Pregnancy is characterized by progressive peripheral resistance to insulin at the receptor and postreceptor levels in the second and third trimesters for all pregnant women (not only those with DM) ( Fig. 43.2 ). The presumed mechanism involves an increase in counterregulatory hormones from the placenta during pregnancy (e.g., lactogen, growth hormone, cortisol, progesterone, and adipokines). The change in placental lactogen is an appealing hypothesis, given that (1) a graph of serum lactogen level during pregnancy is similar in shape to that of insulin requirement in pregnant women with type 1 DM and (2) placental lactogen has growth hormone–like activity. Also, maternal adipokines likely have significant effects on insulin secretion and resistance in pregnancy, while facilitating the provision of maternal fuels to the fetus.

Insulin requirements in euglycemic women with type 1 diabetes mellitus during pregnancy.

From Crombach G, Siebolds M, Mies R. Insulin use in pregnancy: clinical pharmacokinetic considerations. Clin Pharmacokinet . 1993;24:89–100.

GDM develops when a patient cannot mount a sufficient compensatory insulin response during pregnancy. In many patients, GDM can be viewed as a preclinical state of glucose intolerance that is not detectable before pregnancy. After delivery, many patients return to normal glucose tolerance, but have a sevenfold increased risk of type 2 DM in later life. The recurrence rate for GDM in a subsequent pregnancy is 41%.

In patients with pregestational DM , insulin requirement decreases slightly between 11 and 16 weeks’ gestation, and then progressively increases during pregnancy primarily because of peripheral insulin resistance. At term, the daily insulin requirement is approximately 1.0 insulin unit/kg, compared with 0.7 unit/kg before pregnancy. Insulin requirement may be higher in pregnancies with multiple gestation. During late pregnancy in healthy patients, basal and glucose-stimulated plasma insulin levels are twice the postpartum measurements. These changes reflect pregnancy-related increases in pancreatic islet cell mass and glucose sensitivity, probably secondary to the net effect of competing progesterone and lactogenic hormone stimuli in the endocrine pancreas. Near term, maternal overnight insulin requirement may decrease, presumably as a result of a “siphoning of maternal fuels” by the growing fetus during the overnight maternal fast.

Endogenous plasma insulin concentration during labor and delivery in nondiabetic parturients differs from exogenous insulin requirement in laboring diabetic women. In nondiabetic parturients, the plasma glucose concentration is only one of many factors that affect endogenous insulin secretion; glucose production and use are markedly higher during painful labor than postpartum. Plasma insulin concentration remains unchanged except for a brief increase during the third stage of labor and immediately postpartum. This finding suggests that glucose use during labor is largely independent of insulin.

In patients with type 1 DM, insulin requirement decreases with the onset of the first stage of labor. These patients may require no additional insulin during the first stage of labor, although insulin requirement is modified by (1) the level of metabolic control before labor, (2) the residual effect of prior doses of subcutaneous insulin, and (3) the glucose infusion rate. Insulin requirement increases during the second stage of labor via an unknown mechanism. The use of epidural analgesia or oxytocin does not affect exogenous insulin requirement during the first and second stages of labor. After delivery—either vaginal or cesarean—insulin requirement in women with type 1 DM decreases markedly for at least several days, although there is significant variability among individuals ( Fig. 43.3 ). Presumably, the decreased insulin requirement results from the loss of counterregulatory hormones produced by the placenta. Pituitary growth hormone responsiveness to hypoglycemia is blunted in late pregnancy and may contribute to impaired counterregulatory responses during the postpartum period. Insulin requirement gradually returns to prepregnancy levels within several weeks of delivery in women with type 1 DM.

Insulin Requirements in the Postpartum Period.

From Crombach G, Siebolds M, Mies R. Insulin use in pregnancy: clinical pharmacokinetic considerations. Clin Pharmacokinet . 1993;24:89–100.

Before the discovery of insulin in 1921, pregnancies were rare in diabetic patients. Insulin therapy improved the rate of survival in women with severe DM, allowing these women to reach childbearing age and become pregnant. Maternal outcomes improved, but fetal and neonatal morbidity and mortality remained high.

