Version May 2024
INTRODUCTION — The terms "pregestational diabetes" and "preexisting diabetes" refer primarily to type 1 or type 2 diabetes mellitus diagnosed prior to pregnancy. Pregestational diabetes complicates approximately 1 to 2 percent of all pregnancies and accounts for 13 to 21 percent of diabetes in pregnancy, with the remainder due to gestational diabetes [1,2]. The proportion of pregnant patients with type 1 and type 2 diabetes reflects the prevalence of these disorders in the specific population. While rates of both type 1 and type 2 diabetes appear to be increasing [3,4], type 2 diabetes is more prevalent than type 1 diabetes in most populations, the prevalence is rapidly increasing, and accounts for a larger proportion of pregestational cases [5,6].
Type 1 and type 2 diabetes carry a significantly elevated risk of adverse maternal and fetal outcomes, including congenital malformations, early pregnancy loss, preterm birth, preeclampsia, macrosomia, and perinatal mortality [7-9]. Hyperglycemia is the primary driver of these risks, and studies repeatedly show that tight glycemic control in the periconceptional period and during pregnancy is associated with improved outcomes [7,10,11].
Prior to pregnancy, all females of childbearing age with type 1 or type 2 diabetes should be counseled about the potential effects of diabetes and their medications on maternal and fetal outcomes and the potential impact of pregnancy on their diabetes control and any existing complications. Preconception care can improve glycemic control in early pregnancy and, in turn, reduce the risk for some adverse pregnancy outcomes, such as congenital anomalies [12].
This topic will describe the potential maternal and fetal complications associated with pregnancy in females with preexisting diabetes and will discuss preconception risk counseling, evaluation, and management of these patients. Care during pregnancy is reviewed separately.
●(See "Pregestational (preexisting) diabetes mellitus: Antenatal glycemic control".)
●(See "Pregestational (preexisting) diabetes mellitus: Obstetric issues and management".)
GENERAL PRINCIPLES — The key components of preconception diabetes management are:
●Patient education
●Glycemic control
●Proficient diabetes self-care
●Medical optimization of preexisting complications and comorbidities associated with diabetes
Comprehensive and ongoing patient education is critical for shared decision-making about management goals and medication changes and for helping patients meet the considerable demands of self-care.
The intense medical and lifestyle regimens that must be undertaken before and during pregnancy and worry over pregnancy outcome can have an impact on the individual's psychological well-being. While preexisting depression does not appear to worsen during pregnancy for patients with pregestational diabetes, emotional distress (fear, worry, self-blame) can interfere with their enjoyment of pregnancy [13,14]. In the case of prior fetal loss or congenital malformation, patients may also experience grief, guilt, and postpregnancy depression. For this reason, it is important that preconception counseling, evaluation, and management be conducted with a patient-centered approach that emphasizes patient support and minimizes treatment-related distress.
RISK COUNSELING — Risk counseling involves discussion of potential fetal, neonatal, obstetric, and maternal adverse outcomes.
Risks with type 1 versus type 2 diabetes — Pregnancy outcomes are generally similar for patients with type 1 versus type 2 diabetes. Although patients with type 2 diabetes generally have milder glycemic disturbance, lower pregestational glycated hemoglobin (A1C), and a shorter duration of disease than those with type 1 diabetes, this does not necessarily result in better fetal/neonatal outcomes because they are also likely to have a higher preconception body mass index and older age at conception, which are risk factors for adverse pregnancy outcomes independent of diabetes status [15]. (See 'Fetal and neonatal risks' below and 'Obstetric complications' below.)
While the risk of pregnancy complications may be similar, there are some important differences in risk of maternal complications. Patients with type 1 diabetes are more likely to have pregestational microvascular complications that can worsen due to pregnancy, and they are at higher risk of developing severe hypoglycemia and diabetic ketoacidosis. Microvascular complications also increase the risk for some pregnancy complications, such as fetal growth restriction (FGR)/small for gestational age (SGA) infant. (See 'Growth restriction' below.)
Fetal and neonatal risks — Fetal and neonatal complications among patients with pregestational diabetes range in severity from potentially mild (large for gestational age [LGA] infant) to lethal (higher risk of early pregnancy loss, some congenital malformations, and stillbirth). The risk of these complications is directly related to glycemic control throughout pregnancy.
Although the impact of preconception glycemic control on adverse pregnancy outcomes in patients with pregestational diabetes has not been examined in randomized trials for ethical reasons, existing observational data strongly suggest that glucose control from the periconceptional period to birth can reduce these risks. In fact, the risks for congenital malformations and some causes of perinatal mortality can be reduced to levels close to those of patients without diabetes [7,16,17].
Congenital malformations — In patients with pregestational diabetes, the overall risk of congenital malformations is consistently reported to be two- to fourfold higher than that in those without diabetes (table 1) and is strongly related to the degree of hyperglycemia in the periconceptional period. Overall rates of major congenital malformations in pregnant individuals with type 1 diabetes range from 2.9 to 7.5 percent compared with 2.1 to 12.3 percent in those with type 2 diabetes; periconceptional hyperglycemia is associated with the high end of the range [7,18].
●In an analysis of 1997 pregnancies resulting in live births from seven cohort studies, the risk of congenital abnormalities increased with increasing hemoglobin A1C, and the absolute risk of a pregnancy affected by a congenital anomaly was [19]:
•A1C 5.5 percent: 2 to 3 percent
•A1C 7.6 percent: 4 percent
•A1C ≥14 percent: 20 percent
●In a population-based study of a cohort of pregnant people with type 1 or type 2 diabetes in the United Kingdom, for every 1 percent absolute decrease in maternal A1C, there was a 30 percent reduction in risk of major congenital malformations [20].
Pregestational diabetes is associated with a substantially increased risk for major congenital anomalies in all organ systems [21]. The spectrum of major congenital anomalies observed in pregnant people with pregestational diabetes is similar to that in those without diabetes, with some exceptions. The most common abnormality is congenital heart disease (including tetralogy of Fallot, transposition of the great arteries, septal defects, and anomalous pulmonary venous return), which accounts for 35 to 40 percent of major congenital anomalies in pregnancies with pregestational diabetes [19,22]. Central nervous system anomalies (eg, anencephaly, spina bifida, encephalocele, hydrocephaly, anotia/microtia) are the second most common category of anomaly, followed by anomalies in the urogenital system.
On the other hand, sacral agenesis/caudal dysplasia (lack of fetal development of the caudal spine and corresponding segments of the spinal cord) is rare in the general population but highly associated with maternal diabetes (adjusted odds ratio [OR] 80, 95% CI 46-139 [21]), which accounts for 15 to 25 percent of all cases of sacral agenesis [23].
