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Obstentrics_Williams. International Association of Diabetes and Pregnancy Study Group he IADPSG sponsored a workshop conference on the diagnosis and classiication of gestational diabetes in 2008. After reviewing the results of the HAPO study, a panel developed recommendations for the diagnosis and classiication of hyperglycemia during pregnancy. This panel allowed for the diagnosis of overt diabetes during pregnancy as shown in Table 57-4. It also recommended a single-step approach to the diagnosis of gestational diabetes using the 75-g, 2-hour OGTT. hresholds for fasting, 1-, and 2-hour values based on mean glucose concentrations from the entire HAPO study cohort were considered. hese glucose level thresholds were derived using an arbitrary 1.75 odds ratio of outcomes such as LGA birthweight and cord serum C-peptide levels >90th percentile. Only one of these thresholds, shown in Table 57-11, would need to be met or exceeded to make the diagnosis of gestational diabetes.


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Obstentrics_Williams. It is estimated that implementation of these recommendations would raise the prevalence of gestational diabetes in the United States to 17.8 percent! Said another way, the number of women with mild gestational diabetes would grow almost threefold with no evidence of treatment benefit (Cundy, 2012). Feldman and coworkers (2016) evaluated the implementation of the IADPSG paradigm in a before-ater analysis that included more than 6000 women. he new strategy was associated with a significant increase in gestational diabetes by the Agency for Healthcare Research and Quality Evidence-Based Practice Center, expert testimony, and a nonbiased panel to produce the overall report. he panel concluded that there were potential beneits to worldwide standardization. However, it found insuicient evidence to adopt a one-step diagnostic process such as the one proposed by the IADPSG. Moreover, as mentioned previously, after consideration of these indings, the American College of Obstetricians and


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Obstentrics_Williams. to adopt a one-step diagnostic process such as the one proposed by the IADPSG. Moreover, as mentioned previously, after consideration of these indings, the American College of Obstetricians and Gynecologists (2017a) continues to recommend a two-step screening and diagnostic approach to gestational diabetes diagnosis. he College noted no significant improvements in maternal or perinatal outcomes that would ofset the tripling of gestational diabetes incidence that would derive from the one-step approach. We applaud this decision.


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Obstentrics_Williams. Adverse consequences of gestational diabetes difer from those of pregestational diabetes. Unlike in women with overt diabetes, women with gestational diabetes do not appear to have fetuses with substantially higher rates of anomalies than the general obstetrical population (Sheield, 2002). In a study of more than 1 million women from the Swedish Medical Birth Registry, major malformation rates were marginally elevated in fetuses of gestational diabetics compared with those of nondiabetic controls-2.3 versus 1.8 percent (Fadl, 2010). The stillbirth rate was not greater in this study. Similarly, the stillbirth rate was not increased in an analysis by Jovanovic and associates (2015) of more than 800,000 pregnancies from 2005 through 2011. In contrast, and not unexpectedly, women with elevatedfasting glucose levels have elevated rates of unexplained stillbirths similar to those of women with overt diabetes. This increasing risk with progressive maternal hyperglycemia emphasizes the


Obstentrics_Williams

Obstentrics_Williams. glucose levels have elevated rates of unexplained stillbirths similar to those of women with overt diabetes. This increasing risk with progressive maternal hyperglycemia emphasizes the importance of identiying women with evidence of preexisting diabetes early in pregnancy (see Table 57-4). Similar to women with overt diabetes, adverse maternal efects associated with gestational diabetes include a higher frequency of hypertension and cesarean delivery.


Obstentrics_Williams

Obstentrics_Williams. he primary efect attributed to gestational diabetes is exces sive fetal size or macrosomia that is variably defined and dis cussed further in Chapter 44 (p. 857). The perinatal goal is birth trauma associated with shoulder dystocia. In a retrospec tive analysis of more than 80,000 vaginal deliveries in Chinese women, Cheng and associates (2013) calculated a 76-fold greater risk for shoulder dystocia in newborns weighing :4200 g compared with the risk in those weighing <3500 g. Impor tantly, however, the odds ratio for shoulder dystocia in women with diabetes was <2. Although gestational diabetes is certainly a risk factor, it accounts for onl) a small number of pregnancies complicated by shoulder dystocia.


Obstentrics_Williams

Obstentrics_Williams. he excessive shoulder and trunk fat that commonly characterizes the macrosomic newborn of a diabetic mother theoretically predisposes such neonates to shoulder dystocia or cesarean delivery (Durnwald, 2004; McFarland, 2000). Landon and associates (2011) identified shoulder dystocia in approximately 4 percent of women with mild gestational diabetes compared with < 1 percent of women with a 50-g glucose screen result < 120 mg/dL. In a ptospective study of fetal adipose measurements, however, Buhling and coworkers (2012) demonstrated no diferences between measurements in 630 ofspring of women with gestational diabetes and 142 without diabetes. he authors attributed this negative inding to successful treatment of gestational diabetes.


Obstentrics_Williams

Obstentrics_Williams. Extensive evidence supports that insulin-like growth factors also playra role in fetal-growth regulation (Chap. 44, p. 845). hese proinsulin-like polypeptides are produced by virtually all fetal organs and are potent stimulators of cell diferentiation and division. Luo and coworkers (2012) reported that insulinlike growth factor-1 strongly correlated with birthweight. he HAPO study investigators also reported dramatic increases in cord-serum C-peptide levels with rising maternal glucose levels following a 75-g OGTT. C-peptide levels above the 90th percentile were found in almost a third of newborns in the highest glucose categories. Other factors implicated in macrosomia include epidermal growth factor, ibroblast growth factor, platelet-derived growth factor, leptin, and adiponectin (Grissa, 2010; Loukovaara, 2004; Mazaki-Tovi, 2005).


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Obstentrics_Williams. Hyperinsulinemia may provoke severe hypoglycemia within minutes of birth, but only three fourths of these episodes occur in the irst 6 hours (Harris, 2012). he deinition of neonatal hypoglycemia is controversial, with recommended clinical thresholds ranging from 35 to 45 mg/dL. An NIH workshop conference on neonatal hypoglycemia supported using a threshold of 35 mg/dL in term newborns but cautioned that this practice is not strictly evidence based (Hay, 2009). Newborns described by the HAPO study (2008) had an incidence of clinical neonatal hypoglycemia that rose with increasing maternal OGTT result values deined in Figure 57-6. The frequency varied from 1 to 2 percent, but it was as high as 4.6 percent in women with fasting glucose levels : 100 mg/ dL. Similarly,


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Obstentrics_Williams. Cho and colleagues (2016), analyzed more than 3000 Korean women who underwent a 50-g OGTT and found that neonates born to women with a screening result :200 mg/dL were 84 times more likely to have hypoglycemia than those born to women with a result < 140 mg/dL. he risk of neonatal hypoglycemia correlates with umbilical cord C-peptide levels. But, importantly, the risk also rises with birthweight, independent of a maternal diabetes diagnosis (Mitanchez, 2014).


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Obstentrics_Williams. Maternal Obesity. In women with gestational diabetes, maternal body mass index (BMI) is an independent and more substantial risk factor for fetal macrosomia than is glucose intolerance (Ehrenberg, 2004; Mission, 2013). Stuebe and associates (2012) completed a secondary analysis of women with either untreated mild gestational diabetes or normal glucose tolerance testing results. They found that higher BMI levels were associated with rising birthweight, regardless of glucose levels. In one analysis of more than 600,000 pregnant women, gestational diabetes, compared with obesity or gestational weight gain, contributed the least to the population-attributable fraction of LGA neonates (Kim, 2014). he highest fraction of LGA neonates was attributable to maternal obesity plus excessive gestational weight gain. Similarly, Egan and colleagues (2014) found that excessive gestational weight gain is common in women with gestational diabetes and confers an additive risk for fetal macrosomia.


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Obstentrics_Williams. weight gain. Similarly, Egan and colleagues (2014) found that excessive gestational weight gain is common in women with gestational diabetes and confers an additive risk for fetal macrosomia. Weight distribution also seems to playra role because the risk of gestational diabetes is greater with maternal truncal obesity. Suresh and colleagues (2012) veriied that increased maternal abdominal subcutaneous fat thickness as measured by sonography at 18 to 22 weeks' gestation correlated with BMI and was a better predictor of gestational diabetes.


