Diabetes, Kidney Function, and Pregnancy Prevention

More than 21 million births annually are affected by maternal diabetes (DBT) worldwide. In 2016, in the US, the prevalence of pre-existing DBT (type 1 or 2) and gestational DBT mellitus (GDM), in women who gave birth to a live baby, was 0.9% and 6.0% , respectively. Currently, efforts have been redoubled to diagnose and treat DBT earlier in pregnancy. DBT GDM has significant implications for the maternal-fetal dyad.

• Type 1 DBT is associated with a 2-5 times increased risk of major complications, such as congenital anomalies, stillbirths, and neonatal death; while 50% of babies suffer complications such as prematurity, a larger fetus in relation to gestational age and admission to a neonatal intensive care unit.
   
• Women with type 2 diabetes tend to have less dramatic changes in glucose metabolism and are less prone to diabetic ketoacidosis (DKA) and cesarean delivery compared to pregnant women with type 2 diabetes.

However, studies are conflicting about whether offspring have similar or lower rates of congenital malformations and stillbirth compared to those with DBT.

Gestational diabetes mellitus (GDM) is diagnosed in the second or third trimester of pregnancy, in the absence of overt pregestational diabetes.

• Women with GDM have a 30% increased risk of cesarean delivery and a 50% increased risk of gestational hypertension.
   
• Their offspring have a 70% greater risk of prematurity and a 30% greater chance of the fetus being larger for gestational age.
   
• GDM is closely associated with maternal T2DM later in life.
   
• There is increasing evidence that exposure to any form of DBT during pregnancy confers increased risk of childhood adiposity, insulin resistance, and neurodevelopmental disorders.

> Normal maternal glucose metabolism

Although early pregnancy is a time of relative insulin sensitivity , this sensitivity decreases dramatically in the early second and third trimesters of pregnancy. Insulin-dependent glucose uptake in tissues such as muscle and fat is reduced.

The physiological insulin resistance of pregnancy constitutes a maternal physiological adaptation to preserve carbohydrates for rapid growth of the fetus.

Furthermore, impaired insulin-mediated suppression of maternal lipolysis and fat oxidation provides fatty acids as an alternative energy source. This process is probably mediated by a number of factors including an increase in hormones such as progesterone, estrogen, cortisol and human placental growth hormone.

It is common for insulin production to increase 2-3 times, enough to face this challenge: Studies confirm that, in human pregnancy, there is an increase in the fraction of pancreatic ß cells.

It appears, the authors say, that insulin secretion increases significantly in early pregnancy, even before insulin resistance increases. In animal models, lactogenic hormones appear to stimulate this process through a direct effect on β cells. However, it is uncertain whether this is the case in humans.

> Gestational Diabetes Mellitus (GDM). Frequently, the insulin secretory response is inadequate and hyperglycemia develops, leading to the diagnosis of GDM in women without preexisting DBT. The little physiological evidence in such women indicates that there are subtle abnormalities of insulin secretion that precede pregnancy and persist after childbirth.

In studies of high-risk women with GDM, independent predictors of postpartum glucose tolerance abnormalities were hyperglycemia before 22 weeks of gestation, and a low early-phase insulin response in the glucose tolerance test. intravenous glucose (PTG), in the early wave of insulin release, followed by a rising phase of insulin secretion over several hours. This early-phase response plays an important role in maintaining glucose homeostasis in healthy women, and is lost in the early stages of DBT.

The degree of insulin resistance in the third trimester is not a significant predictor of abnormal glucose tolerance in the 6 months after GDM. This suggests a chronic β-cell defect exacerbated by pregnancy.

Women with preexisting DBT experience similar changes in insulin resistance. The compensatory capacity of β cells is more profoundly impaired in T2DM and is negligible in T1DM. Although the clinical impact may be negligible, a pregnancy-induced increase in C-peptide suggests a role for β-cells, even in women with established, undetectable T1DM.

Maternal hyperglycemia, both before pregnancy and during the first trimester, can result in major defects and pregnancy loss.

While these outcomes typically affect pregnancies in women with pre-existing diabetes, in women with GDM they increase with maternal fasting hyperglycemia, body mass index (BMI), and lower gestational age at diagnosis.

