23/2/24, 16:30 Pregestational (preexisting) diabetes: Preconception counseling, evaluation, and management - UpToDate

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Pregestational (preexisting) diabetes: Preconception

counseling, evaluation, and management
AUTHORS: Ellen W Seely, MD, Camille E Powe, MD
SECTION EDITORS: David M Nathan, MD, Erika F Werner, MD, MS
DEPUTY EDITOR: Vanessa A Barss, MD, FACOG

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jan 2024.

This topic last updated: Feb 22, 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 glucose management in the
periconceptional period and during pregnancy is associated with improved outcomes
[7,10,11].

Prior to pregnancy, all females of childbearing age with 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 management and any existing
complications. Preconception care can improve glucose levels in early pregnancy and, in

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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 type 1 or type 2 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) and gestational diabetes: Intrapartum and
postpartum glucose management".)
● (See "Pregestational (preexisting) diabetes mellitus: Obstetric issues and
management".)

GENERAL PRINCIPLES

The key components of preconception diabetes management are:

● Patient education
● Management of hyperglycemia
● 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

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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 management of
hyperglycemia throughout pregnancy.

Although the impact of preconception management of hyperglycemia 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 achieving glucose
targets 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].

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● 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

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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 levels versus other factors (eg, maternal obesity, second- and third-
trimester glucose levels, 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

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<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]. Management of hyperglycemia
periconceptionally and in the first trimester, in addition to later pregnancy, 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 "Fetal growth
restriction (FGR) and small for gestational age (SGA) newborns".)

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

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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 management of
hyperglycemia and risk factors is 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 management [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

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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 management 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 management 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.

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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 'Management of hyperglycemia'
below.)

Progression of microvascular disease — The likelihood of worsening microvascular

complications in pregnancy is related to duration of diabetes and prepregnancy glycemic
management [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 management of hyperglycemia 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 the degree of management of
hyperglycemia 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'.)

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As in nonpregnant patients, rapid tightening of glucose levels 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 management.
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 glucose levels 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.

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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
and heart failure'.)

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
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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:

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● 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 management, with A1C in the normal range if
safely achievable.

● Explaining that preconception management of hyperglycemia is important because

congenital anomalies 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

management of hyperglycemia 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".)

Management of hyperglycemia

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 management needed in pregnancy. (See
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"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 levels before trying to conceive, if glucose levels are not already
optimal.

Continuous glucose monitoring — Many clinicians consider continuous glucose

monitoring (CGM) only as an adjunct to traditional self-monitoring as no data are available
on specific preconception glucose targets for CGM. The practice of one of the authors of this
topic is to target an average glucose on the CGM that would correspond to an A1C <6.5
percent. She also translates the fingerstick targets of <110 mg/dL (6.1 mmol/L) fasting and
peak postprandial <155 mg/dL (8.6 mmol/L) to CGM data, but this is not evidence-based.
Although some CGM devices can be used to dose insulin without additional self-monitoring
of glucose, these devices have not been studied in the preconception period.

In a randomized trial of CGM in pregnant patients with type 1 diabetes, pregnancy outcomes
were not significantly improved for those who began CGM when planning to conceive,
possibly due to the small sample size [85]. Nevertheless, CGM may be helpful for some
patients trying to manage hyperglycemia preconception, and this decision should be made
on a case-by-case basis. (See "Pregestational (preexisting) diabetes mellitus: Antenatal
glycemic control", section on 'Continuous glucose monitoring systems'.)

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 management while allowing discontinuation of noninsulin
agents without safety data in early pregnancy [86].

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 [87], which could lead to increased
fetal growth and macrosomia; however, observational studies in humans do not support this

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concern [88-90]. Emerging but limited data support use of insulin degludec in pregnancy
[91].

We suggest avoiding premixed insulins, which are more difficult to titrate to achieve desired
glucose levels without hypoglycemia.

For patients newly starting insulin in anticipation of pregnancy, we preferentially initiate NPH
insulin or insulin detemir, given the availability of these better-studied and effective insulins.
If this is not desirable due to patient preference, insurance coverage, or inability to achieve
optimal glycemia on an alternative regimen, we use another long-acting insulin. For patients
who are already on another stable long-acting insulin regimen (such as glargine or degludec)
prior to pregnancy and meeting glucose targets, we generally do not switch them to a
different long-acting insulin.

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 management of
the postprandial increase in glucose, and have a rapid offset, which may decrease
hypoglycemia. A randomized trial of 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 aspart and ultra-rapid lispro are newer
insulins that are even more rapid acting than aspart and lispro. A trial of faster aspart
compared with aspart in pregnancy demonstrated similar glucose levels and birthweights
with these two insulins [93]. No data are available to support use of ultra-rapid lispro in
pregnancy or preconception.