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Obstentrics_Williams. Women with gestational diabetes can be divided into two functional classes using fasting glucose levels. Pharmacological methods are usually recommended if diet modiication does not consistently maintain the fasting plasma glucose levels <95 mg/dL or the 2-hour postprandial plasma glucose < 120 mg/dL (American College of Obstetricians and Gynecologists, 2017 a). Whether pharmacological treatment should be used in women with lesser degrees of fasting hyperglycemia is unclear. here have been no controlled trials to identiy ideal glucose targets for fetal risk prevention. On the other hand, the HAPO study (2008) did demonstrate increased fetal risk at glucose levels below the threshold used for diagnosis of diabetes. The Fifth International Workshop Conference recommended that fasting capillary glucose levels be kept ;95 mg/ dL (Metzger, 2007).


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Obstentrics_Williams. In a systematic review, Hartling and colleagues (2013) concluded that treating gestational diabetes resulted in a signiicantly lower incidence of preeclampsia, shoulder dystocia, and macrosomia. For example, the calculated risk ratio was 0.50 for delivering a newborn >4000 g ater treatment. These investigators caution that the attributed risk for these outcomes is low, especially when glucose values are only moderately elevated. Importantly, they were unable to demonstrate an efect on neonatal hypoglycemia or on future metabolic outcomes in the ofspring.


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Obstentrics_Williams. Nutritional instructions generally include a carbohydratecontrolled diet suicient to maintain normoglycemia and avoid ketosis. On average, this includes a daily caloric intake of 30 to 35 kcallkg. Moreno-Castilla and associates (2013) randomly assigned 152 women with gestational diabetes to either a 40-or a 55-percent daily carbohydrate diet and found no diference in insulin levels and pregnancy outcomes. he American College of Obstetricians and Gynecologists (2017 a) suggests that carbohydrate intake be limited to 40 percent of total calories. The remaining calories are apportioned to give 20 percent as protein and 40 percent as fat.


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Obstentrics_Williams. The most appropriate dietary approach for women with gestational diabetes has not been established. One metaanalysis of trials of low-glycemic index diets found that diets higher in complex carbohydrates and dietary iber reduced the risk of macrosomia and likelihood of insulin use in women with gestational diabetes (Wei, 2016). That said, there clearly are limitations to what can be accomplished with various dietary approaches alone. Most and Langer (2012) found that insulin was efective in reducing the risk of excessive birthweight in ofspring of obese women with gestational diabetes. Casey and colleagues (20 15 b) also found that dietary treatment alone for morbidly obese women with mild gestational diabetes did not reduce neonatal fat mass or LGA birthweights.


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Obstentrics_Williams. Few trials have evaluated exercise speciically for women with gestational diabetes. he American College of Obstetricians and Gynecologists (2017a,b) recommends regular physical activity that incorporates aerobic and strength-conditioning exercise during pregnancy and extends this to women with gestational diabetes. Two recent metaanalyses demonstrate that structured exercise programs during pregnancy diminish weight gain during pregnancy and even reduce the risk of developing gestational diabetes (Russo, 2015; Sanabria-Martinez, 2015). Exercise during pregnancy in woman with gestational diabetes also lowers glucose levels Qovanovic-Peterson, 1989).


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Obstentrics_Williams. Hawkins and colleagues (2008) compared outcomes in 315 women with diet-treated gestational diabetes who used personal glucose monitors with those of 615 gestational diabetics who were also diet-treated but who underwent intermittent fasting glucose evaluation during weekly obstetrical visits. Women using daily blood-glucose self monitoring had significantly fewer macrosomic newborns. They also gained less weight after diagnosis than women evaluated during clinic visits only. hese indings support the common practice of blood-glucose self monitors for women with diet-treated gestational diabetes.


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Obstentrics_Williams. Postprandial surveillance for gestational diabetes has been shown to be superior to preprandial surveillance (De Veciana, 1995). At Parkland Hospital, we reviewed the impact of changing to postprandial monitoring in women with diet-treated gestational diabetes and demonstrated a signiicant reduction in maternal weight gain per week-0.63lb/week to 0.45 lb/weekin women managed with a postprandial monitoring schema. The merican College of Obstetricians and Gynecologists (2017 a) and the ADA (20 17b) recommend glucose assessment four times daily. The first check is performed fasting, and the remainder are done 1 or 2 hours ater each meal.


Obstentrics_Williams

Obstentrics_Williams. Historically, insulin has been considered standard therapy in women with gestational diabetes when target glucose levels cannot be consistently achieved through nutrition and exercise. It does not cross the placenta, and tight glycemic control can typically be achieved. Insulin therapy is typically added if fasting levels persistently exceed 95 mg/ dL in women with gestational diabetes. The American College of Obstetricians and Gynecologists (2017 a) also recommends that insulin be considered in women with I-hour postprandial levels that persistently exceed 140 mg/dL or those with 2-hour levelsr> 120 mg/dL. Importantly, all of these thresholds are extrapolated from recommendations for managing women with overt diabetes.


Obstentrics_Williams

Obstentrics_Williams. If insulin is initiated, the starting dose is typically 0.7 to 1.0 units/kg/d and is given in divided doses (American College of Obstetricians and Gynecologists, 2017a). A combination of intermediate-acting and short -acting insulin may be used, and dose adjustments are based on glucose levels at particular times of the day. At Parkland Hospital, the starting daily dose is divided so that two thirds is given in the morning before breakfast and one third in the evening before dinner. In the morning dose, one third is regular insulin and two thirds are NPH (neutral protamine Hagedorn). For the evening dose, one half is regular insulin and the other half is NPH. Insulin instruction for these women is accomplished either in a specialized outpatient clinic or during a short hospital stay. As shown in Table 57-8, insulin analogues such as insulin aspart and insulin lispro have a more rapid onset of action than regular insulin and theoretically could be helpful in postprandial glucose


Obstentrics_Williams

Obstentrics_Williams. As shown in Table 57-8, insulin analogues such as insulin aspart and insulin lispro have a more rapid onset of action than regular insulin and theoretically could be helpful in postprandial glucose management. Experience with these analogues with gestational diabetes is limited, and Singh and coworkers (2009) were unable to demonstrate a beneit compared with conventional insulins.


Obstentrics_Williams

Obstentrics_Williams. Insulin is the preferred first-line agent for persistent hyperglycemia in women with gestational diabetes. However, both the American College of Obstetricians and Gynecologists (2017 a) and the ADA (20 17b) acknowledge that several studies support the safety and eicacy of either glyburide (Micronase) or metformin (Glucophage) (Langer, 2000; Nicholson, 2009; Rowan, 2008). Balsells and colleagues (2015) performed metaanalyses of trials comparing both agents to insulin or to each other. In the seven trials comparing glyburide with insulin, glyburide was associated with higher birthweight, more macrosomia, and more frequent neonatal hypoglycemia. In the six trials comparing metformin with insulin, metformin was associated with less maternal weight gain, more ?reterm birth, and less severe neonatal hypoglycemia. On average from all trials, treatment failures occurred in 6 percent of women treated with glyburide and 34 percent of those treated with metformin. In the two studies comparing


Obstentrics_Williams

Obstentrics_Williams. hypoglycemia. On average from all trials, treatment failures occurred in 6 percent of women treated with glyburide and 34 percent of those treated with metformin. In the two studies comparing oral hypoglycemic agents with each other, metformin treatment was associated with less maternal weight gain, lower birthweight, and less macrosomia. In contrast to trials of each agent compared with insulin, treatment failure rates of both agents in these two studies were equivalent. Importantly, in a randomized trial of glyburide treatment as an adjunct to diet therapy in 395 women with mild gestational diabetes, improvements in pregnancy outcomes in women treated with glyburide.


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Obstentrics_Williams. comes among women treated with glyburide. First, like metfor min, glyburide crosses the placenta and reaches concentrations in the fetus that are more than two thirds of maternal lev els (Caritis, 2013). Additionally, a study of more than 9000 women with gestational diabetes treated with either insulin or glyburide showed a signiicant rise in rates of neonatal intensive care unit admission, respiratory distress, and neonatal hypogly cemia associated with glyburide use (Castillo, 2015).