Most commonly, malformations affect the heart or central nervous system and include transposition of the great vessels, septal defects, neural tube defects, and caudal regression syndrome, the latter of which is almost universally associated with DBT in pregnancy.

Oxidative stress is believed to play a role in the development of such complications, but more studies are needed. Although maternal hyperglycemia in the second and third trimesters is often associated with excessive fetal growth , women with preexisting DBT may have impaired fetal growth through 2 mechanisms.

Maternal microvascular disease confers a significant risk of intrauterine growth restriction, while hyperglycemia in the first trimester may affect placental development and subsequent fetal growth, through poorly understood mechanisms.

Maternal glucose is transferred to the fetus across the placenta down a concentration gradient determined by both maternal and fetal glucose levels.

Maternal hyperglycemia, therefore, promotes fetal hyperglycemia and stimulates fetal insulin secretion. This process constitutes the "hyperglycemia-hyperinsulinemia hypothesis" or “Pedersen hypothesis.”

Taking this as a step further, fetal glucose use increases with hyperinsulinemia , decreasing fetal glucose and increasing the transplacental glucose gradient and the rate of glucose transfer. This is described as the "fetoplacental glucose theft phenomenon" and once established, is believed to promote elevated glucose flux, with stimulation of fetal triacylglycerol formation and deposition of excess fetal adipose tissue, even when blood glucose levels are low. maternal is normal.

Pedersen’s hypothesis was developed at a time when most cases of hyperglycemia in pregnancy were due to T1DM. However, over the past 50 years, the rise in maternal obesity has changed this landscape, and the average metabolism to which the developing fetus is exposed is undoubtedly different in obesity (with or without T2DM). For example, maternal triglyceride levels are 40% to 50% higher in mothers with obesity and GDM than in mothers with normal weight during pregnancy.

Placental lipases can hydrolyze maternal triglycerides to release fatty acids that remain for fetal-placental disposal, and there is increasing evidence that these are also important substrates for fetal fat deposition, accretion, and overgrowth.   

Excessive fetal growth (   macrosomia or large for gestational age [LEG]) is typically defined as an absolute birth weight >4,000 g to 4,500 g; while LPG refers to a birth weight greater than the 90th percentile for gestational age.

• Affected infants are at risk of asphyxia, perinatal death, shoulder dystocia with or without birth injury, respiratory distress, and hypoglycemia.
   
• Additional metabolic complications that may be present at birth, caused by maternal hyperglycemia, are hypocalcemia, hypomagnesemia, polycythemia, and hyperbilirubinemia.

It is difficult to separate the role of fetal exposure to maternal hyperglycemia from factors such as maternal obesity and environmental exposures. However, children of mothers with pre-existing DBT or GDM have higher birth weight and are at greater risk of T2DM at any age, compared to those born to mothers without TD.  

Epigenetic variation established in the uterus may explain the relationship between the uterine environment and subsequent disease susceptibility. Although a number of variants in offspring methylation appear to be independently associated with GDM and T2DM, there has been no development of biomarkers to predict which children are at greatest risk for metabolic diseases.

Another emerging concern is the potentially negative effect of maternal DBT on the cognitive development of offspring, but reports have been conflicting and causal pathways are unclear. 

The risk of T1DM increases in the offspring of a mother or father with type 1 or type 2 diabetes, and may occur more frequently if the diabetes is paternal.

> DMG. Two randomized controlled trials confirm that treating pregnant women between 24 and 28 weeks of gestation improves pregnancy outcomes. In a survey conducted in Australia, 490 women with GDM were assigned to one intervention arm --- dietary counseling, glucose control, and insulin therapy as needed --- and another group of 510 women who received routine care. .

The first result was a reduction in serious perinatal complications (including death, shoulder dystocia, bone fracture and nerve palsy) in GDM cases. Landon et al did a randomized study of pregnant women with mild MGD and separated them into 2 groups: one received nutritional counseling and diet therapy along with insulin if necessary (treatment group). The other (control group) received traditional prenatal care.

