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Incidence of Thyroiditis After Pregnancy Loss
Postpartum autoimmune thyroiditis is well documented after full-term pregnancy and occurs in 3 to 16 percent of women. The same phenomenon, however, has not been clearly associated with early termination of pregnancy. Marqusee and associates report on patients with normal thyroid function before conception or at the time of pregnancy loss who develop thyroiditis within one year of their loss.
Five women with recent pregnancy loss (at five to 20 weeks of gestation) and normal thyroid function before conception were followed for at least 20 months with measurement of thyroid function and antithyroid antibodies. Thyroiditis, defined as transient biochemical hypothyroidism and/or hypothyroidism within one year of pregnancy loss, was diagnosed in all five women. Two patients had subclinical hypothyroidism alone, with elevated thyroid-stimulating hormone levels that resolved within one month. The other three women were diagnosed with hyperthyroidism at three to 11 months after pregnancy loss when they presented with palpitations and tremulousness.
Because of the proximity of the hyperthyroidism to the pregnancy loss and the high likelihood of thyroiditis, patients were not treated with antithyroid medications. Within eight weeks of the diagnosis of hyperthyroidism, all three women became hypothyroid, and all three conceived again during this hypothyroid phase. Two of these women were treated with thyroid supplementation during their pregnancies until after their deliveries and remained euthyroid.
The authors conclude that the immunologic changes resulting from a short-term pregnancy can lead to painless thyroiditis after pregnancy loss. Women who are antithyroid-antibody positive are at greater risk of developing thyroiditis. Women who have had a recent pregnancy loss require evaluation of thyroid function to optimize maternal thyroid hormone levels in early pregnancy.
RICHARD SADOVSKY, M.D.
Marqusee E, et al. Thyroiditis after pregnancy loss. J Clin Endocrinol Metab 1997;82:2455-7.
Guideline for Management of Alcohol Withdrawal
No evidence-based guidelines for the management of alcohol withdrawal have been developed. Mayo-Smith, representing the American Society of Addiction Medicine Working Group on Pharmacological Management of Alcohol Withdrawal, reports on a meta-analysis performed to determine which agents are suitable for treating this condition and to develop an evidence-based guideline forthe pharmacologic management of alcohol withdrawal.
The following outcomes were examined: severity of alcohol withdrawal, occurrence of delirium, withdrawal seizures and cost. The group used a published system to classify the strength of the recommendations. The group reviewed 134 articles on alcohol withdrawal. Sixty-five of the studies were prospective, controlled clinical trials, and 42 different medications were evaluated. The recommendations developed by the Working Group were graded according to the level of the evidence.
Six prospective trials demonstrated that benzodiazepines are more effective than placebo in decreasing the signs and symptoms associated with alcohol withdrawal. Seizures were significantly reduced in patients who received benzodiazepines. Long-acting benzodiazepines were somewhat more effective than short-acting agents in preventing seizures. The data suggested that long-acting agents could be associated with increased sedation in some patients. The Working Group recommends the use of benzodiazepines for relief of alcohol withdrawal (grade A recommendation).
Two prospective, randomized controlled trials have shown that use of symptom-triggered treatment, based on a symptom score generated by using the revised Clinical Institute Withdrawal Assessment-Alcohol, is as effective as fixed-dose therapy. Moreover, this approach results in significantly less medication being given during the course of the withdrawal.
A review of five studies of the use of beta-adrenergic antagonists revealed evidence that these agents reduce the autonomic manifestations of withdrawal. Whether these agents increase or reduce seizures during withdrawal could not be determined. One study found that the incidence of delirium was increased with use of propranolol. The Working Group does not recommend beta-adrenergic antagonists as monotherapy (grade B recommendation). These agents may be used in conjunction with benzodiazepines.
Examples of Specific Treatment Regimens for Alcohol Withdrawal
- Monitoring
- Monitor patients every 4 to 8 hours by means of CIWA-Ar until score has been <8 to 10 for 24 hours
- Symptom-triggered regimens
- Administer one of the following medications every hour when CIWA-Ar is >=8 to 10:
- Chlordiazepoxide, 50 to 100 mg
- Diazepam, 10 to 20 mg
- Lorazepam, 2 to 4 mg
- Repeat assessment with CIWA-Ar one hour after every dose to determine need for further medication
- Fixed-schedule regimens
- Chlordiazepoxide, 50 mg every 6 hours for 4 doses, then 25 mg every 6 hours for 8 doses
- Diazepam, 10 mg every 6 hours for 4 doses, then 5 mg every 6 hours for 8 doses
- Lorazepam, 2 mg every 6 hours for 4 doses, then 1 mg every 6 hours for 8 doses
- Provide additional medication as needed when symptoms are not controlled (i.e., CIWA-Ar >=8 to 10) with above regimens
NOTE: Other benzodiazepines may be used at equivalent doses.
(CIWA-Ar=Clinical Institute Withdrawal AssessmentAlcohol, revised)
Reprinted with permission from Mayo-Smith MF, for the American Society of Addiction Medicine Working Group on Pharmacological Management of Alcohol Withdrawal. Pharmacological management of alcohol withdrawal. A meta-analysis and evidence-based practice guideline. JAMA 1997; 278:144-51.
Studies have consistently demonstrated that centrally acting alpha-adrenergic agonists, such as clonidine, are effective in relieving symptoms of mild to moderate withdrawal. It is not known what effect clonidine may have on the incidence of delirium or seizures. These agents are not recommended as monotherapy (grade B recommendation).
Carbamazepine, used in Europe for alcohol withdrawal, has been shown in clinical studies to be equally as effective as barbital and oxazepam in patients with mild or moderate withdrawal symptoms. Carbamazepine is not recommended as monotherapy (grade B recommendation).
Studies indicate that phenothiazines are less effective than benzodiazepines in preventing seizures and delirium. The Working Group does not recommend neuroleptics as monotherapy because they do not reduce delirium and may increase seizures (grade A recommendation).
Low magnesium levels are known to occur during alcohol withdrawal and then return to normal. A double-blind placebo-controlled trial showed that intramuscular administration of magnesium as an adjunct to benzodiazepine therapy did not decrease the severity of withdrawal symptoms. Routine parenteral administration of magnesium is not recommended (grade B recommendation).
One large trial showed that use of thiamine did not reduce delirium or seizures. But the Working Group states that persons with alcohol dependence frequently have thiamine deficiency. Administration of thiamine is recommended at the time of initial evaluation in all patients with alcohol dependence (grade C recommendation).
The Working Group recommends individualized treatment and use of structured assessment scales for monitoring withdrawal symptoms (grade A recommendation). Such an approach allows titration of doses to meet individual needs. However, the Working Group recognizes that structured assessment and an individualized approach may not always be feasible. A fixed-dose schedule is an acceptable alternative if additional medication is administered when symptoms are not controlled with scheduled doses. The accompanying table gives examples of treatment regimens that meet the recommendations.
