Calcium Homeostasis During Pregnancy

Parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (1,25[OH] ₂ D ₃ ) are responsible for maintaining calcium homeostasis. About 50% of serum calcium is protein bound, mostly to albumin; 10% is complexed to anions; and 40% circulates free as ionized calcium. During pregnancy, active transfer of maternal calcium to the fetus occurs. A full-term infant requires 25 to 30 g of calcium during the course of pregnancy for new bone mineralization, most of it in the third trimester.

Total serum calcium during gestation is 8% below postpartum levels. Ionized calcium levels, however, remain unchanged throughout gestation. Serum phosphate and renal tubular reabsorption of phosphorus also remain normal throughout pregnancy. Maternal serum PTH levels are slightly decreased in the first half of pregnancy (about 20% of the mean nonpregnant values) but return to normal by midgestation.

Blood levels of 1,25(OH) ₂ D ₃ (calcitriol), the active metabolite of vitamin D, increase early in gestation to twice the nonpregnancy level in the third trimester. This increase comes as a result of stimulation of maternal renal 1α-hydroxylase activity by estrogen, placental lactogen, and PTH as well as synthesis of calcitriol by the placenta. Also, 24-hour urinary calcium excretion increases with each trimester of gestation and decreases in the postpartum period, which reflects the increased intestinal calcium absorption induced by higher levels of 1,25-hydroxyvitamin D during gestation.

Parathyroid hormone–related protein (PTHrP), a peptide responsible for the hypercalcemia found in many malignant tumors, increases in early pregnancy. The source of maternal serum PTHrP is multiple, and both fetal and maternal sites have been postulated (placenta, myometrium, amnion, decidua, fetal parathyroid glands, breast, umbilical cord). PTHrP increases 1α-hydroxylase activity with an increase in 1,25(OH ₂ )D ₃ ; in addition, PTHrP plays a role in placental calcium transport and may also help protect the maternal skeleton during pregnancy.

Serum calcitonin levels are higher during pregnancy and in the postpartum period compared with nonpregnant controls.

Osteocalcin is a bone-specific protein released by osteoblasts into the circulation proportional to the rate of new bone formation. Markers of bone resorption increase during pregnancy and reach values in the last trimester of pregnancy up to twice the normal level. These changes are consistent with the increase in bone turnover at the time of maximal transfer of maternal calcium to the fetus.

After delivery, urinary calcium excretion is reduced; ionized serum calcium remains within normal limits; and total calcium, 1,25-hydroxyvitamin D, and serum PTH return to prepregnancy levels. Intestinal absorption of calcium decreases to the nonpregnant rate as a result of the previously mentioned return to normal levels of 1,25(OH) ₂ D ₃ . Early concern for calcium loss in lactating mothers, with the development of osteopenia, has not been confirmed, and extra calcium supplementation during breastfeeding appears to be unnecessary because calcium supplementation above normal does not significantly reduce the amount of lost bone during gestation. The alteration in calcium and bone metabolism that accompanies human lactation represents a physiologic response that is independent of calcium intake.

Hyperparathyroidism

The prevalence of primary hyperparathyroidism (PHPT) is 0.5%. The incidence of the disease in pregnancy is unknown, but it is definitely rare, and most of the reported cases have been single ones complemented with a review of the literature. With the introduction of routine, automated techniques in clinical medicine and with early diagnosis, most patients with PHPT are symptom free, and their serum calcium elevation is mild. In nonpregnant PHPT patients, indications for surgery include (1) serum calcium greater than 1 mg/dL (>0.25 mmol/L) above the upper limit of normal; (2) bone densitometry with a T score of −2.5 or greater at the lumbar spine, total hip, femoral neck, or distal third of the radius; (3) vertebral fracture; (4) creatinine clearance below 60 mL/min; or (5) clinical signs and symptoms of a stone or visualization of a stone on imaging. It is estimated that 10% of PHPT patients have a mutation in one of 11 genes. They may occur as part of complex disorders, such as multiple endocrine neoplasia (MEN) syndromes 1 through 4; as a familial disorder, familial isolated primary hyperparathyroidism (FIHPT); in the syndrome of familial hypocalciuric hypercalcemia (FHH); and in the syndrome of neonatal severe primary hyperparathyroidism (NSPHPT). In practice, genetic testing is indicated in cases of primary hyperparathyroidism (1) in the presence of multigland disease, (2) in the very young (before pregnancy), (3) with parathyroid carcinoma or atypical adenoma, and (4) with a family history of hypercalcemia in first-degree relatives. Genetic testing is expensive; therefore patients should be referred to genetic counselors, and appropriate tests should be performed by accredited centers.

The first case of PHPT during pregnancy was reported in 1931. Shortly thereafter, the first case of neonatal hypocalcemia to cause tetany in a mother with undiagnosed hypercalcemia due to hyperparathyroidism was described by Friderichsen. The most common cause of PHPT in pregnancy is a single parathyroid adenoma, which is present in about 80% of all cases. Primary hyperplasia of the four parathyroid glands accounts for about 15% of the cases reported, 3% are due to multiple adenomas, and only a few cases due to parathyroid carcinoma have been reported in the English literature. In 1962, Ludwig reviewed the literature on the subject and described 21 women with 40 pregnancies: the incidence of fetal wastage was 27.5%; and neonatal tetany as a result of hypocalcemia, representing the first indication of maternal hyperparathyroidism, occurred in 19% of these cases. In contrast to the previous high neonatal morbidity and mortality, reviewing the literature from 1976 to 1990, Kelly found only two perinatal deaths (5%) among 37 infants born of hyperparathyroid mothers. Two additional cases of perinatal deaths were reported in mothers with hypercalcemic crisis.

In the nonpregnant state, almost 70% of patients are symptom free, and the diagnosis is made through the routine use of biochemical screening. In pregnancy, because routine calcium determinations are not routinely performed, manifestations of the disease are present in almost 70% of the diagnosed patients. In a review of 70 pregnant women, gastrointestinal symptoms such as nausea, vomiting, and anorexia were present in 36% of patients, whereas 34% presented with weakness and fatigue. In 26%, mental symptoms that included headaches, lethargy, agitation, emotional lability, confusion, and inappropriate behavior were reported. Nephrolithiasis was detected in 36%, bone disease in 19%, acute pancreatitis in 13%, and hypertension in 10%. Only 24% of these patients were symptom free.

Parathyroid cancer is a rare cause of hyperparathyroidism, with very few cases documented in pregnancy. Serum calcium levels are significantly higher than in other cases of PHPT, and perinatal mortality and morbidity are significant. Hypercalcemia with values above 13 mg/dL in the presence of a palpable neck mass should raise a strong suspicion of parathyroid carcinoma. On the contrary, in the presence of mild hypercalcemia and a neck mass, the most common cause of the neck lesion is a thyroid nodule. One other clinical feature of parathyroid carcinoma is poor response to the usual clinical therapeutic measures such as intensive hydration and loop diuretics. Surgery is the only effective therapy.