Both pregestational DM and GDM are associated with higher rates of gestational hypertension, polyhydramnios, preterm birth, and cesarean delivery. The incidences of preterm labor and delivery and cesarean delivery are higher in women with pregestational DM than in women with GDM. Trial of labor after cesarean delivery in patients with GDM is associated with higher rates of operative vaginal delivery and repeat cesarean delivery compared with that in nondiabetic controls.

Box 43.4 lists the fetal complications of maternal DM during pregnancy. Fetal macrosomia , historically defined as a birth weight > 4000 or 4500 g, is a well-recognized complication of maternal DM. Most studies suggest that both pregestational DM and GDM result in an increased incidence of fetal macrosomia. In GDM, the HAPO study demonstrated that neonatal macrosomia is a linear function of maternal hyperglycemia. In a randomized clinical trial of pregestational DM, the use of continuous glucose monitoring was associated with a lower incidence of macrosomic neonates. In addition to maternal hyperglycemia, other possible factors contributing to fetal macrosomia in DM include maternal obesity, gestational weight gain, variations in maternal blood glucose, and maternal lipid levels.

Macrosomia results in an increased risk for shoulder dystocia and birth trauma with vaginal delivery. Moreover, when comparisons are made within birth weight categories above 4000 g, pregnancies in diabetic women have a higher risk for shoulder dystocia than nondiabetic women. Several mechanisms have been suggested for the development of fetal macrosomia in diabetic pregnancy. Maternal hyperglycemia can result in fetal hyperglycemia, with reactive fetal hyperinsulinemia and an anabolic response in the fetus. Shoulder dystocia may reflect the excessive growth of the fetal trunk (relative to the fetal head) in response to fetal hyperinsulinemia.

Women with pregestational DM are at increased risk for fetal anomalies (see Box 43.4 ). The incidence of major anomalies, estimated to be 6% to 10%, is five times higher than in nondiabetic controls. Overall, cardiovascular anomalies are most common, followed by anomalies of the central nervous system (CNS). Caudal regression syndrome, though uncommon, is 200 times more likely in diabetic than in nondiabetic pregnancies.

Mechanisms that may be involved in the development of fetal structural malformations in diabetic pregnancies include embryonic apoptosis, yolk sac vasculopathy, and altered uptake of glucosamine by embryonic cells. Most fetal structural malformations that occur during pregnancy are likely to have a multifactorial etiology. However, hyperglycemia during the period of critical organogenesis before the 8th week after conception is probably the single strongest etiologic factor in diabetic women. Hemoglobin A1c levels in pregnancy correlate with the incidence of major congenital anomalies that occur in women with pregestational DM.

Studies have suggested that patient education and strict glycemic control during the preconception period may reduce the rate of major congenital anomalies from 10% to 1% in patients with pregestational DM. The latter figure is similar to the baseline risk for major structural malformations in the general population. Strict glycemic control initiated during the preconception period also increases the incidence of maternal hypoglycemic episodes. These studies suggest that hypoglycemia is not a significant factor in the etiology of human malformations, because the rate of anomalies decreased 10-fold despite hypoglycemic episodes. Similarly, strict glycemic control before conception also has been associated with a threefold decrease in the incidence of spontaneous abortion in women with pregestational DM. Dicker et al. observed normal induced ovulation, in vitro fertilization, and early embryonic development in a small series of infertile patients with pregestational DM who attended a preconception diabetes clinic. However, less than one-third of women with known pregestational DM receive appropriate medical care before conception.

In the past 75 years, the perinatal mortality rate in the United States has steadily decreased from 18% to 3%. If the entire population is considered, the perinatal mortality rate likely remains higher in patients with pregestational DM than in nondiabetic controls. The rate in patients with GDM is intermediate between the rate in women with pregestational diabetes and the rate in nondiabetic controls.

