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Valacyclovir — (Valtrex)

International Brand Names

Rapivir (Mexico); Valcyclor (Colombia); Zelitrex (France, South Africa)

Drug Class Antivirals
Indications Genital herpes, herpes zoster
Mechanism Inhibits DNA polymerase
Dosage With Qualifiers Genital herpes— primary: 1000 mg PO bid × 10 d; recurrent: 500 mg PO bid × 3 d; prophylaxis: 1000 mg PO qd
Herpes zoster—1000 mg PO tid × 7 d
NOTE: Renal dosing.

  • Contraindications —hypersensitivity to drug or class, immune compromise

  • Caution —renal dysfunction

Maternal Considerations After ingestion, valacyclovir is metabolized to acyclovir , which enhances bioavailability. It is both effective and well tolerated for HSV suppression for up to 10 y of continuous use. Neonatal herpes affects 1/15,000 newborns. The majority of infected infants are born to women with a primary infection during pregnancy. Although there are no adequate reports or well-controlled studies of valacyclovir in pregnant women, it is used extensively for the listed indications. When initiated prophylactically at 36 w, acyclovir reduces both the risk of recurrence and the frequency of a positive cervical culture at delivery in women who experience either a primary infection or at least one secondary episode during pregnancy. There is insufficient evidence to determine if antiviral prophylaxis reduces the incidence of neonatal herpes. However, patients should be counseled that antenatal antiviral prophylaxis reduces viral shedding and recurrences at delivery and reduces the need for cesarean delivery for genital herpes. In one RCT, valacyclovir (500 mg 2 × daily) given to pregnant women with HIV-1, HSV-2, and CD4 count > 250 at 34 weeks gestation had no effect on timing of infant CMV acquisition or breast milk CMV viral loads, but it modestly reduced cervical CMV shedding.
Side effects include renal failure, dysmenorrhea, N/V, headache, dizziness, arthralgia, depression, facial edema, hypertension, tachycardia, angioedema, rash, confusion, hallucinations, aplastic anemia, thrombocytopenia, anemia, leukopenia, and erythema multiforme.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. Valacyclovir crosses the human placenta. Congenital CMV infection affects 0.7% of live births worldwide and is the leading cause of congenital neurologic handicap of infectious origin. However, systematic screening for this infection has not been implemented in pregnancy or at birth in any country due to gaps in our understanding of this congenital infection. Solid epidemiologic data have emerged along with good evidence for the accuracy of diagnosis and for predicting fetal outcome by a combination of imaging and fetal laboratory parameters. There is also evidence that valacyclovir treatment of mothers carrying an infected fetus is feasible, safe, and possibly effective. Maternal oral administration of valacyclovir leads to therapeutic concentrations in the maternal and fetal compartments and, in the instance of CMV, a decrease in the fetal viral load. In one multicenter phase II study of pregnant women carrying a symptomatic CMV-infected fetus, a high dose of valacyclovir (8 g daily) increased the proportion of asymptomatic neonates from 43% without treatment to 82% with treatment and was shown to be safe and well tolerated. Postmarketing surveys suggest no increased frequency of birth defects. Acyclovir crosses the rodent placenta; rodent studies are reassuring, revealing no evidence of teratogenicity or IUGR despite the use of doses higher than those used clinically.
Breastfeeding Safety Valacyclovir is converted to acyclovir , which enters human breast milk. However, the amount of acyclovir in breast milk during valacyclovir administration is < 5% of the dose used to treat neonates. A randomized, double-blind trial of preventive twice daily valacyclovir (500 mg) beginning at 34 weeks gestation in HIV-1/HSV-2 co-infected pregnant women found valacyclovir significantly decreased early breast milk and plasma HIV-1 RNA.
Drug Interactions Acyclovir - valacyclovir may diminish the therapeutic effect of varicella and zoster vaccines.
References Braig S, Luton D, Sibony O, et al. Eur J Obstet Gynecol Reprod Biol 2001; 96:55-8.
Brown SD, Bartlett MG, White CA. Antimicrob Agents Chemother 2003; 47:991-6.
Drake AL, Roxby AC, Ongecha-Owuor F, et al. J Infect Dis 2012; 205:366-75.
Hollier LM, Wendel GD. Cochrane Database Syst Rev 2008; (1):CD004946.
Jacquemard F, Yamamoto M, Costa JM, et al. BJOG 2007; 114:1113-21.
Kang SH, Chua-Gocheco A, Bozzo P, et al. Can Fam Physician 2011; 57:427-8.
Leruez-Ville M, Ghout I, Bussières L, et al. Am J Obstet Gynecol 2016; 215:462.e1-462.e10.
Pasternak B, Hviid A. JAMA. 2010; 304:859-66.
Roxby AC, Atkinson C, Asbjörnsdóttir K, et al. PLoS One. 2014; 9:e87855.
Scott LL, Hollier LM, McIntire D, et al. Infect Dis Obstet Gynecol 2001; 9:75-80.
Sheffield JS, Fish DN, Hollier LM, et al. Am J Obstet Gynecol 2002; 186:100-2.
Sheffield JS, Hill JB, Hollier LM, et al. Obstet Gynecol 2006; 108:141-7.
Tyring SK, Baker D, Snowden W. J Infect Dis 2002; 186(Suppl 1):S40-6.
Watts DH, Brown ZA, Money D, et al. Am J Obstet Gynecol 2003; 188:836-43.
Summary Pregnancy Category: B
Lactation Category: S