The pathogenesis is unclear. Maternal diabetes may change genes involved in signaling and metabolic pathways essential for normal embryonic development [24-26]. These pathways may involve folate metabolism, oxidative stress, apoptosis, and proliferation. For example, in hyperglycemic animal models, embryopathy appears to be related to induction of high levels of oxidative stress, which leads to dysregulation of gene expression and excess apoptosis in developing organs [27]. The cardiovascular, central nervous, and skeletal systems are particular targets of this process. In addition, pregestational diabetes and obesity often occur together and obesity is an independent, more modest risk factor for development of congenital anomalies [28]. (See "Obesity in pregnancy: Complications and maternal management", section on 'Congenital anomalies'.)
Preterm birth — Infants delivered preterm are at increased risk of respiratory distress syndrome and a variety of other complications related to preterm birth, especially in the setting of poor maternal glycemic management. (See "Overview of short-term complications in preterm infants" and "Overview of the long-term complications of preterm birth" and "Infants of mothers with diabetes (IMD)".)
Pregnancies complicated by pregestational diabetes mellitus are at significantly higher risk of both medically and obstetrically indicated preterm birth and spontaneous preterm birth compared with those without diabetes [9,29,30].
In a Swedish population-based cohort study including over 2400 pregnant people with type 1 diabetes [30]:
●The overall incidence of preterm birth in those with and without diabetes (>2400) was 22.3 and 4.7 percent, respectively.
●The incidence was higher at every level of A1C, progressively increasing from 13 percent at A1C <6.5 percent to 37.5 percent at A1C ≥9.1 percent, for A1C measured any time from 90 days before to 91 days after conception.
●The increase in preterm birth among pregnant people with diabetes was primarily related to indicated preterm birth (adjusted relative risk [RR] 9.1), but spontaneous preterm birth was also increased (adjusted RR 2.6) compared with pregnant people without diabetes.
●Secondary outcomes, including LGA infant, macrosomia, neonatal hypoglycemia or respiratory distress, low Apgar score, and stillbirth or neonatal death, were also increased, but the relationship was not linear.
Although these findings affirm and expand upon previous data on the association between type 1 diabetes and adverse pregnancy outcomes, questions remain regarding the role of periconceptional glucose control versus other factors (eg, maternal obesity, second- and third-trimester glucose control, nonglucose-mediated effects) in this association and whether a target A1C <6.5 percent is adequate.
Large for gestational age/macrosomia — Accelerated fetal growth is common in pregnancies complicated by pregestational diabetes. The infant may be LGA (ie, >90th percentile for gestational age) or, less commonly, macrosomic (variously defined as fetal/newborn weight above 4000 grams, 4500 grams, or 10 pounds). In a prospective study of 340 pregnant patients with type 1 diabetes, the frequencies of LGA and macrosomia (defined as >4000 grams) were 41 and 18 percent, respectively [31].
The body composition of LGA/macrosomic infants of mothers with pregestational diabetes differs from those born to those without diabetes. They are more likely to have a higher percentage of body fat, larger shoulders and extremity circumferences, and a lower head-to-shoulder ratio and head circumference (HC)-to-abdominal circumference (AC) ratio (HC/AC <1) than infants of similar weight and length of mothers without diabetes. The reasons for these differences in body composition are unclear but are thought to be caused by increased maternal transfer of substrates (eg, glucose, amino acids), leading to fetal hyperinsulinemia and subsequent effects of insulin on target tissues to promote growth and store excess nutrients as adipose tissue [32]. (See "Fetal macrosomia".)
Macrosomia is of concern because macrosomic fetuses are at increased risk of shoulder dystocia and birth trauma (eg, brachial plexus injury, fracture) if delivered vaginally. Many are delivered by cesarean either electively or because of abnormal labor progress (see "Shoulder dystocia: Risk factors and planning birth of high-risk pregnancies" and "Shoulder dystocia: Intrapartum diagnosis, management, and outcome"). Both LGA and macrosomia also have long-term consequences. (See "Large for gestational age (LGA) newborn".)
The pathogenetic factors leading to LGA/macrosomia appear to be triggered in early pregnancy but are also present across gestation [33]. Glucose control periconceptionally and in the first trimester, in addition to later pregnancy glycemic control, appears to have an impact on the risk of LGA/macrosomia [34]. Glycemic variability, gestational weight gain, prepregnancy obesity, and maternal lipid levels also play a role in birth weight. (See "Fetal macrosomia", section on 'Pathogenesis'.)
Growth restriction — Although less common than LGA/macrosomia, pregestational diabetes is also associated with an increased risk for failure of the fetus to achieve its genetic growth potential, which is termed FGR or SGA and variously defined as weight <3rd, 5th, or 10th percentile. The risk is higher in pregnant patients with type 1 versus type 2 diabetes and related to prevalence of diabetic vasculopathy, particularly when severe. In the prospective study of 340 pregnant patients with type 1 diabetes discussed above, the frequency of FGR/SGA in patients with no vasculopathy, hypertension, and/or background retinopathy was 4 out of 261 (1.5 percent) versus 8 out of 80 (10 percent) among those with proliferative retinopathy and/or nephropathy [31].
FGR/SGA is important because it is associated with increased fetal/neonatal mortality and short- and long-term morbidity. (See "Fetal growth restriction: Evaluation" and "Infants with fetal (intrauterine) growth restriction".)
Other neonatal morbidity — Neonatal medical complications associated with maternal pregestational diabetes include hypoglycemia, erythrocytosis, hyperbilirubinemia, hypocalcemia, respiratory distress, and cardiomyopathy. These complications are discussed separately. (See "Infants of mothers with diabetes (IMD)".)
Perinatal mortality — Perinatal mortality is increased in pregnancies complicated by pregestational diabetes, and the risk begins to increase at A1C levels between 6 and 6.9 percent [10,11]. Although the risk for perinatal death appears to be similar for pregnancies with type 1 and type 2 diabetes, the underlying causes of death appear to differ:
●In a study of nonanomalous singleton offspring of pregnant people with preexisting diabetes in the North of England from 1996 to 2008 (type 1 diabetes: 1206; type 2 diabetes: 342), fetal or infant death (ie, death from 20 weeks of gestation to one year of life) occurred in 3.6 percent of these pregnancies versus 1 percent of pregnancies without preexisting diabetes and was not significantly different for type 1 versus type 2 diabetes [10].
●In a prospective study of perinatal loss in 341 pregnant people with type 1 and 862 pregnant people with type 2 diabetes, perinatal deaths associated with type 1 diabetes were primarily related to congenital abnormalities or complications of preterm birth, whereas those associated with type 2 diabetes were more likely to be due to stillbirth, birth asphyxia, or intraamniotic infection [16].
Among pregnant people with type 2 diabetes, rates of perinatal mortality do not appear to vary with duration of disease [35]; pregnant people with type 2 diabetes first recognized in pregnancy appear to have rates similar to those with longstanding diabetes [16,36].