GRACE BROOKE HUFFMAN, M.D.
Mayo-Smith MF, for the American Society of Addiction Medicine Working Group on Pharmacological Management of Alcohol Withdrawal. Pharmacological management of alcohol withdrawal. A meta-analysis and evidence-based practice guideline. JAMA 1997;278:144-51.
Treating Hypercholesterolemia in Postmenopausal Women
Estrogen replacement therapy produces clinically important reductions in low-density lipoprotein (LDL) cholesterol concentrations and increases in levels of high-density lipoprotein (HDL) cholesterol. Observational studies have shown a reduction in the incidence of atherosclerotic cardiovascular disease as a result of estrogen replacement therapy. Davidson and associates compared the effects of estrogen replacement therapy and pravastatin in postmenopausal women with hypercholesterolemia.
A total of 76 women with LDL levels greater than 150 mg per dL (3.9 mmol per L) were randomly assigned to one of four treatment groups: conjugated estrogen (0.625 mg per day); pravastatin (20 mg per day); conjugated estrogen (0.625 mg per day) plus pravastatin (20 mg per day); or placebo. The length of the study was 16 weeks. Primary end points in the double-blind, placebo-controlled study were changes in the serum lipid levels.
Levels of non-HDL cholesterol decreased significantly compared with placebo in all three treatment groups: a decrease of 13.0 percent in the estrogen-only group, 23.7 percent in the pravastatin group and 25.2 percent in the estrogenpravastatin group. The difference between the pravastatin and combined treatment groups was not significant.
HDL cholesterol levels rose significantly in both estrogen groups. In the estrogen-only group, HDL cholesterol levels rose 22.5 percent. In the estrogenpravastatin group, they increased by 21.2 percent. A nonsignificant increase (3.7 percent) in HDL cholesterol occurred in the pravastatin group, and a slight decrease (3.3 percent) was noted in the placebo group.
Examination of the values for the combined treatment group showed that the non-HDL cholesterol and HDL cholesterol responses were most significant at week 4, after which the levels tended to drift toward baseline. After 16 weeks of treatment, the mean non-HDL cholesterol value in the estrogenpravastatin group had stabilized and was near that of the pravastatin group, while the mean HDL cholesterol level had stabilized and was close to that of the estrogen-only group.
Triglyceride levels increased by 11.3 percent in the placebo group, as compared with baseline levels. They remained similar to baseline levels in the combined treatment group and the pravastatin group. These changes were significantly different from that of the placebo group, but not different from one another.
Results of this study support the National Cholesterol Education Program recommendation that consideration be given to administering estrogen replacement therapy to postmenopausal women with elevated LDL cholesterol levels.
When estimates of coronary event reduction were calculated according to the percentage of increase in HDL cholesterol levels and decrease in non-HDL cholesterol levels, the predicted risk reduction would be 40 to 50 percent in the estrogen-only and pravastatin-only groups and 60 to 70 percent in the estrogenpravastatin group.
The authors point out that the price of estrogen replacement therapy is substantially lower than the price of therapy with an HMG-CoA reductase inhibitor. Therefore, the cost savings associated with use of estrogen as a first-line pharmacologic therapy for postmenopausal women with mild to moderate hypercholesterolemia could be substantial. Since approximately 33 percent of American women have undergone hysterectomy by the age of 60, a substantial number of women would be candidates for unopposed estrogen therapy. For women who have not undergone hysterectomy, a progestin would be added to the estrogen therapy.
The authors conclude that conjugated estrogen in a dosage of 0.625 mg per day is effective in lowering LDL cholesterol and increasing HDL cholesterol levels in postmenopausal women with hypercholesterolemia. When estrogen was combined with pravastatin, the serum lipid profile appeared to be altered more favorably than with either agent alone.
BARBARA APGAR, M.D., M.S.
Davidson MH, et al. A comparison of estrogen replacement, pravastatin, and combined treatment for the management of hypercholesterolemia in postmenopausal women. Arch Intern Med 1997;157:1186-92.
Plasma Homocysteine Levels and Risk of Atherosclerosis
An elevated plasma homocysteine level is recognized as a risk factor for atherosclerotic vascular disease, although the strength of the relationship is unknown. Graham and colleagues examined the relationship between total plasma homocysteine level and risk of vascular disease and the possible interaction between homocysteine level and conventional risk factors.
The case-control study included 750 persons with coronary, cerebrovascular or peripheral vascular disease and 800 control subjects, all of whom were under 60 years of age. Patients were excluded if they had nonatherothrombotic vascular disease (such as vasculitis), diabetes mellitus, renal or hepatic disease, or thyroid disorders. Plasma cobalamin, pyridoxal 5'-phosphate, red blood cell folate and serum cholesterol levels were measured in addition to plasma homocysteine levels.
Homocysteine levels in the top one fifth of the distribution were considered elevated. Homocysteine levels were elevated in 241 control subjects (30.1 percent) and in 375 of the persons with vascular disease (50.0 percent). The relative risk of vascular disease in persons with homocysteine levels in the top one fifth of the distribution was 2.2 compared with the risk of vascular disease in those with levels in the lower four fifths of the distribution. The relationship between elevated homocysteine levels and the presence of vascular disease was as strong as the relationship between hypercholesterolemia or smoking and vascular disease. Even when the presence of other risk factors was controlled for, an elevated homocysteine level was still strongly predictive of vascular disease.
For a 5-µmol-per-L increment in the plasma homocysteine level, the relative risk of vascular disease was 1.35 in men and 1.42 in women. Patients who were in the top 10th of the distribution of homocysteine levels had a greater than threefold relative risk of vascular disease, compared with those in the bottom 10th of the distribution.
The authors conclude that an elevated plasma homocysteine level is a strong and independent risk factor for atherosclerotic vascular disease. They believe that measurement of the homocysteine level should be part of the risk assessment for vascular disease. The additive and multiplicative effects of an elevated homocysteine level plus other risk factors suggest that interventions to lower blood pressure and encourage smoking cessation are even more important in patients with elevated homocysteine levels. The authors note that studies of the effects of folic acid and, perhaps, pyridoxine on secondary prevention of cardiovascular disease are needed.
GRACE BROOKE HUFFMAN, M.D.
Graham IM, et al. Plasma homocysteine as a risk factor for vascular disease. JAMA 1997;277:1775-81.