The researchers found that increased intensive care of women with mild GDM reduced the risk of secondary outcomes, such as excessive fetal growth, shoulder dystocia, cesarean delivery, and hypertension. There was no effect on the primary outcome (a composite of fetal or perinatal death and neonatal complications, including hyperbilirubinemia, hypoglycemia, hyperinsulinemia, and birth trauma).

Other retrospective data show an increased risk of neonatal hypoglycemia and intensive care admission in women with poor glucose control.

> Pre-existing diabetes. There is much evidence to indicate that applying a structured evidence-based approach to the care of women with pre-existing DBT before and during pregnancy can reduce the risk of adverse outcomes such as congenital malformations and stillbirths.

> Pre-existing DBT. Counseling during the preconception stage should be part of all medical care for women of reproductive age with DBT. Long-acting reversible contraceptive methods, such as intrauterine devices or progestin implants, are very effective and should be recommended until the woman wants to become pregnant.

For women who are already planning pregnancy, management aimed at pre-pregnancy care, provided by a multidisciplinary team, will be applied for 1-2 months. The goal of glycated hemoglobin (HbA1c) equal to or less than 6.5% is associated with a lower risk of congenital anomalies.

A target <6.0% is recommended, although this may not always be achieved, due to problems such as hypoglycemia. Women should be encouraged to maintain their HbA1c target, as this will improve their chances of better pregnancy outcomes. Management of hypoglycemia should be monitored and, if using insulin , glucagon should also be prescribed .

Preconception visits should include basic laboratory studies plus thyroid function tests and assistance with smoking cessation, if the patient is a smoker.

Folic acid should be prescribed and its level monitored until the 12th week of gestation. The dose of folic acid varies according to the criteria of the advisory groups. Doses range from a minimum of 400 mg/day; up to 5 mg/day. Folic acid administration is based on a theoretical benefit of reducing the increased risk of neural tube defect associated with preexisting DBT.

Potentially teratogenic medications such as angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs), and statins should be discontinued.

Women should be screened for complications of DBT. Diabetic retinopathy may worsen during pregnancy, particularly if there is a rapid worsening of glycemic control. This pathology must be followed by an ophthalmologist.

Baseline creatinine, estimated glomerular filtration rate, and albumin/creatinine ratio are important indications of renal function before pregnancy and may play a critical role in determining the timing of delivery, even in women with mild renal involvement. Referral to nephrology should be considered if creatininemia is abnormal or if protein excretion is >2 g/day. Pregnancy does not worsen kidney function in women with diabetic nephropathy and normal creatininemia; But other complications, such as preeclampsia and premature birth, are more common,

Although fertility decreases significantly as kidney disease progresses, pregnancy is still possible, but for women with end-stage kidney disease, it is best to delay pregnancy until after organ transplant. Kidney function is closely related to blood pressure, which should be closely monitored during pregnancy. Its control before and during pregnancy is associated with better results.

Nifedipine and labetolol are commonly used agents. Alpha-methyldopa is also a reasonable option, but is commonly associated with postural dizziness, and requires less frequent dosing. A reasonable blood pressure goal in women with diabetes and chronic hypertension is a pressure <135/85 mmHg.

Perform an electrocardiogram in all women and screen for coronary artery disease in those at high risk (e.g., maternal age, preexisting hypertension, chronic kidney disease, smoking, or family history of premature coronary artery disease. Although all Women with DBT should receive care from a dietitian before pregnancy; for those who are overweight or obese, advice on ways to lose weight before pregnancy is of great importance.

> DMG. Because most women have at least one risk factor for GDM and 50% of pregnancies are unplanned, they do not receive effective GDM prevention. Pre-pregnancy interventions are challenging. Many studies, including a recent large Finnish study and a meta-analysis, have demonstrated the effectiveness of the intervention when patients seek care before pregnancy, so it remains a powerful target for improving care.

There is general agreement that women with risk factors for DBT 2 should be tested for undiagnosed DBT using standard diagnostic criteria at their prenatal visit. Standard screening for GDM at 24 to 28 weeks of gestation is recommended, with several options available.

