The FDA has required a new warning in the labels of prescription and over-the-counter products containing nonsteroidal anti-inflammatory drugs (NSAIDs) advising against their use during pregnancy beginning at 20 weeks’ gestation because of a risk of renal dysfunction in the fetus that could lead to low amniotic fluid levels (oligohydramnios) and neonatal renal impairment. NSAID labels previously warned against use of the drugs beginning at 30 weeks' gestation because of a risk for premature closure of the ductus arteriosus and persistent neonatal pulmonary hypertension

View Table: Safety of Drugs for IBD in Pregnancy

Treatment of epilepsy should begin with a single antiepileptic drug (AED), increasing its dosage gradually until seizures are controlled or adverse effects become intolerable. If seizures persist, specialists generally recommend trying at least one and sometimes a second alternative drug as monotherapy before considering use of two drugs concurrently. When used for the appropriate seizure type, AEDs are roughly equivalent in efficacy. Drug choice is usually based on factors such as ease of use, adverse effects, drug interactions, presence of comorbidities, and cost.

The American College of Obstetricians and Gynecologists (ACOG) and the US Preventive Services Task Force (USPSTF) have recommended that women at risk for preeclampsia take low-dose aspirin daily after the first trimester.

The FDA has approved Diclegis (Duchesnay), a fixed-dose, delayed-release combination of the H₁-antihistamine doxylamine and the vitamin B₆ analog pyridoxine, for treatment of nausea and vomiting of pregnancy in women who do not respond to conservative management. It is only available by prescription. Doxylamine and pyridoxine, both currently available over the counter, were previously available by prescription in a fixed-dose combination (Bendectin) for morning sickness. Bendectin was voluntarily withdrawn in the US in 1983 because of claims of teratogenicity that have since been disproven. The combination has continued to be available in Canada as Diclectin.

The FDA is advising health care professionals not to prescribe valproate sodium (Depacon), valproic acid (Depakene, Stavzor, and generics) or divalproex sodium (Depakote, Depakote ER, and generics) for migraine prevention in pregnant women because a recently published study showed that IQ scores are decreased in children of mothers who took these drugs during pregnancy. The FDA recommends avoiding valproate altogether, if possible, in women of childbearing age.1

VALPROATE — Valproic acid and divalproex sodium dissociate to valproate in the GI tract. Valproate is considered the drug of choice for treatment of primary generalized tonic-clonic seizures. It is one of many drugs used for treatment of bipolar disorder and prevention of migraine.2,3

EFFECTS ON CHILDREN — The recent publication is the third in a series comparing IQ scores in a cohort of children exposed to various antiepileptic drugs throughout pregnancy.4 At 3 years of age, 4.5 years, and now 6 years, IQ scores were 6-11 points lower in children exposed to valproate than in those exposed to carbamazepine, lamotrigine or phenytoin. In addition, valproate taken during pregnancy has the highest demonstrated risk, compared to other antiepileptic drugs, of major congenital malformations, including oral cleft, cardiac, urinary tract and neural tube defects, and most recently, it has been associated with an increased risk of autism.5,6

USE IN MIGRAINE — Beta blockers such as propranolol and timolol and the antiepileptics valproate and topiramate are the drugs generally used for prevention of migraine. There is no evidence that any one is more effective than any other. Because of concerns about possible adverse fetal effects with all of these agents, preventive therapy for migraine is generally not recommended during pregnancy.7

CONCLUSION — Taking valproate during pregnancy can lower the IQ of exposed children and possibly could have other devastating effects. Those risks are certainly not worth taking for prevention of migraine.

1. FDA Drug Safety Communication: Valproate anti-seizure products contraindicated for migraine prevention in pregnant women due to decreased IQ scores in exposed children. Available at www.fda.gov/Drugs/DrugSafety/ucm350684.htm. Accessed May 28, 2013.

2. Drugs for psychiatric disorders. Treat Guidel Med Lett 2013; 11:53.

3. SD Silverstein et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 2012; 78:1337.

4. KJ Meador et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology 2013; 12:244.

5. J Christensen et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA 2013; 309:1696.

6. KJ Meador and DW Loring. Risks of in utero exposure to valproate. JAMA 2013; 309:1730.

7. Drugs for migraine. Treat Guidel Med Lett 2011; 9:7.

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The antipsychotic drugs listed in Table 1 on the next page are more effective for treating the “positive symptoms” of schizophrenia (hallucinations and delusions) than the “negative symptoms” (apathy, social withdrawal, and blunted affect). Some symptoms of schizophrenia and acute psychoses may improve rapidly after treatment with antipsychotic drugs, but chronic schizophrenia improves slowly over many weeks and some patients may continue to improve for months. Most patients with chronic schizophrenia require prolonged maintenance therapy, but the risk of tardive dyskinesia and adverse metabolic effects must be kept in mind.