Value of C-Reactive Protein Measurements in Children
Serum C-reactive protein concentrations closely follow the course of the acute-phase response to inflammation or tissue necrosis and theoretically provide a barometer for many disease processes. This polysaccharide fraction precipitated from Streptococcus pneumoniae is present in acutely ill patients and disappears as the patients recover. C-reactive protein has been detected in bacterial, viral and other infections, as well as in noninfectious diseases such as acute myocardial infarction, rheumatic disorders and malignancies. Synthesis of acute-phase proteins occurs in hepatocytes modulated by cytokines. In vitro studies suggest that C-reactive protein activates neutrophils, inhibits platelet aggregation, potentially facilitates cell-mediated cytotoxic reactions against cells infected with microbes and stimulates monocyte-macrophage tumoricidal activity. Jaye and Waites conducted a study to determine the clinical utility of C-reactive protein measurements in children, especially compared with erythrocyte sedimentation rate determination.
The erythrocyte sedimentation rate, an indirect measurement of fibrinogen levels that influence erythrocyte aggregation, is commonly used to measure the acute-phase response. The erythrocyte sedimentation rate has several disadvantages: it cannot be determined from a stored specimen; it rises slowly and may not return to normal for weeks despite clinical improvement in the patient; it may give false reactions because of red cell concentrations and morphology; and it is difficult to standardize because of age and gender variations.
Healthy persons generally have C-reactive protein levels no higher than 10 mg per L. In patients with invasive acute bacterial infections, the C-reactive protein level tends to range from 150 to 350 mg per L. In patients with viral infections, the C-reactive protein value is usually much lower, less than 20 to 40 mg per L. However, this distinction is not absolute. C-reactive protein values greater than 100 mg per L can occur in uncomplicated infections caused by adenovirus, cytomegalovirus, and the viruses that cause influenza, measles and mumps. C-reactive protein determination cannot be used to classify the precise microbial etiology of an infection, but it is useful in conjunction with other tests in distinguishing between viral and bacterial infection.
Early detection of neonatal sepsis is hampered by vague, nonspecific or nonexistent clinical manifestation. A panel of tests including cultures, white blood cell count and differential, erythrocyte sedimentation rate, C-reactive protein value, platelet count, blood glucose and chest radiographs is used to augment the physical examination in the recognition of the disease. Cerebrospinal fluid/C-reactive protein concentrations are probably not as useful in diagnosing meningitis because C-reactive protein metabolizes in the central nervous system, yielding lower levels. Bacteremia should be considered in the febrile child with elevated C-reactive protein values and no evidence of focal infection. The use of C-reactive protein determinations in the identification of bacterial otitis media have not demonstrated clear value. The utility of C-reactive protein determinations in diagnosing gastrointestinal and respiratory infections is still being evaluated. Serial C-reactive protein determinations have been shown to be useful in monitoring resolution of acute hematogenous osteomyelitis. C-reactive protein values do not appear to be useful in identifying children with acute appendicitis or perforation. Studies of C-reactive protein values in autoimmune and rheumatologic diseases demonstrate better correlation than erythrocyte sedimentation rate with severity of clinical disease activity.
The authors conclude that serial C-reactive protein measurements appear to be most useful in monitoring patient response to therapy after the primary diagnosis of invasive, infectious or inflammatory disease, and in monitoring patients after major surgical procedures and patients with serious burns. A secondary rise in C-reactive protein value during therapy or after surgery may indicate an inflammatory or infectious complication. Although several advantages are apparent in using C-reactive protein values rather than the erythrocyte sedimentation rate to monitor therapy, insufficient information currently supports using C-reactive protein values alone to make management decisions or to distinguish between bacterial and viral infections.
RICHARD SADOVSKY, M.D.
Jaye DL, Waites KB. Clinical applications of C-reactive protein in pediatrics. Pediatr Infect Dis J 1997;16:735-44.
Rate of Airway Hyperreactivity in Children with Sickle Cell
Lung disease is a major cause of morbidity and mortality in patients with sickle cell disease. Acute chest syndrome caused by lung infections, infarction or fat embolism occurs in nearly one half of patients with sickle cell disease. The presence of airway hyperreactivity may be a silent comorbid factor for pulmonary disease in patients with sickle cell disease. Leong and colleagues conducted a study to determine the presence of airway hyperreactivity in children with sickle cell disease and to assess if airway hyperreactivity can exist in these children even without clinical symptoms.
Forty asymptomatic children with sickle cell disease, ranging from six to 19 years of age, were included in the study. Thirty patients had homozygous SS disease, seven patients had sickle-C disease and three patients had sickle-beta+-thalassemia, as diagnosed by hemoglobin electrophoresis. The patients were divided into two groups. Eighteen patients had a history consistent with reactive airway disease, characterized as recurrent wheezing that improved with bronchodilator therapy. Twenty-two patients had no symptoms consistent with reactive airway disease. Ten healthy children were also included in the study as a control group. Baseline pulmonary function tests were performed on all participants. If the baseline forced expiratory volume in one second (FEV1) was less than 70 percent and there was at least a 12 percent increase following bronchodilator therapy, the child was said to have airway hyperreactivity. If the baseline FEV1 was greater than 70 percent, airway hyperreactivity was determined by cold-air challenge. Children who had a decrease in FEV1 from baseline of greater than 10 percent were said to have airway hyperreactivity.
Eighty-three percent of patients in the group with a history consistent with reactive airway disease and 64 percent of patients in the group without symptoms of reactive airway disease had evidence of airway hyperreactivity, for an overall prevalence rate of 73 percent. This is much higher than the estimated 6 percent prevalence rate found in the general population. Airway hyperreactivity frequently leads to ventilation-perfusion mismatch and, consequently, to hypoxia or acidosis. This could result in vaso-occlusive painful episodes.
The authors conclude that there is a high prevalence of airway hyperreactivity in patients with sickle cell disease, in patients both with and without a history of reactive airway disease. Greater effort should be made to recognize and appropriately treat reactive airway disease in this population.
RICHARD SADOVSKY, M.D.
Leong MA, et al. Airway hyperreactivity in children with sickle cell disease. J Pediatr 1997;131:278-83.
Decreased Pain in Blood Collection in Neonates
Suckling is known to reduce neonatal reaction to unpleasant stimuli. Blass studied the effectiveness of milk, milk components, formula or water in the reduction of crying in neonates who had blood drawn for routine testing by heelstick.
Seventy-two infants between the ages of 22 and 40 hours were randomly assigned to one of nine groups. Body weights were similar among the groups, as were distributions of gender and race. Infants in each group were given 2 mL of milk (Similac), Ross Special Formula, dilute fat, concentrated fat, a fat/lactose solution, protein, lactose, sucrose or water for two minutes before undergoing the heelstick procedure. Each infant's heel was also warmed before the procedure. Two minutes after the solution was finished, the infant's heel was stuck for blood collection purposes. Each procedure was videotaped and an observer who did not know which solution was given to which infant rated the amount of crying in each instance.
