Metabolic crisis: hyperemesis gravidarum

Nausea and vomiting during pregnancy affect approximately 50% to 70% of all pregnant women. Although most cases of nausea and vomiting in pregnancy resolve spontaneously and are not associated with compromised nutritional status, a small percentage of cases progress to hyperemesis gravidarum (severe nausea and vomiting during pregnancy). Hyperemesis gravidarum is a serious disorder that can lead to weight loss, dehydration, electrolyte disturbances, and occasionally death if improperly treated or left untreated. The article summarizes recent research on hyperemesis gravidarum, focusing on the definition, etiology, epidemiology, and current treatment of symptoms.     

Experience with oral methylprednisolone in the treatment of refractory hyperemesis gravidarum

OBJECTIVE: Our purpose was to describe the effect of oral methylprednisolone on the course of refractory hyperemesis gravidarum. STUDY DESIGN: Patients with intractable hyperemesis gravidarum were candidates for oral methylprednisolone. Forty-eight milligrams per day was given for 3 days followed by a tapering dose over 2 weeks. If vomiting recurred after 2 weeks of therapy or during tapering, the medication was restarted or extended but not longer than 1 month total. RESULTS: Seventeen of 18 patients (94%) were free of vomiting and were able to tolerate a regular diet within 3 days. Seven did not have further symptoms during their pregnancies. Nine vomited during or after tapering, but 7 of these responded to extension or reinstitution of therapy. Four of 6 patients on total parenteral nutrition at the start of therapy had a complete response within 3 days. CONCLUSIONS: A short course of oral methylprednisolone appears to be a reasonable therapeutic alternative for intractable hyperemesis.     

Nausea and vomiting of pregnancy

NVP is a spectrum of disorders ranging from the physiologically typical mild to moderate nausea and vomiting that is usually self-limited, to the pathologic, intractable symptoms of hyperemesis gravidarum that are associated with metabolic and electrolyte disturbances and weight loss. Up to 90% of pregnant women experience NVP. The pathogenesis remains poorly understood with multifactorial theories proposed combining both biologic and psychological factors. Diagnosing this syndrome is straightforward, but other organic sources should be excluded when symptoms are severe or prolonged. The overall prognosis is excellent for typical NVP, but whether hyperemesis gravidarum increases the risk to the fetus is controversial. Initial management should be conservative, including reassurance of the transient nature of the symptoms and the good prognosis, in addition to dietary modifications. Pharmacologic therapy is reserved for patients with persistent symptoms and is appropriate after discussion of the risks and benefits with informed consent. Alternative treatments, including psychotherapy and other nonpharmacologic modalities, are less proven but potentially safe and effective, thus providing additional therapeutic options. In refractory cases, nutritional supplementation becomes life-saving for both the mother and the fetus. Therapeutic abortion is a rare and last resort, to be used only when maternal life is threatened.     

