Management of Common Medical Comorbidities During Pregnancy

Management of Common Medical Comorbidities During Pregnancy

Wesley P. Eilbert

Medical comorbidities in pregnancy frequently manifest as complex illnesses with maternal and fetal health risks. The prevalence of medical problems in pregnancy is increasing due to a number of factors. Women are delaying childbearing until later in life and older women are more likely to have concomitant medical illnesses. Increasing rates of obesity have led to higher rates of maternal diabetes and hypertension. Finally, medical advances have enabled women to become pregnant despite chronic conditions that would previously have precluded pregnancy. Medical conditions now represent the leading cause of death among pregnant women, with two-thirds of maternal deaths occurring in women with known medical comorbidities.1


One in six live births (16.8%) are to women with some form of hyperglycemia in pregnancy. The majority (84%) of these cases are due to gestational diabetes mellitus (GDM), with the remainder due to preexisting type 1 and type 2 diabetes.2 Pregnancies complicated by diabetes are at increased risk for maternal and neonatal morbidities including spontaneous abortion, fetal anomalies, preeclampsia, fetal demise, macrosomia, and neonatal hypoglycemia.3

Glycemic control is the cornerstone of management of any diabetic pregnancy. Insulin is a traditional, safe, and effective medication used for this purpose. Rapid, intermediate, and long-acting insulin are all considered safe for use in pregnancy.4 Although not recommended for use because of concern about possible teratogenic effects, glyburide and metformin are often used in pregnancy due to patient request or physician discretion. Neither metformin nor glyburide is U.S. Food and Drug Administration (FDA) approved for use in pregnancy.5 Neither drug has been associated with birth defects or short-term adverse neonatal outcomes. However, data on long-term metabolic effects on children with in utero exposure are limited.4 Insulin is considered the first-line therapy for the treatment of diabetes in pregnancy.5

Gestational Diabetes Mellitus

Although controversial, GDM has been defined as “glucose intolerance with onset or first recognition in pregnancy.”6 The prevalence of GDM varies between 1% and 28%, and GDM is a strong risk factor for subsequent permanent diabetes development in the mother.2,6 Maternal risk factors for GDM have been identified (Table 6.1).2,4 All pregnant women should be screened for diabetes early in the pregnancy and receive oral glucose tolerance testing between 24 and 28 weeks of gestation. Management of GDM begins with nonpharmacologic approaches such as dietary modifications, exercise, and glucose monitoring. Studies show that 70% to 85% of women diagnosed with GDM can control it with lifestyle modification alone.3 If lifestyle modification fails to achieve glucose control, insulin is the first line of therapy. Metformin and glyburide may be considered in special circumstances.2

Diabetic Ketoacidosis

Diabetic ketoacidosis (DKA) has been reported to complicate 0.5% to 3% of diabetic pregnancies.7 It usually occurs in patients with type 1 diabetes mellitus, especially of new onset, but may also affect women with type 2 diabetes and rarely women with GDM. It most commonly occurs in the first trimester, although it may occur at any point throughout the pregnancy. Pregnancies complicated by DKA have a 9% to 36% rate of fetal loss.7

Pregnant women are at greater risk for DKA than nonpregnant diabetic women. Factors predisposing the pregnant patient to DKA include increased production of hormones that are insulin antagonists—human placental lactogen, prolactin, and cortisol, an accelerated starvation state, and decreased buffering capacity due to the compensatory respiratory alkalosis of pregnancy. The nausea that frequently accompanies pregnancy may also lead to decreased caloric intake. Common precipitants of DKA in pregnancy include hyperemesis gravidarum, a concomitant viral or bacterial infection, noncompliance with insulin dosing, and concurrent use of medications such as beta-sympathomimetic agents for tocolysis, and steroids used for fetal lung maturation.

The metabolic profile of DKA is the result of an exaggerated counterregulatory response to a perceived lack of glucose. Without adequate insulin availability, cells enter a state of starvation, which in turn activates energy-producing pathways (Figure 6.1). The symptoms of DKA in pregnancy are no different from those experienced by nonpregnant women, except that they tend to develop more rapidly in pregnancy. Patients typically present with malaise, nausea, vomiting, polydipsia, polyuria, tachypnea, and physical signs of dehydration such as dry mucous membranes, tachycardia, and hypotension. The classic fruity smell of acetone may be noted on the breath. Because perfusion may be compromised resulting in ischemia, patients may present with
abdominal pain. In severe cases, patients may present with altered consciousness, usually in the setting of extreme hyperglycemia.

