An algorithm for the treatment of type 2 diabetes in Latin America.

Diabetes is a principal and growing health concern in Latin America, accounting for significant mortality and morbidities. Large, randomized, prospective trials of various interventional therapies in patients with both type 1 and type 2 diabetes have demonstrated that reductions in hyperglycaemia and management of diabetes-related risk factors can significantly reduce the micro- and macrovascular complications of diabetes. Therefore, patients with type 2 diabetes will benefit from more aggressive treatment regimens to help decrease the occurrence and rate of progression of diabetic complications. Given the many complexities of diabetes management, it is often difficult for general practice physicians to stay abreast of emerging treatment strategies and therapies. Owing to the high prevalence of type 2 diabetes in Latin America, the majority of patients with diabetes are treated by generalists rather than specialists. This article was intended to assist physicians and other healthcare professionals in developing and using effective treatment strategies to stem the growing epidemic of diabetes and its complications in Latin America.

Diagnosis and management of maternal and fetal thyroid disorders.

Thyroid diseases in pregnancy are a group of disorders with different clinical manifestations which require a rational approach in their diagnosis and management. In many cases, this involves a team approach including different specialties. Several topics have received particular attention in recently published reports. The syndrome of transient hyperthyroidism of hyperemesis gravidarum, more frequently recognized and considered to be caused by inappropriate concentrations of human chorionic gonadotropin in plasma, has been reported for the first time to be secondary to a mutation in the thyrotropin-releasing hormone receptor. Mutations in the thyrotropin-releasing hormone receptor have also being found in cases, most of them familiar, of congenital hypothyroidism caused by resistance to thyrotropin-releasing hormone. However, other cases of congenital hypothyroidism with resistance to thyrotropin-releasing hormone were not caused by mutations in the thyrotropin-releasing hormone receptor. This is a fascinating new field in molecular medicine, stimulated by clinical observations in infants born with congenital hypothyroidism that did not fulfill the classical clinical descriptions. New studies in the metabolism and transfer of anti-thyroid drugs from mother to fetus have indicated no differences between propylthiouracil and methimazole. Finally, changes in titers and the biological action of thyrotropin-releasing hormone receptors antibodies appear to explain the clinical observation of improvement in Graves' hyperthyroidism during the second half of pregnancy and its recurrence during the postpartum period.

Hyperthyroidism in pregnancy.

Hyperthyroidism is second to diabetes mellitus as the most common endocrinopathy in pregnancy. Inappropriate secretion of hCG is the most common cause of hyperthyroidism in the first part of gestation. In addition to hydatidiform mole and hyperemesis gravidarum, nonpathologic-conditions including multiple gestation, mild nausea and vomiting, and even normal pregnancies may present with transient undetectable or suppressed serum TSH values. The syndrome of transient hyperthyroidism of hyperemesis gravidarum is defined as severe nausea and vomiting, dehydration, ketonuria, and weight loss of more than 5% by 6 to 9 weeks of pregnancy. Thyroid tests are in the hyperthyroid range, and the abnormalities are related to the severity of symptoms. Tests normalize with resolution of the vomiting, and ATD therapy is not indicated. The natural history of Graves' disease in pregnancy is characterized by aggravation in the first trimester, amelioration in the second half, and recurrence in the year following delivery. ATD treatment is the therapy of choice in pregnancy. Either PTU or MMI may be used; the goal is to keep the FT4I in the upper limits of normal with the minimum dose of ATD. In approximately 30% of patients, ATDs may be discontinued in the last few weeks of gestation. Maternal, fetal, and neonatal complications are frequent when hyperthyroidism is not under control. Postpartum hyperthyroidism may be caused by an episode of silent thyroiditis or Graves' disease.

Parathyroid disorders of pregnancy.