Thyrotropic action of human chorionic gonadotropin

Hyperthyroidism or increased thyroid function has been reported in many patients with trophoblastic tumors. In these cases, greatly increased human chorionic gonadotropin (hCG) levels and suppressed TSH levels suggest that hCG has thyrotropic activity. Recent investigations have clarified the structural homology not only in the hCG and TSH molecules but also in their receptors, and this homology suggests the basis for the reactivity of hCG with the TSH receptor. The clinical significance of the thyrotropic action of hCG is now also recognized in normal pregnancy and hyperemesis gravidarum. Highly purified hLH binds to recombinant hTSH receptor and is about 10 times as potent as purified hCG in increasing cAMP. The beta-subunits of hCG and hLH share 85% sequence identity in their first 114 amino acids but differ in the carboxy-terminal peptide because hCG beta contains a 31-amino acid extension (beta-CTP). A recombinant mutant hCG that lacks beta-CTP showed almost identical potency to LH on stimulation of recombinant hTSH receptor. If intact hCG were as potent as hLH in regard to its thyrotropic activity, most pregnant women would become thyrotoxic. One of the roles of the beta-CTP may be to prevent overt hyperthyroidism in the first trimester of pregnancy when a large amount of hCG is produced by the placenta. Nicked hCG preparations, obtained from patients with trophoblastic disease or by enzymatic digestion of intact hCG, showed approximately 1.5- to 2-fold stimulation of recombinant hTSH receptor compared with intact hCG. This suggests that the thyrotropic activity of hCG may be influenced by the metabolism of the hCG molecule itself. Deglycosylation and/or desialylation of hCG enhances its thyrotropic potency. Basic hCG isoforms with lower sialic acid content extracted from hydatidiform moles were more potent in activating adenylate cyclase, and showed high bioactivity/immunoactivity (B/I) ratio in CHO cells expressing human TSH receptors. This is consistent with the finding that the beta-CTP truncated hCG with higher thyrotropic potency is substantially deglycosylated and desialylated in the beta-subunit relative to intact hCG because all four O-linked glycosylation sites occur within the missing C-terminal extension. The desialylated hCG variant also interacts directly with recombinant hTSH receptors transfected into human thyroid cancer cells. There is thyroid-stimulating activity in sera of normal pregnant women, and this correlates with serum hCG levels. The thyroid gland of normal pregnant women may be stimulated by hCG to secrete slightly excessive quantities of T4 and induce a slight suppression of TSH, perhaps being about 1 mU/L less than nongravid levels, but not high enough to induce overt hyperthyroidism. Maternal thyroid glands may secrete more thyroid hormone during early pregnancy in response to the thyrotropic activity of hCG that overrides the normal operation of the hypothalamic-pituitary-thyroid feedback system. Biochemical hyperthyroidism associated with hyperemesis gravidarum has been attributed to hCG. In patients with hyperemesis gravidarum, thyrotropic in serum correlated with hCG immunoreactivity, and the severity of vomiting as indicated by clinical and biochemical parameters correlated with the degree of thyroid stimulation. To understand the thyrotropic action of hCG, it is necessary to know whether hCG activates the same domain of the TSH receptor as does TSH. The identification of the molecular structure of the hCG isoform with the highest thyrotropic potency will resolve the enigma of gestational thyrotoxicosis and the hyperthyroidism associated with trophoblastic disease and hCG-producing tumors.     

Nasoenteral tube feeding in hyperemesis gravidarum. An alternative to parenteral nutrition

A severe form of hyperemesis gravidarum involving maternal weight loss greater than 5% of the prepregnant weight occurs in up to 0.1-0.2% of all pregnancies and may lead to retarded foetal growth. Treatment consists of hospitalisation, antiemetics and correction of fluid and electrolyte deficiencies. If severe vomiting and weight loss continues, the mother must receive supplementary nutrition, usually parenteral. Nasoenteral tube feeding is a well documented method of nutrition for other patients. A gastroscopically placed nasojejunal tube as part of the treatment of hyperemesis gravidarum has not been reviewed before. Seven women with severe hyperemesis gravidarum were treated with nasojejunal tube feeding. The tube was positioned gastroscopically. Enteral feeding continued for up to 41 days, leading to reasonable weight gain. The tube was tolerated well by most patients and no serious adverse effects were seen. Nasoenteral nutrition ought to be considered as an alternative to parenteral nutrition for treatment of hyperemesis gravidarum.     

Neonatal hyperthyroidism caused by TSH receptor antibodies in maternal autoimmune hyperthyroidism

Between July 1993 and December 1994 five term infants of mothers with Graves' disease were hospitalised at the Frühgeburtenstation of the Univ.-Frauenklinik Graz. Four Mothers had elevated TSH-receptor-antibody (TRAb)--levels during pregnancy, one had normalised TRAb-titers. In one case hyperthyroidism was first diagnosed during pregnancy. Three newborns had elevated TRAb-titers; in one of them thyrotoxicosis was diagnosed clinically and biochemically at the second day of life, one newborn had mild hyperthyroidism with tachycardia at the end of the first week of life and one newborn was asymptomatic by immediately initiated therapy. The two other newborns had normal thyroid hormone and antibody levels and no symptoms or signs of hyperthyroidism. The cases are reported and discussed in detail and our overall approach to diagnosis and treatment of neonatal hyperthyroidism in case of maternal Graves' disease will be given.     