The most common is the measurement of blood glucose in venous blood, 1 hour after ingesting 50 g of glucose; without the need for fasting. The thresholds for this glycemia vary from 130 to 140 mg/dl, which varies the specificity and sensitivity. Women whose glucose levels meet or exceed prespecified threshold values ​​should then do another test with a 100 g intake, to measure glucose at 3 hours. The diagnosis of GDM is made when 2 or more abnormal values ​​are found.

The Association of the Diabetes and Pregnancy Study Groups recommends a 1-step oral PTG (OGTT), with 75 g of glucose and measurement at 2 hours, with diagnostic limits based on the results of the Hyperglycemia and Adverse Pregnancy Outcome Study.

The chosen cut points convey an odds ratio of at least 1.75 for outcomes including higher birth weight, neonatal C-peptide greater than the 90th percentile, and neonatal body fat percentage greater than the 90th percentile, compared with women in the study with average glucose levels at 24 to 28 weeks.

Neonatal risks showed a linear relationship with the degree of alteration of maternal glycemia. However, the authors say, with older data showing a low overall frequency of neonatal risks, many institutions are reluctant to introduce these guidelines due to the expectation of higher rates of GDM and resulting resource demands in the context. of a perceived lack of improvement in results.

There are different opinions about how and when to diagnose DBT in early pregnancy. The American College of Obstetricians and Gynecologists (ACOG) accepts the 24-week criteria for an OGTT with 100 g of sugar in early pregnancy, but there is little data to support this practice.

Considering that in women with GDM, accelerated fetal growth can occur before 24 to 28 weeks of gestation, early elevations in blood glucose are usually no longer present at the time of routine PTG. This makes it difficult to identify women at risk. Given this difficulty, there has been interest in discovering alternative diagnostic markers of hyperglycemia in early pregnancy.

ACOG recommends similar glycemic goals for women with pre-existing diabetes and GDM, as follows: fasting blood glucose equal to or less than 95 mg/dL; 1 hour after eating, equal to or less than 140 mg/dl; 2 hours after eating, equal to or less than 120 mg/dl.

HbA1c levels naturally decrease during pregnancy due to increased erythrocyte turnover and may not fully capture transient glycemic variations that can lead to macrosomia.

Therefore, while an HbA1c <6.0% in the first trimester is associated with lower rates of fetal adverse events, a measurement of glycemic control in later pregnancy should be considered. Unfortunately, the authors say, even highly motivated patients can have difficulty achieving these goals, especially in the setting of T1DM and hypoglycemia.

In this scenario, personalized and less strict goals are accessible. It should be noted that, in DBT 2, the contribution of fasting (versus postprandial) glucose to the HbA1c level is greater as control decreases, increasing up to 70% in those with an HbA1c >10 .0%. Fasting hyperglycemia (as opposed to postprandial hyperglycemia) is also more predictive of being associated with fetal macrosomia. This information may be useful when adjusting insulin regimens.

In women with and without DBT, excessive gestational weight gain is associated with worse pregnancy outcomes. The Institute of Medicine’s guide to weight gain during pregnancy is based on body weight before pregnancy.

It is necessary to pay attention to food intake during pregnancy to avoid excessive gestational weight gain, while ensuring strict glycemic control. Dietary reference intakes for pregnant women should be followed and a minimum of 175 grams of carbohydrates, 71 grams of protein and 28 grams of fiber are recommended.

The Endocrine Society recommends limiting carbohydrates, to cover 35% to 45% of total calories, distributed over 3 meals and up to 4 snacks throughout the day. Sugars and refined carbohydrates should be eliminated, turning to carbohydrate sources such as fresh vegetables, some fruits and cereals. Almost 80% of women with GDM can achieve their glycemic goals only by modifying diet and lifestyle.

> Insulin. In women with T1DM, multiple daily subcutaneous injections or continuous infusions of insulin are similarly effective (an insulin pump is also effective). The evidence is insufficient to recommend one or another mode of insulin administration, if indicated.

The currently available hybrid closed-loop system (Medtronic MiniMed Insulin Pump 670G) is not appropriate for use in self-monitoring during pregnancy, as its algorithm targets a blood glucose of 120 mg/dl, which is above the recommended target in fast. 