TABLE 6.1 Risk Factors for Gestational Diabetes Mellitus

Gestational diabetes mellitus in previous pregnancy

Macrosomia in previous pregnancy

High parity

Body mass index > 30 kg/m2

Weight gain of more than 5 kg since 18 years of age

Excessive gestational weight gain

Polycystic ovarian syndrome

Short stature

Maternal age older than 35 years

Diabetes in first-degree relative


Asian, Native American, Pacific Islander, Black, Hispanic

Figure 6.1: Pathophysiology of diabetic ketoacidosis in pregnancy.

Laboratory evaluation of DKA is characterized by the triad of hyperglycemia, anion gap metabolic acidosis, and ketosis. Initial testing should include a complete blood cell count, urinalysis, serum glucose, electrolytes, blood urea nitrogen, creatinine, and ketones. Serum pH should be measured by arterial or venous blood gases if serum ketones are present or if there is an elevated anion gap. The presence of serum ketones and an arterial pH < 7.30 with an anion gap greater than 12 mEq/L is characteristic of DKA. Falsely normal or elevated serum potassium levels may be present; however, most patients have a low total body potassium that will become apparent with treatment. Blood urea nitrogen and creatinine levels may be elevated as a result of dehydration and renal dysfunction. The serum glucose level is usually higher than 300 mg/dL, but lower levels are not uncommon during pregnancy. Euglycemic ketoacidosis is a rare phenomenon that has been described in pregnancy. In this condition, ketoacidosis occurs in the absence of pronounced hyperglycemia.

TABLE 6.2 Management of Diabetic Ketoacidosis in Pregnancy

Fluid Replacement

0.9% sodium chloride 1-2 L/h × 2 h, then 250 mL/h

In cases of hypernatremia, use 0.45% sodium chloride


Potassium: if normal or low, replace at a rate of 15-20 mEq/h; if high, wait until it drops to within normal range, then replace at a rate of 20-30 mEq/h

Bicarbonate: only indicated if serum pH < 7. Infuse at a rate of 44 mEq/h

Insulin (Regular)

Infuse intravenously at a rate of 0.1 units/kg/h. May bolus with 10-15 units before beginning the infusion

Begin infusion of 5% dextrose when glucose levels drop <250 mg/dL

The management principles for DKA in pregnancy are the same as in the nonpregnant patient (Table 6.2). Aggressive volume replacement, intravenous insulin therapy, correction of acidosis as well as electrolyte abnormalities, and management of the underlying pathology are the cornerstones of treatment. The serum glucose levels should be checked every hour and serum electrolytes and ketones checked every 2 hours during treatment. All pregnancies beyond 24 weeks’ gestation should have continuous fetal monitoring during treatment.


Thyroid disease is the second most common endocrine disorder in pregnancy after diabetes.8 Changes in maternal thyroid function during pregnancy result from several factors including increased metabolic demands, increased serum thyroid-binding globulin concentrations, increased mother-to-fetus transfer of thyroxine (T4), and stimulation of the thyroid-stimulating hormone (TSH) receptor by human chorionic gonadotropin (hCG). Maternal TSH is usually within normal limits during pregnancy, but can be decreased in the first trimester due to increased hCG levels and the cross-reactivity of this hormone on TSH receptors. Because hCG has weak thyroid-stimulating activity and its serum levels peak at 10 to 12 weeks’ gestation, TSH levels may decline in the first trimester as a result of negative feedback.