Hyperparathyroidism should be considered in the differential diagnosis of acute pancreatitis during pregnancy, which has been reported in 13% of women with primary hyperparathyroidism. The incidence of acute pancreatitis in nonpregnant hyperparathyroid women is about 1.5% and is less than 1% in normal pregnancy. It is mostly likely to occur during the last trimester of pregnancy or the postpartum period but has also been reported in the first trimester of pregnancy, mimicking hyperemesis gravidarum (HG). Serum calcium should be obtained in any pregnant woman with persistent significant nausea, vomiting, and abdominal pain.

Hyperparathyroid crisis, a serious complication of PHPT, has been reported during gestation and the postpartum period and is characterized by severe nausea and vomiting, generalized weakness, changes in mental status, and severe dehydration. Hypertension may be present and should be differentiated from preeclampsia. The serum calcium level is frequently higher than 14 mg/dL; hypokalemia and elevation in serum creatinine are routinely seen. If not recognized and treated promptly, hyperparathyroid crisis may progress to uremia, coma, and death. Of the 12 cases reported in the literature, four occurred in the postpartum period. Patients presented with severe nausea, vomiting, and elevation in serum creatinine due to dehydration. Serum calcium levels higher than 20 mg/dL were reported in three cases, and three patients died. In addition, six cases have been associated with pancreatitis, and four fetal deaths have also been reported.

Bone disease in patients with PHPT is now unusual , but in early series, it was a common complication. Radiologic evaluation of the bones showed diffuse demineralization, subperiosteal resorption of the phalanges, and in severe cases, single or multiple cystic lesions and generalized osteoporosis.

Shani and associates reported five cases of excessive amniotic fluid in mothers with PHPT and serum calcium levels between 11.3 and 14 mg/dL. The authors suggested that the fetal polyuria was, similar to adult polyuria, a common finding in patients with hyperparathyroidism.

The two most common causes of neonatal morbidity are prematurity and neonatal hypocalcemia, and the latter is related to levels of maternal hypercalcemia. In early reports, it was often the only clue of maternal hyperparathyroidism. Neonatal hypocalcemia develops between the second and fourteenth day of life and lasts for a few days.

Preeclampsia has been reported in some cases of PHPT. Hultin and coworkers examined whether parathyroid adenoma, the main cause of hyperparathyroidism, diagnosed and treated before pregnancy is associated with preeclampsia. They reviewed the records of 52 women, between 1973 and 1997 with the diagnosis of parathyroid adenoma confirmed by surgery and compared them with 519 women without the disease, all of whom had a subsequent singleton pregnancy. They concluded that PHPT due to a single adenoma diagnosed and treated before delivery is significantly associated with preeclampsia (adjusted odds ratio [aOR], 6.89; 95% confidence interval [CI], 2.30 to 20.58; P <.0001). Therefore treated PHPT should be considered a risk factor for preeclampsia in future pregnancies.

The clinical manifestations of PHPT and pregnancy complications—maternal, fetal, and neonatal—are directly related to the serum calcium level. Dochez and Ducarme reviewed 34 published articles in English and French on the characteristics of PHPT, clinical presentations, pregnancy complications, birth outcomes, and management of PHPT during pregnancy. They emphasized the need to rule out FHH and hereditary syndromes such as multiple endocrine neoplasia syndrome (MEN-1 or MEN-2) and familial parathyroid hyperplasia. Nephrolithiasis was the most common finding in symptomatic patients during pregnancy; other maternal complications include depression, constipation, bone fracture, maternal heart rhythm disorders, pancreatitis, parathyroid crisis, and HG. Maternal hypertension and preeclampsia were observed in 25% of these patients.

The diagnosis of PHPT is based on persistent hypercalcemia in the presence of increased PTH or a PTH level inappropriate for the level of serum calcium. In pregnancy, because of the presence of hypoalbuminemia, a persistent total serum calcium value higher than 9.5 mg/dL is suspicious for hypercalcemia. A determination of 24-hour urinary calcium excretion is helpful in the diagnosis, because most women with PHPT have an increase in urinary calcium excretion above the usual hypercalciuria of normal pregnancy. Urinary calcium excretion is low or low normal in the syndrome of familial hypocalciuric hypercalcemia (FHH), another cause of hypercalcemia that must be included in the differential diagnosis. The serum alkaline phosphatase level may be increased in PHPT. However, it is also increased in normal pregnancy. Ultrasonography of the neck is the current first-line investigation during pregnancy for localization of parathyroid diseases, with a sensitivity of 69% and a specificity of 94% in experienced hands. Parathyroid contrast imaging studies are contraindicated in pregnancy.

Hypercalcemia

Differential Diagnosis

Although most young women with hypercalcemia have PHPT, other unusual causes should be ruled out, mainly endocrine disorders, vitamin D or A overdose, the use of thiazide diuretics, or granulomatous diseases ( Box 42-1 ). A brief discussion of three uncommon syndromes associated with hypercalcemia during pregnancy follows.

Box 42-1

Causes of Hypercalcemia in Pregnancy and the Puerperium

• 
  

  Hyperparathyroidism (most common)

  
  
• 
  

  Rare causes related to pregnancy

  
  
  
  
  • 
    

    Familial hypocalciuric hypercalcemia *

    
    

    * Different expression with significant neonatal manifestations.

    
    
    
    
  • 
    

    Postpartum hypercalcemia in hypoparathyroidism

    
    
  • 
    

    Parathyroid hormone–related protein induced hypercalcemia

  
  
  
  
• 
  

  Other causes not related to pregnancy

  
  
  
  
  • 
    

    Malignancy

    
    
  • 
    

    Endocrine

    
    
    
    
    • •
      

      Thyrotoxicosis

      
      
    • •
      

      Adrenal insufficiency

    
    
    
    
  • 
    

    Vitamin overdose

    
    
    
    
    • •
      

      Vitamin D

      
      
    • •
      

      Vitamin A

    
    
    
    
  • 
    

    Drugs

    
    
    
    
    • •
      

      Thiazide diuretics

      
      
    • •
      

      Lithium

    
    
    
    
  • 
    

    Granulomatous disease

    
    
    
    
    • •
      

      Sarcoidosis

      
      
    • •
      

      Tuberculosis

      
      
    • •
      

      Histoplasmosis

      
      
    • •
      

      Coccidioidomycosis

    
    

  
  
  
  
• 
  

  Milk alkali syndrome

  
  
• 
  

  Acute and chronic renal failure

  
  
• 
  

  Total parenteral nutrition

From Mestman JH. Endocrine diseases in pregnancy. In Sciarra JJ, editor. Gynecology and Obstetrics. Philadelphia: Lippincott-Raven; 1997:11.

FHH is an autosomal-dominant condition with a high penetrance for hypercalcemia. The disorder is associated with an inactivating mutation in the gene for the calcium-sensing receptor. Mild hypercalcemia, a slight elevation in serum PTH, mild hypermagnesemia, and low urinary calcium excretion are the typical findings. Infants born to mothers with FHH may present with different clinical manifestations: (1) asymptomatic hypercalcemia can develop in an affected offspring if the mother is a carrier for FHH, (2) severe neonatal hypocalcemia can return to normal a few weeks after delivery, or (3) severe neonatal hypercalcemia can occur in infants homozygous for the FHH gene defect.

