is not known exactly why this is is the case.30,31

It is known that fetal hyperinsulinemia will develop early in pregnancy if exposed to a high glucose load, resulting in an exaggerated fetal glucose theft phenomenon and macrosomia , which explains why even good maternal glycemic control in the third trimester it can still be associated with fetal macrosomia. Hyperinsulinemia increases lipoprotein lipase activity, resulting in greater lipid incorporation into fetal adipocytes.32

Macrosomia , defined by the CAOG as a birth weight greater than 4500 g, correlates with the degree of diabetic control during pregnancy33; However, this is difficult to separate from obesity, which is often associated with DM.34

Macrosomia imposes increased risk of birth injury, cesarean section, postpartum hemorrhage, and maternal trauma, as well as overall perinatal morbidity and mortality.35 The risk of accelerated fetal growth persists even when microvascular disease is present, but diabetic pregnancies complicated by severe vascular disease and or preeclampsia have an associated risk of intrauterine growth restriction (IUGR).36,37

The rate of spontaneous or indicated preterm birth increases in pregnant people with DM-1.38

Iatrogenic preterm birth may be due to preeclampsia and/or IUGR. There is a 5-fold increased risk of intrauterine fetal death (ILFD) due to fetal hyperglycemia and hyperinsulinemia, which lead to increased fetal oxygen consumption that can in turn lead to fetal hypoxemia and acidosis.39 Additional microvascular disease in patients Pregnant diabetics may affect uteroplacental perfusion, further increasing the risk of MFIU.

Polyhydramnios can complicate diabetic pregnancies. The etiology of this association is not clearly defined, but it may be explained by fetal polyuria secondary to maternal and/or fetal hyperglycemia. However, because congenital anomalies are increased in diabetic pregnancies in general, an evaluation of the specific cause of polyhydramnios is important.

Pregnancies complicated by DM pose a risk to the newborn as a consequence of fetal anomalies, birth injuries, and prematurity.

Macrosomia is associated with an increased risk of electrolyte disorders and hypoglycemia in the newborn. However, hypoglycemia, hypocalcemia, hypomagnesemia, polycythemia, and indirect hyperbilirubinemia of the newborn are increased in all diabetic pregnancies, even if macrosomia is not present. Furthermore, these risks, as well as the risk of respiratory distress syndrome (RDS), may occur despite excellent glycemic control during pregnancy.

Inadequate glycemic control during pregnancy and obesity contribute to childhood obesity. Neonatal adiposity correlates with pregnant adiposity (based on BMI and plasma triglycerol levels) but negatively correlates with umbilical cord serum triglycerol, suggesting increased lipid uptake in the fetal tissue.18

Both pregestational DM and GDM are correlated with long-term metabolic and cardiovascular risks for both pregnant people and their children.26 Good glycemic control should reduce this impact, but the effect of therapy during pregnancy is unknown. pregnancy on the long-term metabolic health of the offspring.18 DM in pregnancy may also have a negative impact on the cognitive ability of the offspring and potentially increase the risk of attention-deficit/hyperactivity disorder and autism spectrum disorders. ; however, other confounding factors may be affecting these risks.40

The need to promote good health and well-being before, during and after pregnancy cannot be underestimated. Lifestyle counseling, optimization of glucose control and management of comorbidities, along with frequent self-monitoring of blood glucose levels, are essential for all patients with DM.

> Preconception

The current main causes of perinatal mortality in pregnancy complicated by DM-1 or DM-2 are fetal malformations, and the level of glycemic control during the periconception period is directly correlated with the risk of malformations. Since most pregnancies are unplanned , it is difficult to optimize preconception health. So, rather than waiting until a person is thinking about becoming pregnant, it is critical to educate patients with DM about the importance of good glycemic control; This approach not only decreases risks in a future pregnancy, but also correlates with better overall outcomes for the patient.

Promoting awareness, increasing education, improving access to care, and empowering patients with DM is imperative to improving outcomes in pregnancies complicated by DM.