Historically, intrauterine fetal death was responsible for approximately 40% of perinatal deaths in women with DM, with 68% occurring between 36 and 40 weeks’ gestation. In contemporary reports, the ratio of intrauterine deaths to neonatal deaths in diabetic pregnancies has varied from 0 to 1.0. Fetal macrosomia is a risk factor for intrauterine fetal demise in both diabetic and nondiabetic pregnancies. Recurrent episodes of intrauterine hypoxia can occur in diabetic pregnancies that end in stillbirth; episodes of hypoxia may reflect reduced uteroplacental blood flow and changes in fetal carbohydrate metabolism. Congenital anomalies have now emerged as the leading cause of perinatal mortality in diabetic pregnancies. This change likely reflects better obstetric care during pregnancy, despite the lack of adequate glycemic control before conception in many patients.

Studies have reported a risk of neonatal respiratory distress syndrome (RDS) up to 5.6 times higher in diabetic pregnancies compared with nondiabetic controls. In a metaanalysis, Li et al. reported pooled odds ratios for the association between maternal DM and neonatal RDS of 1.57 (95% confidence interval [CI], 1.28 to 1.93) for GDM and 2.66 (95% CI, 2.06 to 3.44) for pregestational DM. However, some studies have been unable to verify a relationship between diabetic pregnancies and neonatal RDS. Potential confounding factors include more preterm and cesarean deliveries in diabetic pregnancies. Proposed mechanisms linking diabetic pregnancies to neonatal RDS include alterations in specific surfactant proteins and phospholipids.

Neonatal hypoglycemia has an estimated incidence of 27% in diabetic pregnancies. This occurs in both pregestational DM and GDM, with a ninefold higher risk compared with nondiabetic controls. Glucose is freely shared between the fetal and maternal circulations, but their insulin systems are separated by the placenta. Neonatal hypoglycemia likely results from sustained fetal hyperinsulinemia in response to chronic and acute intrauterine hyperglycemia. Studies have demonstrated higher fetal insulin levels and exaggerated fetal insulin responses to acute maternal hyperglycemia in diabetic pregnancies. An acute increase in maternal glucose concentration, as might occur if a dextrose-containing solution is used for intravenous hydration during administration of neuraxial anesthesia, can lead to reactive neonatal hypoglycemia, even in nondiabetic women.

There is a fourfold higher incidence of neonatal hyperbilirubinemia in diabetic pregnancies compared with nondiabetic controls. A mild elevation in neonatal serum bilirubin is a normal physiologic process, perhaps with some advantages via antioxidant effects. Moderate to severe elevations require immediate clinical evaluation and probable treatment with phototherapy, to avoid the kernicterus spectrum disorder with irreversible neuronal damage. Neonatal polycythemia is observed in infants of diabetic mothers, perhaps reflecting chronic intrauterine hypoxemia. Delayed clamping of the umbilical cord during delivery results in increased blood volume in all neonates. In one randomized study, delayed clamping increased the risk of newborn hyperbilirubinemia in diabetic pregnancies but not in nondiabetic pregnancies. There is no evidence that newborns from diabetic pregnancies have a higher rate of kernicterus.

Children of diabetic mothers are at increased risk for development of DM, likely from a combination of genetic and intrauterine environmental factors. In terms of heredity, for both type 1 and type 2 DM, the concordance rate is higher in monozygotic twins compared with dizygotic twins. The risk of a sibling developing DM is 15-fold higher for type 1 DM and 4- to 6-fold higher for type 2 DM, compared with the general population.

Strict glycemic control, ideally beginning in the preconception period, is the best way to prevent fetal structural malformations in women with pregestational DM. Determination of hemoglobin A1c concentrations may help the physician determine the adequacy of preconceptional glycemic control.

The goal of insulin therapy is to provide plasma insulin concentrations that lead to tight glucose control without hypoglycemia. The patient should frequently determine capillary blood glucose concentration using a reflectance meter or a transdermal tissue glucose measurement using a minimally invasive continuous monitoring system. In general, insulin requirement increases progressively during the second and third trimesters of pregnancy. Table 43.1 illustrates glycemic targets recommended by the ADA for pregnant patients with either pregestational DM or GDM. Of course, strict glycemic control increases the risk for maternal hypoglycemia.

Therapeutic insulin is available in several forms. Initially, insulin was isolated as a natural product from domestic animals (e.g., cattle, pigs). In the 1980s, synthetic human insulin became commercially available and has replaced beef and pork insulin in human medicine. The subsequent development of human insulin analogs, beginning in the 1990s, provides many clinical alternatives for therapeutic insulin action ( Table 43.2 ).