Hypothyroidism in pregnancy is defined as a serum TSH level above the trimester-specific range, with a free T4 level below the reference range. It affects 0.3% to 0.5% of pregnancies.8 It is often preexistent, but may develop during pregnancy. The most common cause is chronic autoimmune (Hashimoto) thyroiditis, although it can also be due to previous thyroid surgery, radioactive iodine treatment for hyperthyroidism, and iodine deficiency. The majority of pregnant women with known preexisting hypothyroidism treated with levothyroxine will need to increase their dose during pregnancy. Levothyroxine requirements in pregnant women typically increase by 25% to 50% within 4 to 8 weeks’ gestation and then plateau by 16 weeks’ gestation.8

Symptoms of hypothyroidism including fatigue, constipation, and somnolence may be attributed to the pregnancy itself, delaying the diagnosis. Left untreated, hypothyroidism in pregnancy is associated with several obstetric complications including preterm birth, preeclampsia, placental abruption, anemia, and postpartum hemorrhage.8 Thyroid hormone is critical to the development of the fetal brain, and children born to mothers with hypothyroidism are 3 times more likely to have intelligence quotient (IQ) scores one standard deviation below the general population mean.9

Myxedema coma represents the most extreme form of hypothyroidism with multiple systemic effects. Although rare, it can occur in pregnancy.10 A precipitating factor is often present, such as hypothermia, infection, or use of medications that suppress the central nervous system such as narcotics. Hypothermia is present in virtually all patients. Bradycardia and bradypnea with resultant hypoxia and hypercarbia are frequently present. An altered sensorium ranging from lethargy to coma is very common, as well as the presence of diffuse nonpitting edema. Laboratory evaluation
reveals a markedly elevated serum TSH level and very low free T4 and free triiodothyronine (T3) levels. Hyponatremia is often present. Treatment of myxedema coma in pregnancy should take place in an intensive care setting with fetal monitoring. Large doses of thyroid hormone replacement (levothyroxine 200-250 mg intravenously per day) is the mainstay of treatment. High-dose corticosteroids (hydrocortisone 50-100 mg intravenously every 6-8 hours) are used to decrease systemic symptoms while awaiting the effect of thyroid hormone replacement.


Hyperthyroidism, identified by a low serum TSH and elevated free T3 and free T4 serum levels, complicates 0.4% to 1.7% of all pregnancies.11 Graves disease is the most common cause, responsible for 85% of cases. Toxic nodules and factitious thyrotoxicosis are much less common causes.8 An important distinction should be made between Graves disease and gestational thyrotoxicosis (Table 6.3). Graves disease is a syndrome characterized by hyperthyroidism, goiter, and eye disease (ophthalmopathy). It is caused by circulating TSH receptor antibodies that stimulate thyroid hormone synthesis. Gestational thyrotoxicosis is a transient, usually asymptomatic condition caused by the cross-reactivity of hCG on the TSH receptors of the thyroid. TSH levels then decline as a result of negative feedback. Because hCG levels peak at 10 to 12 weeks’ gestation, gestational thyrotoxicosis occurs during the first half of pregnancy. Unlike Graves disease, free T3 and free T4 serum levels remain in the normal range with gestational thyrotoxicosis. Conditions associated with an elevated serum hCG such as hyperemesis gravidarum and twin pregnancies may predispose to gestational thyrotoxicosis.

Graves disease complicates 0.1% to 1% of all pregnancies. Many of the nonspecific symptoms of pregnancy are similar to those of Graves disease including tachycardia, heat intolerance, and increased perspiration. The disease usually exacerbates within the first trimester and improves thereafter. Graves disease, as with all hyperthyroidism in pregnancy, is associated with several neonatal comorbidities including preterm labor, intrauterine growth restriction, preeclampsia, and fetal demise. The diagnosis of Graves disease in pregnancy is supported by clinical stigmata such as goiter and ophthalmopathy as well as the presence of TSH receptor antibodies. Antithyroid drugs including propylthiouracil (PTU) and methimazole (MMI) are the treatment of choice for Graves disease.8,9,11 Use of radioiodine for this purpose in pregnancy is contraindicated due to fetal toxicity. Although both PTU and MMI have known teratogenic effects, PTU is the preferred agent in the first trimester, and MMI is preferred in the second and third trimesters. Beta-blockers may be used to treat adrenergic symptoms at the lowest effective dose until thyroid function has normalized on the antithyroid drugs.