Improvements in perinatal mortality over time in some studies (eg, stillbirth decreased from approximately 26 to 29 out of 1000 births in 2002 and 2003 to 11 out of 1000 births in 2015 in the United Kingdom [37]) have probably been related to improvements in the provision and uptake of prepregnancy care and tighter glycemic targets [38]. If glucose and risk factor control are optimal, perinatal death rates may approach those of pregnant people without diabetes [39]; however, a small excess risk of perinatal death has been observed even among pregnant people with good glycemic control [10,11,16].
Long-term outcomes — Maternal diabetes has potential long-term impacts on offspring health. Offspring of mothers with diabetes are at increased risk of developing diabetes, obesity, and other adverse cardiometabolic outcomes [40-43]. The diabetes type (1 or 2) in offspring is related, in part, to maternal and paternal diabetes status. Increasingly, however, studies suggest an increased risk of obesity and type 2 diabetes in offspring of pregnant people with pregestational diabetes independent of genetic factors and possibly due to the effects of the uterine environment on neonatal programming [40,44-46]. It is unclear whether cognitive and other neurodevelopmental outcomes of offspring are affected by maternal diabetes. Pregestational and gestational diabetes have been linked with an increased risk of autism in offspring [47,48]. (See "Infants of mothers with diabetes (IMD)", section on 'Long-term outcome' and "Autism spectrum disorder (ASD) in children and adolescents: Terminology, epidemiology, and pathogenesis".)
Obstetric complications
Early pregnancy loss — Rates of early pregnancy loss are two- to threefold higher in pregnant people with pregestational diabetes than among those without diabetes. Possible reasons for this higher risk include an increased rate of congenital malformations, toxic effects of hyperglycemia, and maternal vascular disease leading to uteroplacental insufficiency [10,18,49].
Aneuploidy, a common cause of early pregnancy loss, does not appear to be a factor because the risk of having an aneuploid fetus seems to be the same in pregnant people with and without diabetes. However, it is possible that epigenetic changes in gene expression may be influenced by pregestational diabetes; this is an area of ongoing investigation [7]. (See "Pregnancy loss (miscarriage): Terminology, risk factors, and etiology".)
Preeclampsia and gestational hypertension — The risks of both preeclampsia and gestational hypertension are three- to fourfold higher in pregnant people with pregestational diabetes than those without (for preeclampsia: 12 to 20 percent versus 5 to 7 percent) [50-52]. Pregnant people with type 1 diabetes are at the high end of this range or even higher (50 percent) since preexisting microvascular disease is more prevalent in these patients, and it is a major risk factor for pregnancy-induced hypertensive disorders [18,53].
Although preconception glucose status does not appear to affect risk of preeclampsia and gestational hypertension, evidence suggests that good glycemic control during pregnancy decreases this risk [51,54]. Use of low-dose aspirin, beginning at the end of the first trimester, also reduces risk. In patients with prepregnancy diabetes, the American Diabetes Association (ADA) recommends initiating prophylaxis at 12 to 16 weeks of gestation at a dose of 100 to 150 mg/day (taking two 81 mg tablets [162 mg] is also acceptable if 100 to 150 mg dosing is not available) [55]. (See "Preeclampsia: Prevention" and "Preeclampsia: Prevention", section on 'Low-dose aspirin'.)
Polyhydramnios — Polyhydramnios (excessive amniotic fluid) occurs more frequently in pregnancies associated with pregestational diabetes, especially those with suboptimal glycemic control or an LGA fetus [56]. In one study of 314 singleton pregnancies >24 weeks in patients with pregestational diabetes, 19 percent had polyhydramnios [56]. It occurs in 1 to 2 percent of the general obstetric population and has been associated with a variety of adverse obstetric outcomes. (See "Polyhydramnios: Etiology, diagnosis, and management in singleton gestations".)
The mechanism for polyhydramnios in pregnancies complicated by diabetes is unclear. Fetal hyperglycemia leading to polyuria is one likely etiology and is supported by the observation that polyhydramnios is often associated with high maternal A1C levels and fetal macrosomia [56,57]. Decreased fetal swallowing or an imbalance of water movement between the maternal and fetal compartments are other possible mechanisms.
Cesarean birth — Although maternal diabetes is not an indication for cesarean birth in the absence of the usual obstetric indications, pregnant patients with pregestational diabetes (type 1 or 2) are at higher risk of undergoing cesarean birth than those in the general obstetric population, in part because of their higher rates of LGA, preeclampsia, and obesity [16].
Pregnant people with type 2 diabetes appear to be at lower risk for cesarean birth than those with type 1 diabetes (in one meta-analysis: OR 0.80, 95% CI 0.59-0.94 [35]) but are still at increased risk compared with those with euglycemia. (See "Pregestational (preexisting) diabetes mellitus: Obstetric issues and management", section on 'Route'.)
Maternal medical risks
Hypoglycemia — Pregnant people with pregestational diabetes treated with insulin are at increased risk for severe hypoglycemia in early pregnancy compared with prepregnancy and later in pregnancy [58,59]. This is thought to be due to the lower glucose targets in pregnancy accompanied by an increase in insulin sensitivity [60,61] and often erratic meals due to nausea and/or vomiting of pregnancy [62]. (See 'Glycemic control' below.)
Progression of microvascular disease — The likelihood of worsening microvascular complications in pregnancy is related to duration of diabetes and prepregnancy glycemic control [63]. Although two large prospective studies of females with type 1 diabetes, the Diabetes Control and Complications Trial (DCCT) [64] and the EURODIAB Prospective Complications Study [65], suggest that pregnancy alone is not a risk factor for the de novo development of microvascular complications, pregnancy can exacerbate preexisting microvascular disease, and this effect varies by type of complication.
Diabetic retinopathy — The majority of pregnant people with diabetic retinopathy will not experience clinically important worsening of retinopathy during or following pregnancy. However, for some, particularly those with proliferative retinopathy (marked by new retinal vessel growth), retinopathy may worsen during pregnancy ("transient worsening") because of often rapid intensification of glycemic control and pregnancy-related vascular, volume, and hormonal changes. For a small subset of patients with severe pregestational retinopathy, visual changes may persist postdelivery.
The likelihood of retinopathy progression is related to maternal duration of diabetes, presence and severity of pregestational retinopathy, and to the degree of glycemic control prior to and during pregnancy. Hypertension, smoking, hyperlipidemia, and hypoglycemia have also been associated with acceleration of retinopathy in pregnancy [66]. (See "Diabetic retinopathy: Classification and clinical features", section on 'Prevalence and natural history'.)
As in nonpregnant patients, rapid tightening of glycemic control has been associated with worsening retinopathy in pregnant patients with pregestational diabetes [63,67]. Worsening of retinopathy in this setting is thought to be mediated by closure of small retinal blood vessels, which were narrowed but patent prior to tightening of glucose control. Correction of hyperglycemia may lower intravascular volume, leading to vessel closure. In most pregnant people, the benefits of normoglycemia for the fetus far outweigh the modest and generally transient deterioration in retinopathy from improved glycemic control since milder forms of diabetic retinopathy typically improve after birth. However, some patients with severe proliferative retinopathy or with macular edema may experience persistence or even further progression of retinopathy postpregnancy [67].
