Obstentrics_Williams

Obstentrics_Williams. Earlier studies were suggestive that subclinical hypothyroidism might be associated with adverse pregnancy outcomes. In 1999, interest was heightened by two studies indicating that undiagnosed maternal thyroid hypofunction may impair fetal neuropsychological development. In one study, Pop and associates (1999) described 22 women with free T 4 levels < 10th percentile whose ofspring were at higher risk for impaired psychomotor development. In the other study, Haddow and coworkers (1999) retrospectively evaluated children born to 48 untreated women whose serum TSH values were >98th percentile. Some had diminished school performance, reading recognition, and intelligent quotient (IQ) scores. Although described as "subclinically hypothyroid," these women had an abnormally low mean serum free thyroxine level, and thus, many had overt hypothyroidism.


Obstentrics_Williams

Obstentrics_Williams. To further evaluate any adverse efects, Casey and colleagues (2005) identiied subclinical hypothyroidism in 2.3 percent of 17,298 women screened at Parkland Hospital before midpregnancy. hese women had small but signiicantly higher incidences of preterm birth, placental abruption, and neonates admitted to the intensive care nursery compared with euthyroid women. In another study of 10,990 similar women, however, ClearyGoldman and associates (2008) did not ind such associations. Other studies subsequently conirmed a link between subclinical thyroid function and adverse outcomes (Chen, 2017; Maraka, 2016). One included 24,883 women screened throughout pregnancy and showed an almost twofold greater risk of severe preeclampsia (Wilson, 2012). In an analysis of the same cohort, a consistent relationship was shown between rising TSH levels and the risk for gestational diabetes (Tudela, 2012). Finally, Nelson and colleagues (2014) found an elevated risk for diabetes and stillbirth.


Obstentrics_Williams

Obstentrics_Williams. Lazarus and colleagues (2012) reported the indings of the international multicenter Controlled Antenatal Thyroid Screening (CATS) study. his study evaluated prenatal thyroid screening and randomized treatment of both subclinical hypothyroidism and isolated maternal hypothyroxinemia. They rior in the treated pregnancies.


Obstentrics_Williams

Obstentrics_Williams. Despite these indings, the unanswered question concerned whether treatment of subclinical hypothyroidism would miti gate any or all of these reported adverse outcomes. To address this, the Maternal-Fetal Medicine Units Network screened more than 97,000 pregnant women for thyroid disorders and reported that 3.3 percent had subclinical hypothyroid ism. hese 677 women were randomly assigned to thyroxine replacement therapy or placebo. As reported by Casey and col leagues (2017), and shown in Table 58-5, maternal adverse pregnancy outcomes or cognitive development in the ofspring at 5 years did not difer between groups. Annual developmental disorder results also did not difer.


Obstentrics_Williams

Obstentrics_Williams. Screening in Pregnancy. Because of the findings in the studies from 1999 cited above, some professional organizations began to recommend routine prenatal screening and treatment for subclinical hypothyroidism. Consequent to the Lazarus study, however, clinical practice guidelines from the Endocrine Society, the American hyroid Association, and the American Association of Clinical Endocrinologists uniformly recommended screening only those at greater risk during pregnancy (De Groot, 2012; Garber, 2012). his has been and still is the recommendation of the American College of Obstetricians and Gynecologists (2017). he indings of Casey and colleagues (2017) further buttress these recommendations. Women with low serum free T4 values but a normal-range TSH level are considered to have isolated matenal hypothyroxinemia.


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Obstentrics_Williams. Women with low serum free T4 values but a normal-range TSH level are considered to have isolated matenal hypothyroxinemia. Its incidence in two large trials was l.3 to 2.1 percent (Casey, 2007; Cleary-Goldman, 2008). As shown in Figure 58-2, unlike in subclinical hypothyroidism, these women had a low preva lence of antithyroid antibodies. Evolution of the knowledge of this thyroid disorder was similar to that seen with subclinical hypothyroidism. Initial studies reported that ofspring of women with isolated hypothyroxinemia had neurodevelopmental diiculties (Kooistra, 2006; Pop, 1999, 2003). In another study, Casey and colleagues (2007) found no higher risks for other adverse perinatal outcomes compared with those of euthyroid women. Also, the aforementioned CATS study did not ind improved neurodevelopmental outcomes in women with isolated hypothyroxinemia who were then treated with thyroxine (Lazarus, 2012).


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Obstentrics_Williams. he randomized trial conducted by the Maternal-Fetal Medicine Units Network also provided data to settle this question. Casey and colleagues (2017) noted no higher rates of adverse outcomes between groups and found that early thyroxine treatment ofered no beneits (see Table 58-5). Autoantibodies to TPO and thyroglobulin have been identiied in 6 to 20 percent of reproductive-aged women (Thangaratinam, 201l). Most who test positive for such antibodies, TABLE 58-5. Pregnancy and Perinatal Outcomes According to Diagnosis and Treatment Group of Thyroid Disordersa EGA at delivery (weeks) 39.1 ± 2.5 38.9 ± 3.1 39.0 ± 2.4 38.8 ± 3.1 birth <34 weeks 9.1 % 10.9% 3.8% 2.7% Placental abruption 0.3% 1.5% 1.1% 0.8% Preeclampsia 6.5% 5.9% 3.4% 4.2% Diabetes 7.4% 6.5% 8.0% 9.2% NICU admission 8.6% 6.2% 11.8% 11.9% Birthweight < 10th centile 9.8% 8.1 % 8.8% 7.8% IQ median (25th, 75th 97 (85,105) 94 (85,107) 94(83,101) 91 (82,101) dFor all comparisons, p >0.05.


Obstentrics_Williams

Obstentrics_Williams. NICU admission 8.6% 6.2% 11.8% 11.9% Birthweight < 10th centile 9.8% 8.1 % 8.8% 7.8% IQ median (25th, 75th 97 (85,105) 94 (85,107) 94(83,101) 91 (82,101) dFor all comparisons, p >0.05. EGA = estimated gestational age; IQ = intelligence quotient; [lICU = neonatal intensive care unit. Data from Casey, 201r7.


Obstentrics_Williams

Obstentrics_Williams. EGA = estimated gestational age; IQ = intelligence quotient; [lICU = neonatal intensive care unit. Data from Casey, 201r7. however, are euthyroid. That said, such women carry a two-to ivefold increased risk for early pregnancy loss (Stagnaro-Green, 2004; hangaratinam, 2011). he presence of thyroid antibodies has also been associated with preterm birth (Stagnaro-Green, 2009). In a randomized treatment trial of 115 euthyroid women with TPO antibodies, Negro and coworkers (2006) reported that treatment with levothyroxine astoundingly reduced the preterm birth rate from 22 to 7 percent. Contrarily, AbbassiGhanavati and associates (2010) evaluated pregnancy outcomes in more than 1000 untreated women with TPO antibodies and did not ind an increased risk for preterm birth compared with the risk in 16,000 euthyroid women without antibodies. hese investigators, however, did find a threefold greater risk of placental abruption in these women.


Obstentrics_Williams

Obstentrics_Williams. As with nonpregnant subjects with TPO antibodies, these women are also at increased risk for progression of thyroid disease and postpartum thyroiditis (Jameson, 2015; StagnaroGreen, 2012a). Currently, universal screening for the thyroid autoantibodies is not recommended by any professional organization (De Groot, 2012; Stagnaro-Green, 20lla, 2012a).


Obstentrics_Williams

Obstentrics_Williams. Decreasing iodide fortification of table salt and bread products in the United States during the past 25 years has led to occasional iodide deficiency (Caldwell, 2005; Hollowell, 1998). Importantly, the most recent National Health and Nutrition Examination Survey indicated that, overall, the United States population remains iodine suicient (Caldwell, 201l). Even so, experts agree that iodine nutrition in vulnerable populations, such as pregnant women, requires continued monitoring. In 2011, the Oice of Dietary Supplements of the National Institutes of Health sponsored a workshop to prioritize iodine research. Participants emphasized the decline in median urinary iodine levels to 125 Lg/L in pregnant women and the serious potential efects on developing fetuses (Swanson, 2012).