TABLE 6.3 Differences Between Graves Disease and Gestational Thyrotoxicosis

Gestational Thyrotoxicosis

Graves Disease

Incidence in pregnancy




Thyroid stimulation by cross-reactivity of hCG on TSH receptors

Thyroid stimulation by anti-TSH receptor antibodies


Symptoms usually mild and occur transiently in the first half of pregnancy

Some symptoms usually present before the pregnancy. Most symptomatic in the first trimester, with improvement thereafter

Physical examination findings

Minimal. Occasionally mild tachycardia

Tachycardia, diaphoresis, weight loss, anxiety, ophthalmopathy, and goiter

Thyroid function tests

Low TSH, normal free T3 and free T4

Low TSH, elevated free T3 and free T4


Rarely needed

Antithyroid drugs and possible beta-blockers

hCG, human chorionic gonadotropin; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone.

Thyroid storm

Thyroid storm is a rare, potentially fatal condition characterized by a severe hypermetabolic state precipitated by high levels of endogenous thyroid hormones. It occurs in 1% of women with untreated or inadequately treated hyperthyroidism in pregnancy. Thyroid storm during pregnancy may result in maternal heart failure, shock, and coma and has a maternal mortality rate of up to 25%. Often there is an identified precipitating factor, such as infection, trauma, or labor. The diagnosis of thyroid storm is made clinically, taking into account the constellation of clinical signs and symptoms (Table 6.4). Treatment does not differ from that in nonpregnant women. Pharmacologic treatment is used to block thyroid hormone synthesis, secretion, and action in the peripheral tissues (Table 6.5). General supportive care including antipyretics, cooling blankets, volume resuscitation, and supplemental oxygen should be administered in an intensive care setting, with continuous fetal monitoring for pregnancies beyond 24 weeks’ gestation.

TABLE 6.4 Symptoms and Signs of Thyroid Storm


Visual changes










Atrial fibrillation



Pulmonary edema

TABLE 6.5 Pharmacologic management of Thyroid Storm in Pregnancy

Inhibition of Thyroid Hormone Synthesis

PTU 500-1000 mg loading dose, then 250 mg every 4 h. This is the preferred agent as it also inhibits conversion of T4 to T3 in the peripheral tissues, which limits the active form of thyroid hormone


MMI 60-80 mg/d in divided doses

Inhibition of Thyroid Hormone Secretion

SSKI (50 mg iodide/drop), 1-2 drops by mouth 3 times a day


Lugol iodine solution (8 mg iodide/drop), 5-7 drops by mouth 3 times a day


Sodium iodide, 500 mg intravenously twice a day

(Note: Wait 1 hour after giving PTU or MMI before beginning treatment with iodide-containing compounds.)

Inhibition of Thyroid Hormone Effects

Propranolol 60-80 mg by mouth every 4 h. This is the preferred agent because it also inhibits the conversion of T4 to T3


Metoprolol 25-50 mg by mouth 4 times a day


Esmolol 50-100 µg/kg/min infusion

Administration of Corticosteroids

Hydrocortisone 300 mg intravenously, then 100 mg 3 times a day


Dexamethasone 2-4 mg intravenously 4 times a day

(Corticosteroids inhibit the conversion of T4 to T3, block the release of hormone from the thyroid gland, and will treat adrenal insufficiency that can occur with thyroid storm.)

MMI, methimazole; PTU, propylthiouracil; SSKI, saturated solution of potassium iodide; T3, triiodothyronine; T4, thyroxine.


Asthma is the most common respiratory disorder to complicate pregnancy, with a prevalence of 8.8% in pregnant women in the United States.12 Asthma may worsen, improve, or remain unchanged during pregnancy, with data suggesting these three clinical courses occur with equal frequency. The course of asthma may also vary by stage of pregnancy. The first trimester is generally well tolerated in asthmatic women with few acute episodes. Increased symptoms and more frequent exacerbations often occur between weeks 17 and 36 of gestation, with weeks 37 to 40 marked by a return to fewer symptoms.12 Asthma in pregnancy is strongly associated with preeclampsia, placental abruption, placenta previa, and obstetric hemorrhage.13

The goal of asthma therapy in pregnancy is to maintain adequate oxygenation of the fetus and prevent hypoxic episodes in the mother. The potential teratogenic effects of the most common asthma medications have been extensively studied and, in general, are far outweighed by the benefit of asthma control in pregnancy. Asthma medications can be divided into two main classes: long-term control medications for maintenance therapy and rescue medications to provide immediate relief of symptoms (Table 6.6). Inhaled corticosteroids are the mainstay of long-term control medications in pregnancy, with budesonide the preferred drug in this class.14 An inhaled long-acting beta agonist may be added if long-term control is not achieved with inhaled corticosteroids alone. Salmeterol and formoterol are the two currently available inhaled long-acting beta agonists, with both considered generally safe in pregnancy.