Postpartum hypercalcemia can occur in women with treated hypoparathyroidism, and the mechanism for hypercalcemia is not well understood. Nausea and vomiting develop a few days after delivery; therefore patients with treated hypoparathyroidism should be followed postpartum with serum calcium determinations, and vitamin D should be discontinued if hypercalcemia occurs. In severe cases, intravenous fluids and glucocorticoid therapy are required ( Fig. 42-1 ).

Serum calcium (triangles) and creatinine (squares) levels during pregnancy and 1 month after delivery in a woman with hypoparathyroidism who was treated with vitamin D and calcium. Normal range indicated by green shading.

A few cases of hypercalcemia mediated by PTHrP during pregnancy and postpartum have been reported. In one case, hypercalcemia developed in two successive pregnancies. In the second pregnancy, serum PTHrP levels were elevated to three times normal, and the infant was born with mild hypercalcemia that returned to normal within 24 hours after delivery. In a second case, a 25-year-old woman had massive bilateral breast enlargement at 24 weeks’ gestation. Her serum calcium level was 14.3 mg/dL, but her serum PTH level was undetectable. She underwent bilateral mastectomy during pregnancy. The immunohistochemical studies demonstrated PTHrP antigenic activity in breast tissue.

Hypoparathyroidism

The most common etiology of hypoparathyroidism is damage to or removal of the parathyroid glands in the course of surgery for thyroid gland pathology. The incidence of permanent hypoparathyroidism after thyroid surgery has been estimated to be between 0.2% and 3.5%. In many cases, hypocalcemia in the immediate postoperative period is only transitory. Idiopathic hypoparathyroidism is much less common and is frequently associated with other autoimmune endocrinopathies as part of the polyglandular autoimmune syndrome type 1.

The requirement for calcium supplementation and vitamin D may decrease in some women with hypoparathyroidism during the second half of pregnancy and lactation. In a few cases, hypocalcemic symptoms ameliorate with progression of pregnancy. The explanation for these findings is not clear but may be related to the increased intestinal absorption of calcium and/or the production of vitamin D by the placenta.

Clinical clues for the diagnosis of hypoparathyroidism include a previous history of thyroid surgery and clinical, radiologic, and laboratory information. Typical symptoms of hypocalcemia are numbness and tingling of the fingers and toes and around the lips. Patients may complain of carpopedal spasm, laryngeal stridor, and dyspnea. Convulsions may be a manifestation of severe hypocalcemia. On physical examination, patients with idiopathic hypoparathyroidism demonstrate changes in the teeth, skin, nails, and hair as well as papilledema and cataracts. Chvostek sign, a twitch of the facial muscles—notably those of the upper lip—when a sharp tap is given over the facial nerve, is seen in many patients with hypocalcemia. Chvostek sign has also been described in 10% of normal adults. Trousseau sign is another manifestation of hypocalcemia. It is the induction of spasm of the hand and forearm by reducing the circulation in the arm with a blood pressure cuff. The constriction should be maintained above the systolic blood pressure for 2 minutes before the test is considered negative.

The diagnosis of hypoparathyroidism is confirmed by the presence of persistent low serum calcium and high serum phosphate levels. Serum PTH is low in primary hypoparathyroidism. The differential diagnosis of hypocalcemia includes rickets and osteomalacia.

Radiologic bone changes characterized by generalized skeletal demineralization, subperiosteal bone resorption, bowing of the long bones, osteitis fibrosa cystica, and rib and limb deformities may be present in the newborn as a consequence of intrauterine hyperparathyroidism. Loughead and colleagues described 16 infants of hypoparathyroid mothers, and secondary hyperparathyroidism in the infants resolved by 1 month of age.

Treatment of hypoparathyroidism in pregnancy does not differ from that in the nonpregnant state, including a normal high-calcium diet and vitamin D supplementation. Normal calcium supplementation during pregnancy is about 1.2 g/day. Calcitriol, 1 to 3 µg/day, is used almost routinely in most patients affected with hypoparathyroidism. Calcitriol must be given in divided doses because its half-life is much shorter than that of vitamin D. If vitamin D is used, the dose is in the range of 50,000 to 150,000 IU/wk. Vitamin D requirements may decrease in some patients by the second half of gestation. The importance of compliance with medications should be strongly emphasized, particularly when calcitriol is prescribed, in view of its short half-life. The major problem in the treatment of hypoparathyroidism is the recurrence of hypercalcemia and hypocalcemia; therefore serum calcium determinations should be performed at regular intervals.

Lactation in mothers taking vitamin D may be contraindicated because a metabolite of vitamin D, 25-hydroxyvitamin D, has been detected in breast milk in high concentration in a mother taking 50,000 IU of vitamin D daily. Regardless of the form of vitamin D prescribed, serum calcium determinations should be done in the postpartum period, particularly in breastfeeding mothers.

Pseudohypoparathyroidism

Pseudohypoparathyroidism encompasses several different disorders, having as a common feature varying degrees of target-organ resistance to PTH. In some forms of the syndrome, somatic changes are present that include short stature, obesity, a round face, brachydactyly, and mental retardation with brain calcifications. This variant is known as Albright syndrome type 1a. Most patients suffer from hypocalcemia due to a derangement of renal 1α-hydroxylase and production of calcitriol, and a few cases have been reported during pregnancy. Infants are at risk for intrauterine fetal hyperparathyroidism, perhaps because of the relative maternal hypocalcemia during pregnancy.

Vitamin D Deficiency

Classically, vitamin D deficiency was related to the development of rickets, with its subsequent impact on obstetric care. Deformities of weight-bearing bones, including the pelvis, prevented vaginal delivery in mothers affected by the disease. In recent years, however, conflicting results have been published on the potential deleterious effect of vitamin D deficiency in a variety of medical problems from autoimmune disease to cancer. Several reviews on obstetric, fetal, and neonatal outcomes have been reported. The normal reference range values for serum vitamin D (25[OH]D), the active metabolite of vitamin D, are controversial, with values varying between 20 and 40 ng/mL, equivalent to 50 to 100 nmol/L.

Many studies in the past few years had linked low maternal 25(OH)D levels with maternal, fetal, and neonatal complications. In a report from Amsterdam, mothers with singleton pregnancies and serum 25(OH)D levels below 29.9 nmol/L (12 ng/mL) had infants with a lower birthweight and a higher incidence of growth restriction than mothers with values of over 50 nmol/L (20 ng/mL). Hart and colleagues examined the relationship between maternal vitamin D deficiency at 18 weeks’ gestation and long-term health outcomes in 901 mother-offspring pairs in Perth, Western Australia. The incidence of serum 25(OH)D deficiency (<50 nmol/L [<20 ng/mL]) was present in 36% of the pregnant women. After adjusting for relevant covariates, women with vitamin D deficiency had children with impaired lung development at age 6, neurocognitive deficiencies at age 10, increased risk of eating disorders in adolescence, and lower peak bone mass at age 20.