Obstentrics_Williams

Obstentrics_Williams. Dietary iodine requirements are higher during pregnancy due to augmented thyroid hormone production, increased renal losses, and fetal iodine requirements. Adequate iodine is requisite for fetal neurological development beginning soon after conception, and abnormalities are dependent on the degree of deficiency. he World Health Organization (WHO) has estimated that 38 million children are born every year at risk of lifelong brain damage associated with iodine deiciency (Alipui, 2008).


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Obstentrics_Williams. Although it is doubtful that mild diciency causes intellectual impairment, supplementation does prevent fetal goiter (Stagnaro-Green, 2012b). Severe diciency, on the other hand, is frequently associated with damage typically encountered with endemic cretinism (Delange, 2001). It is presumed that moderate deiciency has intermediate and variable efects. Berbel and associates (2009) began daily supplementation in more than 300 pregnant women with moderate deiciency at three time periods-4 to 6 weeks, 12 to 14 weeks, and after delivery. They found improved neurobehavioral development scores in ofspring of women supplemented with 200 ILg potassium iodide very early in pregnancy. Similarly, Velasco and coworkers (2009) found improved Bayley Psychomotor Development scores in ofspring of women supplemented with 300 ILg of iodine daily in the irst trimester. In contrast, Murcia and colleagues (2011) identified lower psychomotor scores in 1-yearold infants whose mothers reported daily


Obstentrics_Williams

Obstentrics_Williams. women supplemented with 300 ILg of iodine daily in the irst trimester. In contrast, Murcia and colleagues (2011) identified lower psychomotor scores in 1-yearold infants whose mothers reported daily supplementation of more than 150 ILg. To address this, randomized controlled trial of iodine supplementation in mildly to moderately iodinedeficient pregnant women in India and hailand is nearing completion (Pearce, 2016).


Obstentrics_Williams

Obstentrics_Williams. Regarding daily iodine intake, the Institute of Medicine during lactation (Chap. 9, p. 168). he Endocrine Society recommends an average iodine intake of 150 �g/d in repro ductive-aged women, and this should be increased to 250 �g during pregnancy and breastfeeding (De Groot, 2012). The of iodine be added to prenatal vitamins to achieve this average daily intake (Becker, 2006). According to Leung and coworkers (2011), however, only 51 percent of the prenatal multivitamins in the United States contain iodine. It has even been suggested that because most cases of maternal hypothyroxinemia world wide are related to relative iodine deficiency, supplementation may obviate the need to consider thyroxine treatment in such women (Gyami, 2009). However, without evidence of benefit, it is hard to justiy the cost of iodine supplementation of large numbers of pregnant women in areas with mild iodine dei ciency (Pearce, 2016).


Obstentrics_Williams

Obstentrics_Williams. Importantly, experts caution against oversupplementa tion. T eng and associates (2006) contend that excessive iodine intake-deined as > 300 �g/ d-may lead to subclinical hypo thyroidism and autoimmune thyroiditis. he Endocrine Soci ety, in accordance with the WHO, advises against exceeding twice the daily recommended intake of iodine, or 500 �g/ d (De Groot, 2012; Leung, 2011). Universal newborn screening for neonatal hypothyroidism was introduced in 1974 and is now required by law in all states (Chap. 32, p. 614). This develops in approximately 1 in 3000 newborns and is one of the most preventable causes of mental retardation (LaF ranchi, 2011). Developmental disorders of the thyroid gland such as agenesis and hypoplasia account for 80 to 90 percent of these cases. he remainder is caused by hereditary defects in thyroid hormone production (Moreno, 2008).


Obstentrics_Williams

Obstentrics_Williams. Early and aggressive thyroxine replacement is critical for newborns with congenital hypothyroidism. Still, some neonates identified by screening programs who were treated promptly will exhibit cognitive deicits into adolescence (Song, 2001). herefore, in addition to timing of treatment, the severity of congenital hypothyroidism is an important factor in long-term cognitive outcomes. Olivieri and colleagues (2002) reported that 8 percent of 1420 newborns with congenital hypothyroidism also had other major congenital malformations.


Obstentrics_Williams

Obstentrics_Williams. Transient autoimmune thyroiditis is consistently found in approximately 5 to 10 percent of women during the first year after childbirth (Nathan, 2014; Stagnaro-Green, 2011b, 2012a). Postpartum thyroid dysfunction with an onset within 12 months includes hyperthyroidism, hypothyroidism, or both. The propensity for thyroiditis antedates pregnancy and is directly related to increasing serum levels of thyroid autoantibodies. Up to 50 percent of women who are thyroid-antibody positive in the irst trimester will develop postpartum thyroiditis (Stagnaro-Green, 2012a). In a Dutch study of 82 women with type 1 diabetes, postpartum thyroiditis developed in 16 percent and was threefold higher than in the general population (Gallas, 2002). Importantly, 46 percent of those identified with overt postpartum thyroiditis had TPO antibodies in the first trimester.


Obstentrics_Williams

Obstentrics_Williams. In clinical practice, postpartum thyroiditis is diagnosed infre quently because it typically develops months after delivery and causes vague and nonspeciic symptoms (Stagnaro-Green, 2004). he clinical presentation varies, and classically two clinical phases that may develop in succession are recognized.


Obstentrics_Williams

Obstentrics_Williams. The first and earliest is destruction-induced thyrotoxicosis with symptoms from excessive release of hormone from glandular disruption. The onset is abrupt, and a small, painless goiter is common. Although there may be many symptoms, only fatigue and palpitations are more frequent in thyrotoxic women com pared with normal controls. This thyrotoxic phase usually lasts only a few months. hionamides are inefective, and if symp toms are severe, a 3-blocking agent may be given. he second and usually later phase between 4 and 8 months postpartum is hypothyroidism from thyroiditis. hyromegaly and other symp toms are common and more prominent than during the thyro toxic phase. hyroxine replacement at doses of25 to 75 �g/d is typically given for 6 to 12 months.


Obstentrics_Williams

Obstentrics_Williams. Stagnaro-Green and associates (20 11 b) reported postpartum surveillance results in 4562 Italian gravidas who had been screened for thyroid disease in pregnancy. Serum TSH and anti-TPO antibody levels were measured again at 6 and 12 months. Overall, two thirds of 169 women (3.9 percent) with postpartum thyroiditis were identiied to have hypothyroidism only. The other third were diagnosed with hyperthyroidism. Only 14 percent of all women demonstrated the "classic" biphasic progression described above. These indings are consistent with data compiled from 20 other studies between 1982 and 2008 (Stagnaro-Green, 2012a).


Obstentrics_Williams

Obstentrics_Williams. Importantly, women who experience either type of postpartum thyroiditis have a 20-to 30-percent risk of eventually developing permanent hypothyroidism, and the annual progression rate is 3.6 percent (Nathan, 2014). Women at greater risk for developing hypothyroidism are those with higher titers of thyroid antibodies and higher TSH levels during the initial hypothyroid phase. Others may develop subclinical disease, but half of those with thyroiditis who are positive for TPO antibodies develop permanent hypothyroidism by 6 to 7 years (Stagnaro-Green,r2012a).


Obstentrics_Williams

Obstentrics_Williams. n association between postpartum thyroiditis and postpartum depression has been proposed but remains unresolved. Lucas and coworkers (2001) found a 1.7-percent incidence of postpartum depression at 6 months in women with thyroiditis as well as in controls. Pederson and colleagues (2007) found a signiicant correlation between abnormal scores on the Edinburgh Postnatal Depression Scale and total thyroxine values in the low normal range during pregnancy in 31 women. Similarly unsettled is the link between depression and thyroid antibodies. Kuijpens and associates (2001) reported that TPO antibodies were a marker for postpartum depression in euthyroid women. In a randomized trial, however, Harris and coworkers (2002) reported no diference in postpartum depression in 342 women with TPO antibodies who were given either levothyroxine or placebo.


Obstentrics_Williams

Obstentrics_Williams. hyroid nodules can be found in 1 to 2 percent of reproductive-aged women (Fitzpatrick, 2010). Management of a palpable thyroid nodule during pregnancy depends on gestational age and mass size. Small nodules detected by sensitive sonographic methods are more common during pregnancy in some populations. Kung and associates (2002) used high-resolution sonography and found that 15 percent of Chinese women had nodules larger than 2 mm in diameter. Almost half were multiple, and the nodules usually enlarged modestly across preg nancy and did not regress postpartum. Biopsy of thoser> 5 mmrthat persisted at 3 months usually showed nodular hyperplasia, and none were malignant. In most studies, 90 to 95 percent of solitary nodules are benign (Burch, 2016).