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Obstentrics_Williams. Metformin reaches fetal serum concentrations similar to maternal levels. However, in one study of 751 women with gestational diabetes who were randomly assigned to metformin or insulin treatment, short-term perinatal adverse events did not difer between groups (Rowan, 2008). Outcomes included neonatal hypoglycemia, respiratory distress syndrome, photo therapy, birth trauma, 5-minute Apgar score .7, and preterm birth. Overall growth of ofspring at age 2 years also did not difer (Rowan, 2011). Nevertheless, the fat distribution in chil dren exposed to metformin showed a tendency toward a more favorable pattern. From a smaller randomized metformin trial, at 18 months, ofspring exposed to metformin were slightly heavier, but markers of early motor or language development did not difer compared with those in ofspring exposed to insulin (Ijas, 2015).


Obstentrics_Williams

Obstentrics_Williams. The Food and Drug Administration has not approved glyburide and metformin use for treatment of gestational diabetes. However, the American College of Obstetricians and Gynecologists (2017 a) recognizes both as reasonable choices for second-line glycemic control in women with gestational diabetes. Because long-term outcomes have not been fully studied, the committee recommends appropriate counseling, which includes disclosing the limitations in current safety data.


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Obstentrics_Williams. In general, for women with gestational diabetes who do not require insulin, early delivery or other interventions are seldom required. here is no consensus regarding the value or timing of antepartum fetal testing. It is typically reserved for women with pregestational diabetes because of the greater stillbirth risk. The American College of Obstetricians and Gynecologists (2017a) endorses fetal surveillance in women with gestational diabetes and poor glycemic control. At Parkland Hospital, women with gestational diabetes are routinely instructed to perform daily fetal kick counts in the third trimester (Chap. 17, p. 332). Insulin-treated women are ofered inpatient admission after 34 weeks' gestation, and antepartum monitoring is performed three times each week.


Obstentrics_Williams

Obstentrics_Williams. Women with gestational diabetes and adequate glycemic control are managed expectantly. Elective labor induction to prevent shoulder dystocia compared with spontaneous labor remains controversial. Alberico and colleagues (2017) recently described their truncated randomized trial of 425 women with tation. Although underpowered, this GINEXMAL Trial dem onstrated no clinically meaningful diference in the cesarean delivery rate between the induction and expectant management groups-12.6 versus 11.8 percent. However, with early labor induction, neonatal hyperbilirubinemia rates were signiicantly higher, and ironically, there was a nonsigniicant threefold greater shoulder dystocia rate. In a retrospective cohort study of 8392 Canadian women with gestational diabetes, Melamed 39 weeks was associated with a lower rate of cesarean delivery but with an elevated rate of neonatal intensive care unit admis sion. The American College of Obstetricians and Gynecologists 39 weeks' gestation. At Parkland


Obstentrics_Williams

Obstentrics_Williams. with a lower rate of cesarean delivery but with an elevated rate of neonatal intensive care unit admis sion. The American College of Obstetricians and Gynecologists 39 weeks' gestation. At Parkland Hospital, women with diet treated gestational diabetes are not electively induced for this indication. However, those treated with insulin are delivered at 38 weeks' gestation.


Obstentrics_Williams

Obstentrics_Williams. Elective cesarean delivery to avoid brachial plexus injuries in overgrown fetuses is another important issue. The American College of Obstetricians and Gynecologists (2017a) has concluded that data are insuicient to determine whether cesarean delivery in women with gestational diabetes whose fetuses have a sonographically estimated weight �4500 g should be performed to avoid risk of birth trauma. From their systematic review, Garabedian and coworkers (2010) estimated that as many as 588 cesarean deliveries in women with gestational diabetes and an estimated fetal weight of �4500 g would be necessary to avoid one case of permanent brachial plexus palsy. Scifres and colleagues (2015), in their retrospective analysis of 903 women with gestational diabetes who underwent so nographic evaluation within 1 month of delivery, demonstrated that sonographic estimates of fetal weight typically overdiagnosed fetuses as being LGA. Only 22 percent of women estimated to have an LGA fetus actually


Obstentrics_Williams

Obstentrics_Williams. within 1 month of delivery, demonstrated that sonographic estimates of fetal weight typically overdiagnosed fetuses as being LGA. Only 22 percent of women estimated to have an LGA fetus actually delivered an overgrown newborn. Still, the American College of Obstetricians and Gynecologists (2016a) acknowledges that prophylactic cesarean delivery may be considered in diabetic women with an estimated fetal weight �4500 g.


Obstentrics_Williams

Obstentrics_Williams. Recommendations for postpartum evaluation are based on the 50-percent likelihood of women with gestational diabetes developing overt diabetes within 20 years (O'Sullivan, 1982). The Fifth International Workshop Conference on Gestational Diabetes recommended that women diagnosed with gestational diabetes undergo postpartum evaluation with a 75-g OGTT (Metzger, 2007). These recommendations are shown in Table 57-14 along with the classification scheme of the ADA (20 17b). Eggleston and colleagues (2016) reviewed insurance claim data from 2000 to 2013 and found that only 24 percent of women with a pregnancy complicated by gestational diabetes underwent postpartum screening within a year, and less than half of those underwent a 75-g OGTT. he American College TABLE 57-14. Fifth International Workshop-Conference: Metabolic Assessments Recommended after Pregnancy with Fasting or random plasma glucose 75-g, 2-hr OGI 75-g, 2-hr OGTI 75-g, 2-hr OGTI 75-g, 2-hr OGTI


Obstentrics_Williams

Obstentrics_Williams. Fasting or random plasma glucose 75-g, 2-hr OGI 75-g, 2-hr OGTI 75-g, 2-hr OGTI 75-g, 2-hr OGTI Classification of the American Diabetes Association (2013) 2 hr <140 mg/dL 2 hr �140-199 mg/dL Hemoglobin A1c<5.7% 5.7-6.4% OGTI = oral glucose tolerance test. Detect persistent, overt diabetes Postpartum classification of glucose metabolism Assess glucose metabolism 2 hr �200 mg/dL �6.5% Data from American Diabetes Association, 2013, 2017a; Metzger, 2007. of Obstetricians and Gynecologists (2017a) recommends either a fasting glucose or the 75-g, 2-hour OGTT at 4 to 12 weeks postpartum for the diagnosis of overt diabetes. he ADA (2017a) recommends testing at least every 3 years in women with a history of gestational diabetes but normal postpartum glucose screening.


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Obstentrics_Williams. Women with a history of gestational diabetes are also at risk for cardiovascular complications associated with dyslipidemia, hypertension, and abdominal obesity-the metabolic syndrome (Chap. 48, p. 937). In a study of 47,909 parous women, Kessous and coworkers (2013) evaluated subsequent hospitalizations due to cardiovascular morbidity. hey found that almost 5000 women with gestational diabetes were 2.6 times more likely to be hospitalized for cardiovascular morbidity. Another study evaluated 483 women between 5 and 10 years ater being diagnosed with mild gestational diabetes (Varner, 2017). Investigators found no increased risk for developing metabolic syndrome associated with additional pregnancies. However, risk for subsequent diabetes rose almost fourfold if gestational diabetes complicated at least one subsequent pregnancy.


Obstentrics_Williams

Obstentrics_Williams. In a metaanalysis of published reports from 1973 through 2014, the pooled gestational diabetes recurrence rate was 48 percent (Schwartz, 2015). Rates in primiparas were lower (40 percent) than in multiparas (73 percent). The same group of investigators identified maternal BMI, insulin use, fetal macrosomia, and weight gain between pregnancies as additional risk factors for gestational diabetes recurrence (Schwartz, 2016). Thus, lifestyle behavioral changes that include weight control and exercise between pregnancies would seem likely to prevent gestational diabetes recurrence. Gueli and colleagues (2016) were unable to demonstrate a lower recurrence rate in women randomized to an exercise program that started before 14 weeks' gestation in a subsequent pregnancy. Conversely, Ehrlich and colleagues (2011) found that prepregnancy loss of at least two BMI units was associated with a lower subsequent risk of gestational diabetes in women who were overweight or obese in the irst pregnancy.