The greatest reduction in crying occurred in the infants who tasted sucrose, both during the procedure and immediately after the procedure. The fat, protein and Ross Special Formula solutions seemed to be effective during the recovery period but not during the procedure itself. Water and lactose were not effective at reducing crying. The infants who received water cried almost throughout the entire experiment. The sucrose group, however, cried less than one half (47 percent) of the time. Three of the eight infants in the sucrose group did not cry at all. Similac also reduced the amount of crying during treatment but not during the period following the heelstick.
The author concluded that some milk components and sucrose, as well as sucking itself, may help provide relief for mild or moderate pain in neonates.
GRACE BROOKE HUFFMAN, M.D.
Blass EM. Milk-induced hypoalgesia in human newborns. Pediatrics 1997;99:825-9.
EDITOR'S NOTE: The benefits of allowing newborns to suckle before and during even moderately painful procedures seem to outweigh the risks (e.g., aspiration). As with any nonverbal patient, it is often too easy to overlook or minimize the pain an infant may be experiencing. This small study helps remind us to consider the whole patient.
G.B.H.
Inhaled Ipratropium and Oral Theophylline for Asthma
Oral theophylline has recently fallen out of favor in the treatment of asthma because of its side effect profile and narrow therapeutic range. Ipratropium bromide is an inhaled anticholinergic drug used as a bronchodilator in patients with chronic obstructive pulmonary disease. Data suggest that ipratropium may be effective in the treatment of asthma and may produce an additive effect when it is combined with a beta agonist. However, ipratropium is not currently recommended as a first-line drug for asthma. Burki compared the efficacy and safety of oral theophylline in combination with ipratropium in patients with asthma.
The double-blind, placebo-controlled, crossover trial evaluated the effects of both drugs separately and in combination in 19 patients with asthma. The four test regimens evaluated in the study were as follows: theophylline tablets and two placebo inhalations from a metered-dose inhaler; theophylline tablets and two puffs (40 µg) of ipratropium; placebo tablets and two puffs of ipratropium; and placebo tablets and two placebo inhalations. The theophylline dosage ranged from 300 to 700 mg, depending on the optimal dosage to achieve a therapeutic blood level. Patients were excluded from the study if they were smokers, had a history of other systemic diseases or were taking oral steroids or cromolyn sodium.
Before the four regimens were evaluated, patients were seen on three separate screening days. On the first pretest day, a baseline measurement of forced expiratory volume in one second (FEV1) was obtained and was required to be 70 percent or less than the predicted normal value. An increase of at least 15 percent in the FEV1 also was required within 30 minutes of two isoproterenol inhalations. On the second pretest day, patients received two puffs of ipratropium, followed by spirometry at 30 and 60 minutes. On the third pretest day, patients were given 500 mg of theophylline orally, and spirometry was performed two and four hours after the dose. If the theophylline blood level was between 12 and 18 mg per dL, the subject was included in the study. If the level was subtherapeutic, the patient was evaluated again on a different day, and the theophylline dose was adjusted to obtain a therapeutic blood level.
Pre-study baseline spirometry values did not differ significantly, and the FEV1 increased significantly from baseline in response to isoproterenol, ipratropium and theophylline during the three pretest screening procedures.
Patients were then seen on four separate days for administration of the four test regimens. On each day, an electrocardiogram was obtained, baseline and post-test spirometry was performed and a serum theophylline level was measured. A total of 32 patients entered the study, but complete data were available in 19 (eight men and 11 women).
The FEV1 increased significantly after all three drug tests, with the increase occurring more rapidly with ipratropium alone than with theophylline alone. However, the combination of theophylline and ipratropium produced the greatest increase in FEV1 (3.0 L compared with 2.48 L for ipratropium and 2.61 L for theophylline). The effect persisted over a longer period of time with administration of ipratropium and theophylline together as opposed to either agent alone.
No significant side effects occurred in response to the drug and placebo combinations. A significant increase in the heart rate was noted three to five hours following all three drug tests, but the rate did not differ significantly among the drug tests.
The author concludes that since the proposed mechanisms of action of theophylline and ipratropium are different, the bronchodilator effect of this combination is likely to be additive, which would explain the greater increase in FEV1 when the drugs were administered together. In addition, the combination of theophylline and ipratropium did not result in increased side effects or tachycardia. The author notes that this combination may be a reasonable alternative in patients who cannot tolerate the side effects of beta agonists or when tachyphylaxis to the beta agonists is suspected.
JEFFERY T. KIRCHNER, D.O.
Burki NK. The effects of the combination of inhaled ipratropium and oral theophylline in asthma. Chest 1997; 111:1509-13.
EDITOR'S NOTE: This small but interesting study provides further efficacy data on the use of ipratropium in patients with asthma. Ipratropium is often given in combination with albuterol in patients admitted to the hospital because of acute exacerbations of asthma. The synergistic effect with theophylline makes clinical sense, although the recently revised guidelines for the treatment of asthma still consider theophylline a third-line drug, making clinicians hesitant to use this agent in the majority of patients with asthma.
J.T.K.
Effect of St. John's Wort as Treatment for Depression
Because many readers of The Medical Letter on Drugs and Therapeutics asked for an evaluation of St. John's wort, Medical Letter consultants responded with an early report based on current available data. St. John's wort is an herbal remedy derived from the flowering plant Hypericum perforatum and is widely available in health food stores. It is currently licensed in Germany for treatment of anxiety, depression and insomnia. At this time, it has not been evaluated by the U.S. Food and Drug Administration (FDA) and is considered a "dietary supplement."
St. John's wort is an extract with many constituents. The primary one is hypericin, a naphthodianthrone. Although in Germany the dosage of the herb is based on its hypericin content, the actual amount of hypericin varies widely according to growth conditions of the plant. Hypericin inhibits the uptake of the neurotransmitters serotonin, norepinephrine and dopamine. It is not known if hypericin actually crosses the blood-brain barrier. Hypericin may also have some monoamine oxidase inhibitory capability. Following oral administration, serum concentrations reach a peak in about five hours and achieve steady state in about four days. Data on methods of metabolism and excretion are unavailable.
A meta-analysis of 23 randomized trials, published in the British Medical Journal (1,757 outpatients with mild or moderate depression) found hypericum extract to be superior to placebo and about as effective as standard antidepressants. The criticism of this particular analysis rests with the fact that the diagnosis of depression was not well established, the placebo response was lower than could be expected in similar studies, the standard dosage of antidepressants was low and the dosage of hypericum extract varied more than sixfold. The study interval also varied, from two to 12 weeks. To date, there have been no serious adverse effects reported with use of St. John's wort. Some patients have complained of dry mouth, dizziness, constipation and confusion. Overall, very few patients (less than 2 percent) discontinued therapy with the herb because of adverse effects. It has been reported that some grazing animals who have eaten the plant have suffered phototoxic reactions. A similar severe contact-phototoxicity reaction has been reported in a human.