Of note, a 2017 systematic review of different types and regimens of insulin in pregnancy did
not find superiority of any type/regimen over another [94]. (See "Pregestational (preexisting)
diabetes mellitus: Antenatal glycemic control", section on 'Insulin pharmacotherapy'.)

Insulin pumps — 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.

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 management on multiple dose

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injections), with some patients obtaining better glucose levels 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 glucose levels
would be suboptimal 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
glucose levels 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 management
during the period of organogenesis. Insulin is likely to be required in addition to or
instead of metformin to achieve the level of glycemic management 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.
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In a 2023 multinational population-based cohort study that included nearly 2000

exposures to GLP-1 receptor agonists, SGLT-2 inhibitors, and DPP-inhibitors,
periconception exposure to any of these drug classes was not associated with an
increased risk of congenital anomalies compared with insulin [104]. Other potential
adverse outcomes, such as neonatal hypoglycemia, macrosomia, and neonatal
adiposity, were not evaluated [104]. Of note, in unadjusted models, the rate of
congenital anomalies was higher with these drug classes than with exposure to
metformin alone.

Since the study did not adjust for potential differences in A1C, diabetes severity, or
diabetes duration in the subgroups treated with the different medications, the results
may reflect these factors and could obscure true effects of the medications on risk for
congenital anomalies. Of concern, in animals, GLP-1 agonists have caused vascular
(heart, blood vessels) and skeletal (cranial bones, vertebra, ribs) abnormalities at
maternal exposures equivalent to those below the maximum recommended human
dose in early pregnancy. In animals, early pregnancy exposure to SGLT-2 inhibitors was
not associated with adverse effects, but these agents caused kidney toxicity with
exposure during developmental periods equivalent to the second and third trimesters
in humans.

Some of the once-weekly subcutaneous GLP-1 agonists (eg, semaglutide) have long
half-lives and ideally should be stopped at least two months prior to conception
because of the teratogenic effects seen in animals. Given their potent glucose- and
weight-lowering effects, attention to hyperglycemia and weight gain after cessation of
these agents is necessary to optimize glucose levels in the periconception period.

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 management, 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 management, changes in hormone levels, nausea and
vomiting of pregnancy, and reduction in physical activity. Hypoglycemia is more likely to

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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 "Medical nutrition therapy for 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 management 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 management,

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) [84,86,105]; 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'.)
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● 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 management — 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 management — 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'.)

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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, management 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
reduction of glucose levels, improvement in management of hyperglycemia should be made
gradually over months prior to pregnancy, when possible. (See "Diabetic retinopathy:
Prevention and treatment", section on 'Pregnancy'.)

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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 management, 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 [72,84,86]. 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

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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 management of hyperglycemia 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 levels 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".)
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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

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● 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
management and any existing complications. The key components of preconception
diabetes management are management of hyperglycemia, 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 glucose
levels 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
'Management of hyperglycemia' above.)

● Preconception management

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• Contraception – Contraception is recommended until management of

hyperglycemia 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 glucose levels preconception, we initiate insulin once pregnancy is
confirmed. Other non-insulin agents should be stopped and substituted with insulin
prior to conception. (See 'Management of hyperglycemia' 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 management' above and 'Lipid
management' 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

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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.

Use of UpToDate is subject to the Terms of Use.

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Topic 94859 Version 65.0

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GRAPHICS

Risks of specific congenital anomalies in offspring of mothers with

preexisting diabetes

Pre-gestational diabetes
Number
Outcome
of events Number of Pooled RR
I 2 (%) P value
studies (95% CI)

Heterotaxia 1098 4 8.78 (6.66 to 0.0 0.423

11.56)

Conotruncal defects 5495 4 3.76 (2.58 to 68.3 0.024

5.48)

Truncus arteriosus 435 3 12.16 (7.52 0.0 0.866

to 19.68)

Transposition of great 6700 9 3.25 (2.54 to 15.9 0.301

vessels 4.15)

Tetralogy of fallot 5360 6 3.46 (2.27 to 64.4 0.015

5.28)

APVR 1239 4 3.47 (2.13 to 0.0 0.684

5.64)

LVOT defects 6672 7 3.46 (2.59 to 37.8 0.140

4.62)

Coarctation of aorta 6606 5 3.35 (2.25 to 61.4 0.035

4.99)

Hypoplastic left heart 2319 4 2.23 (1.07 to 64.0 0.040

4.64)

RVOT defects 6163 7 3.41 (2.65 to 20.9 0.270

4.38)

Pulmonary artery 17,215 3 2.81 (2.48 to 0.0 0.865

anomalies 3.18)

Pulmonary valve 7273 5 2.51 (1.51 to 76.2 0.002

stenosis 4.17)