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Obstentrics_Williams. Adane A, Mishra GO, Tooth LR: Diabetes in pregnancy and childhood cognitive development: a systematic review. Pediatrics 137(5):pii:e20154234, 2016 lberico S, Erenbourg A, Hod M, et al: Immediate delivery or expectant management in GDM at term: the GINEXMAL randomised controlled trial. B]OG 124(4):669,t201y Alvarez ]R, Fechner A], Williams SF, et al: Asymptomatic bacteriuria in pregestational diabetic pregnancies and the role of group B streptococcus. Am ] Perinat 27(3):231,t2010 Ambia M, Seacely AR, Macias 0, et al: The impact of baseline proteinuria in pregnancy in a contemporary diabetic population. Presented at the 38th Annual Meeting of the Society for Maternal-Fetal Medicine, January 29-February 3,t2018 American Academy of Ophthalmology: Diabetic Retinopathy PPP-Updated 20 16 . Available at: h ttps: / /www.aao. 0rg/ preferred -p ractice-pattern/ diabeticretinopathy-ppp-updated-2016. Accessed November 5, 2017


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Obstentrics_Williams. American College of Obstetricians and Gynecologists: Management of diabetes mellitus in pregnancy. Technical Bulletin No. 92, May 1986 American College of Obstetricians and Gynecologists: Fetal macrosomia. Practice Bulletin No. 173, November 2016a American College of Obstetricians and Gynecologists: Pregestational diabetes mellitus. Practice Bulletin No. 60, 2005, Reairmed 2016b American College of Obstetricians and Gynecologists: Gestational diabetes mellitus. Practice Bulletin No. 180, ]uly 2017a American College of Obstetricians and Gynecologists: Physical activity and exercise during pregnancy and the postpartum period. Committee Opinion No. 650, December 2015, Reairmed 2017b American Diabetes Association: Classification and diagnosis of diabetes-20 17. Diabetes Care 40(1 Suppl):S005, 2017a American Diabetes Association: Standards of medical care in diabetes-2013. Diabetes Care 36(Suppl 1):Sll, 2013


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Obstentrics_Williams. Diabetes Care 40(1 Suppl):S005, 2017a American Diabetes Association: Standards of medical care in diabetes-2013. Diabetes Care 36(Suppl 1):Sll, 2013 American Diabetes Association: Standards of medical care in diabetes-20 17. Diabetes Care 40(1 Suppl):S 114, 2017b Arun CS, Taylor R: Influence of pregnancy on long-term progression of retinopathy in patients with type 1 diabetes. Diabetologia 51: 1041, 2008 Bacon S, Schmid], McCarthy A, et al: The clinical management ofhyperglycemia in pregnancy complicated by maturity-onset diabetes of the young. Am ] Obstet GynecoIt213(2):236.e1, 2015 Balsells v!, Garda-Patterson A, Sola I, et al: Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BM] 350:h102, 2015 Bantle ]P, Wylie-Rosettt], Albright AL, et al: Nutrition recommendations and interventions for diabetes. Diabetes Care 31(1 Suppl):S61, 2008


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Obstentrics_Williams. Bantle ]P, Wylie-Rosettt], Albright AL, et al: Nutrition recommendations and interventions for diabetes. Diabetes Care 31(1 Suppl):S61, 2008 Bargiota A, Kotoula M, Tsironi E, et al: Diabetic papillopathy in pregnancy. Obstet GynecoItI18:457, 2011 BartSch E, Medcalf KE, Park L, et al: Clinical risk factors for pre-eclampsia determined in early pregnancy: systematic review and meta-analysis of large cohort studies. BM] 353:i 1 53, 2016 Bennett SN, Tita A, Owen ], et al: Assessing White's classification of pregestational diabetes in a contemporary diabetic population. Obstet Gynecol 125(5):1217,t2015 Bental Y, Reichman B, Shif Y, et al: Impact of maternal diabetes mellitus on mortality and morbidity of preterm infants (24-33 weeks gestation). Pediatrics 128:e848, 2011


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Obstentrics_Williams. Bental Y, Reichman B, Shif Y, et al: Impact of maternal diabetes mellitus on mortality and morbidity of preterm infants (24-33 weeks gestation). Pediatrics 128:e848, 2011 Boghossian NS, Hansen NI, Bell EF, et al: Outcomes of extremely preteI'm infants born to insulin-dependent diabetic mothers. Pediatrics 137(6):e20 153424, 2016 Bradley R], Nicolaides KH, Brudenell ]M: Are all infants of diabetic mothers "macrosomic"? BM] 297:1583, 1988 Bryant SN, Herrera CL, Nelson DB, et al: Diabetic ketoacidosis complicating pregnancy.t] Neonatal Perinatal Med ,t2017 Buhling K], Doll I, Siebert G, et al: Relationship between sonographically estimated fetal subcutaneous adipose tissue measurements and neonatal skinfold measurements. Ultrasound Obstet Gynecol 39:558, 2012 Caritis SN, Hebert MF: A pharmacologic approach to the use of glyburide in pregnancy. Obstet Gynecol 121(6):1309,t2013


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Obstentrics_Williams. Caritis SN, Hebert MF: A pharmacologic approach to the use of glyburide in pregnancy. Obstet Gynecol 121(6):1309,t2013 Casey BM, Duryea EL, Abbassi-Ghanavati M, et al: Glyburide in women with mild gestational diabetes: a randomized controlled trial. Obstet Gynecol 126(2):303,t2015a Casey BM, Mele L, Landon MB, et al: Does maternal body mass index influence treatment efect in women with mild gestational diabetes? Amt] Perinatol 32(1):93, 2015b Castillo We, Boggess K, Sturmer T, et al: Association of adverse pregnancy outcomes with glyburide vs insulin in women with gestational diabetes. ]AMA Pediatr 169(5):452,t2015 Catalano PM, Thomas A, Huston-Presley L, et al: Increased fetal adiposity: a very sensitive marker of abnormal in utero development. Am ] Obstet GynecoIt189(6):1698,t2003 Centers for Disease Control and Prevention: Diabetes report card 2014. Updated 2015. Available at: https://ww.cdc.gov/diabetesllibrarylreports/ reportcard.html. Accessed November 9, 2017


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Obstentrics_Williams. Centers for Disease Control and Prevention: Diabetes report card 2014. Updated 2015. Available at: https://ww.cdc.gov/diabetesllibrarylreports/ reportcard.html. Accessed November 9, 2017 Centers for Disease Control and Prevention: National diabetes statistics report, 2017. Available at: https://ww.cdc.gov/diabetes/data/statistics/statisticsreport.html. Accessed November 9,t2017 Chen R, Ben-Haroush A, Weismann-Brenner A, et al: Level of glycemic control and pregnancy outcome in type 1 diabetes: a comparison between multiple daily insulin injections and continuous subcutaneous insulin infusions. Am ] Obstet Gynecol 197 :404e.tl, 2007


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Obstentrics_Williams. Cheng K, Lao TT, Sahota OS, et al: Use of birth weight threshold for macrosomia to identiY fetuses at risk of shoulder dystocia among Chinese populations. Int] Gynecol Obstet 120:249,t2013 Cho Hy, lung I, Kim S]: he association between maternal hyperglycemia and perinatal outcomes in gestational diabetes mellitus patients: a retrospective cohort study. Medicine (Baltimore) 95(36):e4712, 2016 Combs CA: Continuous glucose monitoring and insulin pump therapy for diabetes in pregnancy.t] Matern Fetal Neonatal Med 25(10):2025, 2012 Coustan DR: Delivery: timing, mode, and management. In Reece EA, Coustan DR, Gabbe SG (eds): Diabetes in Women: Adolescence, Pregnancy, and Menopause, 3rd ed. Philadelphia, Lippincott Williams & Wilkins, 2004


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Obstentrics_Williams. SUBCLINICAL HYPOTHYROIDISM. . . . . . . . . . . . . . . .. 1124 IODINE DEFICIENCY ...i..............i.........i..... 1126 CONGENITAL HYPOTHYROIDISM ..i....i.....i....i..... 1127 POSTPARTUM THYROIDITIS.. . . . . . . . . . . . . . . . . . . .. 1127 NODULAR THYROID DISEASE .....i...i....i.......i.....i1128 PARATHYROID DISEASE .....i.......i.......i......i.... 1128 ADRENAL GLAND DISORDERS.. . . . . . . . . . . . . . . . . .. 1130 PITUITARY DISORDERS .i....i.........i....i.....i....i... 1132 In a smal number of cases the thyroid gland increases markedy in size, though we are ignorant as to its signicance. -J. Whitridge Williams (1903)


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Obstentrics_Williams. -J. Whitridge Williams (1903) In 1903, little was known of many endocrine disorders. Still, endocrinopathies seem particularly closely related to pregnancy because of its gestational proclivity for prodigious hormone secretion. This is best illustrated by placental lactogen in diabetes, the most common endocrinopathy encountered in pregnancy (Chap. 57, p. 1097). Pregnancy is also interrelated with some endocrinopathies that are at least partially due to autoimmune dysregulation. Clinical manifestations of this result from complex interplay among genetic, environmental, and endogenous factors that activate the immune system against targeted cells within endocrine organs. An extraordinary example of these interactions comes from studies that implicate maternal organ engraftment by fetal cells that were transferred during pregnancy. These cells later provoke antibody production, tissue destruction, and autoimmune endocrinopathies.