Saturated fat intake and the risk of severe hyperemesis gravidarum

We conducted a case-control study to investigate the effect of prepregnancy diet, particularly dietary fats, on the risk of severe hyperemesis gravidarum. Cases were 44 women previously hospitalized at Brigham and Women's Hospital, Boston, MA, for severe hyperemesis gravidarum who delivered a singleton liveborn between January 1, 1993, and December 31, 1995. Controls were 87 women who delivered a singleton liveborn at Brigham and Women's Hospital during the same period and who experienced less than 20 hours of nausea and fewer than three episodes of vomiting over the duration of their pregnancies. Odds ratios were derived from unconditional logistic regression models using data collected via self-administered food frequency questionnaires. Our results indicate that prepregnancy, high daily intake of total fat increases the risk of severe hyperemesis gravidarum (odds ratio = 2.9 for each 25 gm per day increase; 95% confidence interval = 1.4-6.0). This association is driven primarily by saturated fat intake [odds ratio = 5.4 for each 15 gm per day increase (equivalent to one quarter-pound cheeseburger); 95% confidence interval = 2.0-14.8]. We observed no independent effect of total energy intake.     

Adolescent abortion and parental notification: evidence for the importance of family functioning on the perceived quality of parental involvement in U.S. families

Hyperthyroidism is common and affects approximately 2% of women and 0.2% of men. The most common cause of hyperthyroidism is Graves' disease, an autoimmune disorder associated with circulating immunoglobulins that bind to and stimulate the thyrotropin (TSH) receptor, resulting in sustained thyroid overactivity. Toxic nodular goitres cause hyperthyroidism due to autonomous hyperfunctioning of localised areas of the thyroid. There are 3 recognised modalities of treatment for hyperthyroidism: antithyroid drugs, surgery and radioiodine. All are effective but no single method offers an absolute cure. Patients with Graves' disease may be prescribed antithyroid drugs over a period of 12 to 18 months with a view to inducing a long term remission. These drugs are also often given for a short period to render the patient euthyroid before definitive therapy with radioiodine or thyroidectomy. However, antithyroid drugs will not 'cure' hyperthyroidism associated with a toxic nodular goitre. The use of radioiodine as a first-line therapy for hyperthyroidism is growing. It is well tolerated, with the only long term sequelae being the risk of developing radioiodine-induced hypothyroidism. Radioiodine can be used in all age groups other than children, although it should also be avoided in pregnancy and during lactation. Pregnancy should be avoided for 4 months following its administration. Radioiodine may cause a deterioration in Graves' ophthalmopathy and corticosteroid cover may reduce the risk of this complication. The treatment of choice for toxic nodular goitre hyperthyroidism is radioiodine. Surgery, either subtotal or near-total thyroidectomy, has limited but specific roles to play in the treatment of hyperthyroidism: this approach is rarely used in patients with Graves' disease unless radioiodine has been refused or there is a large goitre causing symptoms of compression in the neck. The goal of surgery is to cure the underlying pathology while leaving residual thyroid tissue to maintain postoperative euthyroidism.     

Delayed-interval delivery in a quadruplet pregnancy after intrauterine death of a partial molar pregnancy and preterm delivery. A case report

BACKGROUND: Delayed-interval delivery is infrequent in twin gestation and more rare in triplet and quadruplet gestation. Coexistence of a triploid pregnancy with a normal fetus has not previously been reported to have resulted in survival of the normal fetus. CASE: A 26-year-old woman, gravida 2, para 0-0-1-0, was diagnosed with a quadruplet pregnancy. At 16 1/2 weeks' gestation she developed preeclampsia and severe hyperemesis. Ultrasound was consistent with partial molar pregnancy in quadruplet D. Quadruplet D died in utero, and the preeclampsia and hyperemesis resolved. At 19 5/7 weeks, spontaneous rupture of the membranes and preterm labor occurred, and quadruplet A, stillborn female weighing 260 g, was delivered. With the use of antibiotic therapy, tocolysis and bed rest, the remaining two fetuses were maintained in utero until 32 6/7 weeks' gestation, when quadruplet B, a 1,470-g female, and quadruplet C, a 1,700-g female, were delivered. CONCLUSION: This was the first reported case of surviving fetuses coexisting with a partial molar pregnancy. This case was also complicated by preterm delivery and successful delayed-interval birth in a quadruplet pregnancy.     