Because insulin requirement decreases abruptly at delivery, it is important to verify the times, doses, insulin preparations, and routes of administration in the 24 hours before delivery to avoid maternal postpartum hypoglycemia.

Management of DKA is similar in pregnant and nonpregnant women. It involves (1) intravenous hydration, (2) intravenous insulin, (3) treatment of the underlying cause of DKA, (4) careful monitoring of blood glucose and electrolyte levels, and (5) restriction of bicarbonate therapy to cases of extreme acidosis. Initial management of the critically ill pregnant woman should focus on the effective management of DKA. Fetal compromise is likely to resolve with appropriate maternal medical management.

Incretins are peptide hormones synthesized by specific gut epithelial cells in response to ingested nutrients, with modulatory effects on gastric emptying and pancreatic insulin secretion. The major human incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide. Pharmaceuticals that mimic incretin action, such as GLP-1 receptor agonists (GLP-1-RA), have been available since 2005 for the treatment of type 2 DM. GLP-1-RAs also alter appetite with significant weight loss in obese patients, irrespective of DM, which has led to their widespread use.

One of the major complications of GLP-1-RA medications is gastroparesis, with an increased risk of gastric content regurgitation and pulmonary aspiration during general anesthesia. The gastrointestinal changes of normal pregnancy, including decreased lower esophageal sphincter tone, when combined with the gastroparesis associated with GLP-1-RAs, may increase maternal risk of aspiration.

Data regarding the use of GLP-1-RAs during pregnancy are limited, though some studies suggest they may be safe for the fetus. Nonetheless, the US Food and Drug Administration currently does not recommend their use during pregnancy or lactation, and it is recommended that they should be stopped 2 months prior to conception.

Diet and exercise are the initial therapeutic approaches for glycemic control in women with GDM. Pharmacologic therapy with oral hypoglycemic agents and/or insulin is initiated if the lifestyle changes are not clinically effective. Concerns about the long-term health implications of GDM have resulted in clinical initiatives for postpartum metabolic surveillance. The goal is to identify and treat postpartum type 2 DM, with an emphasis on lifestyle interventions.

Timing of delivery is important in the management of diabetic pregnancies; the obstetric provider must weigh the risks of preterm delivery with the risk of late-term fetal demise. Typically, a nonstress test is performed twice weekly in patients with pregestational DM, beginning at 32 weeks’ gestation. A nonreactive nonstress test should prompt the performance of a fetal biophysical profile (see Chapter 6 ). Patients with poorly controlled GDM should probably undergo antepartum fetal surveillance similar to that in patients with pregestational DM. In the presence of reassuring fetal testing, delivery can be delayed until after 38 weeks’ gestation. Poor glycemic control or maternal nephropathy may necessitate an earlier delivery.

The decision regarding the method of delivery requires consideration of estimated fetal weight, fetal condition, cervical dilation and effacement, and previous obstetric history. The obstetric provider may choose elective cesarean delivery in the diabetic parturient with evidence of fetal macrosomia to decrease the risk for shoulder dystocia.

Hyperthyroidism is defined by an abnormal increase in the serum concentration of unbound or free thyroid hormones. In iodine-replete populations, the prevalence of hyperthyroidism is 0.2% to 1.9%, with a female-to-male ratio of 10:1. The etiology of hyperthyroidism is shown in Box 43.5 . Graves’ disease is responsible for 70% to 90% of cases; thyroiditis and the combined category of toxic adenoma and toxic multinodular goiter each account for approximately 5%.

Graves’ disease is an autoimmune thyroid disease. Its etiology is likely multifactorial and includes both environmental (e.g., stress, hormones) and genetic influences. Several autoantibodies against thyroid tissue have been described in patients with this disease. Autoantibodies known as thyroid receptor antibodies (TRAbs) directed against the TSH receptor in the thyroid gland may either augment or inhibit TSH action, depending on their binding specificities. The binding specificities of TRAbs in the blood of each patient with Graves’ disease determine the net thyroid-stimulating activity. Autoantibodies against thyroid peroxidase, the sodium-iodide symporter, and thyroglobulin also have been described in patients with Graves’ disease and other forms of autoimmune thyroid disorders.