Medical Letter consultants conclude that further well-conducted trials are needed before the effectiveness and safety of St. John's wort are established. Herbal remedies sold in the United States do not have FDA approval, and the active ingredients, and the potency and purity of these remedies are unknown.
BARBARA APGAR, M.D., M.S.
Medical Letter consultants. St. John's wort. Med Lett Drugs Ther 1997;39(1014):107-8.
EDITOR'S NOTE: Although some patients are already using herbal remedies, it is important to remember that many of these remedies have not been adequately studied in a way that will allow appropriate clinical decisions to be made. Practitioners should visit a modern health food store and survey the variety of compounds and remedies available to patients. The intense public interest in these products will perhaps generate well-conducted trials of their effectiveness and safety.
Parental Consent and Rate of HIV Testing in Adolescents
Adolescents represent a significant number of the persons infected with human immunodeficiency virus (HIV) in the United States. However, many adolescents do not receive HIV testing because of the parental consent requirements in most states. Historically, minors have been deemed incompetent to consent to their own medical care. The state of Connecticut amended its confidentiality law in 1992 to include consent by minors for HIV testing. Meehan and associates analyzed the records from HIV counseling and testing sites funded by the Connecticut Department of Public Health to determine the change in the use of HIV testing by minors after removal of the parental consent requirement.
Over a two-year period (the 12 months before and the 12 months after the legislative change), 1,601 minors visited HIV testing and counseling sites. The patients ranged from 13 to 17 years of age. The girls who were tested for HIV outnumbered the boys three to one. During the first 12-month period, 656 minors were counseled, and 392 were tested. During the 12 months after the consent law was amended, 945 minors visited these same sites, and 801 were tested for HIV antibody. This represented a 44 percent increase in patient visits over the first 12-month period. Testing of males increased by 151 percent and of females by 90 percent. Of the total group of patients who visited testing sites, the number of minors at high risk for HIV infection (two or more risk factors) tripled, while the number at low risk remained the same.
The authors conclude that by allowing minors to be tested for HIV without parental consent, the number of persons receiving counseling and testing, when appropriate, would increase considerably. They recommend that states remove legislation currently prohibiting minors to be tested for HIV infection without parental consent. Existing laws impose barriers to the diagnosis of HIV infection and hinder efforts to control the epidemic. Making counseling and testing more available to minors would also provide an opportunity to promote healthy behavior in this at-risk population.
JEFFERY T. KIRCHNER, D.O.
Meehan TM, et al. The impact of parental consent on the HIV testing of minors. Am J Public Health 1997:87: 1338-41.
Needle Length for Effective Immunization in Children
Intramuscular injection is associated with improved immune response when compared with subcutaneous injection of various vaccines. Groswasser and colleagues measured tissue thickness at two sites recommended for vaccine injection to compare injection techniques and to determine optimal needle length for vaccination of pediatric patients.
Eighteen toddlers and 40 infants were included in the study. Tissue thickness was measured with ultrasonography at the anterolateral aspect of the quadriceps muscle or at the deltoid muscle. The first injection technique, widely used in the United States, involves bunching the thigh muscle at the injection site to increase muscle mass and minimize the chance of striking bone. The other injection technique, recommended by the World Health Organization (WHO), involves stretching the skin flat between the finger and thumb, and pushing the needle down at a 90 degree angle through the skin. A 7/8-in (22-mm) needle is widely recommended. However, unit-dose vaccines are often supplied with a 5/8-in (16-mm) needle.
The skin-to-bone depth of the thigh in infants and toddlers was about 17 mm. The subcutaneous thickness in infants was 8 mm, regardless of the gender of the baby. Toddlers had somewhat thicker quadriceps muscle tissue, with a median of 9.3 mm.
The authors conclude that the injection technique chosen should determine the appropriate needle size. The WHO technique was ideally suited for use of the 5/8-in (16-mm) needles that are supplied with many vaccines; use of the longer needle could cause neurovascular or bone damage. However, the "bunching" injection technique that is more widely used in the United States is more suited to the use of a 7/8-in (22-mm) needle, thus minimizing the risk of subcutaneous injection of the vaccine.
GRACE BROOKE HUFFMAN, M.D.
Groswasser J, et al. Needle length and injection technique for efficient intramuscular vaccine delivery in infants and children evaluated through an ultrasonographic determination of subcutaneous and muscle layer thickness. Pediatrics 1997;100(3 Part 1):400-3.
Driving Performance, Mental Status and Alzheimer's Disease
Some studies have suggested that patients with Alzheimer's disease should stop driving. Fox and associates examined the correlation between mental status, neuropsychologic testing and open road driving performance in patients diagnosed with Alzheimer's disease.
Patients were included in the study if they had a diagnosis of probable Alzheimer's disease and wished to continue driving. Patients ranged in age from 59 to 84 years. The average length of time since diagnosis of Alzheimer's disease was four years (range: two to eight years). Each patient underwent an assessment by a physician and a clinical neuropsychologist that included a medical and driving history, administration of the Mini Mental Status Examination (MMSE), a physical examination, and a variety of sensory and motor tests. Visual acuity and visual fields were also tested. Each of the 19 participants then underwent an on-road assessment and was rated on 138 predetermined actions at specific locations along the route. The percentage of correct actions was known as the driving score.
Motor and sensory abnormalities were found in only 5.7 percent of patients, and the mean MMSE score was 21.3. The MMSE and the physician's prediction of the driving score were, in fact, associated with the percentage of correct actions on the road test, with significant numbers of patients correctly predicted to pass and to fail the road test (71 percent and 83 percent, respectively). Duration of Alzheimer's disease was not associated with the driving score.
The authors conclude that a diagnosis of Alzheimer's disease alone may not be a good reason to recommend that someone stop driving. However, the progression of this illness mandates frequent reevaluation of driving ability. An objective measure, such as an MMSE, helped physicians predict which patients would not succeed in actual driving situations but was not a sufficient measure in and of itself. An actual standardized driving test provides the best determination of the driving competence of a patient with Alzheimer's disease.
GRACE BROOKE HUFFMAN, M.D.
Fox GK, et al. Alzheimer's disease and driving: prediction and assessment of driving performance. J Am Geriatr Soc 1997;45:949-53.
HMG-CoA Reductase Inhibitors and Stroke Risk
HMG-CoA reductase inhibitors, or statin drugs, effectively reduce cholesterol levels. A reduction in cholesterol levels is known to decrease the risk of coronary heart disease, but the effect of cholesterol reduction on stroke risk and mortality is unclear. Hebert and colleagues gathered data from trials of statin drugs to determine if the risk of stroke and mortality is reduced with the use of these agents.