To date, achieving excellent glucose control before pregnancy has been the best validated means of improving pregnancy outcomes with DM. In fact, optimization of preconception glycemia has been found to reduce the risk of fetal anomalies and decrease perinatal mortality in patients with DM-1 and DM-2, in addition to being cost-effective.41

Good glycemic control in patients with DM in the first and second trimester reduces the risk of preeclampsia, macrosomia, and prematurity.25,42 The ideal HbA1C level is less than 6.5% at the beginning of pregnancy. An elevated HbA1C in the first trimester is strongly correlated with poor pregnancy, fetal, and infant outcomes.43,44

The ideal approach for patients with DM is to provide preconception counseling about potential risks, offer the opportunity to make shared decisions regarding continuing the pregnancy, and focus on achieving the best possible glycemic control before continuing the pregnancy. Patients with DM-1 and DM-2 may have organic involvement, so it is important that they be evaluated for nephropathy, retinopathy, atherosclerotic heart disease, neuropathy, and gastroparesis. Additionally, an evaluation of other related comorbidities such as hypertension, obesity, and thyroid disease is essential.

In addition to optimizing glycemic control and assessing comorbidities and diabetic complications, preconception care should also include initiation of folic acid and medication review, with discontinuation of medications that are potentially harmful to a developing fetus. Folic acid supplementation at a dose of 400 mg/day before conception for 2 to 3 months with continuation for the remainder of pregnancy, in addition to a balanced diet that includes folate-containing foods, is important as it has been found that reduces the risk of anomalies.45

It is advisable to discontinue medications that are teratogenic (such as angiotensin-converting enzyme inhibitors) and replace them with others that have better safety profiles during pregnancy.

Insulin is the first-line medical treatment for DM during the preconception period and during pregnancy.

Neither insulin nor the insulin analogues that were introduced in the late 1990s cross the placenta.9

Metformin is the most studied oral hypoglycemic agent and has not been found to increase fetal abnormalities.6 Gliclazide is a sulfonylurea for patients with DM-2, but safety data on its use in pregnancy are limited. However, a small study comparing gliclazide with metformin showed no difference in hypoglycemia, fetal abnormalities, or birth weight.6,46 Due to limited safety data, discontinuation of gliclazide before administration is recommended. conception.

BMI should be optimized before any pregnancy, ideally to a level below 30. Obesity is increasing worldwide47 and independently increases the risk of cesarean section, prematurity, fetal anomalies, stillbirth, and macrosomia.48 The changes in lifestyle, with more exercise and weight optimization, have to be well thought out and long-term, since short-term changes before pregnancy have not improved results to date.49

> Medical treatment before delivery

As a result of the increased risk of pregnant DM patients with hypertensive complications, low-dose aspirin (81 mg daily) is recommended after 12 weeks of gestation, ideally beginning between weeks 13 and 16, and continuing until delivery. .16,17

For patients with GDM, general risks include a 30% risk of cesarean delivery, 50% risk of hypertension, 70% risk of prematurity, and 30% risk of macrosomia.1

Treatment of GDM to achieve glycemic control decreases the risk of shoulder dystocia, macrosomia, cesarean section, and hypertension.50 Therefore, universal screening is recommended between 24 and 28 weeks of gestation to allow a reasonable time for start treatment to control glycemia. One-third of patients with GDM will require medications for adequate glucose control.6,51 ADA and CAOG recommend insulin as a first-line medication for those who need treatment.

