Carlos De Las Cuevas, MD, PhD

Although there is a tendency toavoid psychiatric medicationsduring pregnancy, the highprevalence of psychiatric disorders in pregnant women-15% to 25%, according to recent epidemiologic studies

-means that women and their physiciansoften face impromptu decisions regardingthe initiation or continuation ofdrug therapy during pregnancy.

The management of psychiatricproblems and pharmacologic treatmentin pregnancy is complex and burdenedwith many biologic and personalfactors.

 Psychiatrists need to considerthe impact of untreated illness on themother and the fetus, as well as thepossibility of increased risk for obstetriccomplications and congenital malformationsassociated with pharmacologictreatment. It should be stressed thatuntreated psychiatric illnesses pose atremendous threat to the fetus because of maternal behavior and that discontinuingeffective psychotropic treatmentsmay exacerbate maternal mentalillness and cause secondary effects onthe fetus.

All currently available psychopharmacologicagents and their metabolites cross the placenta,

 and in some cases,intrauterine exposure to psychiatricdrugs may lead to neonatal withdrawalsyndrome (NWS), also called neonatalabstinence syndrome.

NWS occurs in newborns goingthrough withdrawal symptoms as aresult of the mother's use of psychoactivedrugs during pregnancy. It is characterizedby signs and symptoms ofCNS hyper-irritability, GI dysfunction, and respiratory distress; and by vagueautonomic signs and symptoms thatinclude yawning, sneezing, mottling,and fever. This syndrome usually beginswithin 72 hours but may appear up to2 weeks after birth.

 The clinicalpresentation of neonatal drug with withdrawalvaries depending on the drug(s),timing, and amount of the last maternaluse, maternal and infant metabolismand excretion, and other unidentifiedfactors.

Psychotropic medications given tothe mother cause pharmacologic effectson the fetus. These effects are relatedto the mechanism of action and therapeuticobjectives of the treatment (forthe mother) and can produce symptoms and signs in the newborn that are distinctfrom those of NWS. In many cases, theclinical picture is very similar and,thus, difficult to differentiate.

This is probably the case with theeffects of antipsychotics, which havebeen associated with tachycardia, GIdysfunction, sedation, and hypotension.In addition, extrapyramidal symptomsmay include hyperactivity,hyperactive deep tendon reflexes, motorrestlessness, and abnormal movements,which can persist for several weeks,

as well as tremors, posturing and flappingof the hands, increased muscletone, vigorous rooting and suckling,arching of the back, and shrill crying.

NWS seems to be related to the pharmacologiceffects of the drug, and oncethe drug is excreted, the symptomsresolve. Nevertheless, it is difficult toconclude that there is no withdrawaleffect associated with the use of antipsy-chotics, because the clinical presentationsare not exclusive. Despite thiscontroversy, antipsychotics have notusually been associated with withdrawalsymptoms but with pharmacologiceffects in the newborn. For that reason,they have been excluded from furtheranalysis in this review.

The adverse effects of prenatal antidepressantexposure in the newborn maybe secondary both to the effects of thedrug and to its withdrawal. Both tricyclicantidepressants (TCAs) and selectiveserotonin reuptake inhibitors (SSRIs)are known to cause neonatal withdrawalsymptoms when used during the thirdtrimester of pregnancy and especiallywhen nearing time of delivery.Symptoms associated with antidepressantwithdrawal are collectively calledNWS or neonatal discontinuation.

 Withdrawal effects of TCAs have beencharacterized since at least 1979.

 Themost common withdrawal symptomsinclude irritability, tremulousness, diarrhea,poor feeding, respiratory distress,and seizures (convulsions). These symptoms can occur in newborns whosemothers were taking either therapeuticor larger doses. Withdrawal can beginwithin 72 hours postpartum and last forseveral days.

NWS associated with the use ofSSRIs has been under discussion for several years and the concept is nowwell established, although it is stillunderresearched; its incidence is estimatedto be around 30% of exposedneonates.

 NWS seems to be a classrelatedproblem because it has beendescribed with almost every SSRI;however, there is speculation that someagents in this class are more prone toinduce this problem than others.

When administered in the thirdtrimester, fluoxetine increased the riskof premature delivery, the need forspecial-care nurseries, and the incidenceof lower birth weight and length.

The most common symptoms associatedwith SSRI deprivation in neonateswere respiratory difficulties, cyanosis on feeding, and jitteriness.

 Othercommon neonatal withdrawal symptomsincluded low Apgar scores, irritability,constant crying, shivering,increased tonus, eating and sleepingdifficulties, and convulsions.

 Thissyndrome is usually self-limited and resolves quickly; in most cases, Apgarscores reach 8 to 9 after 1 minute.

In the World Health Organization caseseries,

 paroxetine was more frequentlyassociated with NWS than were otherSSRIs, but the methodology used canneither confirm nor deny this difference.Because of its pharmacokinetic andpharmacodynamic properties, there maybe a higher risk of NWS with paroxetine.Costei and associates

 followed up55 neonates exposed to paroxetine inthe third trimester and found a significantincrease in respiratory distress,hypoglycemia, and jaundice when comparedwith neonates exposed to paroxetinein the first 2 trimesters or thosewho were not exposed.

The symptoms of NWS seem to beassociated with a serotonergic imbalance.Laine and associates

 used aprospective controlled study of 20 motherstaking either fluoxetine or citalopramduring the third trimester to measureneonatal withdrawal symptoms andlevels of monoamines in the umbilicalcord. Children exposed to an SSRI hadlower Apgar scores during the first 15minutes and presented a 4-fold increasein serotonin-related symptoms (myoclonus,restlessness, tremors, shivering,hyperreflexia, uncoordination, and rigidity)during the first 4 days of lifecompared with controls. Levels of monoamines(serotonin, its metabolite 5-hydroxyindole acetic acid, the dopaminemetabolite homovanillic acid, and noradrenalin)in the umbilical cord were reducedin newborns exposed to SSRIs.