A literature search identified 16 clinical trials of statin drugs in which data for death and stroke were reported. Some of the studies were primary prevention trials and others were secondary prevention trials. Most included patients with elevated cholesterol levels, although one study evaluated patients with normal levels.
Treatment ranged from eight weeks to more than five years. Mean baseline cholesterol levels in the clinical trials ranged from 203 to 296 mg per dL (5.3 to 7.7 mmol per L). Drugs that were studied included lovastatin (six studies), pravastatin (eight studies) and simvastatin (two studies). No significant differences in cholesterol-lowering effects were found among these drugs.
There were 454 strokes and 1,175 deaths during the course of the studies, which included approximately 29,000 participants. Treatment with statin drugs was associated with a statistically significant 29 percent reduction in fatal and nonfatal strokes. The treatment groups also showed a significantly lower rate of cardiovascular disease deaths and deaths resulting from all causes than the placebo groups. Total mortality was reduced 22 percent in the treatment groups, compared with the placebo groups.
The authors conclude that cholesterol reduction with statin drugs reduces stroke, deaths that are due to cardiovascular disease and overall mortality. Treatment with these agents was not associated with an increase in noncardiovascular disease deaths or the incidence of cancer.
GRACE BROOKE HUFFMAN, M.D.
Hebert PR, et al. Cholesterol lowering with statin drugs, risk of stroke, and total mortality: an overview of randomized trials. JAMA 1997;278:313-21.
Topical Tretinoin and Alpha-Hydroxy Acids for Photoaging
Photoaging is the effect on the skin of chronic ultraviolet irradiation superimposed on intrinsic aging. Photoaged skin may be wrinkled and have irregular hyperpigmentation or depigmentation, telangiectasias, actinic keratoses or invasive carcinoma. Over-the-counter topical treatments for photoaging have been used by persons interested in improving the appearance of their skin. Some of these agents have been compounded into cosmetics. Consultants from The Medical Letter on Drugs and Therapeutics reviewed the data on topical tretinoin and alpha-hydroxy acids to determine their effectiveness in improving the appearance of aging skin.
Topical tretinoin, initially approved by the U.S. Food and Drug Administration solely for the treatment of acne, has been used for years to treat photoaging of the skin. It is now approved by the FDA in a 0.05 percent formulation in an emollient cream for the treatment of photoaged skin. Tretinoin is a metabolite of vitamin A, which is known to increase formation of collagen in the dermis. Side effects, which increase at higher concentrations, include erythema, burning, itching and peeling. Tolerance often develops with continued use. Oral tretinoin is a known teratogen; consequently, topical therapy is not advised during pregnancy.
Several three- to six-month double-blind trials have shown that use of tretinoin cream modestly improves fine wrinkling, surface roughness and pigmentary changes in mildly to moderately affected skin. Compared with the vehicle alone, tretinoin cream has also been shown to lighten the appearance of prominent hyperpigmented macules on the face, arms and hands. The 0.025 percent formulation appeared to be as effective as the 0.1 percent strength and was better tolerated. Some histologic improvements in treated skin have continued to occur, although some skin regressed through four years of treatment.
Alpha-hydroxy acids are widely used in cosmetic products. Only one controlled trial has been conducted to date. In this study, more than 70 percent of patients treated with lactic acid or glycolic acid reported improvement in the appearance of photoaged skin compared with 40 percent of patients who did not use lactic acid or glycolic acid. Low concentrations of alpha-hydroxy acids appear to be less irritating than tretinoin, and no adverse effects have been reported, although no long-term studies have been conducted. High-concentration alpha-hydroxy acid peels have been known to cause post-inflammatory hyperpigmentation and have been associated with eruption of herpes simplex lesions.
Other agents such as oral and topical estrogen or vitamins C and E have been reported to reverse some effects of photoaging; however, controlled trials are lacking.
Consultants from the Medical Letter conclude that the topical application of tretinoin for four to six months can cause modest improvement in photoaged skin and that these improvements may persist, especially with continued use. Data on alpha-hydroxy acids are lacking and, despite widespread use in cosmetic products, their effectiveness in improving photoaged skin has not been established.
BARBARA APGAR, M.D., M.S.
Medical Letter consultants. Topical drugs for aging skin. Med Lett Drugs Ther 1997;39(1007):78-9.
Acquisition of Genital Herpes Among Pregnant Women
Neonatal herpes simplex virus (HSV) infection most commonly occurs when the virus is present in the birth canal of an asymptomatic mother during labor and delivery. The virus may be present as a result of reactivation of prior infection or infection acquired at some time during the pregnancy. The consequences of neonatal infection with HSV include neurodevelopmental disability and death. It has also been noted that genital HSV infection acquired during pregnancy may result in preterm labor, intrauterine growth retardation and spontaneous abortion. Brown and colleagues used virologic and serologic methods to determine the rate of acquisition of HSV infection among pregnant women.
Serum samples for antibody to HSV type 1 and type 2 were obtained at the first prenatal visit in 8,538 women. In addition, serum samples were obtained at 14 to 18 weeks of gestation, at 24 to 28 weeks of gestation and at the time of labor. Cultures for HSV were obtained from the external genitalia and from the cervix of these women at the onset of labor. The serum samples from each of the women were tested simultaneously using Western blot assays. The medical records of women who became seropositive for HSV during the pregnancy were reviewed for symptoms of genital herpes during pregnancy.
Of the approximately 8,500 women included in the study, 24 percent were HSV-negative at entry into the study; 48 percent were seropositive for HSV type 1 antibody; 11 percent were seropositive for HSV type 2 antibody; and 17 percent were seropositive for both types of antibodies. During the course of pregnancy, a total of 94 women became seropositive for HSV. After adjustment for a 40-week gestation period, this total represents 2 percent of all susceptible patients. Among the 94 women who became seropositive during the prenatal period, 60 had subclinical infections. Thirty percent acquired the infection in the first trimester, 30 percent in the second trimester, and 40 percent in the third trimester. Thirty-four of the newly infected patients had symptomatic infections. Twenty-one percent of infections occurred in the first trimester, 44 percent in the second trimester, and 35 percent in the third trimester. There were no cases of neonatal herpes and there was no increase in pregnancy-related morbidity among the 94 women who seroconverted.
Nine other women who were diagnosed with genital herpes obtained the infection near the onset of labor; five of these women had lesions at the time of labor. Neonatal infections occurred in four of the nine infants born to these women.
The authors conclude that infection with HSV during the prenatal period did not increase the frequency of pregnancy-related complications if seroconversion was complete before the onset of labor. Approximately 2 percent of susceptible women may acquire HSV infection during pregnancy. However, only an infection obtained near the time of labor and delivery appears to be associated with neonatal infection and accompanying morbidity and mortality. The latter part of pregnancy may be the best time to consider serologic testing for HSV and to recommend preventive methods to susceptible mothers, such as the use of condoms or sexual abstinence.