Recent systemic reviews and meta-analyses of observational studies and randomized controlled trials (RCTs) have failed to corroborate earlier observations. Theodoratou and colleagues concluded that despite a few hundred systematic reviews and meta-analyses, highly convincing evidence for a clear role of vitamin D does not exist for any outcome, but associations with a selection of outcomes are probable. De-Regil and colleagues reviewed six small trials with a total of 1023 women and compared five studies with vitamin D supplementation versus no treatment or placebo. The authors concluded that the use of vitamin D supplements during pregnancy improves vitamin concentrations as measured by 25-hydroxyvitamin D at term. However, the clinical significance of this finding has yet to be determined because quality evidence related to the clinical benefits of vitamin supplementation during pregnancy is insufficient. It is apparent that more studies are needed, preferably an RCT to understand the interrelationship with other factors such as age, ethnicity, seasonal variation, BMI, medical diseases, gestational age, and so on. Further studies on serum PTH and its relationship to serum vitamin D may be warranted. In the meantime, the practicing obstetrician will have to decide for each individual patient whether determination of 25(OH)D levels is indicated, what the normal values for pregnancy are, whether they are trimester specific, what the proper treatment should be, and how often the test needs to be repeated in pregnancy; this must be done also taking into consideration the cost of the tests and the possible implications for the fetus and newborn.

In 2010, the Institute of Medicine (IOM) reviewed nearly 1000 published studies that included reports of protection from cancer, autoimmune disease, heart disease, and diabetes with vitamin D supplementation. In brief, they recommended that the lower normal limit for serum 25(OH)D should be “about” 20 ng/mL or 50 nmol/L. For women who are not pregnant, the authors of the report recommend a daily vitamin D dietary allowance of 600 IU with an upper limit intake of 4000 IU; for calcium, they recommended a 1000-mg dietary allowance and an upper limit intake of 2500 mg a day. In the presence of vitamin D insufficiency/deficiency, it is reasonable to normalize serum levels as early as possible, preferably starting early in pregnancy. Detection of women at risk for vitamin D deficiency by proper history seems reasonable until the results of an RCT become available. Recent evidence suggests that vitamin D deficiency is common during pregnancy, especially among high-risk groups that include vegetarians, women with limited sun exposure (e.g., those who live in cold climates, reside in northern latitudes, or wear sun and winter protective clothing), and ethnic minorities, especially those with darker skin. For pregnant women thought to be at increased risk of vitamin D deficiency, maternal serum 25(OH)D levels can be considered and should be interpreted in the context of the individual clinical circumstance.

The American College of Obstetricians and Gynecologists (ACOG) has stated, “At this time there is insufficient evidence to support a recommendation for screening all pregnant women for vitamin D deficiency. For pregnant women thought to be at increased risk of vitamin D deficiency, maternal serum 25(OH)D levels can be considered and should be interpreted in the context of the individual clinical circumstance. When vitamin D deficiency is identified during pregnancy, most experts agree that 1000 to 2000 IU/day of vitamin D is safe.”

Osteoporosis

The condition of idiopathic osteoporosis related to pregnancy, pregnancy and lactation–associated osteoporosis (PLO), was recognized in the 1950s. In the past few years, interest has increased in several clinical aspects of osteoporosis in pregnancy and lactation. Although the prevalence is unknown, approximately 120 cases have been reported. Another form of rare pregnancy-associated osteoporosis is called transient osteoporosis of pregnancy. It usually presents in the third trimester of pregnancy—sometimes with very severe pain while walking or standing, usually localized in the hip—and it sometimes leads to hip fracture, with complete recovery a few months postpartum. Preexisting secondary causes of osteoporosis such as vitamin D deficiency, celiac disease, anorexia nervosa, mastocytosis, and hyperparathyroidism or hyperthyroidism should always be considered. Severe PLO may prompt screening for an underlying monogenetic bone disorder when associated with one of the following three features: (1) severely reduced bone density; (2) family history of osteoporosis or multiple fractures, joint hypermobility, blue sclerae, congenital blindness, or severely reduced vision; or (3) a history of fractures before pregnancy.

Although osteoporosis has been diagnosed during pregnancy, pregnancy unmasks low bone mass, it does not cause it. Postural changes during pregnancy, including increased lordosis, when superimposed on a small and transient decrease in bone mass may lead to pain and even fractures. In a study of 24 women with symptoms of bone pain for many years, 18 complained of back pain, 5 complained of hip pain, and 1 complained of ankle pain in late pregnancy and up to 8 months after delivery; radiologic examination of the spine showed vertebral deformities in 17, bone mass was measured in 21, evidence of osteoporosis was found in 7, and 13 were osteopenic. The authors concluded that bone mass was probably low before pregnancy and that a transient and slight decrease in bone mass during pregnancy could have weakened the bone further.

A recent study identified 78 cases with exposure to bisphosphonates before conception or during pregnancy. Although it did not demonstrate serious adverse effects, cases of increased spontaneous abortions, shortened gestational age, low neonatal birthweight, and transient hypocalcemia of the newborn were reported. Etidronate appears to be the agent to use in women with severe disease who are planning pregnancy, although the drug should be stopped a few months before conception.

The impact of lactation on the progression of osteoporosis is controversial. It has been suggested that lactation by itself is not a determinant of bone mineral density. Although one investigation reported that lactation for more than 8 months was associated with greater bone mineral density at both the femoral neck and shaft, another study found that nursing for longer than 9 months produced a greater decrease in bone mass than observed during the first 6- to 9-month period of nursing. Given this controversy, the health care provider must decide whether cessation of lactation is advisable in the management of osteoporosis. Bolzetta and colleagues studied 752 women (mean age, 64.5 ± 9.3 years) of whom 23% reported vertebral osteoporotic fractures. The women with vertebral fractures had breastfed their infants for longer periods (11.8 ± 12.9 vs. 9.3 ± 11.2 months, P = .03) and had more pregnancies (2.6 ± 2.2 vs. 2.2 ± 1.3, P = .002). Breastfeeding for more than 18 months was associated with a twofold risk of developing vertebral fractures (OR, 2.12; 95% CI, 1.14 to 5.38; P = .04), particularly in those without current or past use of drugs that positively affect bone. The authors concluded that an association exists between long periods of breastfeeding and vertebral fractures, which supports a role for lengthy lactation as a risk factor for osteoporotic fractures after menopause.

Heparin-associated osteoporosis has been reported during pregnancy that may be related to the total dose of heparin. The authors concluded that heparin adversely affected bone density in about one third of exposed patients.