Obstentrics_Williams

Obstentrics_Williams. Taken in aggregate, disorders of the thyroid gland are common in young women and thus frequently encountered in pregnancy. Maternal and fetal thyroid function are intimately related, and drugs that afect the maternal thyroid also afect the fetal gland. Moreover, thyroid autoantibodies have been associated with increased rates of early pregnancy wastage. Also, uncontrolled thyrotoxicosis and untreated hypothyroidism are both associated with adverse pregnancy outcomes. Finally, evidence suggests that the severity of some autoimmune thyroid disorders may be ameliorated during pregnancy, only to be exacerbated postpartum .


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Obstentrics_Williams. Maternal thyroid changes are substantial, and normally altered gland structure and function are sometimes confused with thyroid abnormalities. These alterations are discussed in detail in Chapter 4 (p. 69), and normal serum hormone level values are found in the Appendix (p. 1258). First, maternal serum concentrations of thyroid binding globulin are increased concomitantly with total or bound thyroid hormone levels (Fig. 4-16, p. 70). Second, thyrotropin, also called thyroidstimulating hormone (TSH) , currently plays a central role in screening and diagnosis of many thyroid disorders. Notably, TSH receptors are cross stimulated, albeit weakly, by massive quantities of human chorionic gonadotropin (hCG) secreted 6 2.0 1.5 1 :J0l� Se3 1.0 �2 : 0.5 0.0 o 10 20 30 40


Obstentrics_Williams

Obstentrics_Williams. Se3 1.0 �2 : 0.5 0.0 o 10 20 30 40 FIGURE 58-1 Gestational age specific values for serum thyroid stimulating hormone (TSH) levels (black lines) and free thyroxine (T4) levels (blue lines). Data were derived from 17,298 women tested during pregnancy. For each color, the dark solid lines represent the 50th percentile, whereas the upper and lower light lines represent the 25th and 975th percentiles, respectively. (Data from Casey, 2005; Dashe, 2005.) by placental trophoblast. Because TSH does not cross the placenta, it has no direct fetal efects. During the irst 12 weeks of gestation, when maternal hCG serum levels are maximal, thyroid hormone secretion is stimulated. he resulting greater serum free thyroxine (T4) levels act to suppress hypothalamic thyrotropin-releasing hormone (TRH) and in turn limit pituitary TSH secretion (Fig.


Obstentrics_Williams

Obstentrics_Williams. Accordingly, TRH is undetectable in maternal serum. Conversely, in fetal serum, beginning at midpregnancy, TRH becomes detectable, but levels are static and do not increase. hroughout pregnancy, maternal thyroxine is transferred to the fetus (American College of Obstetricians and Gynecologists, 2017). Maternal thyroxine is important for normal fetal brain development, especially before the onset of fetal thyroid gland function (Bernal, 2007; Korevaar, 2016). And, even though the fetal gland begins concentrating iodine and synthesizing thyroid hormone after 12 weeks' gestation, maternal thyroxine contribution remains important. In fact, maternal sources account for 30 percent of thyroxine in fetal serum at term (horpe-Beeston, 1991). Still, developmental risks associated with maternal hypothyroidism after midpregnancy remain poorly understood (Morreale de Escobar, 2004; Sarkhail, 2016).


Obstentrics_Williams

Obstentrics_Williams. Most thyroid disorders are inextricably linked to autoantibodies against nearly 200 thyrocyte components. These antibodies variably stimulate thyroid function, block function, or cause thyroid inlammation that may lead to follicular cell destruction. Often, these efects overlap or even coexist. Thyroid-stimulating autoantibodies, also called thyroidstimulating immunoglobulins (TSls), bind to the TSH receptor and activate it, causing thyroid hyperfunction and growth. Although these antibodies are identiied in most patients with classic Graves disease, simultaneous production of thyroidstimulating blocking antibodies may blunt this efect Qameson, ;C ..EJ,50 w)0:J::0 w ...•30 ..•5 -..,20 FIGURE 58-2 Incidence in percent of antithyroid peroxidase anti bodies in 16,407 women who are normal or euthyroid, in 233 with isolated maternal hypothyroxinemia (1M H), in 598 with subclinical hypothyroidism (SCH), and in 134 with overt hypothyroidism. (Data from Casey, 2007).


Obstentrics_Williams

Obstentrics_Williams. (Data from Casey, 2007). 2015). Thyroidperoxidase (TPO) is a thyroid gland enzyme that normally functions in the production of thyroid hormones. Thyroid peroxidase antibodies, previously called thyroid microsomal autoantibodies, are directed against TPO and, as shown in Figure 58-2, have been identiied in 5 to 15 percent of all pregnant women (Abbassi-Ghanavati, 2010; Sarkhail, 2016). These antibodies have been associated in some studies with early pregnancy loss and preterm birth (Negro, 2006; Korevaar, 2013; Plowden, 2017; Thangaratinam, 201l). In another study with more than 1000 TPO antibody-positive pregnant women, the risk for preterm birth was not elevated, however, the risk for placental abruption was greater (Abbassi-Ghanavati, 2010). These women are also at high risk for postpartum thyroid dysfunction and at lifelong risk for permanent thyroid failure (Andersen, 2016; Jameson, 2015).


Obstentrics_Williams

Obstentrics_Williams. Autoimmune thyroid disease is much more common in women than in men. One intriguing explanation for this disparity is fetal-to-maternal cell traicking (Greer, 201l). Fetal cells are known to enter maternal circulation during pregnancy. When fetal lymphocytes enter maternal circulation, they can live for more than 20 years. Stem cell interchange can lead to engraftment in several maternal tissues and is termed etal microchimerism. In some cases, this may involve the thyroid gland (Bianchi, 2003; Boddy, 2015; Khosrotehrani, 2004). A high prevalence of Y-chromosome-positive cells has been identiied using luorescence in situ hybridization (FISH) in the thyroid glands of women with Hashimoto thyroiditis-60 percent, or with Graves disease-40 percent (Renne, 2004). In another study of women giving birth to a male fetus, Lepez and colleagues (201l) identiied signiicantly more circulating male mononuclear cells in those with Hashimoto thyroiditis. Ironically, such micro chimerism may have a


Obstentrics_Williams

Obstentrics_Williams. birth to a male fetus, Lepez and colleagues (201l) identiied signiicantly more circulating male mononuclear cells in those with Hashimoto thyroiditis. Ironically, such micro chimerism may have a protective role for autoimmune thyroid disorders (Cirello, 2015).


Obstentrics_Williams

Obstentrics_Williams. TABLE 58-1. Incidence of Overt Hyperthyroidism in Pregnancy Vaidya (2007)a United Kingdom 0.7% Lazarus (2007)b United Kingdom 1.7% Casey (2006r United States 0.4% Andersen (201n6r,d Denmark 0.4-0.7% aScreened irl the first trimester. bScreened at 9-15 weeks. (Screened before 20 weeks. dDiagnosed in early versus later pregnancy. The incidence of thyrotoxicosis or hyperthyroidism in pregnancy is varied and complicates between 2 and 17 per 1000 births when gestational-age appropriate TSH threshold values are used (Table


Obstentrics_Williams

Obstentrics_Williams. The incidence of thyrotoxicosis or hyperthyroidism in pregnancy is varied and complicates between 2 and 17 per 1000 births when gestational-age appropriate TSH threshold values are used (Table Because normal pregnancy simulates some clinical findings similar to thyroxine excess, clinically mild thyrotoxicosis may be diicult to diagnose. Suggestive indings include tachycardia that exceeds that usually seen with normal pregnancy, thyromegaly, exophthalmos, and failure to gain weight despite adequate food intake. Laboratory testing is confirmatory. TSH levels are markedly depressed, while serum free T4 (IT4) levels are elevated Qameson, 2015). Rarely, hyperthyroidism is caused by abnormally high serum triiodothyronine (T 3) levels-so-called Trtoxicosis.