Transient hyperthyroidism and hyperemesis gravidarum]

Subclinical hyperthyroidism in hyperemesis gravidarum is a well-documented matter in the literature. A case report is present with the main etiologies, clinical manifestations, differential diagnoses, therapeutical guidelines and maternal-infant prognosis are discussed.     

Rapid marked response of severe hyperemesis gravidarum to oral erythromycin

A recent report has noted an association between Helicobacter pylori and hyperemesis gravidarum. We present two cases in which first-trimester patients with severe hyperemesis gravidarum requiring intravenous fluid replacement were placed on oral erythromycin therapy for other nonrelated conditions. Surprisingly, marked rapid improvement of the hyperemesis gravidarum was observed with complete resolution of all symptomatology. Both these patients tested seropositive for Helicobacter pylori. These unexpected, marked therapeutic responses are consistent with the recently reported association between hyperemesis gravidarum and Helicobacter pylori and possibly suggest a new therapeutic modality for similar patients.     

Thyroid hyperfunction during pregnancy

The present report focuses on the two main causes of hyperthyroidism observed in the pregnant state: Graves' disease (GD) and gestational transient thyrotoxicosis. Together, the prevalence of hyperthyroidism may represent 3% to 4% of all pregnancies, and therefore constitutes an important clinical issue. Concerning GD, the variable presentations of the disease (women under treatment, in remission, or considered cured) and specific alterations occurring in pregnancy are discussed: changes in thyrotropin (TSH) receptor antibody titers, the risk of fetal and neonatal thyrotoxicosis, the outcome of pregnancy in relation to the control of hyperthyroidism, and the treatment of active GD during and after pregnancy with antithyroid drugs. Gestational transient thyrotoxicosis is associated with a direct stimulation of the maternal thyroid gland by human chorionic gonadotropin (hCG), and has been shown to be directly related to both the amplitude and duration of peak hCG values. The syndrome is usually transient, observed at the end of the first trimester, and is frequently associated with emesis. Finally, we propose a global strategy for the systematic screening of hyperthyroidism during pregnancy, based on an algorithm that allows for the diagnosis of both autoimmune and nonautoimmune forms of hyperthyroidism in the pregnant state.     

Esophageal achalasia presenting during pregnancy

We report a woman with achalasia cardia who developed dysphagia for the first time during pregnancy. She was initially mistakenly treated elsewhere as hyperemesis gravidarum. The diagnosis and treatment of achalasia during pregnancy is reviewed.     

Recent trends in the management of Graves' hyperthyroidism in Japan: opinion survey results, especially on the combination therapy of antithyroid drug and thyroid hormone

An opinion survey concerning the management of Graves' hyperthyroidism was conducted among the council members of the Japan Thyroid Association. The selection of 3 major treatments by 90 respondents for their patients was 98.6 +/- 4.2% for antithyroid drug (ATD), 7.8 +/- 12.6% for partial thyroidectomy and 5.2 +/- 8.1% for radioiodide. They expressed a movement away from the past trend of surgery because of postoperative complications and unsatisfactory therapeutic results, and they assumed a further reduction in the future. On the other hand, the frequency of radioiodide treatment was not considered to have decreased greatly, and they expected a slight increase in the future. Of the respondents, 65% suggested that hyperthyroidism should be completely cured even if the patient would fall into hypothyroidism. The major reasons for choosing surgery or radioiodide after ATD were the adverse effects of ATD and the age and social backgrounds of the patients. Large goiter size was the 3rd reason for surgery but was a minimal indicator for radioiodide. As for ATD treatment, none of the respondents reported the routine application of any uniform fixed-time therapy protocol. Japanese Graves' patients were shown to be less responsive to ATD than Caucasian patients. This was assumed to result at least from high iodide intake, and half of them had ordered their patients to restrict iodide intake. Furthermore, 78% of them had treated with a combined therapy of ATD and thyroid hormone. Most of them apply this for selected patients mainly to lower TSH receptor antibody activity, to better control their patients and to reduce the goiter size. All but 8 (9%) did not give T4 (or T3) after the cessation of ATD, and they felt this to be unnecessary, doubtful about the effect, unsuitable or even possible to induce recurrence. The excellent findings reported by Hashizume et al. (N Engl J Med 324: 947-953, 1991) are well known among them. However, most of them did not agree with the efficacy of the protocol to reduce TRAb or to improve the remission rate, and 90% of the respondents did not intend to apply the protocol immediately. In conclusion, the Japanese thyroidologists were shown to highly prefer ATD, and they intended to treat their patients for longer periods of time only by ATD until clinical remission is achieved. The combination therapy is widely used, but most of them do not consider it effective. The therapeutic protocol reported by Hashizume et al. was not accepted widely in Japan.     