  • Valacyclovir should be used during pregnancy only if the benefit justifies the potential perinatal risk.

  • Valacyclovir is a first-line agent for the treatment of genital herpes and herpes zoster during pregnancy and lactation.

  • Herpes prophylaxis at 36 w reduces the risk of recurrence and, as a result, the need for cesarean delivery for recurrence.

  • Physicians are encouraged to register pregnant women under the Pregnancy Registry (1-800-336-2176) for a better follow-up of the outcome while under treatment with valacyclovir.

Valganciclovir — (Valcyte)

International Brand Names

Valixa (Colombia)

Drug Class Antivirals
Indications CMV retinitis associated with AIDS
Mechanism Inhibits DNA polymerase
Dosage With Qualifiers CMV retinitis associated with AIDS—begin 900 mg PO bid with food × 21 d, then qd
NOTE: Renal dosing.

  • Contraindications —hypersensitivity to drug or class, ANC < 500/μl, Hb < 8 mg/dL, platelets < 25,000/μl

  • Caution —bone marrow suppression, concomitant radiation, renal dysfunction

Maternal Considerations Valganciclovir is metabolized to ganciclovir. There is no published experience with valganciclovir during pregnancy (see Ganciclovir ).
Side effects include leukopenia, neutropenia, thrombocytopenia, aplastic anemia, bone marrow suppression, infertility, nephrotoxicity, peripheral neuropathy, retinal detachment, seizures, psychosis, N/V, diarrhea, fever, insomnia, abdominal pain, confusion, agitation, and increased creatinine.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. Congenital CMV infection is the leading cause for sensorineural hearing loss and mental retardation in children without genetic diseases worldwide. Valganciclovir crosses the isolated human placenta by passive diffusion. There are nine case reports of valganciclovir or ganciclovir use during pregnancy for fetal or maternal CMV infection. In six cases of treatment for maternal CMV infection, no negative effects on the fetus were reported. In the remaining three cases, valganciclovir or ganciclovir was administered for fetal treatment after proven fetal infections were found. Therapeutic concentrations were achieved in the fetus by maternal oral intake and CMV replication suppressed. Ganciclovir is embryotoxic and teratogenic in various rodent models. Birth defects include cleft palate, craniofacial abnormalities, and pancreas and renal agenesis.
Breastfeeding Safety There is no published experience in nursing women. It is unknown whether valganciclovir enters human breast milk. Breastfeeding is contraindicated in HIV-infected nursing women where formula is available to reduce the risk of neonatal transmission. (See Ganciclovir. )
Drug Interactions See Ganciclovir.
References Hamilton ST, van Zuylen W, Shand A, et al. Rev Med Virol 2014; 24:420-33.
Seidel V, Feiterna-Sperling C, Siedentopf JP, et al. Med Microbiol Immunol 2017. [Epub ahead of print]
Summary Pregnancy Category: C
Lactation Category: U

  • Valganciclovir should be used during pregnancy and lactation only if the benefit justifies the potential perinatal risk.

  • See Ganciclovir.

  • Its use for fetal treatment remains an example of novel fetal therapy in need of greater experience. Physicians are encouraged to register pregnant women under the Pregnancy Registry (1-800-336-2176) for a better follow-up of the outcome while under treatment with valganciclovir.