Thyroid Function Tests

Measurement of serum TSH is the most practical, simple, and economic screening test for thyroid dysfunction. Normal TSH concentrations, as well as serum FT ₄ and TT4 determinations, are trimester specific and depend on iodine intake in a given population, ethnicity, and assay performance; serum TSH is lower in the first trimester compared with prepregnancy values and with the second and third trimester of pregnancy. An elevated serum TSH value is consistent with the diagnosis of primary hypothyroidism, whereas a low one, with few exceptions, is a normal finding in the first trimester ( Fig. 42-2 ) secondary to the stimulatory effect of hCG on the thyroid gland TSH receptor. Significant clinical data support a serum TSH below 2.5 mIU/L in the first trimester, and less than 3.0 mIU/L in the second and third trimesters, as the upper limit of normal. However, studies from China, the United Kingdom, and India that have used a specific reference range for their populations reported TSH reference ranges in the first trimester up to 4.5 mIU/L. Guidelines from the American Thyroid Association (ATA) and the Endocrine Society (ES) recommend the use of trimester-specific reference ranges for serum TSH and FT ₄ in a given population, and when not available, they recommend a serum TSH upper limit of normal of 2.5 mIU/L in the first trimester and up to 3.0 mIU/L in the second and third trimesters, as noted above. Because most pregnant women present for their first obstetric visit after 6 weeks gestation, the upper serum TSH limit of 2.5 mIU/L is reasonable for detection of hypothyroidism.

Algorithm for the interpretation of thyroid function tests in pregnancy. Serum thyroid-stimulating hormone (TSH) upper limit of normal in the first trimester of pregnancy is 2.5 mIU/L; in the second and third trimesters, it is 3 mIU/L. The serum TSH lower limit of normal in the first trimester of pregnancy may be as low as 0.1 mIU/L or may even be undetectable. Subclinical hyperthyroidism in the absence of TSH receptor antibodies (TSHRAbs) is a normal first-trimester physiologic finding. Presence of serum thyroid peroxidase (TPO) antibodies is consistent with a diagnosis of chronic thyroiditis. Presence of TSHRAb is consistent with the diagnosis of Graves disease. FT ₄ , free thyroxine; FT ₄ I, free thyroxine index.

A word of caution is required regarding the determination of FT ₄ levels in the different trimesters of pregnancy. A significant inconsistency is found in FT ₄ values in the second half of pregnancy among the different immunoassays, as reported by commercial laboratories, because of both the methodology used and the variation in dietary iodine intake among the different populations studied. FT ₄ values in the lower limits of normal, and even in the hypothyroid range, are not uncommonly seen in daily clinical practice, particularly in the third trimester of pregnancy. Lee and colleagues compared the diagnostic performances of two different immunoassays to traditional approaches for estimating FT ₄ (total T ₄ and FT ₄ index [FT ₄ I]) relative to the physiologic TSH changes known to occur throughout pregnancy. They studied euthyroid women who were negative for TPO antibody in the first, second, and third trimesters of gestation. Control women were premenopausal nonpregnant women matched for ethnicity. Serum TT ₄ , as expected, was elevated in all three trimesters, and serum FT ₄ I was elevated in the first trimester compared with controls ( P <.05) and returned to the nonpregnant range in the second and third trimesters. In contrast, FT ₄ values were either comparable or lower than controls as measured by two different immunoassays, and by the second and third trimesters, they were about 65% of controls. The authors concluded that TT ₄ and FT ₄ I retained an appropriate inverse relationship with serum TSH throughout pregnancy and appeared to provide a more reliable FT ₄ estimate than the FT ₄ test. Because the determination of FT ₄ by the dialysis method—the gold standard for FT ₄ assessment—or the use of tandem mass spectrometry are not routinely available, the determination of TT ₄ adjusted by a factor of 1.5 for pregnant patients has been suggested. Therefore it is imperative for the practicing physician to be familiar with the interpretation and significance of the thyroid tests as reported by a given commercial laboratory.

A suppressed serum TSH value and high concentrations of FT ₄ or FT ₄ I is diagnostic of hyperthyroidism. However, in rare situations, hyperthyroidism may be diagnosed in the presence of suppressed TSH and normal concentrations of FT ₄ , such as in the case of an autonomous thyroid nodule. In such cases, a serum TT ₃ or free triiodothyronine index (FT ₃ I) determination should be obtained.

Prepregnancy Counseling

The physician may be faced with different clinical situations when counseling a woman suffering from thyroid disease who is contemplating pregnancy:

• 1.
  

  Hyperthyroidism diagnosed “de novo” or under antithyroid drug (ATD) treatment. A choice of the three classic therapeutic options for hyperthyroidism treatment should be given: (1) long-term ATD therapy, (2) radioactive iodine-131 ( ¹³¹ I) ablation, or (3) near-total thyroidectomy. Potential side effects of ATDs on the fetus should be discussed with the future parents. ¹³¹ I ablation therapy should be avoided in patients with positive TRAb titers because serum levels increase following ¹³¹ I therapy, and the effect persists for several years; fetuses whose mothers have titers above three times the normal level in the second half of pregnancy are at risk of fetal and neonatal hyperthyroidism. Surgery is another option selected by some physicians and patients concerned about the potential side effects of ATDs or radioactive treatment . Regardless of the form of therapy chosen, it is important for the patient to be euthyroid at the time of conception . In a large series of untreated hyperthyroid pregnant women, a doubling in the incidence of congenital malformations was reported in the first trimester compared with euthyroid women.

  
  
• 2.
  

  Previous treatment with ¹³¹ I for thyroid carcinoma. It is reasonable for patients treated with ablative doses of ¹³¹ I to wait 6 months to 1 year after completion of treatment before conception. Data obtained from 2673 pregnancies in patients treated for thyroid carcinoma but without significant external radiation to the ovaries were analyzed by Garsi and colleagues, who found no evidence that exposure to radioiodine affects the outcome of subsequent pregnancies and offspring.

  
  
• 3.
  

  Treated hypothyroidism. Women under treatment with thyroid hormone usually require an increase in l -thyroxine dose soon after conception. The increase in requirements is observed as early as the first 6 to 8 weeks after the last menstrual period. As soon as the diagnosis of pregnancy is made, thyroid function tests should be performed, and thyroid doses should be adjusted accordingly. It has been recommended to add two extra doses of l -thyroxine per week to the customary doses as soon as the diagnosis of pregnancy is confirmed until the results of thyroid function tests become available. Recently it was reported that in hypothyroid women (excluding those who underwent thyroidectomy because of thyroid cancer) on l -thyroixine replacement therapy, if the serum TSH was below 1.3 mIU/L before conception, only 17% of women needed an increase in l -thyroxine in the first trimester of pregnancy compared with 58% of those with a serum TSH above 1.3 mIU/L. After delivery, the dose should be reduced to prepregnancy levels in most women. Common medications may affect the absorption of l -thyroxine, such as ferrous sulfate and calcium, among others. Patients should take l -thyroxine at least 2 hours apart from other medications and 1 hour before or after food intake, ideally early in the morning on awakening and 1 hour before food ingestion. However, during pregnancy, in those women affected by nausea or vomiting, the dose may be taken at bedtime on an empty stomach.

  
  
• 4.
  

  Euthyroid chronic thyroiditis. Patients with Hashimoto thyroiditis are at a greater risk for developing hypothyroidism de novo early in pregnancy, spontaneous abortions, prematurity, and postpartum thyroiditis.