Liver disease in pregnancy

The liver is one of the many organs affected by the physiologic and hormonal changes that occur during pregnancy. Hepatic disorders diagnosed before pregnancy may be unaffected or exacerbated by the pregnant state. Liver disorders that are specific to pregnancy, including hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, acute fatty liver of pregnancy, preeclampsia/ eclampsia, HELLP, and hepatic rupture, may have a profound impact on the morbidity and mortality rates of mother and fetus. Although an unequivocal diagnosis is often difficult to make, it should be attempted in a timely manner so that optimal treatment can be determined. After the diagnosis is made, maximizing the health of the mother and fetus determines future management.     

Outcome of Graves' disease after antithyroid drug treatment in Taiwan

The outcome of Graves' disease after treatment with antithyroid drugs (ATDs) varies widely among countries, and large-scale studies in Asia are rare. We investigated the associations of various clinical and laboratory features with the outcome of ATD therapy for Graves' disease in Taiwan. A total of 210 patients (177 women, 33 men; mean +/- SD age, 41.7 +/- 15.1 yr) treated with ATD in Taiwan were included. ATD therapy started with methimazole 30 mg daily or propylthiouracil 300 mg daily and was continued until a euthyroid state was achieved. Afterwards, 154 patients received a maintenance dose of ATD alone, while 56 patients received a combination of an ATD and thyroxine (L-T4). Patients were considered to be in remission if they remained in a euthyroid state for more than 2 years after drug withdrawal. The mean follow-up periods were 45.0 +/- 20.9 months for patients with remission and 30.4 +/- 19.8 months for those with relapse. Relapse occurred in 126 (60%) patients during the follow-up period, within 3 months after drug withdrawal in 47 (37%), and within 6 months in 60 (46%). The relapse rate was 100% among patients with two or more previous relapses. Patients with a second occurrence had a higher relapse rate than those with a first occurrence (84% vs 43%). Past history of recurrence, goiter size, thyroid-stimulating hormone level and thyrotropin-binding inhibition immunoglobulin activity at the end of ATD treatment were independently associated with relapse. Prolonged duration of treatment did not yield better results in patients with larger goiters or a history of recurrence, or both. Combination therapy with L-T4 yielded similar results to those achieved with ATD treatment alone. In conclusion, the relapse rate of Graves' disease after ATD treatment in Taiwanese patients was high, especially in those with a history of recurrence. The treatment duration and drug regimen did not affect the outcome.     

Spontaneous hemoperitoneum due to rupture of a regenerating nodule as primary manifestation of hepatic cirrhosis

Therapy of thyroid dysfunction needs a close cooperation between endocrinologist and gynecologist. In addition to a number of metabolic changes during pregnancy, the diaplacentar transfer of different substances (thionamides, antibodies) has to be considered. Pregnant women with overt and subclinical hypothyroidism should be treated using L-Thyroxine with the bTSH between 1 and 2 mU/l. Many of the women need an increase of the L-Thyroxine dose during pregnancy. Overt hyperthyroidism (mostly due to Graves' disease) has to be treated immediately after diagnosis using thionamides. Because thionamides cross the placenta, the dose should be as low as possible with the fT4 in upper level and bTSH in the lower level of normal range. Most studies show, that both methimazole (MI) and propylthiouracil (PTU) can be used in pregnancy. Although PTU is preferred especially in the USA, an advantage of PTU over MI is not proven. Surgery is necessary in only few cases of hyperthyroidism during pregnancy with the optimal time for surgery during the second trimester. In case of subclinical hyperthyroidism and HCG induced hyperthyroidism several controls of thyroid function should be performed to decide whether treatment is necessary.     