Approximately 6% of pregnant women are hospitalized with an asthma exacerbation.15 Viral infection, allergen exposure, and therapy nonadherence are common exacerbating factors. Peak expiratory flow rates, commonly used to assess asthma severity, are not changed by pregnancy.
Acute asthma exacerbations in pregnancy are managed in the same way as for nonpregnant adults, with inhaled short-acting beta agonists and systemic corticosteroids as the mainstay of therapy. Noninvasive fetal heart rate monitoring after 24 weeks’ gestation is indicated during treatment. Oxygen saturation should be maintained above 95%. Because pregnant patients normally have a physiologic compensated respiratory alkalosis with a serum partial pressure of carbon dioxide (PCO2) range of 28 to 32 mm Hg, a seemingly normal PCO2 on arterial blood gas testing represents CO2 retention and possible impending respiratory failure. Should mechanical ventilation become necessary, efforts must be made to avoid air trapping, also known as dynamic hyperinflation. This condition results in elevated intrathoracic pressures leading to decreased peripheral venous return and maternal hypotension. The strategy of ventilation with permissive hypercapnia to help avoid air trapping is controversial in pregnancy, although it has been used with good outcomes.13 It is also important to place intubated pregnant patients in a left lateral decubitus position, particularly in the third trimester, to avoid aortocaval compression by the gravid uterus.

TABLE 6.6 Medications Used to Treat Asthma in Pregnancy

Drug Category

Inhaled bronchodilators

Short acting


Preferred rescue medication

Long acting



May be added to inhaled corticosteroids for long-term control

Inhaled anticholinergic agents

Ipratropium bromide

May be given with albuterol as a rescue medication

Inhaled corticosteroids






The preferred long-term control medications. Budesonide is the most studied

Systemic corticosteroids

May be added as a rescue medication in more severe cases

Leukotriene receptor antagonist



May be used as a maintenance treatment



May be used for moderate to severe allergic asthma

Cromolyn and theophylline

Alternatives, although not preferred, for long-term control

Magnesium sulfate

2 g IV bolus

May be added as a rescue medication in more severe cases

5-lipoxygenase inhibitor



Contraindicated due to teratogenicity

Contraindicated due to possible uteroplacental perfusion compromise

IgE, immunoglobulin E; IV, intravenous.


The prevalence of headache during pregnancy is 35%, and approximately 5% of pregnancies are affected by a new onset or new type of headache, most often migraine.16,17 The majority of headaches occurring during pregnancy are benign in nature. In general, headaches occurring in the third trimester and postpartum period are more likely to be serious in nature because that is when pathologic conditions such as preeclampsia and hypercoagulability are most prevalent. The main goals of treating headaches during pregnancy are to make the correct diagnosis of the cause and to treat the headache appropriately and safely.

Headaches are divided into two main categories: primary and secondary. Primary headaches are nonlife-threatening conditions, in which the headache itself is the disease. Migraine, tension-type, and cluster headaches fall into this category. Secondary headaches occur when the headache is a symptom of another disease. These headaches can be of significant morbidity and require specific testing and treatment (Table 6.7). The majority (58%-65%) of headaches in gravid women are primary, with the minority (35%-42%) being secondary.16,18

TABLE 6.7 Secondary Headaches in Pregnancy

Secondary Headache Disorder


Preeclampsia and eclampsia

A progressive bilateral headache occurring after 20 wk gestation with concomitant hypertension and proteinuria

Cerebral venous sinus thrombosis

A progressive headache usually in the third trimester or postpartum with signs of increased intracranial pressure. May have focal neurologic deficits

Reversible cerebral vasoconstriction syndrome

Sudden-onset diffuse headache usually in the postpartum period. Associated with hemorrhagic and ischemic strokes

Idiopathic intracranial hypertension

A progressive diffuse headache in obese women usually in the first trimester. May have visual disturbances

Subarachnoid hemorrhage

Sudden-onset severe headache often with loss of consciousness and vomiting. More likely to occur postpartum