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Obstentrics_Williams. he overwhelming cause of thyrotoxicosis in pregnancy is Graves disease, an organ-speciic autoimmune process associated with thyroid-stimulating TSH-receptor antibodies as previously discussed'(De Leo, 2016). Because these antibodies are specific to Graves hyperthyroidism, such assays have been proposed for diagnosis, management, and prognosis in pregnancies complicated by hyperthyroidism (Barbesino, 2013). At Parkland Hospital, these receptor antibody assays are generally reserved for cases in which fetal thyrotoxicosis is suspected. With Graves disease, during the course of pregnancy, hyperthyroid symptoms may initially worsen because ofhCG stimulation but then subsequently diminish with drops in receptor antibody titers in the second half of pregnancy (Mestman, 2012; Sarkhail, 2016). Amino and coworkers (2003) have found that levels of blocking antibodies also decline during pregnancy.


Obstentrics_Williams

Obstentrics_Williams. Treatment. Thyrotoxicosis during pregnancy can nearly always be controlled by thionamide drugs. Propylthiouracil (PTU) has been historically preferred because it partially inhibits the conversion of T4 to T3 and crosses the placenta less readily than methimazole. he latter has also been associated with a rare methimazole embryopathy, characterized by esophageal or choanal atresia as well as aplasia cutis, a congenital skin defect. yoshihara and associates (2012, 2015) analyzed outcomes in Japanese women with irst-trimester hyperthyroidism and found a twofold increased risk of major fetal malformations in pregnancies exposed to methimazole compared with either PTU or potassium iodide. Speciically, seven of nine cases with aplasia cutis and the only case of esophageal atresia were in the group of methimazole-exposed fetuses. here have also been reports of a PTU-associated embryopathy (Andersen, 2014).


Obstentrics_Williams

Obstentrics_Williams. In 2009, the Food and Drug Administration issued a safety alert on PTU-associated hepatotoxicity. his warning prompted the American Thyroid Association and the American Association of Clinical Endocrinologists (201r1) to recommend PTU therapy during the first trimester followed by methimazole beginning in the second trimester. he obvious disadvantage is that this might lead to poorly controlled thyroid function. Accordingly, at Parkland Hospital, we continue to prescribe PTU treatment throughout pregnancy. Transient leukopenia can be documented in up to 10 percent of women taing antithyroid drugs, but this does not require therapy cessation (American College of Obstetricians and Gynecologists, 2017). In approximately 0.3 percent, however, agranuloytosis develops suddenly and mandates drug discontinuance (Thomas, 2013). It is not dose related, and because of its acute onset, serial leukocyte counts during therapy are not helpul.


Obstentrics_Williams

Obstentrics_Williams. Thus, fever or sore throat develops, women are instructed to discontinue medication immediatey and report or a complete blood count. herapy may have other side efects. First, as noted, hepatotoxicity is a possibility and develops in approximately 0.1 percent of treated women. Serial measurement of hepatic enzyme levels does not prevent fulminant PTU-related hepatotoxicity. Second, approximately 20 percent of patients treated with PTU develop antineutrophil cytoplasmic antibodies NC). Despite this, only a small percentage of these subsequently develops serious vasculitis (Kimura, 2013). Finally, although thionamides have the potential to cause fetal complications, these are uncommon. In some cases, thionamides may even be therapeutic for the fetus, because TSH-receptor antibodies cross the placenta and can stimulate the fetal thyroid gland to cause thyrotoxicosis and goiter.


Obstentrics_Williams

Obstentrics_Williams. The initial thionamide dose is empirical. For nonpregnant patients, the American hyroid Association recommends that methimazole be used at an initial higher daily dose of 10 to 20 mg orally followed by a lower maintenance dose of 5 to 10 mg. If PTU is selected, a dose of 50 to 150 mg orally three times daily may be initiated depending on clinical severity (Bahn, 2011). At Parkland Hospital, we usually initially give 300 or 450 mg of PTU daily in three divided doses for pregnant women. Occasionally, daily doses of 600 mg or higher are necessary. As discussed, we generally do not transition women to methimazole during the second trimester. he goal is treatment with the lowest possible thionamide dose to maintain thyroid hormone levels slightly above or in the high normal range, while TSH levels remains suppressed (Bahn, 2011). Serum free T 4 concentrations are measured every 4 to 6 weeks.


Obstentrics_Williams

Obstentrics_Williams. Subtotal thyroidectomy can be performed after thyrotoxicosis is medically controlled. This seldom is done during pregnancy but may be appropriate for the very few women who cannot adhere to medical treatment or in whom drug therapy proves toxic (Stagnaro-Green, 2012a). Surgery is best accomplished in the second trimester. Potential drawbacks of thyroidectomy include inadvertent resection of parathyroid glands and injury to the recurrent laryngeal nerve.


Obstentrics_Williams

Obstentrics_Williams. Thyroid ablation with therapeutic radioactive iodine is contraindicated during pregnancy. The necessary doses may also cause fetal thyroid gland destruction. Thus, when radioactive iodine is given unintentionally, many clinicians recommend abortion. Any exposed fetus must be carefully evaluated, and the incidence of fetal hypothyroidism depends on gestational age and radioiodine dose (Berlin, 2001). There is no evidence that radioiodine given before pregnancy causes fetal anomalies if enough time has passed to allow radiation efects to dissipate and if the woman is euthyroid (Ayala, 1998). The International Commission on Radiological Protection has recommended that women avoid pregnancy for 6 months after radioablative therapy (Brent, 2008). Moreover, during lactation, the breast also concentrates a substantial amount of iodine. This may pose neonatal risk due to I-containing milk ingestion and maternal risk from significant breast irradiation. To limit the latter, a delay of 3 months


Obstentrics_Williams

Obstentrics_Williams. a substantial amount of iodine. This may pose neonatal risk due to I-containing milk ingestion and maternal risk from significant breast irradiation. To limit the latter, a delay of 3 months after breastfeeding cessation will more reliably ensure complete breast involution.


Obstentrics_Williams

Obstentrics_Williams. Pregnancy Outcome. Women with thyrotoxicosis have pregnancy outcomes that largely depend on whether metabolic control is achieved. For example, excess thyroxine may cause miscarriage or preterm birth (Andersen, 2014; Sheehan, 2015). In untreated women or in those who remain hyperthyroid despite therapy, incidences of preeclampsia, heart failure, and adverse perinatal outcomes are higher (Table 58-2). A prospective cohort study from China showed that women with clinical hyperthyroidism had a 12-fold greater risk of delivering an infant with hearing loss (Su, 2011). In most cases, the perinate is euthyroid. In some, however, hyper-or hypothyroidism can develop with or without a goiter (Fig. 58-3). Clinical hyperthyroidism develops in up to 1 percent of neonates born to women with Graves disease (Barbesino, 2013; Fitzpatrick, 2010). If fetal thyroid disease is


Obstentrics_Williams

Obstentrics_Williams. TABLE 58-2. Pregnancy Outcomes in Women with Overt Thyrotoxicosis aData presented as n (%). Data from Davis, 1989; Kriplani, 1994; Luewan, 201n1; Medici, 2014; Millar, 1994. FIGURE 58-3 Term hypothyroid neonate delivered of a woman with a 3-year history of thyrotoxicosis that recurred at 26 weeks' gestation. The mother was given methimazole 30 mg orally daily and was euthyroid at delivery. suspected, nomograms are available for sonographically mea sured thyroid volume (Gietka-Czernel, 2012).


