JOURNAL ON DEVELOPMENTAL DISABILITIES, VOLUME 11 NUMBER 2
Prenatal and Perinatal Effects of Psychotropic Drugs on Neuro-cognitive Development in the Fetus Note: In the text of this paper, the term "mental retardation" has been used in the diagnosticsense and to correspond with terminology used by authors who have been cited. Abstract There has been an increased dependence on prescriptiondrugs for psychological and mood disorders in the lastfew decades. Many women who take these drugs maybecome pregnant and not be aware of their possibleadverse effects. Since thalidomide, a drug used to treatmorning sickness in pregnancy, was found to beteratogenic, many drugs are being screened morestringently for possible teratogenic effects on the fetus. Although newer drugs do not appear to cause congenitalmalformations, some still pose a threat. This review isaimed at summarizing the teratogenic effects of commonlyused antiepileptics, antidepressants and anxiolytics. Theeffects of these drugs on intellectual and developmentaldisabilities or cognitive development have not beenextensively studied. It is hypothesized that these drugs canalter development via two pathways. First, prenataleffects on neurotransmitters can alter brain circuitry,thereby predisposing children to later learning andbehavioural deficits. Second, perinatal events caused bydrug withdrawal upon delivery of the baby, may have longlasting effects on cognitive developments, as suggested bynumerous animal and human studies. Various motor andrespiratory side effects resulting in especially low Apgarscores may have deleterious consequences. Psychotropicdrugs should be avoided during pregnancy unless deemedabsolutely necessary for the benefits of both the motherand fetus. If drugs must be utilized, strict guidelinesshould be set to ensure that fetal withdrawal ordependency from these drugs does not occur. Finally,perinatal events should be meticulously noted for futurereference during the development of the child.
Of the many factors that contribute to the occurrence of intellectual anddevelopmental disabilities, it has been estimated that 15 - 29% may beattributed to teratogens.
One drug with devastating teratogenic effects is thalidomide. This was firstprescribed in the late 1950s in Europe to treat morning sickness in pregnantwomen, as well as anxiety and insomnia generally. It was withdrawn fromthe market in the early 1960s when found to cause devastating birth defects,including major malformations such as missing arms and legs. Interestingly,thalidomide recently has been found to be an effective drug in the treatmentof multiple myeloma (Hussein, 2005). Unfortunately, many of the currentgeneration of young women of child-bearing age are not aware of theoriginal thalidomide catastrophe. Consequently, they may also not be awareof potential teratogenic effects of many other substances, prescribed or notprescribed, that could harm their babies if taken during pregnancy.
Considering etiological factors of intellectual impairments and that 30 - 50%of cases have unknown etiology (Percy & Brown, 1999), it is conceivablethat the effects of teratogens may be higher than previously estimated. Theteratogenicity of many drugs have been classified and made available eitherthrough the U.S. Food and Drug Administration (FDA) pregnancy riskcategories, or the Teratogen Information System (TERIS), which providesinformation for more than 2,800 agents and almost 200 commonlyprescribed drugs (Gilstrap & Little, 1998). Both of these systems havecategorized the risk of congenital malformations caused by prescriptiondrugs. Thus, the public can be made aware of the risk of structuralteratogenesis caused by particular drugs. However, many drugs can alsocause behavioural teratogenesis, in which behavioural or neuropsychatricsymptoms appear well after birth following in utero exposure to drugs ortoxins (Ward & Zamorski, 2002). The behavioural teratogenicity of drugs isneither extensively researched nor explicitly categorized. One of the mainreasons is that structural abnormalities as such are more easily observed inthe newborn and can be easily categorized. That is, researchers and healthcare professionals can easily detect shortened or missing limbs, cleft palates,facial and other abnormalities. In contrast, behavioural abnormalities are notas apparent in the newborn because it is more difficult to test theneurodevelopmental profile of the neonate than those of a child (Nicholls,2000).
Another reason that behavioural teratogenicity is not easily detected is dueto the large variability in phenotypic expression in the developing child(Nicholls, 2000). That is, some drugs may produce neuropsychiatric
EFFECTS OF PSYCHOTROPIC DRUGS ON THE FETUS
sequelae that are apparent only during adolescence and may resembledevelopmental delays. Prenatal ethanol (alcohol) exposure is a primeexample that depicts a wide array of postnatal effects (Koren, 2001). At theinception of the term fetal alcohol syndrome (FAS), it was decided thatmoderate to large amount of alcohol consumption can lead to FAS and causecharacteristic physical deformities and cognitive impairments, often seen inearly childhood (Streissguth & O'Malley, 2000). Recently, however, thename fetal alcohol spectrum disorder (FASD) has been used to encompassdiagnoses that include FAS, partial FAS (pFAS) and others. It ishypothesized that FASD encompasses the variety of symptoms andcognitive impairments seen with varying doses of prenatal alcoholconsumption. For example, low doses of alcohol, insufficient to produce fullFAS features, may nonetheless produce cognitive impairments, althoughsubtle, intellectual and developmental delays associated with FASD maybegin as the child enters the first years of schooling (Health Canada, 2003).