Intracranial mass lesions

A progressive daily diffuse headache often with nausea and vomiting. May have visual disturbances

Pituitary apoplexy

Sudden-onset retro-orbital headache often with nausea and vomiting and visual disturbances

Posterior reversible encephalopathy syndrome

Insidious-onset dull occipital headache often with visual symptoms. Usually associated with preeclampsia/eclampsia

Ischemic stroke

Usually a self-limited headache with neurologic deficits. More common with posterior circulation strokes

Arterial dissection

Sudden-onset unilateral headache often associated with preeclampsia

Primary Headaches

Primary headache disorders reach a peak prevalence in women of childbearing age due to hormonal influences.16 Most primary headaches affecting pregnancy are diagnosed in the individual prior to the pregnancy.


The majority of pregnant women seeking treatment for a primary headache disorder are treated for migraine.19 Migraine is a headache disorder characterized by episodes of severe throbbing, pulsatile headache associated with nausea, vomiting, phonophobia, photophobia, and aversion to physical activity. Migraine headaches may occur with or without associated visual or neurologic symptoms known as aura. The majority of migraine sufferers will experience improvement of their symptoms during pregnancy, with reduction in the frequency and intensity of their attacks. In less than 10% of women, migraine symptoms will worsen during pregnancy, and up to 6% of women will experience their first migraine while pregnant.20,21 It is not uncommon for migraines to occur with new aura symptoms during pregnancy.20 Treatment of migraine headache in pregnancy is similar to that in nonpregnant patients (Table 6.8).

Tension type

Tension-type headaches are the second most common primary headache occurring in pregnancy. These headaches are described as a pressure or tightness all around the head that may wax and wane in intensity. The frequency of these headaches may remain unchanged or lessen during pregnancy, with approximately 5% of pregnant women reporting worsening of their symptoms.20 Acetaminophen is the drug of choice for tension-type headaches in pregnancy. Aspirin and nonsteroidal anti-inflammatory drugs are second-line options that are safest in the second trimester. Caffeine may also be of use and is generally considered safe.


Cluster headache is a relatively rare primary headache, occurring as recurrent, intermittent, unilateral severe headaches with associated cranial autonomic symptoms such as lacrimation, ptosis, and facial sweating. Cluster headaches are more common in males and affect less than 0.5% of all pregnancies.22 Treatment is the same as for nonpregnant patients, with high-flow oxygen and triptans considered generally safe.

Secondary Headaches

Hypertensive disorders account for approximately 50% of all secondary headaches in pregnancy, with preeclampsia the most common cause in this group.19 History and physical examination findings
often indicate the presence of a secondary headache in pregnant women (Table 6.9). Brain imaging is indicated when a secondary headache associated with an underlying central nervous system or systemic disorder is suspected. Magnetic resonance imaging (MRI) is the preferred imaging modality and is considered safe in pregnancy.23 Use of the contrast agent gadolinium is not recommended given its known ability to cross the placenta and lack of safety data. Computerized tomography (CT) is often used for brain imaging during pregnancy due to the speed and ease of availability as compared with MRI. With appropriate abdominal shielding, there is minimal risk to the fetus with a head CT of the mother.21 Iodinated contrast should be avoided as it may suppress fetal thyroid function.

TABLE 6.8 Medications Used to Treat Headache in Pregnancy




Preferred first-line treatment

Nonsteroidal anti-inflammatory drugs including aspirin

Safest in the second trimester, avoid in the third trimester


Generally considered safe


Generally considered safe

Antiemetic drugs (chlorpromazine, prochlorperazine, metoclopramide, droperidol, ondansetron, diphenhydramine)

Generally considered safe


Should be avoided


Generally considered safe


Should be avoided




Generally considered safe

Ergots (ergotamine, dihydroergotamine)

Should be avoided

TABLE 6.9 “Red flags” for Secondary Headaches in Pregnancy

A history of a previous secondary headache

New-onset headache

Sudden increase in severity of a preexisting headache

Headache aggravated by physical activity or Valsalva maneuver

History of pituitary disorder

Altered sensorium

Focal neurologic deficit





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Dec 30, 2020 | Posted by in EMERGENCY MEDICINE | Comments Off on Management of Common Medical Comorbidities During Pregnancy

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