Obstentrics_Williams

Obstentrics_Williams. Evaluation of thyroid nodules during pregnancy should be similar to that for nonpregnant patients. As discussed in Chapter 46 (p. 908), radioiodine scanning in pregnancy is usually not recommended (American College of Obstetricians and Gynecologists, 2017). Sonographic examination reliably detects nodules > 5 mm, and their solid or cystic structure also is determined. According to the American Association of Clinical Endocrinologists, sonographic characteristics associated with malignancy include hypoechogenic pattern, irregular margins, and microcalcifications (Gharib, 2005). Fine-needle aspiration (FNA) is an excellent assessment method, and histological tumor markers and immunostaining are reliable to evaluate for malignancy (Hegedus, 2004). If the FNA biopsy shows a follicular lesion, surgery may be deferred until after delivery.


Obstentrics_Williams

Obstentrics_Williams. Evaluation of thyroid cancer involves a multidisciplinary approach (Fagin, 2016). Most thyroid carcinomas are well differentiated and pursue an indolent course. Messuti and coworkers (2014) provided evidence that persistence or recurrence of these tumors may be more common in pregnant women. When thyroid malignancy is diagnosed during the first or second trimester, thyroidectomy may be performed before the third trimester (Chap. 63, p. 1201). In women without evidence of an aggressive thyroid cancer or in those diagnosed in the third trimester, surgical treatment can be deferred to the immediate puerperium (Gharib, 2010).


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Obstentrics_Williams. The function of parathyroid hormone (PTH) is to maintain extracellular fluid calcium concentration. his 84-amino acid hormone acts directly on bone and kidney and indirectly on small intestine through its efects on synthesis of vitamin D (l,25-(OH)2D) to increase serum calcium (Potts, 2015). Secretion is regulated by serum ionized calcium concentration through a negative feedback system. Cacitonin is a potent parathyroid hormone that acts as a physiological parathyroid hormone antagonist. The interrelationships between these hormones, calcium metabolism, and PTH-related protein produced by fetal tissue are discussed in Chapter 4 (p. 71).


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Obstentrics_Williams. Of fetal demands, calcium requirements reach 300 mg/d in late pregnancy and 30 g for the entire gestation. These needs and greater renal calcium loss from augmented glomerular iltration substantively raise maternal calcium demands. Pregnancy is associated with a twofold rise in serum concentrations of 1,25-dihydroxyvitamin D, which increases gastrointestinal calcium absorption. he efectuating hormone is probably of placental and decidual origin because maternal PTH levels are low normal or decreased during pregnancy (Cooper, 2011; Molitch, 2000). Total serum calcium levels decline with serum albumin concentrations, but ionized calcium levels remain unchanged. Vargas Zapata and colleagues (2004) have suggested a role for insulin-like growth factor-1 (IGF-1) in maternal calcium homeostasis and bone turnover.


Obstentrics_Williams

Obstentrics_Williams. Hypercalcemia is caused by hyperparathyroidism or cancer in 90 percent of cases (Potts, 2015). Because many automated laboratory systems include serum calcium measurement, hyperparathyroidism has changed from being a condition deined by symptoms to one that is discovered on routine screening (Pallan, 2012). It has a reported prevalence of 2 to 3 per 1000 women, but some have estimated the rate to be as high as 14 per 1000 when asymptomatic cases are included. Almost 80 percent are caused by a solitary adenoma, and another 15 percent by hyperfunctioning of all four glands. In the remainder, a malignancy as the cause of increased serum calcium levels is usually obvious. Of note, PTH produced by tumors is not identical to the natural hormone and may not be detected by routine assays.


Obstentrics_Williams

Obstentrics_Williams. In most patients, the serum calcium level is elevated to within only 1 to 1.5 mg/dL above the upper normal limit. This may help to explain why only 20 percent of those who have abnormally elevated levels are symptomatic (Bilezikian, 2004). In a fourth, however, symptoms become apparent when the serum calcium level continues to rise. Hypercacemic crisis manifests as stupor, nausea, vomiting, weakness, fatigue, and dehydration. All women with symptomatic hyperparathyroidism should be surgically treated (Potts, 2015). Indications for parathyroidectomy include a serum calcium level 1.0 mg/dL above the upper normal range, a calculated creatinine clearance < 60 mLi min, reduced bone density, or age >50 years (Bilezikian, 2009). Those not meeting these criteria should undergo annual serum calcium and creatinine level measurement and bone density assessment every 1 to 2 years (Pallan, 2012).


Obstentrics_Williams

Obstentrics_Williams. In their review, Schnatz and Thaxton (2005) found fewer than 200 reported cases of hyperparathyroidism complicating pregnancy. As in nonpregnant patients, parathyroid adenoma is the most common etiology. Ectopic parathyroid hormone production and rare cases of parathyroid carcinoma have been reported in pregnancy (Montoro, 2000; Saad, 2014). Symptoms include hyperemesis, generalized weakness, renal calculi, and psychiatric disorders. Occasionally, pancreatitis is the presenting disorder (Cooper, 2011; Hirsch, 2015).


Obstentrics_Williams

Obstentrics_Williams. Pregnancy theoretically improves hyperparathyroidism because of signiicant calcium shunting to the fetus and augmented renal excretion (Power, 1999). When the "protective efects" of pregnancy are withdrawn, however, postpartum hypercalcemic crisis is a significant danger. his life-threatening complication can be seen with serum calcium levels greater than 14 mgl dL and is characterized by nausea, vomiting, tremors, dehydration, and mental status changes (Malekar-Raikar, 2011). ism. More recent reports, however, described lower rates of stillbirth, neonatal death, and neonatal tetany (Kovacs, 201r1). Other fetal complications include miscarriage,r· fetal-growth restriction, and low birthweight (Chamarthi, 2011). Schnatz (2005) reported a 25-percent incidence of preeclampsia.


Obstentrics_Williams

Obstentrics_Williams. Other fetal complications include miscarriage,r· fetal-growth restriction, and low birthweight (Chamarthi, 2011). Schnatz (2005) reported a 25-percent incidence of preeclampsia. Management in Pregnancy. Surgical removal of a symptomatic parathyroid adenoma is preferable. This should prevent fetal and neonatal morbidities and postpartum parathyroid crises (Kovacs, 2011). Elective neck exploration during pregnancy is usually well tolerated, even in the third trimester (Hirsch, 2015; Schnatz, 2005; Stringer, 2017). In at least two cases, a mediastinal adenoma was removed at midpregnancy (Rooney, 1998; Saad, 2014).


Obstentrics_Williams

Obstentrics_Williams. Medical management may be appropriate in asymptomatic pregnant women with mild hypercalcemia (Hirsch, 2015). If so, patients are careully monitored in the puerperium for hypercalcemic crisis. Initial medical management might include cacitonin to decrease skeletal calcium release, or oral phosphate, 1 to 1.5 g daily in divided doses, to bind excess calcium. For women with dangerously elevated serum calcium levels or those who are mentally obtunded with hypercacemic crisis, emergency treatment is instituted. Diuresis with intravenous normal saline is begun so that urine low exceeds 150 mLlhr. Furosemie is given in conventional doses to block tubular calcium reabsorption. Importantly, hypokalemia and hypomagnesemia should be prevented. Adjunctive therapy includes mithramycin, which inhibits bone resorption.


Obstentrics_Williams

Obstentrics_Williams. Neonatal Efects. Normally, cord blood calcium levels are higher than maternal levels (Chap. 7, p. 139). With maternal hyperparathyroidism, abnormally elevated maternal and thus fetal levels further suppress fetal parathyroid function. Because of this, newborn calcium levels rapidly drop after birth, and 15 to 25 percent of these neonates develop severe hypocalcemia with or without tetany (Molitch, 2000). Neonatal hypoparathyroidism caused by maternal hyperparathyroidism is usually transient and is treated with calcium and 1,25-dihydroxyvitamin D3 (calcitriol). he latter will not be efective in preterm infants, however, because the intestinal vitamin D receptor is not suiciently expressed (Kovacs, 2011) . Neonatal tetany or seizures should stimulate an evaluation for maternal hyperparathyroidism (Beattie, 2000; Ip, 2003).