Diseases of the parathyroid gland are uncommon in women of childbearing age. However, total serum calcium is lower in normal pregnancy, but ionized serum calcium remains within normal limits. Serum parathyroid levels are slightly decreased in the second half of pregnancy. Primary hyperparathyroidism, if unrecognized, may increase maternal and fetal morbidity, which is related to the level of serum calcium. The most common cause is a single parathyroid adenoma, accounting for about 80% of cases. Maternal complications include acute pancreatitis, hypercalcemia crisis, and toxemia. An increased incidence of prematurity and neonatal hypocalcemia has been reported when maternal hypercalcemia is significantly elevated. Other causes of hypercalcemia are rare in pregnancy. Hypoparathyroidism is seldom seen in pregnancy; the most common cause is after surgical throidectomy. The doses of vitamin D and calcium do not change during pregnancy; however, hypercalcemia may develop in the postpartum period. Serum calcium should be determined at every trimester of pregnancy and at regular intervals after delivery, and in a significant number of patients, the dose of vitamin D should be reduced. Osteoporosis has been recognized most frequently in the last few years. It appears that those patients with a family history of osteoporosis and those on heparin therapy have a tendency to develop symptoms of the disease in pregnancy. Finally, lactation is not contraindicated in women with osteoporosis; although there is a slight decrease in bone density in the few months after delivery, this is a transient event and bone densitometry returns to prepregnancy levels in most women. Recent studies indicate that there is no need for calcium therapy during lactation with few exceptions, such as lactating adolescents, mothers nursing more than one child, and mothers with closely-spaced pregnancies.

Hyperthyroidism in pregnancy.

The prevalence of hyperthyroidism in pregnancy is about 0.2%. The most common cause is Graves' disease. Maternal, fetal, and neonatal morbidity and mortality may be reduced to a minimum with careful attention to the clinical symptoms and interpretation of thyroid tests. Ideally, hyperthyroid women should be rendered euthyroid before considering conception. The incidence of maternal and neonatal morbidity is significantly higher in those patients whose hyperthyroidism is not medically controlled. Even the incidence of thyroid storm is high in women who are under poor medical supervision in the presence of a medical or obstetric complication. Maternal morbidity includes a higher incidence of toxemia, premature delivery, placenta abruptio, congestive heart failure, and thyroid crisis. In some series, anemia and infections were also reported. Neonatal morbidity includes SGA neonates, intrauterine growth retardation, LBW infants, and prematurity. Fetal goiter and transient neonatal hypothyroidism is occasionally reported in infants of mothers who have been overtreated with ATD. Propylthiouracil and MMI are equally effective in controlling the disease. In most patients, symptoms improved and thyroid tests returned to normal in 3-8 weeks after initiation of therapy. Resistance to ATD is extremely rare, most cases are caused by patient poor compliance. Surgery for the treatment of hyperthyroidism is reserved for the unusual patient who is allergic to both ATD; to those who have large goiters; to those who require large doses of ATD; or to those patients who poorly comply. Fetal and neonatal hyperthyroidism can be predicted in the majority of cases by the previous maternal medical and obstetric history and by the proper interpretation of thyroid tests. Finally, hyperthyroidism may recur in the postpartum period.

Primary hyperparathyroidism during pregnancy.

OBJECTIVE: To provide an up-to-date review of primary hyperparathyroidism (HPT) as a complication of pregnancy. METHODS: We discuss the initial manifestations of primary HPT in pregnant patients, the diagnosis, the differential diagnosis of hypercalcemia, and the recommended treatment strategies. RESULTS: In the nonpregnant state, 50 to 80% of patients with primary HPT are asymptomatic. In contrast, pregnant patients with primary HPT have a wide variety of symptoms and findings: gastrointestinal symptoms (nausea, vomiting, and anorexia), weakness and fatigue, headaches and confusion, nephrolithiasis, bone disease, pancreatitis, urinary tract infection, and hypertension. Occasionally, neonatal hypocalcemia is the initial manifestation of maternal HPT. Diagnosis of primary HPT during pregnancy is dependent on the clinical history and laboratory findings. In general, management of maternal primary HPT during pregnancy should be individualized and based on the patient's symptoms, general medical condition, severity of disease, and gestational stage at the time of diagnosis. If HPT is diagnosed during the first two trimesters, surgical intervention is the treatment of choice. CONCLUSION: Although uncommon, HPT during pregnancy may be associated with maternal and perinatal complications. Therefore, clinicians should be aware of the usual characteristics of this disorder and the preferred management options.