It is conceivable that intellectual and developmental delays may occurbecause pregnant mothers may be exposing their fetuses to yet unknownbehavioural teratogens (Hoyme, 1990). Since many of the psychotropicdrugs cross the placenta and affect brain neurotransmitters there is a definiterisk of long-term consequences to the developing brain (Mortensen, Olsen,Bendsen, Obel & Sorensen, 2003). It has been estimated that one-third ofwomen take psychotropic drugs at least once during their pregnancy(Nicholls, 2000). Recent evidence demonstrates psychomotordevelopmental delay in children prenatally exposed to at least onepsychotropic drug (Mortensen et al., 2003). However, the risk ofneurobehavioural delays is not well recognized or investigated. Forexample, the FDA has only recently (June 2004) recommended thatantidepressant medication be labelled, cautioning pregnant women of theside effects on the newborn (FDA MedWatch Website, 2004; Richwine,2004). However, other psychotropic medications are being prescribed topregnant mothers without consultation of the risk to the neonate.
In reviewing literature concerning prenatal psychotropic drug exposure, thispaper focusses on two key areas. First, past and current literature is citeddescribing human and animal data suggesting prenatal mechanisms bywhich these drugs may cause neurobehavioural consequences in thedeveloping brain. Second, perinatal effects of psychotropic drugs will bediscussed with respect to withdrawal symptoms. Critical Periods in Human Development
Teratogens can pose harm during any of the three stages of development. During the first two weeks post-conception, the zygote is rapidly dividingand not yet implanted. At this point teratogens that pose the greatest risk willcause imminent death to the developing fetus (Macara, 2000). Onceimplanted, the next 5 weeks are called the embryonic period. During thisperiod, organogenesis, the development of organs, begins. If the embryo issubjected to teratogens, major morphological changes (such as those causedby thalidomide) will occur because this is the stage of rapid cellular divisionand differentiation (Gilstrap & Little, 1998). Teratogens affecting the centralnervous system (CNS) at this stage will probably cause neural tube defects(NTD) because the neural plate does not close properly thereby not formingthe neural tube. During the fetal period, which begins in the 8th week ofdevelopment, the CNS is very sensitive to teratogens, which can causeminor morphological abnormalities (such as neuronal migration disorders)or physiological defects (changes in synaptogenesis, neurogenesis). Thus,the human CNS is vulnerable to teratogenic effects throughout embryonicand fetal development.
The human CNS is very vulnerable perinatally (around the time of birth) tovarious exogenous factors such as teratogens, stress of delivery, physicalinjury, etc (Percy and Brown, 1999). Many of these factors produce insultstermed perinatal events. Neonates at risk of birth complications are testedwith the "Apgar" method of scoring asphyxia. This test measures appearanceof neonate, pulse, grimace, activity and respirations for a total maximumscore of 10. Several studies have shown a relationship between reducedApgar scores and a significantly increased risk of developmental delays inneonates when followed up at various ages of childhood. For example,Stromme (2000) found that Apgar scores of 3 - 6 increased the probabilityof mental retardation in a study of Norwegian children. In a Denmarkpopulation, Holst, Anderson, Philip and Henningsen (1989) found thatApgar scores of 7 or less were adequate to become a predictor of mentalretardation later in life. Perinatal events due to teratogens can occur becauseof neonatal drug withdrawal syndromes. For example, psychotropic drugsgiven in the third trimester produce withdrawal symptoms in the neonateseen up to a few weeks postpartum (Ward & Zamorski, 2002). Thesewithdrawal symptoms include motor or sensory problems, asphyxia(causing low Apgar scores), sleep apnea, and seizures.