Obstentrics_Williams

Obstentrics_Williams. The fetus or neonate who was exposed to excessive maternal thyroxine may have any of several clinical presentations. First, goitrous thyrotoxicosis is caused by placental transfer of thyroidstimulating immunoglobulins. Nonimmune hydrops and fetal demise have been reported with fetal thyrotoxicosis (Nachum, 2003; Stulberg, 2000). The best predictor of perinatal thyrotoxicosis is presence of thyroid-stimulating TSH-receptor antibodies in women with Graves disease (Nathan, 2014). This is especially true if their levels are more than threefold higher than the upper normal limit (Barbesino, 2013). In a study of 72 pregnant women with Graves disease, Luton and associates (2005) reported that none of the fetuses in 31 low-risk mothers had a goiter, and all were euthyroid at delivery. Low risk was defined as no requirement for antithyroid medications during the third trimester or an absence of antithyroid antibodies. Conversely, in a group of 41 women who either were taking antithyroid


Obstentrics_Williams

Obstentrics_Williams. was defined as no requirement for antithyroid medications during the third trimester or an absence of antithyroid antibodies. Conversely, in a group of 41 women who either were taking antithyroid medication at delivery or had thyroid receptor antibodies, 11 fetuses-27 percent-had sonographic evidence of a goiter at 32 weeks' gestation. Seven of these 11 fetuses were determined to be hypothyroid, and the remaining fetuses were hyperthyroid. In response to these results, the merican Thyroid Association and American Association of Clinical Endocrinologists (201r1) recommend routine evaluation of TSH-receptor antibodies between 22 and 26 weeks' gestation in women with Graves disease. he American College of Obstetricians and Gynecologists (2017), however, does not recommend such testing. If the fetus is thyrotoxic, maternal thionamide drugs are adjusted even though maternal thyroid function may be within the targeted range (Mestman, 2012). lthough usually short-lived, neonatal


Obstentrics_Williams

Obstentrics_Williams. If the fetus is thyrotoxic, maternal thionamide drugs are adjusted even though maternal thyroid function may be within the targeted range (Mestman, 2012). lthough usually short-lived, neonatal thyrotoxicosis may require short-course antithyroid drug treatment (Levy-Shraga, 2014; Nathan, 2014).


Obstentrics_Williams

Obstentrics_Williams. A second presentation is goitrous hypothyroidism caused by fetal exposure to maternally administered thionamides (see Fig. 58-3). Although there are theoretical neurological implications, reports of adverse fetal efects seem to have been exaggerated. Available data indicate that thionamides carry an extremely small risk for causing neonatal hypothyroidism (Momotani, 1997; O'Doherty, 1999). For example, in at least 239 treated thyrotoxic women shown in Table 58-1, evidence of hypothyroidism was found in only four newborns. Furthermore, at least four long-term studies report no abnormal intellectual and physical development of these children (Mestman, 1998). If maternal hypothyroidism developed, the fetus can be treated by a reduced maternal antithyroid medication dose and injections of intraamnionic thyroxine if necessary.


Obstentrics_Williams

Obstentrics_Williams. A third presentation, nongoitrous hypothyroidism, may develop from transplacental passage of maternal TSH-receptor blocking antibodies (Fitzpatrick, 2010; Gallagher, 2001). And finally,etal thyrotoxicosis after maternal thyroid gland ablation, usually with 1 radioiodine, may result from transplacental thyroid-stimulating antibodies. In one report of early fetal exposure to radioiodine, neonatal thyroid studies indicated transient hyperthyroidism from maternal transfer of stimulating antibodies (Tran, 2010).


Obstentrics_Williams

Obstentrics_Williams. Fetal Diagnosis. Evaluation of fetal thyroid function is somewhat controversial. Although the fetal thyroid volume can be measured sonographically in women taking thionamide drugs or in those with thyroid-stimulating antibodies, most investigators do not currently recommend this routinely (Cohen, 2003; Luton, 2005). Kilpatrick (2003) recommends umbilical cord blood sampling and fetal antibody testing only if the mother has previously undergone radioiodine ablation. Because fetal hyper-or hypothyroidism may cause hydrops, growth restriction, goiter, or tachycardia, fetal blood sampling may be appropriate if these are identified (Brand, 2005). he Endocrine Society clinical practice guidelines recommend umbilical cord blood sampling only when the diagnosis of fetal thyroid disease cannot be reasonably ascertained based on clinical and sonographic data (Garber, 2012). Diagnosis and treatment are considered further in Chapter 16 (p. 318).


Obstentrics_Williams

Obstentrics_Williams. Both of these are acute and life-threatening in pregnancy. hyroid storm is a hypermetabolic state and is rare in pregnancy. In contrast, pulmonary hypertension and heart failure from cardiomyopathy caused by the profound myocardial efects of thyroxine are common in pregnant women (Sheield, 2004). As shown in Table 58-2, heart failure developed in 8 percent of 90 women with uncontrolled thyrotoxicosis. In these women, cardiomyopathy is characterized by a high-output state, which may lead to a dilated cardiomyopathy (Fadel, 2000; Klein, 1998). The pregnant woman with thyrotoxicosis has minimal cardiac reserve, and decompensation is usually precipitated by preeclampsia, anemia, sepsis, or a combination of these. Fortunately, thyroxine-induced cardiomyopathy and pulmonary hypertension are frequently reversible (Sheield, 2004; Siu, 2007; Vydt, 2006).


Obstentrics_Williams

Obstentrics_Williams. Management. Treatment is similar for thyroid storm and heart failure and should be carried out in an intensive care area that may include special-care units within labor and delivery (American College of Obstetricians and Gynecologists, 2017). Shown in Figure 58-4 is our stepwise approach to medical management of thyroid storm or thyrotoxic heart failure. An hour or two ater initial thionamide administration, iodide is given to inhibit thyroidal release ofT3 and T4. It can be given intravenously as sodium iodide or orally as either saturated solution of potassium iodide (SSKI) or Lugol solution. With a history of iodine-induced anaphylaxis, lithium carbonate, 300 mg every 6 hours, is given instead. Most authorities recommend dexamethasone, 2 mg intravenously every 6 hours for four doses, to further block peripheral conversion ofT4 to T3. If a 3-blocker drug is given to control tachycardia, its efect on heart failure must be considered. Propranolol, labetalol, and esmolol have all been


Obstentrics_Williams

Obstentrics_Williams. further block peripheral conversion ofT4 to T3. If a 3-blocker drug is given to control tachycardia, its efect on heart failure must be considered. Propranolol, labetalol, and esmolol have all been used successfully. Coexisting severe preeclampsia, infection, or anemia should be aggressively managed before delivery is considered.


Obstentrics_Williams

Obstentrics_Williams. Transient biochemical features of hyperthyroidism may be observed in 2 to 15 percent of women in early pregnancy (Fitzpatrick, 2010). Many women with hyperemesis gravidarum have abnormally high serum thyroxine levels and low TSH levels (Chap. 54, p. 1045). his results from TSH-receptor stimulation from massive-but normal for pregnancyconcentrations of hCG. This transient condition is also termed gestational transient thyrotoxicosis. Even if associated with hyperemesis, antithyroid drugs are not warranted (American College of Obstetricians and Gynecologists, 2017). The degree of hCG level elevation does not correlate with thyroxine and TSH values, which become more normal by midpregnancy (Nathan, 2014; Yoshihara, 2015).


Obstentrics_Williams

Obstentrics_Williams. he prevalence of increased thyroxine levels in women with a molar pregnancy ranges between 25 and 65 percent (Hershman, 2004). As discussed, abnormally high hCG levels lead to overstimulation of the TSH receptor. Because these tumors are now usually diagnosed early, clinically apparent hyperthyroidism has become less common. With molar evacuation, serum free T4 levels usually normalize rapidly in parallel with declining hCG concentrations. This is discussed further in Chapter 20 (p. 391).


Obstentrics_Williams

Obstentrics_Williams. hird-generation TSH assays with an analytical sensitivity of 0.002 mU/mL permit identiication of subclinical thyroid disorders. These biochemically defined extremes usually represent normal biological variations but may herald the earliest stages of thyroid dysfunction. Subclinical hyperthyroidism is characterized by an abnormally low serum TSH concentration in concert with normal thyroxine hormone levels (Surks, 2004). Long-term efects of persistent subclinical thyrotoxicosis include osteoporosis, cardiovascular morbidity, and progression After 1-2 hours of thionamide therapy start iodine: if iodine anaphylaxis history, Lithium carbonate 300 mg PO every 6 hr Consider corticosteroid therapy for 24 hours: FIGURE 58-4 One management method for thyroid storm or thyrotoxic heart failure. gtt = drops; IV = intravenous; NGT = nasogastric tube; PO = orally; PTU = propylthiouracil.