These relationships were illustrated by the Diabetes in Early Pregnancy (DIEP) study, a prospective study of 140 pregnant people with pregestational diabetes (all with type 1 diabetes) and no proliferative retinopathy at periconceptional baseline examination [68]. At follow-up examination one month postpartum, progression of retinopathy was noted in 20 percent of patients with microaneurysms or mild nonproliferative retinopathy at baseline and 55 percent of those with moderate to severe nonproliferative retinopathy [68]. Proliferative retinopathy developed in 6 percent of patients with mild baseline retinopathy and 29 percent of patients with moderate to severe baseline retinopathy. Ten percent of patients without retinopathy at baseline had signs of retinopathy postpartum on funduscopic examination.
Data on impact of antepartum progression of retinopathy on the clinically meaningful outcome of postpartum vision are scant. One study reported postpartum patients with diabetes had worse visual acuity as measured by letter recognition at nine weeks after birth compared with nonpregnant females with diabetes followed for the same interval; however, the vision decrement was small, suggesting the impact of pregnancy in most pregnant patients with pregestational diabetes is minimal [69]. The vision change was reported for all subjects with diabetes and pregnancy, without correlation to progression or severity of retinopathy; thus, impact of pregnancy on vision in higher-risk subgroups remains unclear.
Diabetic kidney disease — Patients with diabetes and normal albumin excretion are at low risk for development of kidney disease in pregnancy. Patients with diabetes, moderately increased albuminuria (formerly microalbuminuria), and normal kidney function appear to be at low risk for loss of kidney function during pregnancy but may have a transient increase in albuminuria. For example, in the DCCT study, females with diabetes in the intensive treatment arm who became pregnant had an increase in albumin excretion rate, whereas those in the conventional arm did not [64]. Among patients with overt proteinuria at baseline, urinary protein excretion can rise dramatically as pregnancy progresses, but after birth, protein excretion decreases in most individuals.
By contrast, patients with poorly controlled hypertension or reduced glomerular filtration rate and heavy proteinuria (serum creatinine level >1.5 mg/dL, proteinuria >3 grams in 24 hours) at the onset of pregnancy are at risk of permanent kidney damage, including end-stage kidney disease. As many as 40 percent of patients with serum creatinine >3 mg/dL or creatinine clearance <50 mL/minute will develop permanent worsening of renal function with pregnancy [70].
Diabetic kidney disease also carries risks for the pregnancy. Both moderately increased albuminuria (formerly microalbuminuria) and overt nephropathy are associated with an increased rate of preterm birth, primarily due to preeclampsia. Hypertension and preeclampsia are associated with growth restriction and (rarely) fetal or maternal death. In a meta-analysis of 12 studies of patients with type 1 or 2 diabetes, the frequency of preeclampsia in those with versus without kidney disease was 48.6 and 13.1 percent, respectively [71].
Issues relating to pregnancy in patients with diabetic kidney disease are reviewed in detail separately. (See "Pregnancy and contraception in patients with nondialysis chronic kidney disease".)
Cardiovascular disease — Pregnant people with pregestational diabetes are at increased risk of macrovascular cardiac disease (eg, coronary artery disease, heart failure, stroke) and microvascular cardiac disease (eg, microvascular angiopathy, cardiac autonomic neuropathy). The risk is related both to diabetes and to the frequent presence of other cardiovascular and renal risk factors, such as hypertension and nephropathy [72-74]. In addition, pregnancy-related volume expansion may unmask previously subclinical disease, such as asymptomatic diastolic dysfunction. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Screening for coronary heart disease'.)
Peripheral and autonomic neuropathy — Pregnancy does not appear to affect the course of peripheral or autonomic neuropathy. However, autonomic neuropathy can complicate pregnancy since affected individuals are at increased risk of hyperemesis gravidarum (related to gastroparesis), hypoglycemia unawareness, and orthostatic hypotension. (See "Screening for diabetic polyneuropathy" and "Management of diabetic neuropathy" and "Diabetic autonomic neuropathy".)
Recognizing the presence of gastroparesis before pregnancy is important because it can lead to extreme hypo- and hyperglycemia, increased risk of diabetic ketoacidosis, weight loss, and malnutrition in the absence of appropriate management. In addition, the clinical manifestations of gastroparesis may be confused with hyperemesis of pregnancy. The effects of gastroparesis can be mitigated by utilizing dietary modification, adjusting the insulin regimen, and other medical therapies (eg, antiemetic and prokinetic agents). Patients with significant gastroparesis who become pregnant often have frequent hospitalizations and may require parenteral nutrition [50]. (See "Diabetic autonomic neuropathy of the gastrointestinal tract" and "Treatment of gastroparesis".)
Diabetic ketoacidosis — Diabetic ketoacidosis is more common, occurs at lower levels of glycemia, and carries a higher risk of mortality in pregnant versus nonpregnant females with type 1 diabetes. It can occur at glucose values ≤250 mg/dL (13.9 mmol/L) because the increased insulin resistance and lipolytic state of pregnancy, coupled with compensated respiratory alkalosis with decreased ability to buffer ketoacids, render pregnant people more prone to ketoacidosis [72,75,76].
Diabetic ketoacidosis has been reported in 1 to 10 percent of pregnant people with type 1 diabetes and may be fatal. The risk of fetal demise is substantial: Rates of 9 to 35 percent have been reported [77,78]. Other complications include sequelae of fetal hypoxia and acidosis, preterm birth, and maternal and/or neonatal intensive care unit admission [79].
Diabetic ketoacidosis can occur in ketosis-prone type 2 diabetes but is rare in pregnancy [80]. In addition to the usual precipitants of diabetic ketoacidosis, potential pregnancy-related causes include treatment with beta-mimetic tocolytics and antenatal corticosteroids. (See "Diabetic ketoacidosis in pregnancy".)
PRECONCEPTION EVALUATION AND MANAGEMENT
Overview — Preconception planning is the foundation for a successful outcome of pregnancy in females with pregestational diabetes. In a meta-analysis of 12 cohort studies that evaluated the effectiveness and safety of preconception care in improving maternal and fetal outcomes for individuals with preexisting diabetes, preconception care was associated with a lower first-trimester glycated hemoglobin (A1C) level (average reduction 2.43 percent, 95% CI 2.27-2.58) and significantly reduced rates of congenital malformations (14 out of 896 [1.6 percent] versus 110 out of 1512 [7.3 percent], relative risk [RR] 0.25, 95% CI 0.15-0.42), preterm birth (61 out of 209 [29 percent] versus 155 out of 374 [41 percent], RR 0.70, 95% CI 0.55-0.90), and perinatal mortality (5 out of 381 [1.3 percent] versus 28 out of 634 [4.4 percent], RR 0.35, 95% CI 0.15-0.82) [81]. However, individuals who participate in preconception planning are likely to be different from those who did not, and therefore, the improvement ascribed to prepregnancy care may be reflective of differences in populations [82]. No randomized trials of preconception care versus no care have been performed.