Obstentrics_Williams

Obstentrics_Williams. The most common cause of hypocalcemia is hypoparathyroidism that usually follows parathyroid or thyroid surgery. Hypoparathyroidism is estimated to follow up to 7 percent of total thyroidectomies (Shoback, 2008). It is characterized by facial muscle spasms, muscle cramps, and paresthesias of the lips, tongue, fingers, and feet. This can progress to tetany and seizures (Potts, 2015). Chronically, hypocalcemic pregnant women may also have a fetus with skeletal demineralization resulting in multiple bone fractures in the neonatal period (Alikasifoglu, 2005).


Obstentrics_Williams

Obstentrics_Williams. Maternal treatment includes calcitriol, dihydrotachysterol, or large vitamin D doses of 50,000 to 150,000 U/d; calcium gluconate or calcium lactate in doses of 3 to 5 g/d; and a lowphosphate diet. Fetal risks from large doses of vitamin D have not been established. During treatment, the therapeutic challenge in women with known hypoparathyroidism is management of blood calcium levels. It is possible that the greater calcium absorption typical of pregnancy will result in lower calcium requirements or that the fetal demand for calcium will result in greater need. he goal during pregnancy is to maintain a corrected calcium level in the low normal range.


Obstentrics_Williams

Obstentrics_Williams. In most gravidas, even with their remarkably increased calcium requirements, it is uncertain whether pregnancy causes osteopenia (Kaur, 2003; To, 2003). In one study of200 pregnant women in which bone mass was measured, Kraemer and colleagues (2011) demonstrated a decline in bone density during pregnancy. Women who breastfed, carried twin pregnancies, or had a low body mass index were at higher risk of bone loss. From their review, Thomas and Weisman (2006) cite a 3-to 4-percent average reduction in bone mineral density during pregnancy. Lactation also represents a period of negative calcium balance that is corrected through maternal skeletal resorption. Feigenberg and coworkers (2008) found cortical bone mass reductions using ultrasound in young primiparas in the puerperium compared with nulligravid controls. Rarely, some women develop idiopathic osteoporosis while pregnant or lactating (Hellmeyer, 2007).


Obstentrics_Williams

Obstentrics_Williams. The most common symptom of osteoporosis is back pain in late pregnancy or postpartum. Other symptoms are hip pain, either unilateral or bilateral, and diiculty in weight bearing until the woman is nearly immobilized (Maliha, 2012). In more than half of women, no apparent reason for osteopenia is found. Some known causes include heparin (unfractionated only), prolonged bed rest, and corticosteroid therapy (Cunningham, 2005; Galambosi, 2016). In a few cases, overt hyperparathyroidism or thyrotoxicosis eventually develops. Treatment is problematic and includes calcium and vitamin D supplementation and standard pain management. Shown in Figure 58-5 is a hip radiograph from a woman FIGURE 58-5 Anteroposterior plain hip radiograph of a 25-yearold woman at 26 weeks' gestation. She complained of left hip and knee pain and progressive weakness. Transient osteoporosis of the left femur responded over 3 months to physical therapy combined with vitamin 0 and calcium supplementation.


Obstentrics_Williams

Obstentrics_Williams. treated at Parkland Hospital during the third trimester for transient osteoporosis of pregnancy. For women with pregnancy-associated osteopenia, long-term surveillance indicates that although bone density improves, these women and their ofspring may have chronic osteopenia (Carbone, 1995). Related, prenatal supplementation of normal women with cholecalciferol, 1000 IU / d, did not increase ofspring bone mineral content, although it did ensure maternal vitamin D repletion (Cooper, 2016). Pregnancy has profound efects on adrenal cortical secretion and its control or stimulation. These interrelationships were reviewed by Lekarev and New (2011) and are discussed in detail in Chapter 4 (p. 71).


Obstentrics_Williams

Obstentrics_Williams. Pheochromocytomas are chromain tumors that secrete catecholamines and usually are located in the adrenal medulla, although 10 percent are located in sympathetic ganglia. They are called the 10-percent tumor because approximately 10 percent are bilateral, 10 percent are extraadrenal, and 10 percent are malignant. These tumors can be associated with medullary thyroid carcinoma and hyperparathyroidism in some of the autosomally dominant or recessive multiple endocrine neoplasia syndromes, as well as in neurofibromatosis and von HippelLindau disease (Neumann, 2015).


Obstentrics_Williams

Obstentrics_Williams. These tumors complicate approximately 1 per 50,000 pregnancies (Quartermaine, 2017). Notably, they are found in 0.1 percent of hypertensive patients (Abdelmannan, 2011). However, they are more commonly found at autopsy but with infrequent clinical recognition. Symptoms are usually paroxysmal and manifest as hypertensive crisis, seizure disorders, or anxiety attacks. Hypertension is sustained in 60 percent of patients, but half of these also have paroxysmal crises. Other symptoms during paroxysmal attacks are headaches, profuse sweating, palpitations, chest pain, nausea and vomiting, and pallor or flushing.


Obstentrics_Williams

Obstentrics_Williams. The standard screening test is quantification of metanephrines and catecholamine metabolites in a 24-hour urine specimen (Neumann, 2015). Diagnosis is established by measurement of a 24-hour urine collection with at least two of three assays for free catecholamines, metanephrines, or vanillylmandelic acid (VMA). Determination of plasma catecholamine levels is the most sensitive test. In nonpregnant patients, adrenal localization is usually successful with either computed tomography (CT) or magnetic resonance (MR) imaging. For most cases, preferred treatment is laparoscopic adrenalectomy (Neumann, 2015).


Obstentrics_Williams

Obstentrics_Williams. These tumors are rare but result in dangerous pregnancy complications. Geelhoed (1983) provided an earlier review of 89 cases in which 43 mothers died. Maternal death was much more common if the tumor was not diagnosed antepartum-58 versus 18 percent. As seen in Table 58-6, maternal mortality rates are now lower but still formidable. In their review of 77 cases, Biggar and Lennard (2013) reported that antepartum diagnosis is the most important determinant of maternal mortality risk. That said, Salazar-Vega and colleagues (2014) described good outcomes in women diagnosed after delivery. TABLE 58-6. Outcomes of Pregnancies Complicated by Pheochromocytoma and Reported in Four Contiguous Epochs


Obstentrics_Williams

Obstentrics_Williams. TABLE 58-6. Outcomes of Pregnancies Complicated by Pheochromocytoma and Reported in Four Contiguous Epochs Diagnosis of pheochromocytoma in pregnancy is similar to that for nonpregnant patients. MR imaging is the preferred technique because it almost always locates adrenal and extraadrenal pheochromocytomas (Fig. 58-6). In many cases, the principal challenge is to diferentiate preeclampsia from the hypertensive crisis caused by pheochromocytoma. Grimbert and colleagues (1999) diagnosed two pheochromocytomas during 56 pregnancies in 30 women with von Hippel-Lindau disease. FIGURE 58-6 Coronal magnetic resonance image taken in a 32-week pregnant woman shows a right-sided pheochromocytoma (arrow) and its position relative to the liver above it.


Obstentrics_Williams

Obstentrics_Williams. FIGURE 58-6 Coronal magnetic resonance image taken in a 32-week pregnant woman shows a right-sided pheochromocytoma (arrow) and its position relative to the liver above it. Immediate control of hypertension and symptoms with an .-adrenergic blocker such as phenoxybenzamine is impera tive. he dose is 10 to 30 mg, two to four times daily. After .-blockade is achieved, 3-blockers may be given for tachycar dia. In many cases, surgical exploration and tumor removal are performed during pregnancy, preferably during the second trimester (Biggar, 2013; Dong, 2014). Successfulrlaparoscopic removal of adrenal tumors has become the norm (Miller, 2012; Zuluaga-G6mez, 2012). If diagnosed later in pregnancy, either planned cesarean delivery with tumor excision or postpartum resection is appropriate.