Harvesting of autogenous bone, most commonly from the iliac crest, for use as the interbody graft in spinal fusion procedures has been standard practice, but is associated with a high rate of morbidity, including graft site pain, infection, fracture, bleeding and damage to the femoral nerve. Use of recombinant human bone morphogenetic protein (rhBMP-2; Infuse Bone Graft - Medtronic) was first approved by the FDA in 2002 for single-level anterior lumbar spinal fusion in adults with degenerative disc disease who had not responded to at least 6 months of nonoperative treatment. Now it has also been approved for treatment of open tibial fractures and for use in oral and maxillofacial bone grafting procedures.

Recent news articles about mercury in fish may lead some patients to seek more information from their healthcare providers. For most Americans, seafood is the major source of exposure to mercury. The mercury in seafood is in the form of methylmercury, a potential neurotoxin formed by the organification of elemental mercury by marine microorganisms like plankton, which are then consumed by aquatic animals and concentrated up the food chain.

Currently circulating influenza virus is almost universally pandemic 2009 influenza A H1N1, but seasonal influenza strains could also appear soon. Antiviral drugs are an important adjunct to influenza vaccination for treatment and chemoprophylaxis of both pandemic and seasonal influenza. They may, however, interfere with the efficacy of FluMist, the live-attenuated intranasal vaccine, if they are administered within 48 hours before or <2 weeks after FluMist administration. Inactivated vaccines are not affected by antiviral drug therapy.

Even though the incidence continues to decline in the United States, tuberculosis (TB) is still a common cause of death worldwide, and the prevalence of drug-resistant TB poses severe challenges to its treatment and control. Guidelines with detailed management recommendations are available from the Centers for Disease Control and Prevention (CDC), American Thoracic Society and Infectious Diseases Society of America (IDSA).

Primary hypothyroidism is usually the result of Hashimoto's thyroiditis, thyroidectomy for hyperthyroidism, goiter or cancer, or radioactive iodine therapy for hyperthyroidism.

The majority of patients with insomnia do not have a predisposing psychiatric disease. Rather, untreated insomnia may be a risk factor for development of psychiatric problems such as depression or anxiety.

New guidelines for use of antiretroviral agents have been published, with a shift towards earlier and more continuous treatment. HIV infection is treated with combinations of antiretroviral drugs depending on the patientÆs HIV RNA levels ("viral load") and CD4 cell count. Increases in viral load while on therapy may indicate development of drug resistance, requiring further testing and a change in treatment regimen. Resistance testing is now recommended when a patient is first seen, regardless of when therapy will be started.

No truly new drugs have been approved for treatment of asthma since omalizumab (Xolair) in 2003, but some randomized controlled trials of older drugs have been published, and new guidelines have become available.

Depression occurs in up to 20% of pregnant women, and the use of selective serotonin reuptake inhibitors (SSRIs) in these women has been increasing. Maternal depression has itself been associated with intrauterine growth problems and low birth weight, so the risks of exposure to antidepressants during pregnancy must be weighed against the risks of untreated depression, which also include self-harm, poor bonding and poor parenting. SSRIs available in the US for treatment of depression include citalopram (Celexa, and others), escitalopram (Lexapro), fluoxetine (Prozac, and others), paroxetine (Paxil, and others) and sertraline (Zoloft).

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The pathogenesis of acne is multifactorial: follicular hyperkeratinization, bacteria, sebum production, androgens and inflammation all play a role. The gram-positive microaerophilic bacteria Propionibacterium acnes promote development of acne lesions by secreting chemotactic factors that attract leukocytes to the follicle, causing inflammation.

Peptic ulcers caused by treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) are mainly gastric ulcers. The greater the number of office visits and the longer the counseling time, the higher the smoking cessation rates have been.

Aliskiren (Tekturna - Novartis), the first direct renin inhibitor for treatment of hypertension, has been approved for use in a fixed-dose combination with the diuretic hydrochlorothiazide (Tekturna HCT - Novartis). Many angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are also available in fixed-dose combinations with hydrochlorothiazide (HCTZ).

Peptic ulcers caused by treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) are mainly gastric ulcers. Most duodenal and other gastric ulcers are caused by the gram-negative bacillus Helicobacter pylori. Gastroesophageal reflux disease (GERD) is caused by gastric acid reflux into the esophagus. Drugs that suppress gastric acid production are the primary treatment for GERD and peptic ulcers.

The most common cause of travelers' diarrhea, usually a self-limited illness without fever lasting several days, is infection with noninvasive enterotoxigenic (ETEC) or enteroaggregative (EAEC) strains of Escherichia coli. Campylobacter, Shigella, Salmonella, Aeromonas, viruses and parasites are less common.

Treatment of epilepsy should begin with a single drug, increasing the dosage gradually until seizures are controlled or adverse effects become unacceptable. If seizures continue and further dosage increases appear inadvisable because of adverse effects, most Medical Letter consultants generally prescribe at least one and sometimes a second alternative drug as monotherapy before considering use of two drugs at the same time. Most antiepileptic drugs initially approved by the FDA only as adjunctive therapy for partial seizures may also be effective for other types of seizures and as monotherapy. Studies suggest that when used for the appropriate seizure type, antiepileptic drugs are roughly equivalent in efficacy. The choice of a drug is usually based on factors such as ease of use, adverse effects and cost.