Congenital malformations in pregnancies complicated by NIDDM.

OBJECTIVE: To determine whether the use of oral hypoglycemic agents during early pregnancy is associated with a risk of congenital malformations in infants of mothers with non-insulin-dependent diabetes mellitus (NIDDM) independent of maternal metabolic control. RESEARCH DESIGN AND METHODS: From a prospectively collected data-base of pregnancies complicated by diabetes at a large urban medical center, we identified 332 consecutive infants born to women with NIDDM who did not participate in a preconceptional diabetes care program. Stepwise logistical regression was used to identify maternal characteristics that were independently associated with risks of major and minor congenital malformations in infants. RESULTS: Overall, 56 (16.9%) of the 332 infants were born with congenital anomalies (11.7% major anomalies and 5.1% minor anomalies). Analysis of data from subgroups of women who were treated with diet therapy, exogenous insulin, or sulfonylurea compounds during the first 8 weeks of gestation did not reveal statistically significant differences in major or minor malformation rates among the three groups. Stepwise logistic regression analysis revealed two maternal characteristics that were independently associated with major malformations in infants: maternal HbA1c at initial presentation for care (direct relationship; P = 0.0007) and the maternal age at onset of diabetes (inverse relationship; P = 0.009). The risk of major malformations was unrelated to the mode of antidiabetic therapy during early pregnancy. No relationship was found between maternal glycemia or treatment modality and rates of minor congenital anomalies. CONCLUSIONS: These data indicate that, in the absence of special preconceptional care, NIDDM is associated with a risk for major congenital anomalies that is in the range reported for pregnancies complicated by insulin-dependent diabetes mellitus. Moreover, the risk in individual patients appears to be related to maternal glycemic control rather than to the mode of antidiabetic therapy during early pregnancy.

Thyroid disorders of pregnancy.

Practical aspects in the management of thyroid diseases in pregnancy are reviewed. Information on the hypothalamic-pituitary thyroid axis function in pregnancy and transplacental passages of thyroid hormones is discussed. Diagnosis and management of thyroid dysfunction in pregnancy are updated together with the management of women on thyroid replacement therapy at the time of conception. A practical evaluation of thyroid nodules in pregnancy is suggested. Finally, the syndrome of postpartum thyroid dysfunction is reviewed, stressing the importance of proper diagnosis and the need for long-term follow-up evaluation of these patients.

Management of thyroid nodules during pregnancy.

Guidelines for the management of thyroid nodules discovered during pregnancy have not yet been established. The authors reviewed the records of 23 patients with thyroid nodules that were first detected during pregnancy. These patients were divided into three groups according to how they were managed. Seven patients who presented early in pregnancy had their work-up completed during pregnancy, 11 patients underwent biopsy after delivery, and 5 patients were managed with observation alone. The incidence of malignancy in the series was 39%. Four patients underwent surgery during pregnancy, and 7 patients were operated on in the postpartum period. No fetal morbidity or mortality occurred. The authors recommend that fine-needle aspiration be performed in patients who present before 20 weeks of gestation with rapidly enlarging thyroid nodules, nodules associated with palpable cervical adenopathy, solid nodules larger than 2 cm, or cystic nodules larger than 4 cm. Growth of a nodule while a patient is receiving thyroid hormone suppression therapy is highly suspicious for malignancy; in this situation, consideration should be given to performing biopsy later in gestation.

Low birth weight and preeclampsia in pregnancies complicated by hyperthyroidism.