Obstentrics_Williams

Obstentrics_Williams. Zuluaga-G6mez, 2012). If diagnosed later in pregnancy, either planned cesarean delivery with tumor excision or postpartum resection is appropriate. Recurrent tumors are troublesome, and even with good blood pressure control, dangerous peripartum hypertension may develop. We have cared for three women in whom recur rent pheochromocytoma was identiied during pregnancy. Hypertension was managed with phenoxybenzamine in all three. Two newborns were healthy, but a third was stillborn in a mother with a massive tumor burden who was receiving phenoxybenzamine, 100 mg daily. In all three women, tumor was resected postpartum.


Obstentrics_Williams

Obstentrics_Williams. his syndrome is rare and the female:male ratio is 3: 1 (Arit, 2015). Most cases are iatrogenic from long-term corticosteroid treatment. Cushing disease refers to bilateral adrenal hyperplasia stimulated by corticotropin-producing pituitary adenomas. Corticotropin is also called adrenocorticotropic hormone (ACTH). Most adenomas are microadenomas measuring < 1 em, and half measure <5 mm. Rarely, abnormal secretion of hypothalamic corticotropin-releasing factor may cause corticotropic hyperplasia. Such hyperplasia may also be caused by nonendocrine tumors that produce polypeptides similar to either corticotropin-releasing factor or corticotropin. Less than a fourth of cases of Cushing syndrome are corticotropin independent, and most of these are caused by an adrenal adenoma. Tumors are usually bilateral, and half are malignant. Occasionally, associated androgen excess may lead to severe virilization.


Obstentrics_Williams

Obstentrics_Williams. he typical cushingoid body habitus is caused by adipose tissue deposition that characteristically results in moon acies, a builo hump, and truncal obesiy. Fatigability and weakness, hypertension, hirsutism, and amenorrhea are each encountered in 75 to 85 percent of nonpregnant patients (Hatipoglu, 2012). Personality changes, easy bruisability, and cutaneous striae are common. Up to 60 percent may have impaired glucose tolerance. Diagnosis can be diicult and is suggested by elevated plasma cortisol levels that cannot be suppressed by dexamethasone or by elevated 24-hour urine free cortisol excretion (Arit, 2015; Loriaux, 2017). Neither test is totally accurate, and each is more diicult to interpret in obese patients. Serum corticotropin levels and CT and MR imaging are used to localize pituitary and adrenal tumors or hyperplasia. Because most women have corticotropin-dependent Cushing syndrome, associated androgen excess may cause anovulation,


Obstentrics_Williams

Obstentrics_Williams. Because most women have corticotropin-dependent Cushing syndrome, associated androgen excess may cause anovulation, TABLE 58-7. Maternal and Perinatal Complications Data from Lindsay, 2005. and pregnancy is rare. In their review, Lekarev and New (2011) identiied fewer than 140 reported cases of Cushing syndrome in pregnancy. These difer compared with nonpregnant women in that half are caused by corticotropin-independent adrenal adenomas (Kamoun, 2014; Lacroix, 2015). Approximately 30 percent of cases are from a pituitary adenoma, and 10 percent from adrenal carcinomas. All reports stress diiculties in diagnosis because of pregnancy-induced increases in plasma cortisol, corticotropin, and corticotropin-releasing factor levels. Measurement of24-hour urinary free cortisol excretion is recommended, with consideration for the normal elevation seen in pregnancy.


Obstentrics_Williams

Obstentrics_Williams. Pregnancy outcomes in women with Cushing syndrome are listed in Table 58-7. Heart failure is common during pregnancy and is a major cause of maternal mortality (Buescher, 1992). Hypercortisolism in pregnancy may also cause poor wound healing, osteoporotic fracture, and psychiatric complications (Kamoun, 2014).


Obstentrics_Williams

Obstentrics_Williams. Long-term medical therapy for Cushing syndrome usually is inefective, and deinitive therapy is resection of the pituitary or adrenal adenoma or bilateral adrenalectomy for hyperplasia (Lacroix, 2015; Motivala, 2011). During pregnancy, management of hypertension in mild cases may suice until delivery. In their review, Lindsay and associates (2005) described primary medical therapy in 20 women with Cushing syndrome. Most were successfully treated with meyrapone as an interim treatment until deinitive surgery after delivery. A few cases were treated with oral ketoconazole. However, because this drug also blocks testicular steroidogenesis, treatment during pregnancy with a male fetus is worrisome. Miepristone, the norethindrone derivative used for abortion and labor induction, has shown promise for treating Cushing disease but should not be used in pregnancy for obvious reasons. If necessary, pituitary adenomas can be treated by transsphenoidal resection (Boscaro, 2001; Lindsay, 2005).


Obstentrics_Williams

Obstentrics_Williams. for treating Cushing disease but should not be used in pregnancy for obvious reasons. If necessary, pituitary adenomas can be treated by transsphenoidal resection (Boscaro, 2001; Lindsay, 2005). Unilateral adrenalectomy has been safely performed in the early third trimester and can also be curative (Abdelmannan, 2011).


Obstentrics_Williams

Obstentrics_Williams. Primary adrenocortical insuiciency is rare because more than 90 percent of total gland volume must be destroyed for symptoms to develop. Autoimmune adrenalitis is the most common cause in the developed world, but tuberculosis is a more frequent etiology in resource-poor countries (Arit, 2015; Kamoun, 2014). The incidence has been cited as being as high as 1 in 3000 births in Norway (Lekarev, 2011). In the United States, the prevalence was 1 per 10,000 to 20,000 pregnancies (Schneiderman, 2017). here is an increased incidence of concurrent Hashimoto thyroiditis, primary ovarian insuiciency, type 1 diabetes, and Graves disease. These poyglandular autoimmune syndromes also include pernicious anemia, vitiligo, alopecia, nontropical sprue, and myasthenia gravis.


Obstentrics_Williams

Obstentrics_Williams. Untreated adrenal hypofunction frequently causes infertility, but with replacement therapy, ovulation is restored. If untreated, symptoms often include weakness, fatigue, nausea and vomiting, and weight loss. Because serum cortisol levels are increased during pregnancy, the inding of a low value should prompt a cosyntropin test to document the lack of response to infused corticotropin (Salvatori, 2005).


Obstentrics_Williams

Obstentrics_Williams. In a large Swedish cohort study, 1188 women with Addison disease were compared with more than 11,000 age-matched controls who delivered between 1973 and 2006 (Bjornsdottir, 2010). Women diagnosed with adrenal insuiciency within 3 years of delivery were signiicantly more likely to deliver preterm, to deliver a low-birthweight newborn, and to undergo cesarean delivery. Others have reported similar adverse outcomes (Quartermaine, 2017). Most pregnant women with Addison disease are already taking glucocorticoid and mineralocorticoid replacement drugs. hese should be continued and women observed for evidence of either inadequate or excessive corticosteroid replacement (Lebbe, 2013). During labor, delivery,r and postpartum, or after a surgical procedure, corticosteroid replacement must be increased appreciably to approximate the normal adrenal response-the so-called stress dose. Hydrocortisone, 100 mg, is usually given intravenously every 8 hours for 48 hours. It is important that shock


Obstentrics_Williams

Obstentrics_Williams. appreciably to approximate the normal adrenal response-the so-called stress dose. Hydrocortisone, 100 mg, is usually given intravenously every 8 hours for 48 hours. It is important that shock from causes other than adrenocortical insuiciency-for example, hemorrhage or sepsis-be recognized and treated promptly.


Obstentrics_Williams

Obstentrics_Williams. Hyperaldosteronism is caused by an adrenal adenoma-Conn syndrome-in approximately 75 percent of cases. Idiopathic bilateral adrenal hyperplasia makes up the remainder, except for rare cases of adrenal carcinoma (Abdelmannan, 2011; Eschler, 2015). Findings include hypertension, hypokalemia, and muscle weakness. High serum or urine levels of aldosterone confirm the diagnosis.