Preconception counseling should be tailored to the patient's type of diabetes (type 1 or type 2) and take into account the patient's personal history of diabetic complications. Preconception care should include:
●Counseling about the impact of glycemic status on maternal-fetal outcome, the risk of development or progression of preexisting complications of diabetes, and the types and risks of adverse maternal, fetal, and neonatal outcomes. (See 'Risk counseling' above.)
●Helping patients achieve good glucose control, with A1C in the normal range if safely achievable.
●Explaining that preconception glucose control is important because congenital malformations induced by hyperglycemia (diabetic embryopathy) occur in the first few weeks of pregnancy before patients know they are pregnant [11,83].
●Adjusting medications (eg, antihypertensive drugs, oral antihyperglycemic agents) as needed for fetal safety.
●Beginning folic acid supplementation (at least 400 micrograms per day).
●Evaluating for comorbidities and complications of diabetes.
●Initiating treatment of comorbidities and complications or optimizing the status of existing medical conditions.
●Discussing and providing effective contraception to avoid unplanned pregnancy until glucose control is achieved.
In females with advanced complications of diabetes, weighing the risk of a pregnancy to their health versus the desire for childbearing is particularly important. For example, those at risk for deteriorating renal function leading to dialysis may decide not to pursue becoming pregnant.
The following text describes issues of preconception evaluation and management specific to females with diabetes. Routine aspects of preconception care applicable to all females are reviewed separately. (See "The preconception office visit".)
Glycemic control
Target glucose levels — Successful preconception care programs have used the following preconception glucose targets [70]:
●Before meal capillary blood glucose concentration: 80 to 110 mg/dL (4.4 to 6.1 mmol/L)
●Two-hour postprandial glucose concentration: <155 mg/dL (8.6 mmol/L)
Although still quite low, these targets are slightly higher than pregnancy targets and probably more pragmatic for patients who are not yet pregnant. Glucose self-monitoring is an important tool for achieving the tight glucose control needed in pregnancy. (See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus" and "Patient education: Glucose monitoring in diabetes (Beyond the Basics)".)
Target A1C level — Our preconception A1C goal for all patients with diabetes is <6.5 percent. The American Diabetes Association (ADA) recommends aiming for an A1C <6.5 percent (48 mmol/mol), and the Endocrine Society recommends aiming for an A1C level "as close to normal as possible" (ie, <6.5 percent [48 mmol/mol]) without causing undue hypoglycemia [55,84]. There are limited high-quality clinical trial data on the effects and risks/benefits of very low A1C levels during pregnancy.
Patients with diabetes should be encouraged to allow a minimum of three to six months to achieve optimal glucose control before trying to conceive, if glucose levels are not already well controlled.
Insulin therapy — In patients with type 1 or type 2 diabetes, insulin remains the standard drug for glucose management during pregnancy. In patients with type 2 diabetes taking noninsulin antihyperglycemic agents, insulin is often started preconception to attain the optimal degree of glycemic control while allowing discontinuation of noninsulin agents without safety data in early pregnancy [85].
In the preconception period, we suggest using insulins with a good fetal safety profile, such as neutral protamine hagedorn (NPH), lispro, aspart, and detemir insulins. Insulin glargine, a long-acting insulin, has greater mitogenic potential and higher affinity in binding to the insulin-like growth factor 1 receptor than other insulins [86], which could lead to increased fetal growth and macrosomia. However, small observational studies in humans do not support this concern [87-89]. Insulin degludec has not been well studied in pregnancy, though a case series including 22 pregnancies did not suggest an increased risk of adverse perinatal outcomes in pregnant people using this basal insulin as compared with insulin glargine [90]. We also suggest avoiding premixed insulins, which are more difficult to titrate to achieve desired levels of glycemic control without hypoglycemia.
Given the availability of better-studied and effective alternatives, we consider substituting NPH insulin or insulin detemir for insulin glargine or degludec prior to pregnancy. If this is not desirable due to patient preference, insurance coverage, or inability to achieve optimal glucose control on an alternative regimen, we discuss the theoretic risks of insulin glargine or degludec on pregnancy and help the patient make an informed decision. The amount of observational data supporting the safety of glargine are greater than that for insulin degludec. A randomized trial comparing glycemic control and outcomes with the use of insulin degludec versus insulin detemir in pregnancy is near completion [91].
For a short-acting insulin, we generally use a rapid-acting insulin, such as lispro or aspart, instead of regular insulin. These insulins have a rapid onset, which improves control of the postprandial increase in glucose, and have a rapid offset, which may decrease hypoglycemia. A randomized trial of rapid-acting aspart versus regular insulin in pregnancy demonstrated less of a glucose rise postprandially with aspart than regular insulin, but there was no significant difference in hypoglycemia rates [92]. Glulisine has not been well studied in pregnancy, thus we generally avoid it. Faster-acting insulin aspart and ultra-rapid lispro also do not have data supporting their use in pregnancy or preconception. Of note, a systematic review of different types and regimens of insulin in pregnancy did not find superiority of any type/regimen over another [93]. (See "Pregestational (preexisting) diabetes mellitus: Antenatal glycemic control", section on 'Insulin pharmacotherapy'.)
If a nonpregnant female is considering switching to insulin pump therapy, initiation should ideally occur prior to attempts at conception to allow ample time for training, acclimatization to pump use, and troubleshooting before pregnancy. We generally avoid switching patients to pump therapy during pregnancy because of the risks for significant hypo- or hyperglycemia (including diabetic ketoacidosis) during the transition period.
One group that ran two parallel trials of continuous glucose monitoring (CGM), one in pregnant patients with type 1 diabetes and the other in patients with type 1 diabetes planning pregnancy, reported that pregnancy outcomes were not significantly improved for patients who began CGM during pregnancy planning, possibly due to the small sample size [94]. However, CGM during pregnancy resulted in improved pregnancy outcomes. Nevertheless, CGM may be helpful to some patients trying to achieve glucose control preconception, and this decision should be made on a case-by-case basis. While some CGM devices can be used to dose insulin without additional self-monitoring of glucose, this has not been studied in the preconception period or during pregnancy; thus, many clinicians consider CGM only as an adjunct to traditional self-monitoring.
Patients on preconception insulin pumps — Patients already using insulin pumps can continue to use them as they attempt to conceive and during pregnancy. Of note, at least one study suggested multiple daily injections of insulin were superior to pump therapy in achieving lower A1C levels [95]. There may be individual exceptions (eg, patients with poor glucose control on multiple dose injections), with some patients obtaining better glucose control with pump therapy initiated during pregnancy.