Obstentrics_Williams

Obstentrics_Williams. FIGURE 58-4 One management method for thyroid storm or thyrotoxic heart failure. gtt = drops; IV = intravenous; NGT = nasogastric tube; PO = orally; PTU = propylthiouracil. to overt thyrotoxicosis or thyroid failure. Casey and Leveno (2006) reported that subclinical hyperthyroidism was found in 1.7 percent of pregnant women. Importantly, subclinical hyperthyroidism was not associated with adverse pregnancy outcomes. In separate retrospective analyses of almost 25,000 women who underwent thyroid screening throughout pregnancy, Wilson and colleagues (2012) and Tudela and coworkers (2012) also found no relationship between subclinical hyperthyroidism and preeclampsia or gestational diabetes. Treatment of subclinical hyperthyroidism is unwarranted in pregnancy because antithyroid drugs may afect the fetus. hese women may beneit from periodic surveillance, and approximately half eventually have normal TSH concentrations.


Obstentrics_Williams

Obstentrics_Williams. Overt or symptomatic hypothyroidism, as shown in Table 58-3, more likely in women in areas of endemic iodine deiciency or those with Hashimoto thyroiditis. Other indings include edema, dry skin, hair loss, and prolonged relaxation phase of deep tendon relexes. Clinical or overt hypothyroidism is conirmed when an abnormally high serum TSH level is accompanied by an abnormally low thyroxine level. Subclinical TABLE 58-3. Frequency of Overt Hypothyroidism Wang (201n1)a China 0.3% Cleary-Goldman (2008)a United States 0.3% Vaidya (2007)d United Kingdom 1.0% Casey (200S)b United States 0.2% Andersen (2016)d Denmark 1.2% has been reported to complicate between 2 and 12 per 1000 aScreened during first trimester. pregnancies. It is characterized by insidious nonspeciic clini bScreened before 20 weeks. cal indings that include fatigue, constipation, cold intolerance, (Includes those treated before pregnancy.


Obstentrics_Williams

Obstentrics_Williams. pregnancies. It is characterized by insidious nonspeciic clini bScreened before 20 weeks. cal indings that include fatigue, constipation, cold intolerance, (Includes those treated before pregnancy. muscle cramps, and weight gain. A pathologically enlarged thy dDiagnosed in early versus later pregnancy. roid gland depends on the etiology of hypothyroidism and is hypothyroidism, discussed later, is defined by an elevated serum TSH level and normal serum thyroxine concentration Qameson, 2015). Sometimes included in the spectrum of subclinical thyroid disease are asymptomatic individuals with high levels of anti-TPO or anti thyroglobulin antibodies. Autoimmune euthyroid disease represents a new investigative frontier in screening and treatment of thyroid dysfunction during pregnancy.


Obstentrics_Williams

Obstentrics_Williams. he most common cause of hypothyroidism in pregnancy is Hashimoto thyroiditis, characterized by glandular destruction from autoantibodies, particularly anti-TPO antibodies. Another cause is postablative Graves disease. Clinical identiication of hypothyroidism is especially diicult during pregnancy because many of the signs or symptoms are also common to pregnancy itself. Thyroid analyte testing should be performed on symptomatic women or those with a history of thyroid disease (American College of Obstetricians and Gynecologists, 2017). Severe hypothyroidism during pregnancy is uncommon, probably because it is often associated with infertility and higher spontaneous abortion rates (De Groot, 2012). Even women with treated hypothyroidism undergoing in vitro fertilization have a significantly lower chance of achieving pregnancy (Scoccia,r2012).


Obstentrics_Williams

Obstentrics_Williams. Treatment. The American hyroid Association and American Association of Clinical Endocrinologists (2011) recommend replacement therapy for overt hypothyroidism beginning with levothyroxine in doses of 1 to 2 ILg/kgl d or approximately 100 Lg daily. Women who are athyreotic after thyroidectomy or radioiodine therapy may require higher doses. Surveillance is with TSH levels measured at 4-to 6-week intervals, and the thyroxine dose is adjusted by 25-to 50-lLg increments until TSH values become normal. Pregnancy is associated with an increased thyroxine requirement in approximately a third of supplemented women (Abalovich, 2010; Alexander, 2004). The increased demand in pregnancy is believed to be related to augmented estrogen production (Arafah, 2001).


Obstentrics_Williams

Obstentrics_Williams. Greater thyroxine requirements begin as early as 5 weeks' gestation. In a randomized trial that provided an increased levothyroxine dose at pregnancy confirmation in 60 mothers, Yassa and coworkers (2010) found that a 29-to 43-percent increase in the weekly dose maintained serum TSH values <5.0 mUlL during the first trimester in all women. Importantly, however, this increase caused TSH suppression in more than a third of women. Significant hypothyroidism may develop early in women without thyroid reserve, such as those with a previous thyroidectomy, those with prior radioiodine ablation, or those undergoing assisted reproductive techniques (Alexander, 2004; Loh, 2009). Anticipatory 25-percent increases in thyroxine replacement at pregnancy conirmation will reduce this likelihood. All other women with hypothyroidism should instead undergo TSH testing at initiation of prenatal care.


Obstentrics_Williams

Obstentrics_Williams. Pregnancy Outcome with Overt Hypothyroidism. Observational studies, although limited, indicate that excessive adverse perinatal outcomes are associated with overt thyroxine TABLE 58-4. Pregnancy Complications in 440 Women with Hypothyroidism a,bBirthweight <2000 gr apreterm or term deliveries were the only outcomes reported by Abalovich, 2002. SU,r2011. COne infant died from syphilis. Data from Abalovich, 2002; Davis, 1988; leung, 1993; Mannistb, 2009; Su, 2011. deficiency (Table 58-4). Preterm birth rates, for example, are higher (Sheehan, 2015). With appropriate replacement therapy, however, rates of adverse efects are not increased in most reports (Bryant, 2015; Matalon, 2006; Tan, 2006). In one dissenting study, however, risks for some pregnancy complications were greater even in women taking replacement therapy (Wikner, 2008). Most experts agree that adequate hormone replacement during pregnancy minimizes the risk of adverse outcomes and most complications.


Obstentrics_Williams

Obstentrics_Williams. Fetal and Neonatal Efects. Undoubtedly, maternal and fetal thyroid abnormalities are related. In both, thyroid unction is dependent on adequate iodide intake, and its deiciency early in pregnancy can cause both maternal and fetal hypothyroidism. And, as discussed, maternal TSH-receptor-blocking antibodies can cross the placenta and cause fetal thyroid dysunction. Rovelli and colleagues (2010) evaluated 129 neonates born to women with autoimmune thyroiditis. They found that 28 percent had an elevated TSH level on the third or fourth day of life, and 47 percent of these had TPO antibodies on day 15. Still, autoantibodies were undetectable at 6 months of age. It seems paradoxical that despite these transient laboratory findings in the neonate, TPO and anti thyroglobulin antibodies have little or no efect on etalthyroid function (Fisher, 1997). Indeed, prevalence of fetal hypothyroidism in women with Hashimoto thyroiditis is estimated to be only 1 in 180,000 newborns (Brown, 1996).


Obstentrics_Williams

Obstentrics_Williams. Although common in women, the incidence of subclinical hypothyroidism varies depending on age, race, dietary iodine intake, and serum TSH thresholds used to establish the diagnosis Qameson, 2015). In two large studies totaling more than 25,000 pregnant women screened in the first half of pregnancy, subclinical hypothyroidism was identified in 2.3 percent (Casey, 2005; Cleary-Goldman, 2008). he rate of progression to overt thyroid failure is afected by TSH level, age, other disorders such as diabetes, and presence and concentration of antithyroid antibodies. nant women with subclinical hypothyroidism for 5 years and reported that in a third, TSH values became normal. In the other two thirds, those women whose TSH levels were 10 to 15 mUlL developed overt disease at a rate of 19 per 100 patient years. Those women whose TSH levels were < 10rm U IL devel oped overt hypothyroidism at a rate of 2 per 100 patient years.


Obstentrics_Williams

Obstentrics_Williams. pregnant individuals, the U.S. Preventative Services Task Force (Helfand, 2004; Karmisholt, 2008). For gravidas, in a 20-year follow-up study of 5805 women who were screened in early pregnancy, only 3 percent developed thyroid disease. Of the 224 women identified with subclinical hypothyroidism during pregnancy, 17 percent developed thy roid disease in the next 20 years, and most of these had either TPO or thyroglobulin antibodies during pregnancy (Mannisto, 2010). hus, the likelihood of progression to overt hypothy roidism during pregnancy in otherwise healthy women with subclinical hypothyroidism seems remote.