Obstentrics_Williams

Obstentrics_Williams. In normal pregnancy, as discussed in Chapter 4 (p. 72), progesterone blocks aldosterone action, and thus there are very high aldosterone levels (Appendix, p. 1258). Accordingly, the diagnosis of hyperaldosteronism during pregnancy can be diicult. Since renin levels are suppressed in pregnant women with hyperaldosteronism, a plasma aldosterone-to-renin activity ratio may be helpful for diagnosis (Kamoun, 2014). Hypertension worsens as pregnancy progresses, and medical management includes potassium supplementation and antihypertensive therapy. In many cases, hypertension responds to spironolactone, but 3-blockers or calcium-channel blockers may be preferred because of the potential fetal antiandrogenic efects of spironolactone. Mascetti and coworkers (201r1) reported successful use of amiloride in a pregnant woman. Use of eplerenone, a selective aldosterone-receptor antagonist, has also been reported (Cabassi, 2012). Laparoscopic tumor resection is curative (Eschler, 2015; Miller,


Obstentrics_Williams

Obstentrics_Williams. amiloride in a pregnant woman. Use of eplerenone, a selective aldosterone-receptor antagonist, has also been reported (Cabassi, 2012). Laparoscopic tumor resection is curative (Eschler, 2015; Miller, 2012).


Obstentrics_Williams

Obstentrics_Williams. The pituitary enlarges impressively during pregnancy, predominately from lactotrophic cellular hyperplasia induced by estrogen stimulation (Chap. 4, p. 68). Several pituitary disorders can also complicate pregnancy. These adenomas are found often in nonpregnant women since the advent of widely available serum prolactin assays. Serum levels <25 pg/mL are considered normal in nonpregnant women (Nlotivala, 2011). Adenoma symptoms and indings include amenorrhea, galactorrhea, and hyperprolactinemia. Tumors are classiied arbitrarily by their size measured by CT or MR imaging. A micro adenoma is :;10 mm, and a macro adenoma is >10 mm. Treatment for microadenomas is usually with bromocriptine, a dopamine agonist and powerful prolactin inhibitor, which frequently restores ovulation. For suprasellar macroadenomas, most recommend surgical resection before pregnancy is attempted (Araujo, 2015).


Obstentrics_Williams

Obstentrics_Williams. In a pooled analysis of more than 750 pregnant women with prolactinomas, only 2.4 percent with microadenomas developed symptomatic enlargement during pregnancy (Molitch, 2015). Symptomatic enlargement of macroadenomas, however, is more frequent and was found in 21 percent of 238 pregnant women. Schlechte (2007) also reported that 15 to 35 percent of suprasellar macroadenomas have tumor enlargement that causes visual disturbances, headaches, and diabetes insipidus. Nonfunctioning adenomas can also cause symptoms of pituitary expansion in pregnancy (Lambert, 2017).


Obstentrics_Williams

Obstentrics_Williams. Pregnant women with microadenomas should be queried regularly for headaches and visual symptoms. Those with macroadenomas are followed more closely and have visual field testing during each trimester. CT or MR imaging is recommended only if symptoms develop (Fig. 58-7). Serial serum prolactin levels serve little use because of normal rises during pregnancy (Appendix, p. 1259). Symptomatic tumor enlargement should be treated immediately with a dopamine antagonist. he safety of bromocriptine in pregnancy is well established. The safety profile is less well known for cabergoline, which is increasingly used in nonpregnant women because it is better tolerated and more efective. Cabergoline is generally considered safe for use in pregnancy (Araujo, 2015; Auriemma, 2013). Lebbe and colleagues (2010) described 100 pregnancies exposed to cabergoline and found no adverse efects. Similar indings were reported in 85 exposed Japanese pregnant women (Ono, 2010). Surgery is recommended for women


Obstentrics_Williams

Obstentrics_Williams. (2010) described 100 pregnancies exposed to cabergoline and found no adverse efects. Similar indings were reported in 85 exposed Japanese pregnant women (Ono, 2010). Surgery is recommended for women with no response.


Obstentrics_Williams

Obstentrics_Williams. suprasellar mass (arrow). Note the layering of complex fluid within the mass, which was found during surgery to be hemorrhage. (Used with permission from Dr. April Baily.) his is caused by excessive growth hormone, usually from an acidophilic or a chromophobic pituitary adenoma. In normal pregnancy, pituitary growth hormone levels decrease as placental epitopes are secreted. Diagnosis is confirmed by elevated IGF-1 serum levels (Katznelson, 2014). Fewer than 100 cases of acromegaly have been reported during pregnancy (Cheng, 2012; Dias, 2013; Motivala, 2011). Pregnancy is probably rare in women with acromegaly because half are hyperprolactinemic and anovulatory. During pregnancy, afected women are at marginally greater risk for gestational diabetes and hypertension (Caron, 2010; Dias, 20l3).


Obstentrics_Williams

Obstentrics_Williams. Management is similar to that for prolactinomas, with close monitoring for symptoms of tumor enlargement. Dopamine agonist therapy is less efective than for prolactinomas. And, transsphenoidal resection, generally considered irst-line treatment outside of pregnancy, may be necessary for symptomatic tumor enlargement during pregnancy (Motivala, 2011). Guven and associates (2006) reported a case of pituitary apoplexy necessitating emergent transsphenoidal adenoma resection and cesarean delivery at 34 weeks. Successful treatment of pregnant women with the somatostatin-receptor ligand octreotide and with the GH analogue pegvisomant has also been reported (Dias, 2013; Fleseriu, 2015). The vasopressin deficiency evident in diabetes insipidus is usually due to agenesis or destruction of the neurophypophysis (Robertson, 2015). True diabetes insipidus is a rare complication of pregnancy.


Obstentrics_Williams

Obstentrics_Williams. Diabetes insipidus therapy is intranasal administration of a synthetic analogue of vasopressin, desmopressin, which is 1-deamino8-D-arginine vasopressin (DDA P). Ray (1998) reviewed 53 cases in which DDAP was used during pregnancy with no adverse sequelae. Most women require increased doses during pregnancy because of an increased metabolic clearance rate stimulated by placentl vasopressinase (Lindheimer, 1994). By this same mecha nism, subclinicaL diabetes inspidus may become symptomatic or cases of transient diabetes inspidus may be encountered during pregnancy (Bellastella, 2012; Robertson, 2015). he prevalence of vasopressinase-induced diabetes insipidus is estimated at 2 to 4 per 100,000 pregnancies (Wallia, 20l3). In our experiences, as described in Chapter 55 (p. 1062), transient secondary diabetes insipidus is more likely encoun tered with acute atty Liver of pregnancy (Nelson, 20 l3). This probably is due to altered vasopressinase clearance because of hepatic dysfunction.


Obstentrics_Williams

Obstentrics_Williams. Sheehan (1937) reported that pituitary ischemia and necrosis associated with obstetrical blood loss could result in hypopituitarism. With modern methods of hemorrhagic shock treatment, Sheehan syndrome is now seldom encountered (Feinberg, 2005; Pappachan, 2015; Robalo, 2012). Afected women may have persistent hypotension, tachycardia, hypoglycemia, and lactation failure. Because deficiencies of some or all pituitary-responsive hormones may develop after the initial insult, Sheehan syndrome can be heterogenous and may not be identified for years (Tessnow, 2010). In one cohort study of 60 women from Costa Rica with Sheehan syndrome, the average time to diagnosis was 13 years (Gei-Guardia, 2011). Because adrenal insuiciency is the most life-threatening complication, adrenal function should be immediately assessed in any woman suspected of having Sheehan syndrome. Mter glucocorticoid replacement, subsequent analyses and replacement of thyroid, gonadal, and growth hormones is considered.


Obstentrics_Williams

Obstentrics_Williams. This rare autoimmune pituitary disorder is characterized by massive iniltration by lymphocytes and plasma cells with parenchymal destruction of the gland. vIany cases are temporally linked to pregnancy (Foyouzi, 2011; Honegger, 2015; Melmed, 2015). here are varying degrees of hypopituitarism or symptoms of mass efect, including headaches and visual ield defects. A sellar mass is seen with CT or MR imaging. A mass accompanied by a modestly elevated serum prolactin level-usually < 100 pgl mL-suggests lymphocytic hypophysitis. In contrast, levels >200 pg/mL are encountered with a prolactinoma. he etiology is unknown, but nearly 30 percent have a history of coexisting autoimmune diseases including Hashimoto thyroiditis, Addison disease, type 1 diabetes, or pernicious anemia. Treatment is with glucocorticoids and pituitary hormone replacement. he disease may be self-limited, and a careful withdrawal of hormone replacement is attempted after inflammation subsides (Foyouzi, 2011; Melmed,


Obstentrics_Williams

Obstentrics_Williams. glucocorticoids and pituitary hormone replacement. he disease may be self-limited, and a careful withdrawal of hormone replacement is attempted after inflammation subsides (Foyouzi, 2011; Melmed, 2015).