Valproate — (Depacon; Epival)

International Brand Names

Convulex (Germany); Depakin (Bulgaria, Turkey); Depakine (Austria, Belgium, France, Greece, Hungary, Israel, Korea, Netherlands, Portugal, Spain, Switzerland, Thailand); Depakine Chrono (Belgium, Hungary, Poland, Portugal, Taiwan, Thailand); Depakine Druppels (Netherlands); Depalept (Israel); Depalept Chrono (Israel); Epilam (Korea); Epilex (Turkey); Epilim (China, England, Hong Kong, Ireland, Malaysia, Puerto Rico); Epilim Chrono (Malaysia); Epival (Costa Rica, Dominican Republic, El Salvador, Guatemala, Honduras, Israel, Nicaragua, Panama); Leptilan (Ecuador, Indonesia, Malaysia, Mexico, Puerto Rico, South Africa, Taiwan); Orfil (Korea); Orfiril (Hong Kong, Israel, Peru); Orfiril Retard (Singapore); Petilin (Israel, Puerto Rico, South Africa); Valcote (Ecuador); Valeptol (Korea); Valoin (Korea); Valpakine (Costa Rica, Dominican Republic, Ecuador, El Salvador, Guatemala, Honduras, Peru); Valparin (Thailand); Valporal (Israel); Valprax (Peru); Valpro (Hong Kong, New Zealand); Valsup (Colombia)

Drug Class Anticonvulsants
Indications Seizures
Mechanism Unknown
Dosage With Qualifiers Seizures—10–15 mg/kg/d IV in divided doses qd to tid, increase by 5–10 mg/kg/d q7d to achieve therapeutic trough of 50–100 mcg/mL; max 60 mg/kg/d
NOTE: Switch to PO when feasible.

  • Contraindications —hypersensitivity to drug or class, hepatic disease or dysfunction

  • Caution —renal dysfunction, bone marrow suppression, bleeding tendencies, congenital metabolic disorders, anticonvulsant use