We generally continue sensor-augmented pump therapy (with automatic suspension of insulin delivery for hypoglycemia), though this has not specifically been evaluated in pregnancy. In contrast, hybrid closed-loop devices, which provide automatic adjustments to basal insulin delivery rates with or without automatic correction boluses for high-sensor glucose levels, have not been studied in pregnancy. Moreover, they do not allow users to adjust the target glucose lower to accommodate pregnancy glycemic goals [96]. Patients using hybrid closed-loop devices who desire pregnancy should be counseled that use is off-label in pregnancy and that they may need to turn off these features or obtain a new pump to achieve pregnancy glycemic goals. In select cases, for example, where control would be poor without the aid of the hybrid closed-loop algorithm, we use shared decision-making with patients to determine whether to continue the hybrid closed-loop device in the preconception period and during pregnancy.
Patients on preconception noninsulin antihyperglycemic agents
●Metformin, glyburide – Insulin remains the preferred therapy of diabetes in pregnant patients. However, for patients with type 2 diabetes on metformin monotherapy with glycemic control at goal for preconception, we suggest continuing metformin through the first trimester and adding insulin to achieve pregnancy glycemic goals once pregnancy is confirmed. Studies of metformin use in the first trimester suggest that it is not teratogenic [97-100] and use of metformin may help maintain glycemic control during the period of organogenesis. Insulin is likely to be required in addition to or instead of metformin to achieve the level of glycemic control recommended in pregnancy. Consideration can be given to continuing metformin beyond the first trimester [101], but there are concerns related to transplacental passage and metabolic effects in children exposed in utero; this issue is covered separately. (See "Pregestational (preexisting) diabetes mellitus: Antenatal glycemic control", section on 'Patients on noninsulin antihyperglycemic agents prior to pregnancy'.)
For patients on other noninsulin antihyperglycemic agents, we suggest switching to metformin and/or insulin therapy prior to conception. While glyburide has been studied in gestational diabetes and was previously the most frequently prescribed agent for this indication, its use is declining because of evidence of transplacental transfer [102] and a possible increase in the risk of adverse outcomes in comparison with insulin [103].
●GLP-1 agonists, SGLT-2 inhibitors, and DPP-4 inhibitors – There are limited data for other commonly used non-insulin agents such as GLP-1 agonists, SGLT-2 inhibitors, and DPP-4 inhibitors, which should be avoided. An increased frequency of congenital malformation or other harmful effects on the human fetus has not been observed [104], but animal studies have reported increased occurrence of fetal damage. For example, in animals, SGLT-2 inhibitors have caused renal toxicity at developmental periods equivalent to the second and third trimesters in humans and GLP-1 agonists have caused vascular (heart, blood vessels) and skeletal (cranial bones, vertebra, ribs) abnormalities at maternal exposures below the maximum recommended human dose.
Management of hypoglycemia — It is important to review signs and symptoms of hypoglycemia (eg, tremor, palpitations, anxiety/arousal, sweating, hunger, dizziness, weakness, drowsiness, confusion) with the patient, as well as actions the patient (and close contacts) should take if hypoglycemia develops.
●Patients should be instructed to carry a snack at all times.
●If patients have a history of hypoglycemia or begin to experience hypoglycemia when tightening glucose control, they should be given a prescription for glucagon and taught or retaught how to administer it.
Reinforcement of hypoglycemia management is particularly important prepregnancy so that the patient is prepared in early pregnancy, when the frequency of hypoglycemia may increase due to tightened glucose control, changes in hormone levels, nausea and vomiting of pregnancy, and reduction in physical activity. Hypoglycemia is more likely to occur in patients with type 1 diabetes due to autoimmune destruction of the alpha cells that produce glucagon.
The symptoms, risk factors, prevention, and treatment of hypoglycemia in adults with diabetes are reviewed in detail separately. (See "Hypoglycemia in adults with diabetes mellitus".)
Diet, weight, and exercise — Diet is one of the most important behavioral aspects of diabetes treatment. Referral to a registered dietitian is usually helpful for patients with diabetes who are planning pregnancy. Understanding how different food intakes affect glycemia and developing a food plan of meals and snacks help reduce glucose fluctuations and manage fluctuations that occur. Nutritional considerations for patients with type 1 and type 2 diabetes are discussed in detail separately. (See "Nutritional considerations in type 1 diabetes mellitus" and "Nutritional considerations in type 2 diabetes mellitus".)
Patients who are overweight or have obesity should be encouraged to lose weight prior to conception. In addition to improving prepregnancy glycemic control and potential benefits on metabolic profile (eg, hypertension, hyperlipidemia, fatty liver disease), weight reduction prior to pregnancy may decrease the risk of other pregnancy complications associated with obesity (eg, preeclampsia, some congenital anomalies, cesarean birth, macrosomia). (See "Obesity in pregnancy: Complications and maternal management".)
In adults with diabetes, regular exercise is important to improve glycemic control, assist with weight maintenance, and reduce the risk of cardiovascular disease and overall mortality. An appropriate exercise program for nonpregnant patients with diabetes is described separately (see "Exercise guidance in adults with diabetes mellitus", section on 'Exercise guidance'). Exercise can be maintained during pregnancy. (See "Exercise during pregnancy and the postpartum period".)
Folic acid and iodine supplementation
●Folic acid 400 micrograms/day is recommended for most reproductive-age females to decrease the occurrence of neural tube defects (NTDs).
Because pregnant people with pregestational diabetes are at increased risk of having a child with an NTD, some authorities have opined that they may benefit from a higher dose of folic acid (0.8 to 5 mg per day) [84,85,105]; however, the optimum dose of folic acid in this population has not been studied, and recommendations vary. We agree with the ADA's recommendation for a minimum dose of at least 400 micrograms/day [55], which was effective in at least two case-control studies [106,107] and in at least one study in animals [108]. The recommended dietary allowance in pregnancy is 600 micrograms/day. (See "Preconception and prenatal folic acid supplementation", section on 'Preexisting diabetes'.)
●Females who are planning pregnancy or are currently pregnant should supplement their diet with a daily oral supplement that contains 150 micrograms of iodine in the form of potassium iodide [55,109].
Blood pressure control — In pregnant patients with diabetes and chronic hypertension, the ADA suggests a blood pressure target of 110 to 135/85 mmHg [55], which aligns with data that all pregnant patients with chronic hypertension and blood pressures ≥140/90 mmHg should be treated [110]. However, there are minimal data to guide blood pressure targets in preconception and early pregnancy in patients with diabetes. Preferred agents for treatment of hypertension in pregnancy include labetalol, methyldopa, and extended-release nifedipine. (See "Chronic hypertension in pregnancy: Prenatal and postpartum care".)
Angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) should be discontinued and replaced with another class of antihypertensive drug (eg, labetalol or a long-acting calcium channel blocker) when patients with diabetes and hypertension are planning pregnancy and before stopping contraception (see "Treatment of hypertension in pregnant and postpartum patients"). Although ACE inhibitors and ARBs are commonly used for management of hypertension and may be recommended for management of moderately increased albuminuria (formerly microalbuminuria) in nonpregnant individuals with diabetes, both classes of drugs are contraindicated in the second and third trimesters of pregnancy because they have been associated with fetal renal injury and neonatal renal failure [111]. Whether first-trimester exposure to these drugs is also teratogenic is controversial, but switching to an agent(s) with a better safety profile is prudent [112,113]. If not already discontinued, ACE inhibitors and ARBs should be stopped when pregnancy is confirmed. (See "Adverse effects of angiotensin converting enzyme inhibitors and receptor blockers in pregnancy".)