Hyperthyroidism presents as a physiologic state dominated by an increased metabolic rate. A hyperthyroid symptom scale has been developed on the basis of the following 10 clinical factors: nervousness, sweating, heat intolerance, hyperactivity, tremor, weakness, hyperdynamic precordium, diarrhea, appetite, and level of incapacitation. This symptom scale has been useful to follow the clinical course of patients with Graves’ disease. Exophthalmos or infiltrative ophthalmopathy is clinically apparent in many patients, although the reported prevalence varies from 25% to 70%. Other physical signs may occur at low frequency, including pretibial myxedema or dermopathy (1% to 2%) and nail changes or acropachy (<1%). The thyroid-associated orbitopathy (TAO) in Graves’ disease is caused by an inflammatory process with enlargement of the extraocular muscle bodies, and deposition of adipose tissue and extracellular glycosaminoglycans within the bony orbit. In addition to hyperthyroidism and TRAbs, the risk factors for TAO include smoking and radioactive iodine treatment. The pathogenetic targets are orbital fibroblasts with a “cross-talk” mechanism between TSH receptor and insulin-like growth factor-1 (IGF-1) receptor pathways. Traditional therapies for TAO have included conservative measures to maintain eye moisture, plus glucocorticoids, radiotherapy, or orbital decompressive surgery for severe cases. Recent clinical trials with teprotumumab , a monoclonal antibody that blocks IGF-1 signals, have demonstrated therapeutic efficacy in TAO, but it is contraindicated in pregnancy.

Hyperthyroidism stimulates the cardiovascular system in excess of the underlying increased metabolic rate, resulting in a hyperkinetic circulatory state. Heart rate, myocardial contractility, cardiac output, ventricular size, systolic blood pressure, pulse pressure, and pulmonary vascular resistance all increase, and peripheral vascular resistance decreases. Sinus tachycardia is the most common arrhythmia, but the incidence of atrial fibrillation is also increased. Cardiomyopathy can be demonstrated during exercise in hyperthyroid patients, independent of beta-adrenergic receptors; it is reversible with normalization of thyroid function.

The diagnosis of hyperthyroidism depends on increased serum concentrations of free T ₄ . The more common forms of hyperthyroidism (e.g., Graves’ disease, toxic adenoma, toxic multinodular goiter) may be differentiated from the less common forms by a radioiodine uptake study. The identification of TSH receptor autoantibodies may have a role in distinguishing Graves’ disease from toxic adenoma or multinodular goiter.

Normal human pregnancy is a euthyroid state, with normal plasma concentration of free T ₄ despite increased plasma concentrations of TBG and total T ₄ . During pregnancy, hyperthyroidism results from the same causes as in nonpregnant patients (see Box 43.5 ). Graves’ disease is the leading cause of hyperthyroidism during pregnancy, with a prevalence of 0.2%, which is lower than in the general population. The lower prevalence may reflect a beneficial effect of the immunotolerance of pregnancy on autoimmune disorders. Human pregnancy also is associated with a change in the specificity of TSH receptor antibodies between stimulatory and blocking activities.

Gestational trophoblastic neoplasms (GTNs) are frequently associated with elevated serum hCG concentration. A high concentration of hCG may possess significant thyroid-stimulating bioactivity because of the structural homology between hCG and TSH. This is the underlying mechanism for both relatively common gestational transient thyrotoxicosis and rare hyperthyroidism in association with GTNs. Also, hyperemesis gravidarum and gestational transient thyrotoxicosis may be parallel disease processes in pregnancy, with elevated hCG a shared mechanism. Hyperthyroidism can, on rare occasions, result from two coincident disease processes (e.g., Graves’ disease and struma ovarii) in both pregnant and nonpregnant women.