OBJECTIVE: To determine whether control of hyperthyroidism during pregnancy reduces the risk of low birth weight infants and severe preeclampsia. METHODS: Labor, delivery, and postpartum records of 181 hyperthyroid women were reviewed for maternal and fetal outcomes. Subjects were separated into three groups based on their thyroid status: controlled (n = 34), including women who were euthyroid at presentation and delivery; controlled during pregnancy (n = 90), including women who were hyperthyroid at presentation and euthyroid at delivery; and uncontrolled (n = 57), including women who were hyperthyroid at presentation and delivery. RESULTS: The risk of low birth weight infants was 0.74 (95% confidence interval [CI] 0.18-3.08) among controlled women, 2.36 (95% CI 1.36-4.12) among women who were controlled during pregnancy, and 9.24 (95% CI 5.47-15.6) among women who were uncontrolled during pregnancy compared to the incidence among nonhyperthyroid mothers. The risk of severe preeclampsia was significantly higher (odds ratio 4.74, 95% CI 1.14-19.7) among uncontrolled women compared with those who were controlled during their pregnancies. Elevated TSH-receptor antibody levels were not related to preeclampsia. Maternal thioamide therapy did not adversely affect neonatal outcomes. CONCLUSION: Lack of control of hyperthyroidism significantly increases the risk of low birth weight infants and severe preeclampsia.

A comparison of propylthiouracil versus methimazole in the treatment of hyperthyroidism in pregnancy.

OBJECTIVE: Our purpose was to demonstrate that propylthiouracil and methimazole are equally effective and safe in the treatment of hyperthyroidism during pregnancy. STUDY DESIGN: Between 1974 and 1990 records were available on 185 pregnant patients with a history or diagnosis of hyperthyroidism. Ninety-nine patients were treated with propylthiouracil and 36 with methimazole. The response to therapy was compared with respect to the time to normalization of the free thyroxine index and the incidences of congenital anomalies and hypothyroidism. RESULTS: The time to normalization of the free thyroxine index was compared in the two groups by means of survival analysis. The median time to normalization of the free thyroxine index on propylthiouracil and methimazole was 7 and 8 weeks, respectively (p = 0.34, log-rank test). The incidence of major congenital malformations in mothers treated with propylthiouracil and methimazole was 3.0% and 2.7%, respectively. No neonatal scalp defects were seen. One infant was overtly hypothyroid at delivery. CONCLUSION: Propylthiouracil and methimazole are equally effective and safe in the treatment of hyperthyroidism in pregnancy.

Insulin-requiring diabetes in pregnancy: a randomized trial of active induction of labor and expectant management.

OBJECTIVE: Our purpose was to assess whether a program of expectant management of uncomplicated pregnancies in mothers with insulin-requiring gestational or pregestational class B reduces the incidence of cesarean birth. STUDY DESIGN: Two hundred women with uncomplicated, insulin-requiring diabetes at 38 weeks' gestation who were compliant with care and whose infants were judged appropriate for gestational age were randomly assigned to (1) active induction of labor within 5 days or (2) expectant management. The expectant management group was monitored with weekly physical examination and twice-weekly nonstress tests and amniotic fluid volume estimation until delivery. RESULTS: Expectant management increased the gestational age at delivery by 1 week. Approximately half (49%) of the mothers in the expectant management group required induction of labor for obstetric indications. The cesarean delivery rate was not significantly different in the expectant management group (31%) from the active induction group (25%). The mean birth weight (3672 +/- 407 gm) and percentage large for gestational age, as defined by birth weight > or = 90th percentile, of infants in the expectantly managed group (23%) was greater than those in the active induction group (3466 +/- 372 gm, p < 0.0001, 10% large for gestational age). This difference persisted after controlling for gestational age and maternal age and body weight (p < 0.01). CONCLUSION: In women with uncomplicated insulin-requiring gestational or class B pregestational diabetes, expectant management of pregnancy after 38 weeks' gestation did not reduce the incidence of cesarean delivery. Moreover, there was an increased prevalence of large-for-gestational-age infants (23% vs 10%) and shoulder dystocia (3% vs 0%). Because of these risks, delivery should be contemplated at 38 weeks and, if not pursued, careful monitoring of fetal growth must be performed.

Diabetes mellitus and fertility control: contraception management issues.