Half of GDM patients treated with oral hypoglycemic agents such as glyburide or metformin achieve adequate glucose control and then require a switch to insulin.52

Patients treated with metformin are twice as likely to require insulin compared to patients treated with glyburide. However, due to concerns about the increased risk of macrosomia and neonatal hypoglycemia with glyburide, the Society for Maternal-Fetal Medicine opined that although insulin is considered the first-line treatment, metformin is a reasonable and safe alternative. 52 However, Barbour et al. do not coincide with the widespread adoption of metformin given that fetal concentrations of metformin are equivalent in the pregnant woman and the fetus.53

Metformin may impose epigenetic modifications on gene expression and also affects postnatal gluconeogenic responses.53

For people with DM-1 or DM-2, insulin or an insulin analog is the first-line treatment during pregnancy. Sulfonylureas cross the placenta and are associated with neonatal hypoglycemia.19 Glyburide is no longer recommended given the higher rates of neonatal hypoglycemia and macrosomia compared with metformin or insulin.54

For patients with DM-2 who have been treated with metformin before pregnancy, it is recommended to discontinue metformin at least during the first trimester. An exception to this approach is when a patient’s insulin resistance is so significant that large amounts of insulin are required, and the addition of metformin is considered reasonable after counseling the patient about the risks.

> Additional prenatal care

A multidisciplinary team approach to the care of pregnant women with DM is ideal and includes a certified diabetes educator, endocrinologist, nutritionist, obstetrician, and neonatologist; however, it is often not feasible. Telemedicine has been extremely helpful in this approach.

For preconception or overt DM, a management approach is recommended as described in Table 2.16,17,39,48,55,56,57,58,59,60 DM does not increase the risk of aneuploidy, but Non-invasive screening for aneuploidies should be offered to all pregnant women.

Ultrasound should be performed in the first trimester not only to date and evaluate viability, but also to detect abnormalities that may be observed in this period (e.g., enlarged nuchal translucency, anencephaly, anterior abdominal wall defect). This should be followed by a detailed anatomical examination at approximately 20 weeks’ gestation and fetal echocardiography between 22 and 24 weeks’ gestation.

Assessing fetal growth with ultrasonography is challenging, particularly in the presence of obesity when the sensitivity of weight estimates deviates by up to 20%. 3D fractional thigh volume would be the best predictor of neonatal body fat stores in those with suspected fetal macrosomia, but this technique is not widely available outside of academic medical centers.57

Fetal MRI is more specific but not more sensitive than 2D ultrasound in predicting macrosomia and is much more expensive.58 Therefore, neonatologists must understand the limitations of prenatal assessments of fetal weight and that the only true measure for macrosomia will be the evaluation/measurement of the newborn.

The frequency of evaluation of fetal growth in pregnancies complicated with DM is based on expert opinion; Some recommend serial monitoring (every 3 to 4 weeks) if medications such as insulin or metformin are needed regardless of whether the patient has GDM, overt DM, or pregestational DM, although this approach is often not practical in low-resource areas. For patients with GDM who do not require medication, the current recommendation is an ultrasound growth scan in the third trimester. (17)

Recommendations for prenatal surveillance also vary for pregnant patients with DM. The most common approach is to perform prenatal testing starting at 32 weeks’ gestation for those requiring glucose control medication; this is accomplished with biweekly non-stress testing or weekly biophysical profiles. For patients with GDM who do not require medication, prenatal evaluation for that diagnosis alone is not recommended.17

The goal for pregnant patients with DM is to avoid DKA and hypoglycemia, which lead to substantial risks to the pregnant woman and the developing fetus. Traditionally, it is recommended that patients with DM-1, DM-2, or GDM obtain a fasting blood glucose measurement and a 1- or 2-hour postprandial fingerstick glucose measurement every day with the following objectives:

• Fasting blood glucose = 70–95 mg/dl (3.9–5.3 mmol/l)
• Blood glucose 1 hour postprandial = 110–140 mg/dl (6.1–7.8 mmol/l), or
• Blood glucose 2 hours postprandial = 100–120 mg/dl (5.5–6.6 mmol/L)

All pregnant people can experience nausea, vomiting, and loss of appetite in the first trimester. Furthermore, insulin sensitivity increases and therefore the risk of hypoglycemia also increases in the first trimester in all pregnancies.11 Therefore, for patients with DM, target insulin levels may need to be relaxed. glucose in the first trimester until gastrointestinal symptoms resolve. Thereafter, patients with DM must achieve their target glucose levels.