Maternal Considerations Valproate is the sodium salt of valproic acid. Pregnancy is especially challenging for women with bipolar disorder, predominantly because of the heightened probability of relapse, potential fetal harm caused by bipolar medication, and a 250-fold risk of puerperal psychosis compared with the general population. Valproate is a known teratogen and is discouraged in pregnancy, but what choice is open to women who rely on this medication to stabilize their mood? There are no adequate reports or well-controlled studies of valproate in pregnant women. It does not alter the efficacy of hormonal contraception. Patients planning pregnancy should be counseled on the risks and the importance of periconceptional folate supplementation.
Side effects include potentially fatal hepatotoxicity, pancreatitis, bone marrow suppression, pancytopenia, aplastic anemia, thrombocytopenia, bleeding, hyponatremia, hyperammonemia, erythema multiforme, Stevens-Johnson syndrome, N/V, appetite and weight changes, dyspepsia, abdominal pain, diarrhea, asthenia, somnolence, tremor, alopecia, rash, peripheral edema, petechiae, blurred vision, nystagmus, tinnitus, SIADH, psychosis, and respiratory disorders.
Fetal Considerations Valproate is a recognized human teratogen, increasing the relative risk by a factor of 4 reaching an overall prevalence of about 6%. The risk is compounded by a low serum folate. Valproate is rapidly and actively transported across the human placenta, reaching an F:M ratio exceeding 2. Recent pregnancy databases suggest valproate is significantly more teratogenic than carbamazepine, and the combination of valproate and lamotrigine is particularly teratogenic. For unknown reasons, valproate accumulates in the fetal plasma. A distinct facial appearance, coupled with a cluster of minor and major anomalies and CNS dysfunction, characterizes the fetal valproate syndrome. The likelihood of the offspring being affected is dose dependent. Ten percent die in infancy, and one-fourth of survivors have either developmental deficits or mental retardation. Affected fetuses may have an increased nuchal translucency measurement. A fetal medicine specialist should evaluate women taking valproate during pregnancy. As with most psychotropic drugs, monotherapy and the lowest effective quantity given in divided doses to minimize the peaks can theoretically minimize the risks. In one study, the outcomes of 154 valproate -exposed pregnancies (96% at least in the first trimester) were compared with those of 1315 unexposed pregnancies. The major anomaly rate in the valproate group exposed in the first trimester was higher than controls after exclusion of genetic or cytogenetic anomalies (6.7% vs. 2.5%, relative risk [RR] = 2.66). Five of the 8 major anomalies in the valproate group were CV, 2/8 were mental retardation, 2/5 male infants with major anomalies had hypospadias, and 3/8 were suspected of having fetal valproate syndrome. A daily dose > 1000 mg was associated with the highest teratogenic risk (RR = 8.72). In the subgroup exposed to polytherapy, there was a fourfold increase in the rate of major anomalies compared with controls. All major anomalies were in the group treated for epilepsy. In another study, those exposed to polytherapy in utero had significantly lower developmental quotients than those exposed to monotherapy. Polytherapy was a stronger predictor of lower developmental quotients than dose. Compared with carbamazepine monotherapy, valproate monotherapy was associated with significantly lower mental and motor developmental scores.
Breastfeeding Safety Valproate enters human breast milk; the relative infant dose is 1%–5.6%. The neonatal concentration is < 10% of the maternal. In a large prospective cohort study on the children of women with epilepsy, prenatal exposure to antiepileptic drugs was associated with impaired fine motor skills by 6 months, especially when the child was exposed to multiple drugs. Continuous breastfeeding was associated with less impairment at ages 6 and 18 months compared with those with no breastfeeding or breastfeeding for less than 6 months. At 36 months, prenatal antiepileptic drug exposure was associated with adverse development regardless of breastfeeding status during the first year.
Drug Interactions The following information about the potential for several commonly prescribed medications to alter valproate pharmacokinetics is not exhaustive nor could it be, because new interactions are continuously being reported.
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases, may increase clearance. For example, carbamazepine, phenobarbital (or primidone ), and phenytoin can double valproate clearance. Thus patients on monotherapy will generally have longer t/2s and higher concentrations than patients receiving polytherapy with AEDs.
Aspirin at antipyretic doses may decrease protein binding and inhibit valproate metabolism. Valproate free fraction was increased fourfold in the presence of aspirin compared with valproate alone. Caution is indicated when using aspirin.
Felbamate increased the mean valproate peak level by 35%–50% depending on the dose of felbamate. A decrease in the valproate dose may be necessary.
Rifampin may increase valproate clearance by some 40% and may necessitate a dose adjustment.
May decrease the clearance of amitriptyline by 20% and nortriptyline by 30%. Use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered, as should lowering the dose of amitriptyline/nortriptyline.
Decreases carbamazepine levels 17% while increasing its 10,11-epoxide metabolite by 45%.
Use with clonazepam may induce absence status in patients with a history of absence-type seizures.
Displaces diazepam from its plasma albumin binding sites and inhibits its metabolism, resulting in an almost doubling of the diazepam free fraction.
Increases by 25% the elimination t/2 of ethosuximide and decreases its total clearance by some 15%. Patients using both agents, especially along with other AEDs, should be monitored for changes in the serum concentrations of both drugs.
Increases the elimination t/2 of lamotrigine by 165%. The lamotrigine dose should be reduced. Serious skin reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported in association with this combination.
Increases the t/2 of phenobarbital by 50%, and decreases the plasma clearance by one-third. The fraction of phenobarbital excreted unchanged increases by 50%.
All patients receiving barbiturate therapy should be closely monitored for neurologic toxicity. If possible, serum barbiturate levels should be obtained and the barbiturate dose decreased as appropriate. Primidone, which is metabolized to a barbiturate, may have a similar interaction with valproate.
Displaces phenytoin from its plasma albumin binding sites, and inhibits its hepatic metabolism, increasing the free fraction some 60%. Total plasma clearance and apparent volume of distribution of phenytoin increase 30% in the presence of valproate. As there have been reports of breakthrough seizures occurring with this combination, the dose of phenytoin should be adjusted as clinically required.
The clearance of zidovudine was decreased by 38% in HIV-seropositive patients.
References Chaudron LH, Jefferson JW. J Clin Psychiatry 222; 61:79-90.
Crawford P. CNF Drugs 2002; 16:263-72.
Diav-Citrin O, Shechtman S, Bar-Oz B, et al. CNS Drugs 2008; 22:325-34.
Kaaja E, Kaaja R, Hiilesmaa V. Neurology 2003; 60:575-9.
Kozma C. Am J Med Genet 2001; 98:168-75.
Mawer G, Clayton-Smith J, Coyle H, Kini U. Seizure 2002; 11:512-8.
Nakamura H, Ushigome F, Koyabu N, et al. Pharm Res 2002; 19:154-61.
Nau H, Kuhnz W, Egger HJ, et al. Clin Pharmacokinet 1982; 7:508-43.
Philbert A, Pedersen B, Dam M. Acta Neurol Scand 1985; 72:460-3.
Samren EB, van Duijn CM, Koch S, et al. Epilepsia 1997; 38:981-90.
ten Berg K, Lindhout D. Clin Dysmorphol 2002; 11:227-8.
Thomas SV, Ajaykumar B, Sindhu K, et al. Epilepsy Behav 2008; 13:229-36.
Thomas SV, Ajaykumar B, Sindhu K, et al. Pediatr Cardiol. 2008; 29:604-8.
Tsuru N, Maeda T, Tsuruoka M. Jpn J Psychiatry 1988; 42:89-96.
Veiby G, Engelsen BA, Gilhus NE. JAMA Neurol 2013; 70:1367-74.
Veroniki AA, Rios P, Cogo E, et al. BMJ Open. 2017; 7:e017248.
Witters I, Van Assche F, Fryns JP. Prenat Diagn 2002; 22:834-5.
Summary Pregnancy Category: D
Lactation Category: S (possibly)