JEFFERY T. KIRCHNER, D.O.
Brown ZA, et al. The acquisition of herpes simplex virus during pregnancy. N Engl J Med 1997;337:509-15.
Single-Dose Fosfomycin for Urinary Tract Infection
Fosfomycin tromethamine is a broad-spectrum antibiotic approved by the U.S. Food and Drug Administration for single-dose oral treatment of uncomplicated urinary tract infections in women. Consultants for The Medical Letter on Drugs and Therapeutics summarize the data comparing fosfomycin with other antibiotics used in the treatment of urinary tract infections.
Fosfomycin is moderately active in vitro against Escherichia coli and other common urinary tract pathogens, including most strains of enterococci. When fosfomycin is used in multiple-dose regimens, resistance to the drug emerges rapidly, but cross-resistance with other antimicrobials is uncommon. Fosfomycin is excreted unchanged in the urine, where it reaches high concentrations that persist for 24 hours or longer.
In three randomized trials comparing a single 3-g dose of fosfomycin with nitrofurantoin given for seven days, norfloxacin for five days and cephalexin for five days, treatment with fosfomycin eradicated bacteriuria in 91 to 94 percent of women. Cultures were obtained once about five days after the start of treatment and again approximately one month after treatment. Bacteriuria was eradicated one month later in 73 to 81 percent of patients treated with fosfomycin. The eradication rates for fosfomycin were similar to those for norfloxacin and nitrofurantoin but were superior to those for cephalexin.
In two unpublished trials, a single dose of fosfomycin was less effective in eradicating bacteriuria than seven days of treatment with ciprofloxacin or 10 days of treatment with trimethoprim-sulfamethoxazole.
Although fosfomycin is generally well tolerated, diarrhea developed in 9 percent of patients participating in clinical trials. Vaginitis occurred in a lower percentage of patients.
Medical Letter consultants advise that a single dose of fosfomycin is moderately effective in the treatment of acute cystitis in women. Although single-dose therapy with fosfomycin may improve compliance, it is a relatively expensive treatment.
BARBARA APGAR, M.D., M.S.
Medical Letter consultants. Fosfomycin for urinary tract infections. Med Lett Drugs Ther 1997;39(1005):66-8.
Levomethadyl Acetate for Opioid-Dependent Patients
Levomethadyl acetate hydrochloride (also known as LAAM) was approved in 1993 by the U.S. Food and Drug Administration for use in the treatment of opioid dependence. Unlike methadone, which requires daily administration, LAAM is administered three times a week. Eissenberg and colleagues compared the clinical efficacy of different dosages of LAAM.
Patients in the randomized, controlled study were assigned to one of three treatment groups, with the drug given on Mondays, Wednesdays and Fridays: low-dose LAAM (25 mg, 25 mg and 35 mg), medium-dose LAAM (50 mg, 50 mg and 70 mg) and high-dose LAAM (100 mg, 100 mg and 140 mg). The Friday dosages were higher to compensate for the longer dosage interval between Friday and Monday. The low-, medium- and high-dose groups had 62, 59 and 59 patients, respectively. Treatment goals were established for each patient, and individual and group therapy was provided. Patients' self-reports of illicit drug use and observed urine specimens were also obtained on the dosing days. Of the 180 patients who entered the study, 108 (60 percent) completed the entire 17-week study. No significant differences in retention were noted among the three treatment groups.
The percentage of patients who remained abstinent from opioid use (as verified by urine samples) increased as the LAAM dosage increased, with 11 percent of the low-dose group and 14 percent of the medium-dose group remaining abstinent for four consecutive weeks, compared with 34 percent of the high-dose group. Self-reported heroin use decreased to a greater degree in the high-dose group. After 16 weeks of LAAM treatment, patients in the high-dose group reported that they used heroin on 2.5 days of the previous 30 days, compared with 4.1 days and 6.3 days of the previous 30 days in the medium- and low-dose groups, respectively. Adverse effects were not dosage-related, and the most common adverse effect was constipation.
The authors conclude that LAAM treatment of opioid dependence has several advantages over the more commonly used methadone treatment--administering doses three times a week is more convenient and decreases the need for patients to take their medication at home. High-dose LAAM appears to be more effective than lower doses in decreasing heroin use.
GRACE BROOKE HUFFMAN, M.D.
Eissenberg T, et al. Dose-related efficacy of levomethadyl acetate for treatment of opioid dependence: a randomized clinical trial. JAMA 1997;277:1945-51.
Cholesterol Awareness Among Patients Following Screening
An elevated cholesterol level (greater than 240 mg per dL) is an established risk factor for coronary artery disease; however, 60 percent of all deaths from coronary heart disease occur among persons with lower cholesterol levels. Since 1991, the National Cholesterol Education Panel (NCEP) has encouraged physicians to screen patients for hyperlipidemia and provide dietary counseling in order to reduce the risk for heart disease. The NCEP recommends that physicians inform patients of their cholesterol test results in a clear, understandable manner and encourage all patients, regardless of concurrent risk factors, to reduce their fat intake. Previous studies have shown that patients who were screened for high blood cholesterol and were informed of their cholesterol status were more motivated to modify other cardiac risk factors and to reduce their serum cholesterol levels. Murdoch and Wilt surveyed patients within a year of their cholesterol measurement to assess compliance with the NCEP guidelines.
Any patient at a midwestern Veterans Affairs hospital who had a cholesterol level checked by a physician's order between January 1993 and 1994 was eligible for the study. Multiphasic blood screening was not done at that institution during the study period, so cholesterol testing could only be performed if specifically requested by a physician. A total of 250 patients (125 men and 125 women) who had cholesterol screening were randomly selected by a computer-generated list. A 17-item questionnaire was mailed to study participants within one year of their last cholesterol measurement. The participants were asked to identify their cholesterol status in two different ways: as a category (i.e., desirable versus undesirable) and as the actual number. Respondents were also asked to estimate their perceived risk of coronary artery disease due to high cholesterol levels, their overall health perceptions, their other cardiac risk factors, if they had been prescribed a specific cholesterol-lowering diet and if a physician had told them their actual cholesterol number.
Eighty-three percent of study participants responded to the survey. The average age of the participants was 61 years for the men and 55 years for the women. The mean length of time between the survey and respondents' last cholesterol measurement was 4.4 months. Almost all respondents (99 percent) either agreed or strongly agreed that a high cholesterol level increases the risk for coronary heart disease, and the majority (76 percent of men and 83 percent of women) believed that lowering their cholesterol level would decrease their personal risk of coronary disease.
When asked if a physician had checked their cholesterol level in the past year, 60 percent of the men and 65 percent of the women answered affirmatively. Yet only 50 percent of men and 55 percent of women stated that they were told their cholesterol results by a physician. Less than one half of the study participants said they were given dietary instructions by a physician.