Drugs that lower low-density lipoprotein cholesterol (LDL-C) concentrations can prevent formation, slow progression and cause regression of atherosclerotic lesions. They should not be used as a substitute for lifestyle changes; a combination of diet, exercise and lipid-lowering drugs is optimal for prevention of coronary disease. Lipid-regulating drugs must be taken indefinitely; when they are stopped, plasma lipoprotein levels return to pretreatment levels in 2-3 weeks.

The drugs of choice for treatment of some fungal infections are listed in the tables. Some of the indications and dosages recommended here have not been approved by the FDA. Other guidelines are available from the Infectious Diseases Society of America (www.idsociety.org).

Treatment of epilepsy should begin with a single drug, increasing the dosage gradually until seizures are controlled or adverse effects become unacceptable. If seizures continue and further dosage increases appear inadvisable because of adverse effects, most Medical Letter consultants generally prescribe at least one and sometimes a second alternative drug as monotherapy before considering use of two drugs at the same time. Most antiepileptic drugs initially approved by the FDA only as adjunctive therapy for partial seizures may also be effective for other types of seizures and as monotherapy.

Patients with mild, infrequent asthma symptoms may require only intermittent, asneeded use of an inhaled short-acting beta2-adrenergic agonist. Use of a short-acting beta2-agonist more than twice weekly, other than for exercise-induced bronchospasm, indicates a need for anti-inflammatory treatment. Inhaled corticosteroids are the most effective anti-inflammatory medication; leukotriene modifiers are less effective alternatives. If regular use of an inhaled corticosteroid in a low dose does not prevent symptoms, a long-acting beta2-agonist should be added; addition of a second drug is more effective than raising the dose of the inhaled steroid. A leukotriene modifier can also be used as the second drug. Omalizumab may be considered as adjunctive therapy for patients more than 12 years old who have allergic asthma not controlled by other drugs. A short course of oral corticosteroids may be useful for acute exacerbations. Treatment of acute severe asthma as a medical emergency is not included here; it has been reviewed elsewhere (ER McFadden Jr, Am J Respir Crit Care Med 2003; 168:740).

The drugs of choice for non-HIV viral infections with their dosages and cost are listed in the tables that begin on page 24. Some of the indications and dosages recommended here have not been approved by the FDA.

Drugs that lower low-density lipoprotein cholesterol (LDL-C) concentrations can prevent formation, slow progression and cause regression of atherosclerotic lesions. In controlled trials in patients with coronary disease, some of these drugs have reduced mortality by 20% to 30%.

The drugs of choice for treatment of some fungal infections are listed in the table that begins on page 8. Some of the indications and dosages recommended here have not been approved by the FDA.

Tuberculosis (TB) is still a problem in the United States, even though the incidence continues to decline in most of the country (MMWR Morbid Mortal Wkly Rep 2004; 53:209). Treatment of TB can be divided into treatment of latent infection diagnosed by a positive PPD and treatment of active clinical TB. Guidelines with detailed management recommendations are available from the US Centers for Disease Control and Prevention (CDC) (MMWR Morbid Mortal Wkly Rep 2003; 52RR-11:1).

Many women of child-bearing age now take folic acid supplements of 400 ╡g per day to prevent neural tube defects in their offspring (Medical Letter 1998; 40:75). An FDA advisory committee has recommended development of a combination tablet containing an oral contraceptive and 400 ╡g of folic acid. A recent editorial in the New England Journal of Medicine suggested that folic acid doses should be higher (NJ Wald, N Engl J Med 2004; 350:101).

New drug approvals as well as continuing concerns about drug toxicity and the development of resistance have prompted new antiretroviral treatment guidelines (Panel on Clinical Practices for Treatment of HIV Infection, November 10, 2003, www.aidsinfo.nih.gov).

Treatment of epilepsy should begin with a single drug, increasing the dosage gradually until seizures are controlled or adverse effects become unacceptable. If seizures continue and further dosage increases appear inadvisable because of adverse effects, most Medical Letter consultants generally prescribe at least one and sometimes a second alternative drug as monotherapy before considering use of two drugs at the same time. Most antiepileptic drugs initially approved by the FDA only for adjunctive therapy are probably also effective as monotherapy. Many of the drugs used to treat epilepsy interact with each other (see table beginning on page 63) and with other drugs; for interactions with other drugs, see The Medical Letter Handbook of Adverse Drug Interactions, 2003. The treatment of status epilepticus is not included here.

Cefuroxime axetil (Ceftin - Glaxo), an oral form of the second-generation parenteral cephalosporin cefuroxime (Zinacef), was recently marketed in the USA. Previously available oral cephalosporins are the first-generation drugs cephalexin (Keflex; and others), cephradine (Anspor; and others) and cefadroxil (Duricef; and others), and the second-generation cefaclor (Ceclor); second-generation cephalosporins have more activity against gram-negative bacteria.