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Obstentrics_Williams. Abalovich I, Alcaraz G, Kleiman-Rubinsztein ], et al: he relationship of preconception thyrotropin levels to requirements for increasing the levothyroxine dose during pregnancy in women with primary hypothyroidism. Thyroid 5,t2010 Abalovich , Gutierrez S, Alcaraz G, et al: Overt and subclinical hypothyroidism complicating pregnancy. hyroid 12(1):63,t2002 Abbassi-Ghanavati M, Casey B, Spong C, et al: Pregnancy outcomes in women with thyroid peroxidase antibodies. Obstet Gynecol 116(2, Pt 1) :381, 2010 Abdelmannan D, ron D: Adrenal disorders in pregnancy. Endocrinol Metab Clin North Am 40:779,t2011 Ahlawat SK, Jain S, Kumari S, et al: Pheochromocytoma associated with pregnancy: case report and review of the literature. Obstet Gynecol Surv 54:728, 1999 Alexander EK, Marquesee E, Lawrence ], et al: Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl] Med 351:241,t2004


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Obstentrics_Williams. Alexander EK, Marquesee E, Lawrence ], et al: Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl] Med 351:241,t2004 Alikasifoglu A, Gone EN, Yalcin E, et al: Neonatal hyperparathyroidism due to maternal hypoparathyroidism and vitamin D deficiency: a cause of multiple bone fractures. Clin Pediatr 44:267, 2005 Alipui N: Sustained elimination of iodine deficiency. World Health Organization, 2008. Available at: https:llwww.unicef.org/publications/files/Sustain able_Elimination_oCIodine_Deficiency. pdf. Accessed] anuary 7, 2017 American College of Obstetricians and Gynecologists: Thyroid disease in pregnancy. Practice Bulletin No. 148, April 2015, Reairmed 2017


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Obstentrics_Williams. American hyroid Association and American Association of Clinical Endocrinologists: Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the merican hyroid Association and merican Association of Clinical Endocrinologists. Endocr Pract 17(3):456, 2011 Amino N, Izumi Y, Hidaka Y, et al: No increase of blocking type anti-thyrotropin receptor antibodies during pregnancy in patients with Graves' disease. ] Clin Endocrinol Metab 88(12):5871, 2003 Andersen SL, Olsen ], Laurberg P: Maternal thyroid disease in the Danish National Birth Cohort: prevalence and risk factors. Eur ] Endocrinol 174(2):203,t2016 Andersen SL, Olsen], W u CS, et al: Severity of birth defects after propylthiouracil exposure in early pregnancy. hyroid 24(10):1533,t2014 Arafah BM: Increased need for thyroxine in women with hypothyroidism during estrogen therapy. N Englt] Med 344:t1743,t2001


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Obstentrics_Williams. Arafah BM: Increased need for thyroxine in women with hypothyroidism during estrogen therapy. N Englt] Med 344:t1743,t2001 Araujo PB, Vieira Neto L, Gadelha MR: Pituitary tumor management in pregnancy. Endocrinol Metab Clin North Am 44(1):181, 2015 Arit W: Disorders of the adrenal cortex. In Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, cGraw-Hill Education, 2015 Auriemma RS, Perone Y, Di Sarno A, et al: Results of a single-center observational 10-year survey study on recurrence of hyperprolactinemia after pregnancy and lactation.] Clin Endocrinol Metab 98(1):372, 2013 Ayala C, Navarro E, Rodriguez]R, et al: Conception after iodine-131 therapy for diferentiated thyroid cancer. hyroid 8: 1009, 1998


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Obstentrics_Williams. Bellastella A, Bizzarro A, Colella C, et al: Subclinical diabetes insipidus. Best Pract Res Clin Endocrinol Metab 26(4):471,t2012 Berbel P. Mestre ]L, Santamaria A, et al: Delayed neurobehavioral development in children born to pregnant women with mild hypothyroxinemia during the first month of gestation: the importance of early iodine supplementation. Thyroid 19:511, 2009 Berlin L: Malpractice issues in radiology: iodine-131 and the pregnant patient. A]RAm] RoentgenoIt176:869, 2001 Bernal ]: Thyroid hormone receptors in brain development and function. Nat Clin Pract Endocrinol Metab 3(3):249, 2007 Bianchi DW, Romero R: Biological implications of bi-directional fetomaternal cell traicking summary of a National Institute of Child Health and Human Development-sponsored conference.] Matern Fetal Neonatal Med 14: 123, 2003 Biggar viA, Lennard TW: Systematic review of phaeochromocytoma in pregnancy. Br] Surg 100(2):182, 2013


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Obstentrics_Williams. Biggar viA, Lennard TW: Systematic review of phaeochromocytoma in pregnancy. Br] Surg 100(2):182, 2013 Bilezikian ]P, Khan A, Potts]T]r: Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement of the Third International Workshop. ] Clin Endocrinol Metab 94(2):335, 2009 Bilezikian ]P, Silverberg S]: Asymptomatic primary hyperparathyroidism. N Engl] Med 350:1746,2004 Bjornsdottir S, Cnattingius S, Brandt L, et al: Addison's disease in women is a risk factor for an adverse pregnancy outcome. ] Clin Endocrinol Metab 95(12):5249,t2010 Boddy AM, Fortunato A, Wilson Sayres M, et al: Fetal micro chimerism and maternal health: a review and evolutionary analysis of cooperation and conlict beyond the womb. Bioessays 37(10):1106,t2015


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Obstentrics_Williams. Caron P, Broussaud S, Bertherat ], et al: Acromegaly and pregnancy: a retrospective multicenter study of 59 pregnancies in 46 women. ] Clin Endocrinol Metab 95(10):4680, 2010 Casey BM, Dashe ]S, Spong CY, et al: Perinatal significance of isolated maternal hypothyroxinemia identified in the first half of pregnancy. Obstet Gynecol 109:1129,t2007 Casey BM, Dashe ]S, Wells CE, et al: Subclinical hypothyroidism pregnancy outcomes. Obstet Gynecol 105:38,t2005 Casey BM, Leveno K]: Thyroid disease in pregnancy. Obstet Gynecol 108:1283,t2006 Casey BM, Thon A, Peaceman AM, et al: Treatment of subclinical hypothyroidism or hypothyroxinemia during pregnancy. N Engl] Med 376:815,2017 Chamarthi B, Greene M, Dluhy R: A problem in gestation. N Engl ] Med 365(9):843,t201t1 Chen S, Zhou X, Zhu H, et al: Preconception TSH levels and pregnancy outcomes: a population-based cohort study in 184,611 women Clin Endocrinol (Oxf) 86(6):816,t2017


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Obstentrics_Williams. Chen S, Zhou X, Zhu H, et al: Preconception TSH levels and pregnancy outcomes: a population-based cohort study in 184,611 women Clin Endocrinol (Oxf) 86(6):816,t2017 Cheng S, Grasso L, Martinez-Orozco ]A, et al: Pregnancy in acromegaly: experience from two referral centers and systematic review of the literature. Clin Endocrinol (Oxf) 76(2):264, 2012 Cirello V, Rizzo R, Crippa M, et al: Fetal cell microchimerism: a protective role in autoimmune thyroid diseases. Eur] EndocrinoIt173(1):111, 2015 Cleary-Goldman], Malone FD, Lambert-Messerlian G, et al: Maternal thyroid hypofunction and pregnancy outcome. Obstet Gynecol 112(1):85,2008 Cohen 0, Pinhas-Haniel 0, Sivian E, et al: Serial in utero ultrasonographic measurements of the fetal thyroid: a new complementary tool in the management of maternal hyperthyroidism in pregnancy. Prenat Diagn 23:740,t2003