  • Valproate is a recognized human teratogen.

  • The risk of a defect is compounded by folate deficiency.

  • Valproate should be avoided during pregnancy and while breastfeeding, as there are numerous alternatives for most indications.

  • When valproate treatment cannot be avoided, the lowest effective dose should be prescribed, preferably as monotherapy in divided doses to minimize the peaks.

  • Women taking valproate during pregnancy should be evaluated by a fetal medicine specialist.

Valproic acid — (Depakene; Myproic acid)

International Brand Names

Atemperator (Ecuador); Convulex (Austria, Belgium, Bulgaria, Czech Republic, England, Ireland, Russia, Singapore, South Africa, Switzerland, Taiwan); Depakene (Japan); Depakin (Italy); Depakine (Russia, Taiwan, Venezuela); Epilim (Malaysia); Epilim Chrono 500 (Malaysia); Leptilan (Portugal); Orfiril (Germany); Valpakine (Costa Rica, El Salvador, Guatemala, Honduras); Valporal (Israel); Valprosid (Mexico)

Drug Class Anticonvulsants; Bipolar agents; Migraine agents
Indications Seizures, mania, migraine prophylaxis
Mechanism Unknown
Dosage With Qualifiers Seizures—10–15 mg/kg/d PO with meals in divided doses qd to tid, increase by 5–10 mg/kg/d q7d to achieve therapeutic trough of 50–100 mcg/mL; max 60 mg/kg/d
Mania—10–15 mg/kg/d PO with meals in divided doses qd to tid, increase by 5–10 mg/kg/d q7d to achieve therapeutic trough of 50–100 mcg/mL; max 60 mg/kg/d
Migraine prophylaxis—250–500 mg PO with meals bid

  • Contraindications —hypersensitivity to drug or class, hepatic disease or dysfunction

  • Caution —renal dysfunction, bone marrow suppression, bleeding tendencies, congenital metabolic disorders, anticonvulsant use