Sexual behavior in married women with chronic gynecologic inflammation]

In patients with the first manifestation of hyperthyroidism of Graves' disease, antithyroid drug treatment is the therapy of first choice. Treatment has to be carried out depending on iodine supply of the individual patient with the lowest possible drug dose. Controls of treatment have to be done in short intervals (every 2 weeks) until euthyroidism is reached, afterwards controls of thyroid function have to be done every three months. After euthyroidism is established, the combination of antithyroid drug therapy with thyroid hormones may be useful to avoid hypothyroidism or goiter development during treatment in contrast to a monotherapy with antithyroid drugs. Antithyroid drug treatment has to be carried out for one year. The remission rate of patients does not increase with higher doses of antithyroid drugs or a longer treatment duration. The determination of TSH receptor antibodies does not help predicting a relapse of hyperthyroidism of Graves' disease in the individual patient at the end of treatment. Regular follow-up controls after antithyroid drug treatment are necessary to recognize relapse of Graves' disease in time.     

Effect of antithyroid medication on the effective half-life and uptake of 131-iodine following radioiodine therapy

AIM: A radioiodine therapy (RIT) in thyrotoxic patients receiving antithyroid drugs (ATD) leads in comparison to nonpretreated patients either to higher therapeutic doses or to higher treatment failure rates. Aim of this study was to optimize the effect of RIT in patients pretreated with ATD. METHODS: Therefore, the influence of ATD was assessed in 109 patients with shortened effective half-life of 131I. RIT was performed under stationary conditions. Radioiodine activity of the thyroid gland was measured twice a day. In 77 patients antithyroid medication was stopped three days after RIT. The progress of the first RIT and of a second radioiodine application, which still was necessary in 29 patients, was compared to 32 patients receiving ATD, continuously. RESULTS: Values of effective half-life for 131I rose significantly from 3.2 +/- 0.2 to 5.7 +/- 0.2 days (Graves' disease: 3.4 to 5.7 days; toxic goiters' disease: multifocal autonomy 3.2 to 6.2 days; unifocal autonomy 2.5 auf 5.0 days) 2-3 days after stopping ATD. There was an increase of the 131I-uptake of a second after stopping ATD, too. In contrast, 131I-uptake of a second RIT decreased significantly in patients receiving ATD, continuously. CONCLUSION: Effective half-life and uptake of 131I was affected significantly by ATD. The stop taking of ATD after RIT is useful to improve an apparent insufficient RIT in thyrotoxic patients receiving ATD.     

Ca2+-dependence of the depolarization-inducible Na+ current of Xenopus oocytes

PURPOSE: The incidence and consequences of pregnancy during therapy for childhood acute lymphoblastic leukemia (ALL) are largely unknown. To explore the issues involved in this complication of ALL treatment, two recent cases are presented. PATIENTS: Two 15-year-old girls with "high risk" ALL became pregnant while receiving maintenance therapy. RESULTS: In one case, the patient experienced a spontaneous abortion at approximately 5 to 6 weeks gestation. The patient completed maintenance therapy and is in remission 8 months after the end of treatment. The second patient, known to be non-compliant during therapy, was found to be 5 months pregnant at the end of maintenance therapy. She developed HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), was induced at approximately 34 weeks, and delivered an apparently normal baby girl. Both the patient and her baby continue to do well 10 months after delivery. CONCLUSIONS: A variety of factors may influence the incidence of pregnancy during ALL therapy. Gonadal function, which is likely to return to normal during maintenance therapy, may also be affected by alterations in the dose intensity of treatment. Social factors may also alter the incidence of pregnancy. Adverse effects on the fetus are more likely to occur in the first trimester, depending on the drug or drugs used. Although all chemotherapies may have mutagenic and teratogenic effects, they do not invariably cause abnormalities. Survival of adolescents who become pregnant during treatment does not appear to be adversely affected when therapy is not modified or discontinued.