The CONCEPTT study found that pregnant women who used continuous glucose monitoring (pump or non-pump therapy) had a lower incidence of larger infants at birth and a lower incidence of neonatal hypoglycemia. Currently, there is no evidence to support the use of technology such as continuous glucose monitoring or insulin pumps in women with T2DM or GDM.

The safest and most effective, fast-acting insulins during pregnancy are aspartic and lispro. Isophane (neutral protamine) insulin was traditionally used as the longest-acting insulin; But insulin analogues are increasingly used. Insulin detemir, for example, has been studied during pregnancy and there is extensive experience, as has glargine. Newer insulin analogs have not been studied.

The use of other sulfonylureas together with thiazolidinediones, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium glucose cotransporter-2 inhibitors is not recommended during or during pregnancy.

During pregnancy there is hyperglycemia and glycemic goals are not met (>15% to 20% of readings above the goal), the treatment of hyperglycemia must be intensified, within 1 to 2 weeks It is recommended to use insulin for women with Preexisting DBT, as alternative agents are ineffective in T1DM and cannot counteract the significant increases in insulin resistance associated with T2DM.

For the treatment of GDM, the guidelines are different. For example, the American Diabetes Association considers insulin to be the first-line therapy for women with GDM and does not recommend metformin or glyburide when an alternative is required.

ACOG recommends insulin as first-line therapy, with metformin (or rarely, glibenclamide) at a reasonable alternative dose while the Society for Maternal Fetal Medicine states that metformin or insulin are reasonable first-line drugs. Until now, treatment must be considered on a case-by-case basis, taking into account the degree of hyperglycemia, health care, financial resources, and patient preferences.

> Aspirin. Women with preexisting DBT are at increased risk of preeclampsia, and after 12 weeks of gestation, low-dose aspirin (81 mg per day) is recommended.

> Diabetic ketoacidosis. DKA during pregnancy is a life-threatening emergency caused by absolute or relative insulin deficiency. Pregnancy is a ketogenic state and DKA can occur, even with normal blood glucose levels. Although women with T1DM are at higher risk, DKA can occur during pregnancy with any type of T1D. If there is suspicion or diagnosis of DKA during pregnancy, it should be treated as an emergency. In the past, fetal mortality rates from DKA reached 35%, but this has decreased in recent years following improvements in diagnosis and treatment.

> Pre-existing diabetes. Most women have an ultrasound in early pregnancy to check fetal viability. Between weeks 18 and 20 of gestation, the fetal anatomy will be detailed, and in some cases, a fetal echocardiogram may be necessary, especially if glycemic control in the first trimester did not reach the objectives or there is suspicion of a heart defect. . Ultrasound is commonly used to evaluate fetal growth in the third trimester, but there are no recommendations about its frequency.

Given the risk of macrosomia, a higher fundus height, excessive maternal weight gain, and persistent poor glycemic control should prompt evaluation for rapid growth.

From the 32nd week of gestation it is reasonable to start monitoring, 1-2 times/week, such as the resting test, the biophysical profile or the modified biophysical profile. This can be started earlier, or the frequency can be increased individually. Women with well-controlled DBT and reassuring fetal testing can be managed expectantly between 39 0/7 and 39 6/7 weeks, but women with DBT-related complications, poor glycemic control, or prior fetal death, the time of delivery should be planned for weeks 36 0/7 and 38 6/7.

During labor, women should have continuous electronic fetal monitoring. Due to the abnormal adiposity of newborns of diabetic mothers, if the estimated fetal weight is >4,500 grams, cesarean delivery may be recommended.

> DMG . Women with GDM with poor control or who require pharmacological intervention should undergo fetal surveillance, similar to women with preexisting DBT. For women whose hyperglycemia is controlled only with lifestyle interventions, it is not necessary to advance the delivery date before 39 weeks of gestation. These women do not require induction at later gestational ages, unless otherwise indicated.

In pregnant women who are well controlled but require pharmacological intervention, delivery is recommended between weeks 39 0/7 and 39 6/7. Finally, in women who are poorly controlled, delivery may be justified between 37 0/7 and 38 6/7 weeks. Although there is less evidence to support such delivery in women with GDM, cesarean delivery may be recommended if the estimated fetal weight is <4,500 grams.