The reported prevalence of thyroid nodules, currently 34% to 66% of adults, has increased because of identification of incidental asymptomatic nodules with improved diagnostic imaging modalities. Pregnancy is associated with increases in the number and size of thyroid nodules. Pregnancy probably does not affect the development or recurrence of thyroid carcinoma, and the effect on the progression of active disease remains controversial. Evaluation of a thyroid nodule that presents during pregnancy should include measurement of serum TSH and free T ₄ concentrations, plus ultrasonographic examination of the thyroid gland and cervical lymph nodes. Sonographic features of concern include a nodule greater than 1 to 2 cm in diameter, a solid hypoechoic nodule, irregular margins, or microcalcifications. Suspicious thyroid nodules can be further evaluated with fine-needle aspiration or percutaneous needle biopsy. Malignant lesions, depending on the level of cellular differentiation, can be resected in the second trimester or observed until after delivery. Radioactive iodine therapy is contraindicated during both pregnancy and lactation because it readily crosses the placenta and transfers into breast milk.

Current therapies for Graves’ disease in nonpregnant patients include radioactive iodine, antithyroid medications, and surgery.

Radioactive iodine is administered orally as iodine-131 ( ¹³¹ I), a radionuclide that emits beta and gamma radiation. The specific dose is based on individual factors and severity of disease. All forms of iodine are sequestered by the thyroid gland, with any excess excreted in the urine. ¹³¹ I exerts a therapeutic effect in Graves’ disease, primarily through local emission of beta radiation. In most patients with Graves’ disease, hypothyroidism develops after a therapeutic dose of radioactive iodine, necessitating careful follow-up and long-term thyroid hormone replacement therapy. Otherwise, in nonpregnant patients, the long-term health risks of radioactive iodine therapy are minimal. Currently recommended treatment is to delay pregnancy for 6 months to 1 year after radioactive iodine therapy, despite ¹³¹ I having a half-life of only 8 days.

Propylthiouracil and methimazole are the antithyroid medications used to treat Graves’ disease. Both drugs interfere with the incorporation of iodine into thyroglobulin and with subsequent coupling reactions in the thyroid gland, and propylthiouracil inhibits iodothyronine deiodinase in peripheral tissues. Typical oral doses are 10 to 30 mg daily for methimazole and 100 to 150 mg three times daily for propylthiouracil. The long-term clinical strategy is to adjust the dose downward as tolerated. Some patients with Graves’ disease experience remission after the administration of an antithyroid medication. Asymptomatic agranulocytosis is a rare complication of antithyroid medications, with an incidence of 0.1% to 0.3% and typical onset within 3 months of initiating therapy. Another rare complication of both antithyroid drugs is hepatotoxicity, with an estimated incidence of less than 0.1%. Immunomodulation therapies are likely to have an impact on the treatment of Graves’ disease in the near future.

Surgical therapy for Graves’ disease is typically reserved for patients unable or unwilling to undergo treatment with radioactive iodine or antithyroid medications. Total thyroidectomy is the most common procedure. Perioperative complications of thyroid surgery include: (1) unilateral or bilateral vocal cord paralysis secondary to recurrent laryngeal nerve injury, (2) wound hematoma, (3) pneumothorax, (4) hypoparathyroidism, and (5) thyroid storm. Hypocalcemia secondary to acute hypoparathyroidism may manifest as laryngospasm during the postoperative period.

Hyperthyroidism during pregnancy increases the risk for preeclampsia, fetal growth restriction, and preterm birth. Pregnant patients with treated hyperthyroidism have perinatal outcomes intermediate between untreated hyperthyroidism and euthyroid parturients. Treatment with ¹³¹ I at least 6 months prior to conception is associated with normal pregnancy outcomes. The presence of hyperthyroidism does not affect the obstetric management of preeclampsia.

In women with Graves’ disease, the placental transfer of antithyroid medications or TRAbs may result in the development of fetal goiter , which can interfere with vaginal delivery or lead to airway obstruction in the newborn. Fetal goiter can occur with either fetal hypothyroidism or hyperthyroidism. Fetal goiter can be diagnosed with ultrasonography, and the etiology determined by color Doppler blood flow patterns within the fetal thyroid. Appropriate intrauterine therapy depends on the cause of the fetal goiter and may include adjustments of maternal antithyroid drug doses or intraamniotic injection of levothyroxine. In pregnant women with Graves’ disease, maternal serum concentrations of TRAbs during the third trimester, and their net stimulatory or inhibitory effects, may predict neonatal thyroid function.