Maternal-Placental-Fetal Interactions

Studies over the past few decades have shown an important role of maternal thyroid hormones in embryogenesis. Maternal T ₄ crosses the placenta in the first half of pregnancy at a time when the fetal thyroid gland is not functional, and maternal TSH does not cross the placenta. Thyrotropin-releasing hormone (TRH) does cross the placental barrier, but its physiologic significance is unknown.

Methimazole (MMI), propylthiouracil (PTU), and carbimazole (CMZ)—a drug that is metabolized to methimazole—do cross the placenta, may induce congenital malformations if given early in pregnancy, and if given in inappropriately high doses may produce fetal goiter and hypothyroidism. Preparations that contain iodine given in large doses or for prolonged periods are contraindicated in pregnancy because accumulation by the fetal thyroid may induce goiter and hypothyroidism.

As mentioned above, TRAb crosses the placenta, and serum concentrations decrease with progression of pregnancy. However, its titers increase significantly in Graves hyperthyroidism after therapy with ¹³¹ I.

Hyperthyroidism

Autoimmune hyperthyroidism affects pregnancy in about 0.1% to 0.4% of patients. Classically, it has been stated that Graves disease is the most common cause of hyperthyroxinemia in pregnancy; other etiologies are uncommon ( Box 42-2 ). As will be discussed subsequently, hyperthyroidism due to inappropriate secretion or action of hCG is recognized as the most common cause of transient hyperthyroidism in pregnancy. In our experience, single toxic adenoma and multinodular toxic goiter are found in less than 10% of cases. Subacute thyroiditis is rarely seen during gestation.

Gestational Hyperthyroidism

Also known as gestational thyrotoxicosis, transient hyperthyroidism of hyperemesis gravidarum, and transient nonautoimmune hyperthyroidism of early pregnancy, this condition is defined as transient hyperthyroidism in the first trimester of pregnancy due, with few exceptions, to high titers of hCG secretion that stimulate the TSH receptor. The most common causes of gestational hyperthyroidism are HG, multiple gestation, and hydatidiform mole. Other isolated reports included hyperplacentosis.

Transient Hyperthyroidism of Hyperemesis Gravidarum

Hyperemesis gravidarum (HG) is characterized by severe nausea and vomiting with onset between 4 and 8 weeks’ gestation that requires frequent visits to the emergency department and sometimes repeated hospitalizations for IV hydration. Weight loss of at least 5 kg, ketonuria, abnormal liver function tests, and hypokalemia are common findings, depending on the severity of vomiting and dehydration. FT ₄ and TT ₄ levels are elevated, sometimes up to four to six times the normal values, whereas TT ₃ and FT ₃ values are elevated in up to 40% of affected women, although FT ₃ values are not as high as those of serum FT _4. The TT ₃ /TT ₄ ratio is less than 20, compared with Graves hyperthyroidism, in which the ratio is more than 20. Serum TSH measured by a sensitive assay is consistently undetected or suppressed. Despite the significant biochemical hyperthyroidism, signs and symptoms of hypermetabolism are mild or absent. Patients may complain of mild palpitations and heat intolerance, but perspiration, proximal muscle weakness, and frequent bowel movements are rare. On physical examination, ophthalmopathy and goiter are absent, a mild tremor of the outstretched fingers is occasionally seen, and tachycardia may be present due in part to dehydration. Significant in the medical history is the lack of hyperthyroid symptoms before conception because most patients with Graves disease diagnosed for the first time during gestation give a history of hypermetabolic symptoms that antedate conception. Spontaneous normalization of hyperthyroxinemia parallels the improvement in vomiting and weight gain, and most cases resolve spontaneously between 14 and 20 weeks’ gestation, although persistence of hyperthyroidism beyond 20 weeks’ gestation has been reported in 15% to 25% of cases. Suppressed serum TSH may lag for a few more weeks after normalization of free thyroid hormone levels ( Fig. 42-3 ). Antithyroid medications are not needed. In one series in which antithyroid medication was used, pregnancy outcome was not significantly different from that of a similar group of patients who received no therapy. Occasionally, severe vomiting and hyperthyroidism may require parenteral nutrition.

A representative example of transient hyperthyroidism of hyperemesis gravidarum. By week 6, vomiting begins; it becomes severe by week 10. Serum free thyroxine index (FT ₄ I) is elevated, and thyrotropin is suppressed. By weeks 16 to 18, vomiting subsides with marked improvement of the FT ₄ I value. During this period, the patient loses 3.6 kg. By week 18, the serum FT ₄ I returns to normal, but the serum thyrotropin remains suppressed until week 26. The patient improves and gains weight and delivers a healthy infant at term. The orange band indicates the reference range. LNMP, last normal menstrual period; TSH, thyroid-stimulating hormone.

The degree of thyroid abnormalities is directly related to the severity of vomiting and weight loss. In 67 patients studied by Goodwin and colleagues, liver and electrolyte abnormalities were routinely found in women with worse symptoms, including severe vomiting, weight loss of at least 5 kg, and significant dehydration. They also presented with more significant elevations in FT ₄ levels and suppression of serum TSH values; indeed, in 30% of their patients, serum TSH was undetectable (<0.04 mIU/L). Those with a lesser degree of hyperemesis had a less severe disorder of thyroid function.

Transient hyperthyroidism due to HG should be suspected in women who present in the first few weeks after conception with sudden onset of severe nausea and vomiting and thyroid tests in the hyperthyroid range. These patients do not complain of hypermetabolic symptoms that antedate pregnancy, goiter is not detected by palpation, and symptoms or signs of tissue thyrotoxicosis are mild or absent. In addition, screens for thyroid anti-TPO antibodies and TRAbs, markers of autoimmune thyroid disease, are negative. The differential diagnosis may also be difficult because vomiting can also be a presenting symptom of the hyperthyroidism of Graves disease ( Table 42-1 ).

The cause of the elevations of thyroid hormones in patients with HG is the endocrine effect of hCG. Most likely, high levels of hCG—a known stimulator of the TSH receptor—play an important role, as does the prolongation in its biologic activity seen in twin pregnancies. A significant, albeit weak, correlation has been found between the degree of thyroid stimulation and total hCG levels in normal women and in those with hyperemesis. Titers of more than 200,000 mIU/mL of hCG consistently bring serum TSH to undetectable values. A case has been reported in a mother and daughter with recurrent hyperemesis, in whom hCG levels were not elevated. Both were heterozygous for a missense mutation in the extracellular domain of the thyrotropin receptor. The mutant receptor was more sensitive than the wild-type receptor to hCG, which accounted for the occurrence of hyperthyroidism despite the presence of normal hCG levels.

As noted previously, the diagnosis of transient hyperthyroidism of HG should be considered in women with severe vomiting, no clinical manifestations of Graves disease, biochemical evidence of hyperthyroidism in early pregnancy, suppressed or undetectable serum TSH values, and elevated serum FT ₄ . Normal serum TSH in early pregnancy may be as low as 0.01 mIU/L; therefore the presence of elevated serum FT ₄ is required for the diagnosis. Vomiting should be persistent and severe with a significant weight loss because most women with morning sickness of pregnancy have normal thyroid function tests. The syndrome may repeat in future pregnancies.