The need to prevent complications in the woman and fetus mandates that pregnancies in diabetic women always be planned and that safe and effective contraceptives be used at all times until it is determined that pregnancy is a safe and desired option. Pregnancy may aggravate complications of diabetes such as retinopathy and coronary artery disease. A pregnant diabetic woman is also more likely to experience such complications as hypertension, urinary tract infection, polyhydramnios, and cesarean section. Her fetus is at increased risk for congenital malformations, prematurity, stillbirth, neonatal morbidity, and diabetes later in life. Good diabetic control must be maintained before and throughout the pregnancy to minimize the risk of these and other complications. Until such time as good control is achieved and the woman desires pregnancy, a reliable method of contraception should be used. Most recent research supports the use of barrier methods, low-dose monophasic or triphasic oral contraceptives, or progestin-only methods, at least for the short-term. Under some circumstances the intrauterine device may be an appropriate option. Long-term data regarding the use of these methods is lacking. The decision regarding which method of contraception is used should be made by the woman in consultation with her physician.

Perinatal outcome in hypothyroid pregnancies.

OBJECTIVE: To relate hypothyroidism to perinatal outcome. METHODS: A cohort of 68 hypothyroid patients with no other medical illnesses was divided into two groups according to the initial thyroid function tests. The first group had 23 women with overt hypothyroidism, and the second had 45 subjects with subclinical hypothyroidism. We sought to identify the pregnancy outcomes of gestational hypertension, low birth weight, fetal death, congenital anomalies, maternal anemia, and postpartum hemorrhage. RESULTS: Gestational hypertension--namely, eclampsia, preeclampsia, and pregnancy-induced hypertension--was significantly more common in the overt and subclinical hypothyroid patients than in the general population, with rates of 22, 15, and 7.6%, respectively. In addition, 36% of the overt and 25% of the subclinical hypothyroid subjects who remained hypothyroid at delivery developed gestational hypertension. Low birth weight in both overt and subclinical hypothyroid patients was secondary to premature delivery for gestational hypertension. Except for one stillbirth and one case of clubfeet, hypothyroidism was not associated with adverse fetal and neonatal outcomes. CONCLUSION: Normalization of thyroid function tests may prevent gestational hypertension and its attendant complications in hypothyroid patients.

Outcome of pregnancy in diabetic ketoacidosis.

To evaluate the outcome of pregnancy in diabetic women who had an episode of ketoacidosis during gestation, 20 consecutive cases of ketoacidosis in type I diabetic pregnant women were studied. They were divided into two groups for comparison: Group 1, 13 patients (65%), had a live fetus and group 2, seven patients (35%), had a fetal death on admission. Both groups were similar in age, gravidity, parity, abortions, height, weight, serum sodium and potassium, arterial pH, carbon dioxide tension, bicarbonate, base excess, and anion gap. Significantly different between groups 1 and 2 were: gestational age (24 versus 31 weeks; p < 0.05), serum glucose (374 versus 830 mg/dl; p < 0.005), blood urea nitrogen (14 versus 23 mg/dl; p < 0.025), osmolality (295 versus 311 mmol/kg; p < 0.025), insulin requirements (127 versus 202 U; p < 0.05), and length of resolution (28 versus 38 hours; p < 0.05). Two patients had serum glucoses less than 200 mg/dl despite profound ketoacidosis. Precipitating factors included infections, poor compliance, and very importantly, unrecognized new onset of diabetes (6 patients). All stillborns were grossly normal and those autopsied had no discernible cause of death. There were no maternal deaths. A high fetal mortality (35%) was found but there were no fetal losses once therapy was initiated. The unrecognized new onset diabetics accounted for almost a third (30%) of the cases of ketoacidosis and for 57% of the fetal deaths. Attentiveness to the symptoms of uncontrolled diabetes and appropriate screening can be effective preventive measures.

The role of chorionic gonadotropin in transient hyperthyroidism of hyperemesis gravidarum.