Septal defects 12,368 2 3.23 (2.20 to 86.2 0.007

4.74)

AVSD 5126 6 3.94 (2.95 to 40.0 0.139

5.26)

VSD 64,844 10 3.10 (2.32 to 90.2 <0.001

4.16)

ASD 91,683 7 3.12 (2.42 to 81.9 <0.001

4.02)

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VSD + ASD 1089 2 6.36 (4.38 to 0.0 0.527

9.24)

Single ventricle 1228 4 5.91 (2.43 to 80.2 0.002

14.38)

Nervous system defects 42,339 9 2.54 (1.73 to 94.8 <0.001

3.73)

Neural tube defects 8791 6 2.74 (1.46 to 75.5 0.001

5.14)

Anencephaly 3859 3 2.72 (2.16 to 0.0 0.416

3.44)

Encephalocele 1108 3 5.53 (3.24 to 52.8 0.120

9.45)

Spina bifida 9948 8 1.89 (1.15 to 71.1 0.001

3.09)

Hydrocephaly 10,733 5 3.46 (1.62 to 85.0 <0.001

7.42)

Holoprosencephaly 301 2 18.18 (4.03 66.3 0.085

to 82.06)

Eye, ear, face, and neck 39,570 6 3.14 (2.90 to 0.0 0.444
defects 3.39)

Orofacial clefts 6,602 5 1.27 (0.54 to 90.4 <0.001

2.98)

Cleft palate 11,259 6 1.75 (1.04 to 74.6 0.001

2.94)

Cleft lip with or 32,641 7 1.89 (1.22 to 81.1 <0.001

without cleft palate 2.92)

Digestive system 14,286 7 2.02 (1.24 to 92.3 <0.001

defects 3.28)

Diaphragmatic hernia 5882 3 1.66 (1.32 to 0.0 0.520

2.10)

Abdominal wall defects 1691 2 1.31 (0.80 to 0.0 0.729

2.15)

Omphalocele 4163 3 1.90 (1.48 to 0.0 0.447

2.44)

Gastroschisis 9268 3 0.92 (0.68 to 0.0 0.399

1.24)

Genitourinary system 128,657 10 1.73 (1.35 to 89.2 <0.001

defects 2.21)

Renal 5239 6 5.63 (2.48 to 86.1 <0.001

agenesis/dysgenesis 12.76)

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Hypospadias 44,963 9 1.57 (1.22 to 74.1 <0.001

2.02)

CAKUT 4143 3 1.80 (1.41 to 0.0 0.865

2.30)

Musculoskeletal 123,365 11 1.98 (1.45 to 94.4 <0.001

system defects 2.72)

Limb reduction 23,963 9 2.73 (1.98 to 81.7 <0.001

3.76)

Polydactyly/syndactyly 20,328 4 0.95 (0.57 to 71.8 0.003

1.57)

Multiple congenital 2448 5 3.06 (2.36 to 39.6 0.158

anomalies 3.96)

Major congenital 52,171 6 2.14 (1.65 to 81.8 <0.001

anomalies 2.77)

Rates (95% CI) of major groups and selected subtypes of congenital anomalies* in pregnancies of
women with and without pre-existing diabetes per 1000 singleton pregnancies and relative risk (95%
CI).

APVR: anomalous pulmonary venous return; ASD: atrial septal defect; AVSD: atrioventricular septal
defect; CAKUT: congenital anomalies of the kidney and urinary tract; CHD: congenital heart defect; CI:
confidence interval; LVOT: left ventricular outflow tract; RR: relative risk; RVOT: right ventricular
outflow tract; VSD: ventricular septal defect.

* European Surveillance of Congenital Anomalies (EUROCAT) coding.

Adapted from: Zhang TN, Huang XM, Zhao XY, et al. Risks of specific congenital anomalies in offspring of women with
diabetes: A systematic review and meta-analysis of population-based studies including over 80 million births. PLoS Med 2022;
19:e1003900. Copyright © The Authors. Available at: https://journals.plos.org/plosmedicine/article?
id=10.1371/journal.pmed.1003900 (Accessed on March 18, 2021). Adapted under the terms of the Creative Commons
Attribution License 4.0.

Graphic 108112 Version 5.0

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Targeted preconception physical examination for women with diabetes

Dilated funduscopic examination by an ophthalmologist

Examination for thyromegaly

Cardiac auscultation

Evaluation for carotid bruits and pulses present to the periphery

Blood pressure measurement in both arms and pulse, lying and standing to check for orthostasis

Lung auscultation

Check for succession splash if patient not fasting

Check sensation and check for tremor, hypo- or hyperreflexia

Graphic 97118 Version 2.0

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