HG may also occur in women with Graves hyperthyroidism. It may occur during remission of the disease, explained by the additional action of hCG early in gestation ; the differential diagnosis between the two entities may be difficult, but the presence of TRAb favors the diagnosis of Graves hyperthyroidism.

Obstetric outcome is not affected by gestational hyperthyroidism. Birthweight may be slightly lower, but not significantly different, compared with fetuses of control mothers and is related to maternal weight loss.

Gestational trophoblastic diseases, partial and complete hydatidiform moles, and choriocarcinoma are other causes of hyperthyroidism early in pregnancy.

Graves Disease

The natural course of hyperthyroidism due to Graves disease in pregnancy is characterized by an exacerbation of symptoms in the first trimester and during the postpartum period and an amelioration of symptoms in the second half of pregnancy. Stimulation of the thyroid gland by hCG in the first trimester and an elevation in TRAb values have been suggested as the cause of the exacerbation. Immunologic responses caused by changes in lymphocyte subsets could explain spontaneous improvement in the second half of pregnancy and recurrences in the postpartum period. In a study that compared Graves disease in pregnant and nonpregnant women, Kung and Jones postulated that the amelioration of symptoms seen with progression of pregnancy was due to a decrease in the titers of TRAbs with stimulating activity and an increase in TRAbs with thyroid-blocking activity. The reverse was true in the postpartum period, when aggravation of Graves hyperthyroidism usually occurs. In another study, it was suggested that the amelioration of Graves disease in the last half of pregnancy is induced by a decrease of thyroid receptor antibodies (TRAbs, TSIs) but not by the appearance of thyroid stimulation–blocking antibodies (TSBAs).

When hyperthyroidism is properly managed throughout pregnancy, the outcome for mother and fetus is good; however, maternal and neonatal complications for mothers with untreated or poorly controlled hyperthyroidism are significantly increased ( Box 42-3 ).

In most patients in whom the diagnosis is made for the first time during pregnancy, hyperthyroid symptoms antedate conception. The clinical diagnosis of thyrotoxicosis may present difficulties during gestation because many symptoms and signs are commonly seen in normal pregnancy, such as mild palpitations, heart rate between 90 and 100 beats/min, mild heat intolerance, shortness of breath on exercise, and warm skin. However, some clinical clues increase the likelihood of the diagnosis of hyperthyroidism: presence of goiter, ophthalmopathy, proximal muscle weakness, tachycardia with a pulse rate of more than 100 beats/min, and weight loss or inability to gain weight despite a good appetite. Occasionally, the patient may be seen for the first time in congestive heart failure, and the etiologic diagnosis is difficult because many of the physical findings are suggestive of cardiac valvular disease, particularly mitral insufficiency or stenosis. Hyperthyroidism under poor control is frequently complicated by preeclampsia, small-for-gestational-age (SGA) infants, and preterm delivery. The physician should suspect hyperthyroidism in the presence of systolic hypertension with an inappropriately low diastolic blood pressure and a wide pulse pressure, which is also seen in other conditions such as aortic insufficiency.

Classic symptoms of hyperthyroidism include nervousness, increased sweating, increased appetite, heat intolerance, insomnia, proximal muscle weakness, irritability, changes in personality, frequent bowel movements, decreased tolerance to exercise (sometimes manifested as shortness of breath), eye irritation, frequent lacrimation, pruritus, and weight loss. Not all symptoms are present in a given patient; therefore the physician should be aware of subtle complaints, particularly in the presence of weight loss or inability to gain weight. As mentioned previously, in the first trimester of pregnancy, differentiating the diagnosis from transient hyperthyroidism of HG presents a real challenge for the health care professional.

On physical examination, the thyroid gland is enlarged in almost every pregnant woman with Graves disease. Indeed, the absence of a goiter makes the diagnosis unlikely in young people. The gland is diffusely enlarged, between two and six times the normal size, and varies from soft to firm; sometimes it is irregular to palpation, with one lobe being more prominent than the other. A thrill may be felt or a bruit may be heard, indications of a hyperdynamic circulation. Examination of the eyes may reveal obvious ophthalmopathy, but in most cases, exophthalmos is absent or mild, with one eye slightly more prominent than the other with retraction of the upper lid. Extraocular movements may be impaired on careful eye examination. Stare is common, as is injection or edema of the conjunctiva. Severe ophthalmopathy is rare in pregnancy; glucocorticoid therapy and surgical orbital wall decompression may be required to restore visual acuity. Pretibial myxedema is rare, seen in less than 10% of women. A hyperdynamic heart with a loud systolic murmur is a common finding. Proximal muscle weakness, fine tremor of the outstretched fingers, and hyperkinetic symptoms are seen frequently. The skin is warm and moist, and palmar erythema is accentuated.

As discussed previously (see Thyroid Function Tests ), almost every patient with Graves disease will have an elevated FT ₄ concentration. An undetected TSH value in the presence of a high FT _4, or FT4I or TT ₄ adjusted for pregnancy confirms the diagnosis of hyperthyroidism. In some unusual situations, the serum FT ₄ may be at the upper limit of normal or slightly elevated, in which case the determination of TT ₃ or adjusted TT ₃ will confirm the diagnosis of hyperthyroidism. Thyroid peroxidase antibodies (TPOAbs) or thyroid antimicrosomal antibodies, markers of thyroid autoimmune disease, are elevated in most patients with Graves disease, although it is of no clinical relevance for the diagnosis; the titers of TRAb, both TBII and TSI, are elevated, which confirms the clinical diagnosis of Graves hyperthyroidism, and their actual titers have a prognostic importance for fetal and neonatal hyperthyroidism (see later discussion).

Significant maternal and perinatal morbidity and mortality were reported in early studies of pregnancies complicated by hyperthyroidism. In the past 25 years, however, there has been a significant decrease in the incidence of maternal and fetal complications directly related to improved control of maternal hyperthyroidism (see Box 42-3 ). In patients whose hyperthyroidism is poorly controlled, one of the most common maternal complications is pregnancy-induced hypertension (PIH). In women with uncontrolled hyperthyroidism, the risk for severe preeclampsia was five times greater than that in patients with controlled disease. Other complications include preterm delivery, placental abruption, birthweight less than 2500 g, stillbirth, and miscarriage. Congestive heart failure may occur in women untreated or treated for a short period in the presence of PIH or operative delivery. Left ventricular dysfunction is usually detected by echocardiography in women with cardiovascular manifestations. Although these changes are reversible, they may persist for several weeks or months after achieving a euthyroid state. In one study, reduction in peripheral vascular resistance and higher cardiac output were still present despite normalization of T ₄ levels. This is an important finding with significant clinical implications. Left ventricular decompensation in hyperthyroid pregnant women may develop in the presence of superimposed preeclampsia, at the time of delivery, or with undercurrent complications such as anemia or infection. We have seen congestive heart failure in the first half of pregnancy in women with long-standing hyperthyroidism. It is likely that the aggravation of hyperthyroidism seen in the first part of pregnancy played an important role in the development of this complication. Careful monitoring of fluid administration is imperative in these situations. Thyroid storm has been observed in pregnancy and was reported 2 weeks postpartum in a woman whose hyperthyroidism was uncontrolled during pregnancy in association with multiorgan failure.