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Obstentrics_Williams. Cooper C, Harvey NC, Bishop N], et al: Maternal gestational vitamin D supplementation and ofspring bone health CMAVIDOS): a multicentre, double-blind, randomised placebo-controlled trial. Lancet Diabetes Endocrinol 4:393, 2016 Cooper MS: Disorders of calcium metabolism and parathyroid disease. Best Pract Res Clin Endocrinol Metabol 25:975, 2011 Cunningham FG: Screening for osteoporosis. N Engl ] Med 353: 1975, 2005


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Obstentrics_Williams. Dias M, Boquszewski C, Gadelha M, et al: Acromegaly and pregnancy: a prospective study. Eur J EndocrinoIt170(2):301, 2013 Diez J], Iglesias P: Spontaneous subclinical hypothyroidism in patients older than 55 years: an analysis of natural course and risk factors for the development of overt thyroid failure. J Clin Endocrinol Metab 89:4890, 2004 Dong 0, Li H: Diagnosis and treatment of pheochromocytoma during pregnancy. J Matern Fetal Neonatal Med 2 (18):1930,t2014 Eschler DC, Kogekar N, Pessah-Pollack R: Management of adrenal tumors in pregnancy. Endocrinol Metab Clin North Am 44(2):381,t2015 Fadel BM, Ellahham S, Ringel MD, et al: Hyperthyroid heart disease. Clin Cardiol 23:402, 2000 Fagin JA, Wells SA Jr: Biologic and clinical perspectives on thyroid cancer. N Engl J Med 375(11):1054,t2016 Feigenberg T, Ben-Shushan A, Daka K, et al: Ultrasound-diagnosed puerperal osteopenia in young primiparas. J Reprod Med 53(4):287, 2008


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Obstentrics_Williams. Feigenberg T, Ben-Shushan A, Daka K, et al: Ultrasound-diagnosed puerperal osteopenia in young primiparas. J Reprod Med 53(4):287, 2008 Feinberg EC, Molitch ME, Endres LK, et al: The incidence of Sheehan's syndrome after obstetric hemorrhage. Fertil Steril 84:975, 2005 Fisher DA: Fetal thyroid function: diagnosis and management of fetal thyroid disorders. Clin Obstet Gynecol 40: 16, 1997 Fitzpatrick DL, Russell MA: Diagnosis and management of thyroid disease in pregnancy. Obstet Gynecol Clin North Am 37(2): 173,t2010 Fleseriu M: Medical treatment of acromegaly in pregnancy, highlights on new reports. Endocrine 49(3):577,t2015 Foyouzi N: Lymphocytic adenohypophysitis. Obstet Gynecol Surv 66(2): 109, 201t1 Galambosi P, Hilsemaa V, Ulander VM, et al: Prolonged low-molecularweight heparin use during pregnancy and subsequent bone mineral density. Thromb Res 143:122,t2016


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Obstentrics_Williams. Wallia A, Bizhanova A, Huang W, et aI: Acute diabetes insipidus mediated by vasopressinase after placental abruption. ] Clin Endocrinol Metab 98:881, 20t13 Wang W, Teng W, Shan Z, et al: he prevalence of thyroid disorders during early pregnancy in China: the beneits of universal screening in the irst trimester of pregnancy. Eur] Endocrinol 164(2):263, 2011 Wikner BN, Sparre LS, Stiller CO, et al: Maternal use of thyroid hormones in pregnancy and neonatal outcome. Acta Obstet Gynecol Scand 87(6):617, 2008 Wilson KL, Casey BM, McIntire DO, et al: Diagnosis of subclinical hypothyroidism early in pregnancy is a risk factor for the development of severe preeclampsia. Clin Thyroidol 24(5):15, 2012 Yassa L, Marqusee E, Fawcett R, et al: hyroid hormone early adjustment in pregnancy (the THERAPy) trial. ] Clin Endocrinol Metab 95(7):3234, 2010


Obstentrics_Williams

Obstentrics_Williams. Yassa L, Marqusee E, Fawcett R, et al: hyroid hormone early adjustment in pregnancy (the THERAPy) trial. ] Clin Endocrinol Metab 95(7):3234, 2010 Yoshihara A, Noh ]Y, Mukasa K, attel: Serum human chorionic gonadotropin levels and thyroid hormone levels in gestational transient thyrotoxicosis: is the serum hCG level useful for diferentiating berween active Graves' disease and GTT? Endocr] 62(6):557,t2015 Yoshihara A, Noh ]Y, Yamaguchi T, et al: Treatment of Graves disease with antithyroid drugs in the irst trimester of pregnancy and the prevalence of congenital malformation. ] Clin Endocrinol Metab 9 :2396, 2012 Zuluaga-Gomez A, Arrabal-Polo A, Arrabal-Martin M, et al: Management of pheochromocytoma during pregnancy: laparoscopic adrenalectomy. Am 8(3):E156,t2012 IMMUNE-MEDIATED CONNECTIVE TISSUE DISEASES.. 1138 SYSTEMIC LUPUS ERYTHEMATOSUS ............... 1139


Obstentrics_Williams

Obstentrics_Williams. IMMUNE-MEDIATED CONNECTIVE TISSUE DISEASES.. 1138 SYSTEMIC LUPUS ERYTHEMATOSUS ............... 1139 ANTI PHOSPHOLIPID SYNDROME ......i.......i.... 1i143 ..RHEUMATOID ARTHRITIS .....i................i.... 1146 SYSTEMIC SCLEROSIS-SCLERODERMA.. . . . . . . . . .. 1148 VASCULITIS SYNDROMES.. . . . . . . . . . . . . . . . . . . . . .. 1149 INFLAMMATORY MYOPATHIES .........i......... 1150 HEREDITARY CONNECTIVE TISSUE DISORDERS.. . . .. 1151 Owing to the great vasculariy incident to pregnancy, the various pelvic joints always show a somewhat increased motiliy. In rare instances, particulary when the pelvis is contracted in the lower portion, spontaneous rupture of the symphysis pubis or one or both sacro-iliac joints has been observe. -]. Whitridge Williams (1903)


Obstentrics_Williams

Obstentrics_Williams. -]. Whitridge Williams (1903) The principal concerns in the 1st edition of Williams Obstetrics with disorders of the joints were the obstructed pelvis caused by rickets. There is no mention of the arthritides complicating pregnancy. And of course, immune-mediated disease had not yet been elucidated.


Obstentrics_Williams

Obstentrics_Williams. Connective tissue disorders, which are also termed collagen vascular disorders, have two basic underlying causes. First are the immune-complex diseases in which connective tissue damage is caused by deposition of immune complexes. Because these are manifest by sterile inflammation-predominately of the skin, joints, blood vessels, and kidneys-they are referred to as rheumatic diseases. Many of these immune-complex diseases are more prevalent in women, for example, systemic lupus erythematosus (SLE) and rheumatoid arthritis. Second are the inherited disorders of bone, skin, cartilage, blood vessels, and basement membranes. Some examples include Marfan syndrome, osteogenesis imperfecta, and Ehlers-Danlos syndrome.


Obstentrics_Williams

Obstentrics_Williams. hese disorders can be separated into those associated with and those without autoantibody formation. The rheumatoid actor (F) is an autoantibody found in many autoimmune inflammatory conditions such as SLE, rheumatoid arthritis, systemic sclerosis (scleroderma), mixed connective tissue disease, dermatomyositis, polymyositis, and various vasculitis syndromes. he F-seronegative spondyloarthropathies are strongly associated with expression of the human leukocyte antigen B27 (HLAB27) antigen and include ankylosing spondylitis, psoriatic arthritis, Reiter disease, and other arthritis syndromes.


Obstentrics_Williams

Obstentrics_Williams. Pregnancy may mitigate activity in some of these syndromes as a result of the immunosuppression that also allows successful engraftment of fetal and placental tissues. These changes are discussed in detail in Chapters 4 (p. 58) and 5 (p. 95). One example is pregnancy-induced predominance ofT2 helper cells compared with cytokine-producing T 1 helper cells (Keeling, 2009). Pregnancy hormones also alter immune cells. Namely, estrogens upregulate and androgens down regulate T-cell response, and progesterone is immunosuppressive (Cutolo, 2006; Haupl, 2008a; Robinson, 2012).