Lipid control — Statins are usually discontinued in pregnancy because of limited and contradictory data as to whether there is an increased risk of congenital anomalies with first-trimester exposure [114]. This discordance may reflect confounding by indication. Accordingly, the US Food and Drug Administration (FDA) removed the words "contraindicated in pregnancy" in regard to statins in 2021 [115]. We suggest discontinuing statins in patients who are planning to become pregnant and resuming these drugs after birth/completion of breastfeeding. However, individual decisions need to be made about benefit versus risk in patients at very high risk of a myocardial infarction or stroke, such as those with homozygous familial hypercholesterolemia or established cardiovascular disease. (See "Statins: Actions, side effects, and administration", section on 'Risks in pregnancy and breastfeeding'.)
Evaluation of and approach to complications of diabetes mellitus — Evaluation for complications of diabetes should be up to date before patients attempt to conceive. We perform both physical examination (table 2) and laboratory evaluation (A1C, serum creatinine, estimated glomerular filtration rate, aspartate aminotransferase and alanine aminotransferase, thyroid-stimulating hormone [TSH], urine albumin-to-creatinine ratio on a spot urine or 24-hour urine collection for protein and creatinine).
A baseline evaluation is important because some diabetes-related complications should be treated prior to conception (eg, retinopathy). In addition, this information is important for counseling and pregnancy management since some complications, such as diabetic kidney disease, are associated with an increased risk of pregnancy complications, may worsen during pregnancy, and may make the diagnosis of pregnancy complications (eg, preeclampsia) more difficult.
Diabetic kidney disease — As discussed above (see 'Diabetic kidney disease' above), pregnancy does not appear to increase the risk of developing diabetic kidney disease if not present before pregnancy, but patients with established nephropathy can develop permanent worsening of renal functioning during pregnancy. The risk of permanent loss of renal function is significant in pregnant patients with uncontrolled hypertension, baseline serum creatinine >1.5 mg/dL, or protein ≥3 grams in a 24-hour urine collection [72,116].
Patients with significant diabetic kidney disease should be referred to a nephrologist skilled in the care of pregnant people to assist them in balancing their desire for pregnancy and the risks and consequences of deterioration of renal function. (See "Pregnancy and contraception in patients with nondialysis chronic kidney disease".)
Major treatment options for preservation of renal function in nonpregnant patients (ACE inhibitors or ARBs) are contraindicated in pregnancy. However, control of hypertension with agents preferred in pregnancy may be beneficial. (See "Treatment of diabetic kidney disease" and "Adverse effects of angiotensin converting enzyme inhibitors and receptor blockers in pregnancy".)
Retinopathy — As discussed above (see 'Diabetic retinopathy' above), retinopathy can worsen during pregnancy, sometimes rapidly, and result in permanent loss of vision, although generally only in patients who started with advanced retinopathy in the pregravid state. To reduce this risk, patients with diabetes should have a dilated eye examination before pregnancy [55,84], and if proliferative retinopathy is detected, it should be treated prior to attempts at conception. Since exacerbation of retinopathy can occur with rapid control of glucose levels, improvement in glucose control should be made gradually over months prior to pregnancy, when possible. (See "Diabetic retinopathy: Prevention and treatment", section on 'Pregnancy'.)
Gastroparesis — Evaluation for gastroparesis (see 'Peripheral and autonomic neuropathy' above) is performed by history and physical examination after a meal. A report of nausea, vomiting, early satiety, postprandial fullness, abdominal pain, bloating, or presence of succussion splash suggests the diagnosis. In some cases, evaluation of gastric emptying by scintigraphy is performed to make a definitive diagnosis. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis".)
Initial management of gastroparesis consists of dietary modification, optimization of glycemic control, and hydration. In patients with continued symptoms, pharmacologic therapy with prokinetic and antiemetic medications with a good fetal safety profile may be needed (eg, metoclopramide). (See "Treatment of gastroparesis".)
Cardiovascular disease — Patients with type 1 or type 2 diabetes of long duration may have cardiovascular disease. Extended evaluation should be based on the patient's history and physical examination (table 2). For example, a carotid bruit can be an indicator of ischemic cardiac disease, and angina may present as atypical chest pain or shortness of breath. Patients with abnormal cardiac findings on examination, electrocardiogram (ECG), or by history should be referred to a cardiologist for further evaluation (such as exercise tolerance testing), management, and counseling. (See "Acquired heart disease and pregnancy".)
The ADA recommends a preconception ECG for females ≥age 35 with diabetes who have cardiac signs/symptoms or risk factors; if the ECG is abnormal, further evaluation is indicated [55].
Thyroid disease — Although not caused by diabetes, autoimmune thyroid dysfunction is frequently associated with type 1 diabetes; hypothyroidism is more common than hyperthyroidism. The American College of Obstetricians and Gynecologists, ADA, and Endocrine Society recommend screening patients with type 1 diabetes prior to pregnancy with a TSH level [72,84,85]. Hypothyroidism is treated with levothyroxine. The TSH should be <2.5 milliunits/mL before pregnancy is attempted [117,118]. (See "Diagnosis of and screening for hypothyroidism in nonpregnant adults" and "Overview of thyroid disease and pregnancy".)
If the TSH is low, a thyroxine (T4) level should be obtained. Goals and medications for the treatment of hyperthyroidism prior to and during pregnancy are complex and should be managed by an endocrinologist or other clinician experienced in the management of hyperthyroidism during pregnancy. (See "Diagnosis of hyperthyroidism" and "Hyperthyroidism during pregnancy: Treatment".)
Females with type 2 diabetes also have a higher prevalence of hypothyroidism than the general population. Whether this is a true association or confounding by indication due to increased testing is unclear; however, the ADA [72] recommends checking the TSH level prior to pregnancy in patients with type 2 diabetes and initiating treatment when indicated.
Routine measurement of antithyroid antibodies is not necessary for the assessment of thyroid function. Whether to treat euthyroid thyroid peroxidase antibody-positive females to improve pregnancy outcome is controversial and is reviewed separately. (See "Overview of thyroid disease and pregnancy", section on 'Thyroid peroxidase antibodies in euthyroid women'.)
Contraception and timing of pregnancy — Family planning with use of effective contraception until glucose control is achieved should be a key feature in the management of all females with diabetes and should be discussed at regular intervals. Given the importance of optimization of glucose control at conception, evaluation for and management of diabetes complications, and change in medication prior to conception, it is recommended that patients with prepregnancy diabetes plan their pregnancies to optimize the likelihood for a healthy pregnancy both for the mother and the baby.