The type of insulin used in pregnancy depends on the doctor’s experience and preference and includes a split-mix subcutaneous injection approach or an insulin pump. There is no clear evidence that the insulin pump is superior to the split-mix approach.19 The split-mix subcutaneous insulin approach uses an intermediate- or long-acting insulin in combination with insulin lispro or insulin aspart, the latter to cover meals. There is a need to validate the safety and efficacy of new insulin analogues and concentrated insulin preparations.

Continuous blood glucose monitoring , with a target glucose range of 63 to 140 mg/dl (3.5–7.8 mmol/l) with more than 70% of measurements in the target range, appears promising for use in pregnancy. However, this is not regularly or easily available to date. A recent randomized controlled clinical trial comparing continuous versus capillary glucose monitoring in pregnant patients with DM-1 showed that continuous monitoring increased the percentage of time blood glucose was in the target range and reduced neonatal complications (50 % reduction in macrosomia, NICU admissions and neonatal hypoglycemia).61

Combining an insulin pump with continuous blood glucose monitoring has also shown promise in certain pregnant patients, with more stable glucose measurements seen in pregnant women and newborns.62

For pregnant women with DM who are candidates for receiving corticosteroids before 34 weeks of gestation to improve fetal lung maturity, it is important to note that this medication can result in severe hyperglycemia even if glucose control is good.

If it occurs, hyperglycemia usually lasts 5 days. Because pregnant diabetic patients were considered high risk, they were not included in the only trial in which corticosteroids were administered at late preterm gestational age (i.e., 34-37 weeks gestation) and therefore the Administration of corticosteroids in pregnant patients with diabetes is not recommended during this period.63,64

For pregnant women with well-controlled DM, delivery is recommended between 39 0/7 and 39 6/7 weeks of gestation.16,17

Expectant management is not recommended beyond 39 6/7 weeks of gestation.

If there is concern about impending macrosomia, no additional benefit has been demonstrated for delivery before 39 0/7 weeks of gestation and this approach may impose an increased risk of RDS due to delayed fetal lung maturity as a result of Fetal hyperglycemia and its impact on cellular maturation and function.65,66

The timing of delivery in the face of uncontrolled hyperglycemia, lack of compliance, previous fetal death, and/or vascular disease in patients with DM should be considered on an individual basis.15,59,67

Caesarean section is recommended for a fetus with an estimated weight greater than or equal to 4,500 g in pregnant patients with diabetes because the risk of shoulder dystocia is 20% to 50%.68 For pregnant diabetic patients with an estimated fetal weight between 4,000 and 4,499 g, the risk of shoulder dystocia is lower, but still substantial, up to 15%, therefore, counseling with shared decision making is important and care should be individualized.68

> Intrapartum approach

Pregnant patients with DM should ideally schedule cesarean sections or inductions in the early morning because euglycemia is much easier to achieve when a patient is in a fasting state. Typically, the day before delivery, the nighttime insulin dose is reduced by half and the morning insulin dose is maintained; If insulin is needed during labor, it is provided via an insulin drip.

For patients in active labor, the target blood glucose should be 70 to 125 mg/dL (3.9–6.9 mmol/L) because higher blood glucose levels have been associated with fetal acidemia and neonatal hypoglycemia.17 .69

Patients being treated with metformin should not receive metformin during labor, and if necessary, intravenous insulin may be administered. It is important to realize that insulin requirements decrease dramatically after delivery of the placenta and therefore any insulin infusion should be stopped after delivery. There are no contraindications to regional anesthesia, although dextrose-free solutions should be used for intravenous boluses.

> Postpartum approach

The amount of subcutaneous insulin a patient needs is typically much lower in the first 48 hours of the postpartum period, and this can continue indefinitely, particularly if the patient is breastfeeding.