Biochemical evidence of hyperthyroidism is frequently encountered in hyperemesis gravidarum, but its relationship to the cause of hyperemesis is unknown. We studied the relationship of serum hCG, thyroid function, and severity of vomiting among 57 hyperemesis patients and 57 controls matched for gestational age. TSH was suppressed in 60% of hyperemesis patients and 9% of controls. hCG correlated directly with free T4(r = 0.45, P < 0.001) and inversely with TSH (r = -0.48, P < 0.001). Hyperemesis patients had significantly greater mean serum hCG, free T4, total T3, and estradiol, and lesser serum TSH compared to controls. Hyperemesis patients with suppressed TSH had significantly greater free T4 and hCG compared to those with TSH in the normal range. Control and hyperemesis subjects were divided into four groups based on the severity of vomiting. The degree of biochemical hyperthyroidism and hCG concentration varied directly with the severity of vomiting. Unextracted serum was tested for thyrotropic activity by measuring its effect on iodide uptake in cultured FRTL-5 rat thyroid cells. Thyrotropic activity correlated with serum hCG (r = 0.50, P < 0.001). These data show that biochemical hyperthyroidism is a common finding in patients with hyperemesis gravidarum and suggest that hCG is the thyroid stimulator in this state. The increased estradiol concentration in patients with hyperemesis gravidarum may be attributed to the effects of hCG on steroidogenesis.

Transient hyperthyroidism and hyperemesis gravidarum: clinical aspects.

OBJECTIVES: Our objectives were to describe the presentation and course of hyperemesis gravidarum with respect to thyroid function and to test the hypothesis that patients with biochemical hyperthyroidism differ in clinical presentation from euthyroid hyperemesis patients. STUDY DESIGN: Sixty-seven patients seen at Los Angeles County Women's Hospital over a 10-month period with hyperemesis gravidarum were studied prospectively with respect to thyroid function. RESULTS: Forty-four patients (66%) had biochemical hyperthyroidism (increased free thyroxine index [n = 39] or suppressed thyroid-stimulating hormone [n = 40]) that was self-limited, resolving by 18 weeks' gestation. Hyperthyroid patients were more likely than euthyroid patients to have abnormal electrolyte levels (23/39 [59%] vs 6/28 [21%] and increased liver enzyme levels (23/59 [59%] vs 5/28 [18%], p less than 0.01). The severity of hyperemesis was found to vary directly with the degree of hyperthyroidism. CONCLUSIONS: Hyperthyroidism is a common, self-limited finding in hyperemesis. The cause of the hyperthyroidism may be linked to the cause of hyperemesis itself.

Serum lipids within 36 mo of delivery in women with recent gestational diabetes.

We prospectively evaluated fasting serum total cholesterol (chol), low- and high-density lipoprotein cholesterol (LDL-chol and HDL-chol), and triglycerides (TGs) in a large cohort of Hispanic women during the first 36 mo after pregnancies complicated by gestational diabetes mellitus (GDM). In 1340 women studied 6-12 wk postpartum (PP-GDM group), chol and LDL-chol were similar to levels in 43 postpartum control subjects without prior GDM. Compared with control subjects (2.01 +/- 1.24 mM), TG was elevated in the PP-GDM women with diabetes mellitus (DM) (2.86 +/- 2.21 mM, P less than 10(-5)) and impaired glucose tolerance (IGT) (2.64 +/- 1.68 mM, P = 0.02) but not in those with normal glucose tolerance (2.00 +/- 1.21 mM). HDL-chol was decreased in PP-GDM women with DM compared with those with normal glucose tolerance. A subgroup of 157 women with prior GDM returned for at least one annual follow-up test on nonhormonal contraception (FU-GDM: n = 60 at 3-11 mo after delivery, n = 78 at 12-23 mo, and n = 39 at 24-35 mo). The cumulative prevalence of DM by 36 mo was 40%. Chol or LDL-chol levels did not significantly change during the 1-yr intervals in the FU-GDM group and were similar to a control group of 36 women without prior GDM. TG was elevated and HDL-chol was decreased in the FU-GDM women with DM at 3-11 mo but not thereafter. Overall, the prevalence of moderate- and high-risk LDL-chol in the FU-GDM group was not different from that of control subjects. These findings suggest that lipid abnormalities are uncommon during the first 36 mo after delivery in women with recent GDM. The abnormalities found consisted of increased TG and decreased HDL-chol in subjects who had developed DM during the study period.