Normal somatic and intellectual development have been reported in the children of hyperthyroid mothers treated with antithyroid medications, and such treatment does not contraindicate breastfeeding.

No prospective randomized studies have evaluated the efficacy or safety of various anesthetic techniques in patients with hyperthyroidism. The following features of hyperthyroidism may affect anesthetic management: (1) the hyperdynamic cardiovascular system and the possibility of cardiomyopathy, (2) partial airway obstruction secondary to an enlarged thyroid gland, (3) respiratory muscle weakness, and (4) the rare possibility of thyroid storm.

Halpern described two patients with uncontrolled hyperthyroidism who required anesthesia for cesarean delivery and suggested that either neuraxial or general anesthesia can be safely administered in these parturients. On the basis of theoretical concerns, he suggested the omission of epinephrine from epidural local anesthetic solutions and the use of an alpha-adrenergic receptor agonist (e.g., phenylephrine) for the treatment of hypotension. However, earlier clinical studies in nonpregnant subjects with spontaneous hyperthyroidism have shown normal hemodynamic responses to exogenous epinephrine, norepinephrine (noradrenaline), phenylephrine, and clonidine. Therefore it appears safe to use epinephrine to minimize local anesthetic uptake and toxicity during the administration of epidural anesthesia in both euthyroid and hyperthyroid patients. Low-dose combined spinal-epidural anesthesia for urgent cesarean delivery in a patient with uncontrolled hyperthyroidism, thyrotoxic heart disease, and severe preeclampsia has been described.

Hyperthyroid women should receive glucocorticoid supplementation because they have a relative deficiency of glucocorticoid reserves. It seems prudent to avoid medications associated with tachycardia (e.g., ketamine, atropine). Patients with Graves’ disease may have exophthalmos and need additional care to prevent corneal abrasions or excess pressure on the globe during general anesthesia.

Adequate preoperative preparation minimizes the risk for perioperative thyroid storm; when time permits, the goal is to make the patient euthyroid. In an emergency, the hyperthyroid patient can be prepared for surgery with oral propylthiouracil, an intravenous glucocorticoid, sodium iodide, and a beta-adrenergic receptor antagonist. The anesthesia provider should be prepared to treat perioperative thyroid storm (see Box 43.8) .

Hypothyroidism is defined by an abnormally low serum concentration of free T ₄ . The prevalence of overt hypothyroidism in the iodine-sufficient population is 1% to 2%, which is similar to that of hyperthyroidism. Hypothyroidism is more common in women and the elderly.

The etiology of hypothyroidism can be divided into primary and secondary categories ( Box 43.9 ); primary hypothyroidism is more common than secondary hypothyroidism. The most common etiologies of hypothyroidism are iodine deficiency and Hashimoto’s thyroiditis.

The clinical presentation of hypothyroidism is dominated by constitutional signs and symptoms such as dry skin, decreased sweating, hoarseness, paresthesias, periorbital edema, and delayed reflexes. The constitutional symptoms are common in the general population of patients without hypothyroidism, particularly the elderly. A diagnosis of hypothyroidism may be suggested by detection of the following factors during the preanesthetic history and physical examination: (1) a history of neck irradiation or radioiodine therapy; (2) the use of lithium, iodine, amiodarone, antithyroid medications, or thyroid replacement medications; and (3) a history of thyroid surgery or the presence of a surgical scar overlying the site of the thyroid gland.

Hypothyroidism is diagnosed by measuring a decreased serum concentration of free T ₄ . In the presence of an intact feedback loop, the serum concentration of TSH should be increased in patients with primary hypothyroidism. Serum TSH concentration is a more sensitive indicator of primary hypothyroidism than serum T ₄ concentration and is therefore the best initial laboratory test in suspected hypothyroidism. ^, Patients with subclinical hypothyroidism have a normal serum concentration of free T ₄ , but an elevated serum concentration of TSH. The estimated prevalence of subclinical hypothyroidism in the iodine-sufficient population is 4% to 9%. Although patients with subclinical hypothyroidism are “euthyroid,” there are a number of controversial elements associated with their clinical management, including the chance of progressing to overt hypothyroidism, and the risk-benefit of levothyroxine therapy versus observation. One approach is to stratify patients with subclinical hypothyroidism and individualize levothyroxine therapy based on the magnitude of TSH elevation.