Fetal and neonatal complications are also related to maternal control of hyperthyroidism. Intrauterine growth restriction (IUGR), prematurity, stillbirth, and neonatal morbidity are the most common complications. Millar and coworkers demonstrated that uncontrolled hyperthyroidism during the entire gestation was associated with a ninefold greater incidence of low-birthweight (LBW) infants compared with the control population. The incidence of LBW infants was almost 2.5 times greater in those whose hyperthyroidism was treated during pregnancy but who became euthyroid at some time during gestation. In mothers who achieved a euthyroid state before or early in pregnancy, the incidence of LBW infants was no different from that in the control population. Delivery of an SGA infant is correlated with the presence of maternal thyrotoxicosis lasting more than 30 weeks of pregnancy, a duration of Graves disease of approximately 10 years, and the onset of Graves disease before age 20 years. The reported incidences of spontaneous abortions (25.7%) and premature delivery (14.9%) in mothers who were hyperthyroid at the time of conception are higher than those in euthyroid mothers, 12.8% and 9.5%, respectively. Neonatal central hypothyroidism has been reported in infants whose mothers remained hyperthyroid throughout their pregnancies. Many of these infants recovered normal thyroid function in a few weeks, whereas another group had long-standing hypopituitary dysfunction.

The use of ultrasonography for monitoring the size of the fetal thyroid gland as an indicator of thyroid dysfunction and possible need for therapeutic intervention was evaluated by Luton and associates in France. In a group of hyperthyroid women considered to be at high risk (presence of TRAbs) and on antithyroid therapy, fetal goiter was detected in 11 of 41 patients. Four fetuses were hyperthyroid, and seven were hypothyroid secondary to high doses of maternal antithyroid drug treatment; all of them benefited from adjusting drug therapy. The authors concluded that ultrasonography of the fetal thyroid gland by an experienced ultrasonographer is an excellent diagnostic tool, in conjunction with close teamwork, to ensure normal fetal thyroid function.

Treatment of hyperthyroidism is essential to prevent maternal, fetal, and neonatal complications ( Fig. 42-4 ). The goal of treatment is normalization of thyroid tests as soon as possible and maintenance of euthyroidism with the minimal amount of antithyroid medication. Excessive amounts of ATDs crossing the placenta may affect the fetal thyroid, with the development of fetal hypothyroidism with or without goiter. Patients should be monitored at regular intervals, and the dose of their medications should be adjusted to keep the FT ₄ or FT ₄ I or TT ₄ very close to the upper limit of the reference range for pregnancy, or just above it. Momotani and associates showed that fetal serum TSH was elevated even in mothers with FT ₄ within the normal range; furthermore, they demonstrated that normalization of maternal serum TT ₃ is a risk factor for the development of fetal hypothyroidism, which supports the recommendations that serum TT ₃ determination should rarely be used to assess maternal thyroid function during gestation.

A representative example of management of hyperthyroidism in pregnancy. The patient is hyperthyroid at time of conception on methimazole (MMI) 10 mg daily. When pregnancy is diagnosed, MMI is discontinued, and propylthiouracil (PTU) is added at a dosage of 150 mg three times daily. By the end of the first trimester, PTU is discontinued and MMI is given at a dosage of 20 mg daily. By week 20, the free thyroxine index (FT ₄ I) is almost normal, and the MMI dosage is reduced to 10 mg. By week 26, the FT ₄ I is in the upper reference range and thyrotropin remains suppressed; the MMI dosage is reduced to 5 mg daily. The FT ₄ I remains in the upper reference range, and by week 34 MMI is discontinued (D/C), and the patient remains euthyroid until delivery. The orange band indicates the reference range. LNMP, last normal menstrual period; TSH, thyroid-stimulating hormone.

To achieve a euthyroid state, and with the aim to keep the FT ₄ in the upper limit of the nonpregnant reference range and even slightly above normal, thyroid tests should be performed every 2 weeks at the beginning of treatment and every 2 to 4 weeks when euthyroidism is achieved. Because of the immunologic changes that occur with the progression of pregnancy, the requirement for antithyroid medications decreases after the second half of gestation. Some women with small goiters, a short duration of symptoms, low serum TRAb titers, and taking minimal amounts of antithyroid medication are able to discontinue ATDs by 34 weeks’ gestation or beyond. It is estimated that 30% to 40% are able to remain euthyroid without antithyroid therapy in the last few weeks of pregnancy.

In a study of 44 women in 46 pregnancies, the correlation among TRAb activity, the dose of antithyroid therapy, and neonatal outcome was studied. Medication was discontinued in 30 pregnancies 3 to 18 weeks before delivery. Neonatal thyrotoxicosis was seen in four infants whose mothers’ TBII levels exceeded 70% (normal, <15%). Interestingly, of the infants born with elevated serum TSH, maternal TBII was less than 30% in most, suggesting that in Graves disease–associated hyperthyroid pregnancies, a low TBII titer is an indication to use the minimal amount of antithyroid therapy to avoid the development of fetal hypothyroidism with or without goiter.

In the United States, the two available ATDs are PTU and MMI. Both drugs are effective in controlling symptoms. Recently, the risk for hepatic toxicity with PTU was revisited. An alarming number of deaths and cases requiring liver transplantation were noted ( Box 42-4 ). MMI can also induce liver toxicity, but these effects are milder, confined to cholestasis, not associated with liver failure, and seen more frequently in patients older than 61 years. It is estimated that about 4000 pregnant women per year in the United States would be expected to be treated with ATDs, most of them with PTU, as recommended per previous practice guidelines. Taylor and Vaidya found six reported cases of PTU-induced liver failure; it has been estimated that four women per year will have severe PTU-related hepatic complications. Although the incidence of both liver toxicity with PTU and embryopathy from MMI are very low, a panel convened by the U.S. Food and Drug Administration (FDA) and the ATA recommended the use of PTU only in the first trimester of pregnancy with a change to MMI in the second trimester (see Fig. 42-4 ). Other indications for the preferential use of PTU over MMI are drug allergy to MMI and in thyroid storm, because of the ability of PTU to inhibit peripheral conversion of T ₄ to T ₃ .

Box 42-4

Side-Effect Profiles of Methimazole Versus Propylthiouracil

METHIMAZOLE	PROPYLTHIOURACIL
Skin rash Pruritus Migratory polyarthritis Lupus-like syndrome Cholestatic jaundice Agranulocytosis Methimazole embryopathy • Choanal atresia ± esophageal atresia • Aplasia cutis • Hearing loss • Dysmorphic facial features • Developmental delay • Congenital cardiac malformations	Skin rash Pruritus Migratory polyarthritis Lupus-like syndrome Propylthiouracil hepatotoxicity • Hepatitis • Fulminant liver failure Propylthiouracil embryopathy • Neck • Urinary tract

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