For those who had DM before pregnancy, a reasonable approach is to restart their subcutaneous insulin regimen at half the prepartum dose, with adjustments as needed. Breastfeeding should be encouraged, as insulin requirements are approximately 20% lower compared to non-breastfeeding women.70,71 Both insulin and metformin are considered safe for breastfeeding. After delivery, patients with GDM often have normal glucose values ​​without insulin treatment, even if they required a substantial amount of insulin before or during delivery.

Other morbidities are associated with DM in pregnancy. Postpartum depression is more common in patients with pregestational DM and GDM. Patients with GDM have an increased risk of developing diabetes later in life (>50% risk compared to 20% in patients without GDM) and should be formally re-evaluated 6 weeks after delivery.72

The Diabetes Prevention Program Outcomes Study (a multicenter trial that evaluated the effects of an intensive lifestyle program or metformin treatment to prevent or delay DM-2 in high-risk patients) found that treatment with Metformin reduced the risk of DM-2 by 35% compared to placebo for those at risk.1,9,73,74 Therefore, starting metformin in patients with GDM after delivery should be considered given that potential benefit.

Epigenetics is implicated in in utero exposure to hyperglycemia, which could affect the long-term metabolic health of children born from pregnancies complicated by DM.1,75 DM can change genes involved in pathways essential for embryogenesis, including oxidative stress, apoptosis, folate metabolism, and proliferation.6 With oxidative stress, there is an imbalance between nitric oxide and reactive oxygen species, leading to an increased risk of developing abnormalities in the fetus.6 Stress Oxidative directly damages DNA, causing lipid/protein oxidation.6

Evidence suggests that exposure to smoking, certain infections, and endocrine disruptors (discussed below) can lead to developmental programming in the fetus that leads to obesity and DM-2 later in life.76 In fact, Epigenetic modifications of DNA methylation and microRNA interactions have been causally linked to obesity and DM-2.76 Interventions such as diet and exercise can reverse epigenetic changes and therefore affect future generations.

An endocrine disruptor is a substance that can interfere with the action of a hormone, with 15 such disruptors defined to date. Examples include bisphenol-A (BPA) and phthalates, which are food and water contaminants found in plastics that are easily absorbed and can increase the risk of obesity and GDM.77 The exact mechanism is not clear. defined but appear to alter adipose cells and B cells of pancreatic islets, causing dysfunction and transgenerational damage.77 Endocrine disruptors alter organ development, immunity, metabolism, and behavior.78

They interfere with the developing epigenome of the fetus, resulting in conditions such as obesity, diabetes, and cardiovascular disease later in life.78 They also affect placental health in the current pregnancy, posing a risk for GDM, preeclampsia, and RCIU.78

A child who was exposed to endocrine disruptors in utero may be at increased risk for cognitive dysfunction and attention deficit disorders.79

Therefore, eliminating such exposures is an important health measure. Data on the impact of BPA on pregnant women is conflicting. A recent meta-analysis by Taheri et al, for example, found no association between BPA exposure and the risk of GDM in a concurrent pregnancy.80

Arsenic exposure during pregnancy has been associated with GDM, but evidence does not clearly point to an adverse impact on postpartum insulin resistance of pancreatic islet B cell function.81 The association between environmental exposure to phenol and paraben and GDM, but the impact of a mixture of these chemicals on exposures has not been clearly delineated.82

In summary, the epigenetic impact of DM in pregnancy includes an increased incidence of childhood obesity, insulin resistance/diabetes, and neurocognitive problems in offspring, which appears to extend to all forms of DM that complicate pregnancy.1,73 ,83 Epigenetic changes are modifiable and reversible, as they do not change the innate DNA sequence, but rather change the way the body reads a DNA sequence and how genes are expressed. This is an area of ​​active research, as well as an opportunity to modify outcomes and improve health during pregnancy.

Table 1. Criteria for the diagnosis of GDM.

Table 2. Clinical management of patients with preconception diabetes or overt DM during pregnancy.