The effects of anxiolytics, especiallybenzodiazepines (BZDs), in thenewborn are a mixture of the pharmacologiceffects of the substance andpossible withdrawal symptomatology.Even if some investigators have describedlower birth weights, shorterbirth length, and significantly moreperinatal complications than in their unexposed control groups,

 there are 2 different neurologic consequences in thenewborn: the floppy infant syndromeand NWS. When diazepam and otherBZDs were administered close to delivery,the neonates frequently presentedwith floppy infant syndrome, which ischaracterized by muscular hypotonia,hypothermia, lethargy, respiratory problems,and feeding difficulties. Although some investigators claim that infantsrecover without long-lasting effects, itis speculated that these effects causesome types of neurocognitive developmentaldelays.

Although it is difficult to ascribethese effects to BZD action on the brainor to sudden deprivation, NWS symptomsafter exposure have been welldocumented for a variety of BZDs.

 NWS symptoms included low Apgarscores, hypertonia, irritability, abnormalsleep patterns, constant crying,tremors, myoclonus, bradycardia,cyanosis, suckling difficulties, apnea,feeding aspirations, diarrhea, vomiting, and growth retardation.

Both pharmacologic effects andNWS can be present at the same time,making the clinical picture more bizarre.The frequency and severity of NWS canbe related to the pharmacokinetic profileof the particular BZD. Diazepam is longactingand has a long half-life

; a longerhalf-life can be associated with a prolongedeffect of the drug in the newborn,whereas a shorter half-life can, morefrequently, be associated with deprivationsyndrome.

It has been hypothesized that thereis a relationship between long-termeffects of BZD and brain developmentinvolving neurocognitive function. Thetopic is highly controversial, but studieshave only been conducted in animalmodels, which showed that BZD exposureproduced immediate and long-lastingeffects. Rats prenatally exposed todiazepam had significant deficits inacquisition and retention of spatialdiscrimination tasks.

 Another investigatedsubstance, alprazolam, givenprenatally to mice

 producedsignificant increases in anxiety inoffspring that were tested as either juvenilesor adults. These long-lasting effectsmay be related to the desensitization ofthe γ-aminobutyric acid (GABA) receptor. A recent study showed that malerats exposed to BZD had behavioraldeficits and were hypersensitive to pentylenetetrazol,a GABA antagonist.

This effect seemed to be less pronouncedin female rats, but the gender differenceshave to be more thoroughly explored.

A mother's use of AEDs is linked tothe immediate withdrawal effects of thenewborn and to long-term neurologicdysfunctions. Valproate was shown tobe associated with immediate NWS symptoms, such as hyperexcitability,causing neurologic deficits, seizures,and jitteriness.

 Furthermore, in aretrospective study based on hospitalrecords, Dean and associates

 foundsignificant NWS symptoms, includingjitteriness, hypotonia, seizures, apneicepisodes, hypoglycemia, and feedingdisorder, after exposure in utero tovalproate, phenytoin, or combinationtherapy.

Long-term effects of AEDs havealso been demonstrated. In the study byKoch and associates,

 when childrenwere examined 6 years later, theycontinued to have long-term neurologicdysfunctions, which are more congruentwith drug toxicity than withdrawaleffects. Similar results are reported inthe study by Moore and associates

 of57 children prenatally exposed to AEDs:77% had learning difficulties, 81% hadspeech delay, 60% had gross motordelay, and 42% had fine motor delay.Eighty percent of these children hadprenatal exposure to valproate alone orin combination with another AED.Seventy-four percent of school-agedchildren were enrolled in special educationclasses or were receiving learningsupport, and 81% had some type ofbehavioral dysfunction; of these, 60%had some autistic features and 39% hadhyperactivity, but autism or Aspergersyndrome had actually been diagnosedin only a few. The developmental effectsseem to be associated not only withvalproate but also with carbamazepine,phenytoin, and polypharmacy.

Although these investigators did not finda link between NWS and cognitivedysfunction, this is a topic in whichfurther research is badly needed.

Pregnant women with psychiatric conditionsmust be adequately treated.Pharmacologic treatment should be initiated or maintained when the disorder issevere and the efficacy of the psychopharmacologicapproach has beendemonstrated, giving attention to nonpharmacologicalternatives in order toprevent the relapse of the disease in themother. Psychiatric clinical practiceshows that most pregnant women withpsychiatric conditions are treated withpolypharmacy,

 making it even morecomplex to identify the effects of thesedrugs on the newborn. Psychopharmacologicagents can induce directeffects on the newborn, as well as withdrawalsymptoms associated with theirsuppression. The clinical picture of bothcases is often similar and confounding.Nevertheless, NWS has clearly beenassociated with TCAs, SSRIs, andAEDs. However, with the exception ofAEDs, the clinical picture for most ofthese drugs appears to be self-limitedand moderate, most frequently needingonly supportive therapy.

Dr Sanz is associate professor in clinical pharmacologyat the University of La Laguna inTenerife, Canary Islands, Spain, and a memberof the Review Panel of Experts of the WHOCollaborating Centre for International DrugMonitoring. He reports that he has no conflictsof interest concerning the subject matterof this article.

Dr De las Cuevas is associate professor ofpsychiatry at the University of La Laguna inTenerife, Canary Islands, Spain, a specialist inpsychiatry with clinical responsibilities, and asenior member of the Educational LiaisonsNetwork of the World Psychiatric Association.He reports that he has no conflicts of interestconcerning the subject matter of this article.

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