Twenty-eight percent of the men and 37 percent of the women said they knew their cholesterol number, but only 40 percent of the numbers they reported were accurate. Overall, only 19 percent of the survey respondents accurately reported their cholesterol level.
Respondents were more likely to accurately recall their cholesterol numbers if they remembered being told their test results or remembered receiving dietary advice. Female gender and more years of education were correlated with cholesterol awareness.
The authors conclude that physician compliance with the NCEP guidelines is poor. Even among better-educated patients, knowledge of the importance of cholesterol level and the need for dietary intervention was found to be significantly lacking. Physicians should endeavor to improve patient awareness by following up cholesterol screening with meaningful feedback and by being diligent in prescribing dietary therapy.
JEFFERY T. KIRCHNER, D.O.
Murdoch M, Wilt TJ. Cholesterol awareness after case-finding: do patients really know their cholesterol numbers? Am J Prev Med 1997;13:284-9.
Family History as a Risk Factor for Testicular Cancer
Testicular cancer has a few well-established risk factors, including undescended testes and a history of contralateral germ cell tumor. Family history has also been suggested as a possible risk factor, even though no convincing data clearly identify a prevalence of familial testicular cancer in populations with testicular cancer. Dieckmann and Pichlmeier conducted a three-part investigation, including a prospective study, a retrospective analysis of a large patient population, and a review of the literature, to identify relative risk estimates and assess the prevalence of familial testicular cancer.
A total of 1,692 patients with testicular germ cell tumors were given a questionnaire to evaluate their family history of testicular cancer. In a retrospective analysis, 518 patients with testicular cancer were asked if they had any relatives who had been diagnosed previously with testicular cancer. Another group of 531 patients were used as age-matched control subjects. The literature review included only reports that addressed the prevalence of familial testicular cancer and included at least 200 patients.
In the patients from the prospective study, 28 reported that a family member had a germ cell testicular tumor, corresponding to an overall prevalence of familial testicular cancer of 1.7 percent. In the retrospective analysis, 13 of the 518 patients with testicular cancer had a family history of the disease, corresponding to an overall prevalence of 2.5 percent. Only three of the 531 control subjects reported a family history of testicular cancer, for a prevalence of 0.56 percent. The literature review identified 10 studies that examined the prevalence of familial testicular cancer in populations of more than 200 patients. The reported prevalence of familial testicular cancer ranged from 1.0 to 2.8 percent, with a mean prevalence of 1.35 percent.
The authors concluded that genetic predisposition is a definite independent risk factor for testicular germ cell tumors. Having a first-degree family history of testicular cancer confers a three- to 10-fold increased relative risk. The goal for future research is to identify this inherited predisposing defect for familial testicular cancer on a molecular genetic level.
JEFFERY T. KIRCHNER, D.O.
Dieckmann KP, Pichlmeier U. The prevalence of familial testicular cancer. An analysis of two patient populations and a review of the literature. Cancer 1997;80:1954-60.
Risk of Maternal-Infant Transmission of Hepatitis C
Perinatal transmission of hepatitis C virus from mother to infant has been well-documented; however, reports about the risk of infection vary widely, ranging from zero to 100 percent. Transmission of hepatitis C virus may occur in utero, at the time of delivery and through breast-feeding, all of which are identical to the modes of transmission for human immunodeficiency virus (HIV) infection. In fact, several studies have reported a higher incidence of hepatitis C virus transmission by mothers with HIV coinfection, although these results are somewhat controversial. Tovo and colleagues attempted to quantify the risk of infection by evaluating the incidence of hepatitis C virus transmission in infants born to mothers with or without HIV coinfection. Other potential factors for transmission were also investigated, including the progression of maternal HIV, a history of intravenous (IV) drug use, the length of the pregnancy, infant birth weight, mode of delivery and type of infant feeding.
A total of 245 singleton at-risk infants born to mothers who were positive for hepatitis C virus were enrolled in the study two weeks after birth and were followed for at least 18 months. Maternal data collected included risk factors for hepatitis C virus infection (i.e., IV drug use, history of transfusion, infected partner), HIV status, length of pregnancy, mode of delivery, infant birth weight and type of feeding. Baseline infant data included the presence of HIV and hepatitis C virus antibodies at birth. All 245 children were seen every three to five months, for up to 18 months after birth. At each visit, hepatitis C virus and HIV testing was repeated, including determination of hepatitis C virus RNA levels.
After 18 months, only the children who remained positive for hepatitis C virus and/or HIV were followed, since they were considered to be infected and no longer carriers of maternal antibody. These children were followed for an additional mean period of 28 months. To further assess the impact of maternal HIV infection on hepatitis C virus transmission, the children were divided into two groups. Group A included children of women with hepatitis C virus only, and group B included children of women with hepatitis C virus and HIV coinfection.
Twenty-eight children (11.4 percent) became infected with hepatitis C virus, including 3.7 percent (three of 80) from group A and 15.1 percent (25 of 165) from group B. Of the children in group B, 22 (13.3 percent) acquired HIV, including six children who were coinfected with hepatitis C virus.
Overall, children delivered vaginally were more often infected with hepatitis C virus (13.9 percent) than those delivered by cesarean section (5.6 percent). A similar pattern was seen for HIV infection, in which children delivered vaginally (16.8 percent) had a higher risk for infection than those delivered by cesarean section (4.3 percent). The presence of HIV-related symptoms in the mother was not associated with an increased risk of hepatitis C virus or HIV transmission. Similarly, maternal IV drug use, premature delivery and low birth weight did not affect the risk of hepatitis C virus transmission. Infants in group B were bottle-fed. Infants in group A who were breast-fed showed no increased risk for hepatitis C virus infection.
The authors concluded that vertical transmission of hepatitis C virus is uncommon, which supports other studies that found that maternal HIV coinfection significantly increases the risk of hepatitis C virus infection in an infant. Infants exposed perinatally usually clear maternal hepatitis C virus-IgG antibody by six to 12 months of age, although some have persistent maternal antibody for up to 18 months. Thus, these infants cannot be considered infected before 18 months when tested by conventional serologic methods only. Delivery by cesarean section appears to decrease the risk of hepatitis C virus transmission, suggesting that most infants become infected at the time of delivery and are not infected in utero. The authors further state that mothers with hepatitis C virus should not be discouraged from breast-feeding, since transmission through lactation is unlikely.
JEFFERY T. KIRCHNER, D.O.
Tovo PA, et al. Increased risk of maternal-infant hepatitis C virus transmission for women coinfected with human immunodeficiency virus type 1. Clin Infect Dis 1997; 25:1121-4.
"Tips from Other Journals" are written by the medical editors of American Family Physician.
Copyright © 1998 by the American Academy of Family Physicians.
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