All women with complications can benefit from an anesthesiology consultation in the third trimester of pregnancy, to review the birth plan and analgesic options. If steroids are needed to accelerate fetal lung maturation, the insulin requirement over the next 3 to 5 days may be greater to control blood glucose. advised. In women with diabetes treated with insulin, additional insulin is usually administered intravenously, with hourly infusion doses adjusted, usually with a glycemic target of 70 to 126 mg/dl.

Maternal hyperglycemia during labor and delivery is associated with neonatal hypoglycemia and fetal distress. Women with DB T who require pharmacological intervention during pregnancy are generally treated with intravenous insulin infusion and hourly glucose testing. Regarding the intrapartum glycemic target, there are no randomized trials supporting a specific target; but most local policies specify a range between 70 and 126 mg/dl.

If appropriate experience is available, women can continue using their personal insulin pumps during this time. Women with GDM controlled with diet during pregnancy should also have glycemic control during labor, starting insulin if blood glucose is >100 to 126 mg/dl. At the time of delivery, a neonatologist should examine the infant; Delivery units should have the expertise to provide neonatal care if necessary.

Unless there is a concern, newborns should remain with their mother leading to feeding as soon as possible. 2 to 4 hours after delivery, a neonatal blood glucose test should be done to exclude neonatal hypoglycemia. Clinical signs such as severe irritability and seizure-like activity warrant immediate evaluation.

Measures such as tube feeding or intravenous dextrose infusion are generally reserved for when capillary glucose is <36 mg/dL despite feeding. Additional testing for polycythemia, hyperbilirubinemia, and electrolyte abnormalities should be considered based on clinical evaluation.

Due to a rapid increase in insulin sensitivity after a placental birth, women with pre-existing DBT often require a drastic reduction in postpartum insulin doses. ACOG recommends between one-third and one-half the doses of slow-acting and short-acting insulins prior to delivery---the latter should be initiated once the diet has been resumed.

Frequent glucose monitoring is essential to reduce the risk of severe hypoglycemia. Women with GDM should stop all glucose-lowering medications after delivery, but postpartum glucose testing (capillary or venous) should be done before hospital discharge, to exclude persistent DBT.

Breastfeeding is encouraged as it facilitates postpartum weight loss and is likely to be associated with lower future risk of obesity and DBT in offspring. Breastfeeding women receiving insulin often require additional snacks and lower doses of insulin to prevent hypoglycemia. Based on extensive clinical experience, metformin is considered safe during breast-feeding, but there is insufficient data to recommend agents other than insulin.

 At 6 weeks postpartum follow-up, women should be counseled about the importance of planning future pregnancies. Reversible contraception is ideal and can be used during breastfeeding. However, the risk of pregnancy likely outweighs the risk of any contraceptive option.

Women with GDM should have an OGTT at 4 to 12 weeks postpartum to rule out preexisting undiagnosed DBT. HbA1c is not reliable as it will be affected by changes during recent pregnancy. Postpartum glucose testing attendance rates are as low as 5%, but verbal and written contact with women can increase rates up to 75% 

Women with GDM require assessment of their blood glucose and other lifelong cardiovascular risks, as GDM is a major risk factor for progression to T2DM, stroke, and heart disease. The tests may be HbA1c, fasting blood glucose, or OGTT with 75 g (without using the thresholds used during pregnancy) every 1 to 3 weeks, depending on whether there are additional risk factors for T2DM.

A major study found that in women with a history of GDM and prediabetes, metformin can reduce progression to DBT by 40%, and lifestyle intervention by 35% over 10 years, compared with placebo. In this study, there was a median interval of 12 years between the index pregnancy with GDM, and the start of metformin, and whether metformin would be more effective in women closer to their pregnancy with GDM remains to be tested.

DBT in pregnancy poses a unique set of challenges for both the mother and the developing baby. Women with preexisting DBT may benefit from prepregnancy care, optimizing glycemic control and evaluation and treatment of comorbidities.

During pregnancy, women with pre-existing DBT and GDM benefit from a multidisciplinary approach to care, with the goal of minimizing maternal complications and ensuring normal fetal development and growth. GDM confers a high risk of future T2DM and affected women should receive appropriate counseling and long-term follow-up.