In iodine-sufficient populations, the prevalences of overt and subclinical hypothyroidism during pregnancy are 0.2% to 1%, and 2% to 5%, respectively. Overt hypothyroidism is associated with a lower fertility rate compared with euthyroid women, reflecting differences in neuroendocrine and ovarian functions.

Hypothyroidism is treated by replacement therapy with oral thyroid hormones. The medication most commonly used in replacement therapy is levothyroxine , which has a half-life of 5 to 7 days. Numerous studies have shown that the required replacement dose of thyroid hormone increases in most hypothyroid women during pregnancy. Ideally, the increased dose of thyroid hormone replacement should begin as soon as pregnancy is recognized and be titrated to serum TSH levels at 4- to 6-week intervals.

Overt hypothyroidism is associated with an increased incidence of the following obstetric complications: anemia, preeclampsia, fetal growth restriction, GDM, preterm delivery, placental abruption, and postpartum hemorrhage. Observations on obstetric complications in subclinical hypothyroidism are less consistent. Recommendations on levothyroxine therapy for subclinical hypothyroidism during pregnancy are variable, even among expert organizations. There is consensus that early diagnosis and treatment of overt hypothyroidism are associated with improved maternal and fetal outcomes. Postpartum follow-up of subclinical hypothyroidism is important because of the significant subsequent risk of overt hypothyroidism.

In most instances of maternal hypothyroidism, neonatal thyroid function is normal because fetal thyroid development is typically independent of maternal thyroid function. The fetus, however, depends on maternal thyroxine until the fetal thyroid system is fully functional at 18 to 20 weeks’ gestation. Therefore maternal hypothyroidism in the first half of pregnancy may affect fetal brain development. In addition, fetal hypothyroidism during the second half of pregnancy may also affect normal maturation of the CNS. With universal screening of neonates for hypothyroidism, these neonates should be readily identified. Published data suggest that cognitive development is relatively normal in hypothyroid infants who receive timely and appropriate thyroid hormone replacement with an initial dose of 10 to 15 µg/kg/day.

The clinical manifestations of hypothyroidism that may affect anesthetic management include the following :

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  Reversible myocardial dysfunction

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  Hypertension

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  Bradycardia

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  Coronary artery disease

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  Reversible defects in hypoxic and hypercapnic ventilatory drives

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  Obstructive sleep apnea

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  Paresthesias

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  Prolonged somatosensory-evoked potential central conduction time

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  Abnormal peripheral nerve conduction

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  Increased peripheral nociceptive thresholds

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  Hyponatremia

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  Decreased glucocorticoid reserves

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  Anemia

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  Abnormal coagulation factors and platelets

Hypothyroid patients may have an abnormal response to peripheral nerve stimulation, which decreases the clinical utility of a nerve stimulator during neuromuscular blockade. Clinical studies of vasoactive medications in nonpregnant hypothyroid patients have shown diminished responses to isoproterenol (isoprenaline) and phenylephrine . One case report of a pregnant patient with partially treated hypothyroidism described diminished response to intravenous phenylephrine during spinal anesthesia for cesarean delivery.

Delaying elective surgery to treat mild overt hypothyroidism remains controversial in terms of improving outcomes. For emergency procedures, anesthesia care should include intravenous glucocorticoid supplementation because 7% to 18% of hypothyroid patients have impaired cortisol production. Myxedema (hypothyroid) coma is likely the only circumstance in which acute intravenous thyroid hormone replacement is indicated. In most hypothyroid patients, acute intravenous replacement therapy entails a significant risk for myocardial ischemia.

No prospective randomized studies have compared the safety or efficacy of different anesthetic techniques in pregnant or nonpregnant hypothyroid patients. Existing evidence suggests that overt hypothyroidism is associated with decreased coagulation and increased fibrinolysis. The anesthesia provider should use findings from the history and physical examination and consider laboratory testing to verify the presence of normal coagulation before administering neuraxial anesthesia to a patient with severe untreated hypothyroidism.