Maternal Considerations Please see Valproate .
Side effects include potentially fatal hepatotoxicity, pancreatitis, SIADH, thrombocytopenia, pancytopenia, aplastic anemia, bone marrow suppression, bleeding, hyponatremia, hyperammonemia, erythema multiforme, Stevens-Johnson syndrome, psychosis, N/V, appetite and weight change, dyspepsia, diarrhea, abdominal pain, asthenia, somnolence, tremor, alopecia, rash, peripheral edema, petechiae, blurred vision, nystagmus, tinnitus, and respiratory disorders.
Fetal Considerations Please see Valproate.
Breastfeeding Safety Please see Valproate.
Drug Interactions The following information about the potential for several commonly prescribed medications to alter valproate pharmacokinetics is not exhaustive, nor could it be, because new interactions are continuously being reported.
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases, may increase clearance. For example, carbamazepine, phenobarbital (or primidone ), and phenytoin can double valproate clearance. Thus patients on monotherapy will generally have longer t/2s and higher concentrations than patients receiving polytherapy with AEDs.
Aspirin at antipyretic doses may decrease protein binding and inhibit valproate metabolism. Valproate free fraction was increased fourfold in the presence of aspirin compared with valproate alone. Caution is indicated when using aspirin.
Felbamate increased the mean valproate peak level by 35%–50% depending on the dose of felbamate. A decrease in the valproate dose may be necessary.
Rifampin may increase valproate clearance by some 40% and may necessitate a dose adjustment.
May decrease the clearance of amitriptyline by 20% and nortriptyline by 30%. Use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered, as should lowering the dose of amitriptyline/nortriptyline.
Decreases carbamazepine levels 17% while increasing its 10,11-epoxide metabolite by 45%.
Use with clonazepam may induce absence status in patients with a history of absence-type seizures.
Displaces diazepam from its plasma albumin binding sites and inhibits its metabolism, resulting in an almost doubling of the diazepam free fraction.
Increases by 25% the elimination t/2 of ethosuximide and decreases its total clearance by some 15%. Patients using both agents, especially along with other AEDs, should be monitored for changes in the serum concentrations of both drugs.
Increases the elimination t/2 of lamotrigine by 165%. The lamotrigine dose should be reduced. Serious skin reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported in association with this combination.
Increases the t/2 of phenobarbital by 50% and decreases the plasma clearance by one-third. The fraction of phenobarbital excreted unchanged increases by 50%.
All patients receiving barbiturate therapy should be closely monitored for neurologic toxicity. If possible, serum barbiturate levels should be obtained and the barbiturate dose decreased as appropriate. Primidone, which is metabolized to a barbiturate, may have a similar interaction with valproate.
Displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism, increasing the free fraction some 60%. Total plasma clearance and the apparent volume of distribution of phenytoin increase 30% in the presence of valproate. As there have been reports of breakthrough seizures occurring with this combination, the dose of phenytoin should be adjusted as clinically required.
The clearance of zidovudine was decreased by 38% in HIV-seropositive patients.
References Chaudron LH, Jefferson JW. J Clin Psychiatry 222; 61:79-90.
Crawford P. CNF Drugs 2002; 16:263-72.
Crawford P. Epilepsia 2005; 46(Suppl 9):117-24.
Diav-Citrin O, Shechtman S, Bar-Oz B, et al. CNS Drugs 2008; 22:325-34.
Kaaja E, Kaaja R, Hiilesmaa V. Neurology 2003; 60:575-9.
Kozma C. Am J Med Genet 2001; 98:168-75.
Mawer G, Clayton-Smith J, Coyle H, Kini U. Seizure 2002; 11:512-8.
Nakamura H, Ushigome F, Koyabu N, et al. Pharm Res 2002; 19:154-61.
Nau H, Kuhnz W, Egger HJ, et al. Clin Pharmacokinet 1982; 7:508-43.
Philbert A, Pedersen B, Dam M. Acta Neurol Scand 1985; 72:460-3.
Samren EB, van Duijn CM, Koch S, et al. Epilepsia 1997; 38:981-90.
ten Berg K, Lindhout D. Clin Dysmorphol 2002; 11:227-8.
Thomas SV, Ajaykumar B, Sindhu K, et al. Epilepsy Behav 2008; 13:229-36.
Thomas SV, Ajaykumar B, Sindhu K, et al. Pediatr Cardiol. 2008; 29:604-8.
Tsuru N, Maeda T, Tsuruoka M. Jpn J Psychiatry 1988; 42:89-96.
Veiby G, Engelsen BA, Gilhus NE. JAMA Neurol 2013; 70:1367-74.
Veroniki AA, Rios P, Cogo E, et al. BMJ Open. 2017; 7:e017248.
Witters I, Van Assche F, Fryns JP. Prenat Diagn 2002; 22:834-5.
Summary Pregnancy Category: D
Lactation Category: S (possibly)

  • Valproic acid is a recognized human teratogen.

  • The risk of a defect is compounded by folate deficiency.

  • Valproic acid should be avoided during pregnancy and while breastfeeding, as there are numerous alternatives for most indications.

  • When valproic acid treatment cannot be avoided, the lowest effective dose should be prescribed, preferably as monotherapy in divided doses to minimize the peaks.

  • Women taking valproic acid during pregnancy should be evaluated by a fetal medicine specialist.