Guidelines from the United States Centers for Disease Control and Prevention Medical Eligibility Criteria for Contraceptive Use are helpful for advising patients with diabetes about the safety of contraceptive methods [119]. Estrogen-progestin and progestin-only contraceptives are safe and effective for many patients with type 1 or type 2 diabetes. However, patients with nephropathy, retinopathy, neuropathy, other vascular disease, or diabetes >20 years in duration have conditions in which the theoretical or proven risks of using an estrogen-progestin method or depot medroxyprogesterone acetate may outweigh the advantages of using the method or represent an unacceptable health risk if the contraceptive method is used. Other progestin-only methods (eg, pill, implant, intrauterine device [IUD]) and the copper-releasing IUD are preferable for patients with these conditions since they are associated with a lower rate of thromboembolic events than estrogen-progestin contraceptives [120]. Long-acting reversible contraception methods are generally most effective at preventing unplanned pregnancy. (See "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Cardiovascular effects' and "Intrauterine contraception: Background and device types" and "Intrauterine contraception: Candidates and device selection".)
The selection of a contraceptive method for an individual patient should be based on the same guidelines that apply to patients without diabetes. Considerations of potential side effects of contraceptive agents should be weighed against the risk of an unplanned pregnancy.
Types of hormonal and nonhormonal contraception and important factors in choosing a contraceptive method are reviewed separately. (See "Contraception: Counseling and selection".)
Multidisciplinary programs — Prior to and during pregnancy, patients with preexisting diabetes may benefit from being followed in a multidisciplinary care program with providers including an obstetrician, an endocrinologist (or other clinician with expertise in diabetes management in pregnancy), a dietician, and a diabetes educator (with other health professionals as needed). Data supporting the benefit of these programs in improving pregnancy outcomes are limited by the lack of randomized trials and the caveat that patients who are more motivated to manage their diabetes are likely to be those who attend these programs. Nevertheless, observational data, including a prospective cohort including both type 1 and type 2 diabetes, suggest that individuals who attend preconception programs have better pregnancy outcomes, including decreased congenital malformation, stillbirth, and neonatal mortality [17,121].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diabetes mellitus in pregnancy".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Preparing for pregnancy when you have diabetes (The Basics)")
SUMMARY AND RECOMMENDATIONS
●General principles – Prior to pregnancy, all females of childbearing age with type 1 or type 2 diabetes should be counseled about the potential effects of diabetes on maternal and fetal outcomes and the potential impact of pregnancy on their diabetes control and any existing complications. The key components of preconception diabetes management are glycemic control, proficient diabetes self-care, and medical optimization of preexisting complications and comorbidities associated with diabetes. Patient education also includes insulin management, prevention and identification of hypoglycemia and diabetic ketoacidosis, and diet and exercise counseling. (See 'General principles' above.)
●Pregnancy risks
•The risk of adverse pregnancy outcome is increased in pregnant people with diabetes but appears to be similar for type 1 versus type 2 diabetes. Pregnant people with type 1 diabetes are more likely to have microvascular-disease-related complications than those with type 2 diabetes, and they are at higher risk of developing severe hypo- and hyperglycemia. (See 'General principles' above.)
•Adverse pregnancy outcomes include miscarriage, congenital anomaly, macrosomia, preeclampsia, preterm birth, cesarean birth, and perinatal mortality. Short- and long-term morbidity in offspring are also concerns. Maternal medical risks include progression of retinopathy and nephropathy, diabetic ketoacidosis, serious hypoglycemia, and complications related to gastroparesis. (See 'Risk counseling' above.)
●Preconception glucose/A1C targets
•Hyperglycemia in the periconception period and during the course of pregnancy is the single most important determinant of excess risk of adverse fetal outcome in pregnant people with pregestational diabetes. Achieving preconception glycemic control as close to normal as possible while avoiding hypoglycemia is of critical importance. (See 'General principles' above and 'Risk counseling' above.)
•Our primary preconception A1C goal for all patients is A1C <6.5 percent. Glucose targets are fasting capillary blood glucose concentration 80 to 110 mg/dL (4.4 to 6.1 mmol/L) and two-hour postprandial glucose concentration <155 mg/dL (8.6 mmol/L). Although still quite low, these targets are slightly higher than pregnancy targets and probably more pragmatic for patients who are not yet pregnant. (See 'Glycemic control' above.)
●Preconception management
•Contraception – Contraception is recommended until glycemic control is achieved, management of complications or comorbidities is optimized, and pregnancy is desired. (See 'Contraception and timing of pregnancy' above.)
•Laboratory evaluation – Preconception evaluation includes physical examination (table 2) and laboratory evaluation (glycated hemoglobin [A1C], serum creatinine, estimated glomerular filtration rate, aspartate aminotransferase and alanine aminotransferase, thyroid-stimulating hormone, urine albumin-to-creatinine ratio on a spot urine or 24-hour urine collection for protein and creatinine). Further evaluation may be indicated based on the patient's history and examination. (See 'Evaluation of and approach to complications of diabetes mellitus' above.)
•Folic acid supplementation – We agree with the American Diabetes Association's (ADA) recommendation for supplemental folic acid 400 micrograms/day and potassium iodide 150 micrograms/day. (See 'Folic acid and iodine supplementation' above.)
•Pharmacotherapy – Insulin is the preferred treatment for hyperglycemia in pregnancy. In patients with type 2 diabetes on metformin monotherapy with adequate glycemic control for preconception, we initiate insulin once pregnancy is confirmed. Other non-insulin agents should be stopped and substituted with insulin prior to conception. (See 'Glycemic control' above.)
•Avoid angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and statins – These drugs should be discontinued before pregnancy is attempted. (See 'Blood pressure control' above and 'Lipid control' above.)
•Gastroparesis – Gastroparesis may influence dietary approach, insulin regimen, and other medical therapies. Severe gastroparesis is one of the few relative contraindications to pregnancy. (See 'Gastroparesis' above.)
•Diabetic kidney disease – Patients with significant diabetic kidney disease should be referred to a nephrologist skilled in the care of pregnant patients to assist them in balancing their desire for pregnancy and the risks and consequences of deterioration of renal function. Patients with established nephropathy may develop permanent worsening of renal functioning during pregnancy. (See 'Diabetic kidney disease' above.)
•Ophthalmology evaluation – A dilated eye examination should be performed before pregnancy, and if proliferative retinopathy is detected, it should be treated prior to attempts at conception. Diabetic retinopathy can worsen during pregnancy. (See 'Retinopathy' above.)
•Cardiac evaluation – Signs and symptoms of cardiovascular disease on history or physical examination (eg, carotid bruits, absent peripheral pulse) are an indication for further cardiac evaluation and possible referral to a cardiologist. (See 'Cardiovascular disease' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Michael F Greene, MD, and Emma B Morton-Eggleston, MD, MPH, who contributed to earlier versions of this topic review.
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