Valsartan — (Diovan)

International Brand Names

Nisis (France); Provas (Germany); Tareg (France)

Drug Class ACEI/A2R-antagonists
Indications Hypertension
Mechanism Selective AT-1 antagonist
Dosage With Qualifiers Hypertension—begin 80–160 mg PO qd if monotherapy; max 320 mg/d

  • Contraindications —hypersensitivity to drug or class

  • Caution —CHF, history of ACEI-induced angioedema, renal artery stenosis, hepatic or renal dysfunction, volume depletion, hyponatremia

Maternal Considerations There are no adequate reports or well-controlled studies of valsartan in pregnant women. Valsartan has no significant advantages over similar agents in its class for which there is more experience. Nor has it been demonstrated to reduce the complications of arterial hypertension. The dozen or so case reports during pregnancy document the poor outcomes typical of this drug class. Inhibitors of the renin-angiotensin system should be avoided during pregnancy because of their fetal implications.
Side effects include angioedema, severe hypotension, hyperkalemia, URI symptoms, dizziness, fatigue, dyspepsia, back pain, and diarrhea.
Fetal Considerations Drugs that act directly on the renin-angiotensin system cause perinatal morbidity and death. Adverse outcomes are reported for valsartan, suggesting it crosses the human placenta. Drugs that inhibit the fetal renin-angiotensin system are all potential teratogens and dangerous to the fetus throughout gestation. The risks are greatest after the first trimester. The mechanisms may well be different for ACEIs and AT-1 receptor antagonists. In the second and third trimesters, morbidity includes hypotension, neonatal skull hypoplasia, anuria, and reversible or irreversible renal failure. Oligohydramnios may be associated with limb contractures, craniofacial deformation, and hypoplastic lung development. Rarely is an alternative drug not available. In these cases, the women should be counseled on the hazards, and serial ultrasound examinations should be performed to assess the intraamniotic environment. If oligohydramnios is observed, the valsartan should be discontinued unless lifesaving for the mother. Antenatal surveillance may be appropriate depending on gestation. Oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Breastfeeding Safety There is no published experience in nursing women. It is unknown whether valsartan enters human breast milk.
Drug Interactions As with other drugs that block angiotensin II or its effects, potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene ), potassium supplements, or salt substitutes containing potassium may increase serum potassium and, in heart failure, increase serum creatinine.
Valsartan may nearly double digoxin levels.
References Berkone N, Carlier P, Verstraete L, et al. Birth Defects Res A Clin Mol Teratol 2004; 70:547-9.
Biswas PN, Wilton LV, Shakir SW. J Hum Hypertens 2002; 16:795-803.
Briggs GG, Nageotte MP. Ann Pharmacother 2001; 35:859-61.
Roger N, Popovic I, Madelenat P, Mahieu-Caputo D. Gynecol Obstet Fertil 2007; 35:556-60.
Summary Pregnancy Category: C (first trimester), D (second and third trimesters)
Lactation Category: U

  • Valsartan should be used during pregnancy and lactation only if the benefit justifies the potential perinatal risk.

  • Women should be counseled on the risks and switched to a different class of antihypertensives prior to conception or during the first trimester.

  • There are alternative agents for which there is more experience regarding use during pregnancy and lactation.

Vancomycin — (Balcorin; Edicin; Ledervan; Lyphocin; Vancocin; Vancoled; Vancor)

International Brand Names

Amplobac (Brazil); Balcorin (Mexico); Diatracin (Spain); Edicin (Thailand); Icoplax (Argentina); Ifavac (Mexico); Vagran (Venezuela); Vanauras (Mexico); Vancam (Mexico); Vanccostacin (Korea); Vanco (Germany); Vancocid (Brazil); Vancocina (Italy, Peru); Vancocina CP (Chile); Vancocin CP (Bulgaria, China, Czech Republic, Hong Kong, Hungary, Malaysia, Mexico, South Africa, Taiwan, Thailand); Vancocine (France); Vancocin HCl (Argentina, Belgium, Canada, Denmark, England, Finland, Hong Kong, Ireland, Korea, New Zealand, Norway, Philippines, Sweden, Switzerland, Taiwan); Vancocin HCl Pulvules (Australia); Vancoled (Israel, Malaysia, Taiwan); Vancomax (Paraguay); Vancomicina (Ecuador); Vanco-Teva (Israel); Vancox (Mexico); Vanmicina (Mexico); Varedet (Uruguay); Voncon (Greece)

Drug Class Antibiotics; Glycopeptides
Indications Bacterial infections, endocarditis prophylaxis
Mechanism Bactericidal—inhibits cell wall and RNA synthesis
Dosage With Qualifiers Bacterial infections—500 mg IV q6h; peak 25–40 mcg/mL, trough 5–10 mcg/mL
Endocarditis prophylaxis—1 g slow IV over 1 h
NOTE: Renal dosing.

  • Contraindications —hypersensitivity to drug or class

  • Caution —hepatic or renal dysfunction, hearing loss, nephrotoxic agents

Maternal Considerations Vancomycin is most commonly used to treat MRSA infections. Several reports suggest longer infusion times and weight-adjusted doses should be used. One study enrolled every woman admitted in labor with a positive GBS culture and a high-risk penicillin allergy with resistance to clindamycin or unknown sensitivity. Maternal and umbilical cord blood vancomycin levels (20 mg/kg IV every 8 h with a maximum individual dose of 2 g) were obtained at delivery. Time from last dose completion to delivery, number of doses administered, and body mass index were assessed. Thirty-one women consented; in 23/30 (77%), the maternal and cord blood levels were therapeutic. In 8 women, maternal and/or cord blood values were nontherapeutic. There was a dosing violation in 6. Of the 24 patients where the dosing regimen was correctly followed, 22 (92%) had therapeutic maternal and cord blood levels.
Vancomycin is used as a second-line agent for the treatment of postpartum endomyometritis and as a first-line agent and alternative to metronidazole for the treatment of C. difficile diarrhea. Other applications during pregnancy include listeriosis and bacterial endocarditis in IV drug users.
Side effects include neutropenia, Stevens-Johnson syndrome, thrombocytopenia, toxic epidermal necrolysis, nephrotoxicity, ototoxicity, chills, fever, nausea, tinnitus, superinfection, urticaria, rash, “red man” syndrome, and phlebitis.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. Vancomycin crosses the human placenta in a predictable manner, achieving concentrations that exceed the usual GBS inhibitory level. Vancomycin (20 mg/kg IV every 8 h; maximum 2 g) produced therapeutic levels in more than 75% of mother/newborn pairs. In contrast, transplacental passage of vancomycin was minimal in an ex vivo human placental perfusion model, yielding no detectable accumulation. There is no obvious explanation. Concern that vancomycin exposure might cause ototoxicity has not been substantiated. Rodent studies are reassuring, revealing no evidence of teratogenicity or IUGR despite the use of doses higher than those used clinically.
Breastfeeding Safety Vancomycin enters human breast milk, but the kinetics remain to be elucidated. Considering the poor oral absorption; the relative infant dose approximates 6.5%. It is unlikely the breastfed neonate would ingest a clinically relevant amount.
Drug Interactions Use with anesthetic agents has been associated with erythema and histamine-like flushing and anaphylactoid reactions.
Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, bacitracin, cisplatin, colistin, polymyxin B, viomycin) requires careful monitoring.
References Adam MP, Polifka JE, Friedman JM. Am J Med Genet 2011; Part C:175-82.
Bonacorsi S, Doit C, Aujard Y, et al. Clin Infect Dis 1993; 17:139-40.
Bourget P, Fernandez H, Delouis C, Ribou F. Obstet Gynecol 1991; 78:908-11.
Hnat MD, Gainer J, Bawdon RE, Wendel GD Jr. Infect Dis Obstet Gynecol 2004; 12:57-61.
James AH, Katz VL, Dotters DJ, Rogers RG. South Med J 1997; 90:889-92.
Laiprasert J, Klein K, Mueller BA, Pearlman MD. Obstet Gynecol 2007; 109:1105-10.
Lamont HF, Blogg HJ, Lamont RF. Expert Opin Drug Saf 2014; 12:1569-81.
Nanovskaya T, Patrikeeva S, Zhan Y, et al. 2012; 207:331.e1-6.
Reyes MP, Ostrea EM Jr, Cabinian AE, et al. Am J Obstet Gynecol 1989; 161:977-81.
Towers CV, Weitz B. J Matern Fetal Neonatal Med 2017; 28:1-4.
Summary Pregnancy Category: B
Lactation Category: S

  • Vancomycin should be used during pregnancy only if the benefit justifies the potential perinatal risk.

  • It should probably be reserved for antibiotic-resistant bacterial infections.

Vardenafil — (Levitra; Staxyn)

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