EFFECTS OF PSYCHOTROPIC DRUGS ON THE FETUS
Psychiatric Disorders and Pregnancy
Mental illnesses are common in women during their childbearing years. Mood disorders such as anxiety and depression may be exacerbated by theonset of pregnancy and may ensue after delivery. The prevalence ofdepression can be as high as 10 - 16% during pregnancy (Laine, Heikkinen,Ekblad & Kero, 2003). The risk of relapsing into a post-partum depressioncan be very high depending on the level of depression and treatment course. For example, women who become depressed during pregnancy are at thehighest risk of relapse into post-partum depression (Ward & Zamorski,2002). Similarly, women who have bipolar or anxiety disorders are also athigh risk for developing postpartum relapse. Thus, pharmacologicaltreatment may be necessary in mental illness as an adjunct to other forms oftherapy or mandatory and essential. Drugs currently prescribed for mentalillnesses have a variety of effects on the fetus during pregnancy and delivery. It should be stressed that untreated psychiatric illnesses pose a tremendousthreat to the fetus due to maternal behaviour and that discontinuingpsychotropic drugs may also exacerbate maternal mental illnesses and causesecondary effects to the fetus. This review will focus on the effects of thesedrugs on the fetus from human and animal studies. Finally, a special sectionwill focus on anticonvulsants because they are crucial to the control ofepilepsy, but also because they are also largely prescribed as moodstabilizers (Lee, Inch & Finnigan, 2000). Antidepressants
Antidepressant drugs are those given for minor or major depression,obsessive-compulsive disorder, bipolar disorder and various other relatedmental illnesses. Their mechanism of action usually involves increasingbrain concentration of the biogenic amine/catecholamine neurotransmitters. For example first generation antidepressants called monoamine oxidaseinhibitors (MAOI), inhibit the breakdown of serotonin, norepinephrin anddopamine. However, their side effects were much too strong and the effectsnon-specific. The second generation drugs called tricyclic antidepressants(TCA) blocked reuptake channels for serotonin and norepinephrin. Blockingthe neuronal reuptake channel prevented degradation of theneurotransmitters thereby increasing their synaptic concentrations. In recentyears, drugs have become more specific in blocking the serotonin reuptakeand not norepinephrin. These third generation antidepressants are calledselective serotonin reuptake inhibitors (SSRI). SSRI antidepressants tend tohave even fewer side effects than TCA and fewer than MAOI.
Monoamine oxidase inhibitors (MAOI) are usually not indicated for use
during pregnancy because of their adverse side effects. Gilstrap and Little(1998) point out the lack of case and epidemiological studies regardingeffects of prenatal exposure of MAOI on rates of congenital malformations. The effect of MAOI on brain development comes from various rodentstudies. Mejia, Ervin, Baker and Palmour (2002) administered inhibitorsduring gestation and lactation. They found that the mice exhibitedsignificantly more aggression towards other mice. In another study,Whitaker-Azmitia, Zhang and Clarke (1994) administered the inhibitorsduring gestation to investigate the effect on the brain neurochemistry. Theyfound reduced serotonergic innervation in the cortex. Tricyclic antidepressants (TCA) are generally considered safe for use
during pregnancy (Gilstrap & Little, 1998, Lee et al., 2000). The birthincidence of congenital malformations is not increased nor does there seemto be any alteration of brain anatomy based on human studies. Consideringcognitive and behavioural assessments there seem to be no negative effectsof prenatal TCA administration. For example, Simon, Cunningham andDavis (2002) used a prospective study to investigate the effects of prenatalTCA. The authors did not find any significant increase seizure incidence ordelay in motor and speech development after prenatal exposure to TCA. However, these authors did not clarify the age at which the children weretested and it is assumed that they had not entered school. In another recentprospective study, Nulman et al. (2002) also investigated the effects ofprenatal TCA exposure on child development. The authors of this studyfound no change in cognition, language development or behaviour inpreschool or early school children. Selective serotonin reuptake inhibitors (SSRI) may be among the most
highly prescribed drugs in North America. SSRIs are far safer for humanconsumption than TCAs or MAOIs. Their pharmacokinetic properties affordthem low prevalences of major side effects. Also, because they are relativelyspecific for the serotonin reuptake channel, they do not produce undesiredCNS effects, often seen with MAOIs. However, as Koren (2001) points out,manufacturers of Prozac brand SSRIs, such as Eli Lilly, Ltd., suggest thatthe drug should not be consumed during pregnancy because its safety hasnot been properly documented. Despite this, SSRIs are still prescribed andindicated for use in moderate to severe depression during pregnancy (Lee etal., 2000). Several studies have found no increased risk of congenitalmalformations when using SSRIs during the first trimester (Koren, 2001;Kulin et al., 1998; Nulman et al., 2002). In another study, Chambers,Johnson, Dick, Felix and Jones (1996) investigated the outcomes of
EFFECTS OF PSYCHOTROPIC DRUGS ON THE FETUS
fluoxetine on fetal anomalies. Similar to other studies, they found noassociation between fluoxetine and major structural abnormality. However,they found a significant difference of minor anomalies in fetuses prenatallyexposed to fluoxetine as compared to controls. This study demonstrates thatcareful analysis must be performed so that minor anomalies will not beoverlooked. With respect to cognitive development, Nulman et al. (2002)carried out a prospective controlled study using SSRI exposure throughoutpregnancy. They found no increase in delay of cognitive or languagedevelopment in pre-school or early school aged children. Similarly, Simonet al. (2002) found no increased risk of developmental delay or congenitalmalformations after SSRI exposure. However, a recent study by Casper etal. (2003) showed a different trend after SSRI exposure. In a well-controlledstudy, the children of depressed mothers exposed to SSRI or unexposeddepressed mothers were followed up to age of 40 months. They found thatchildren prenatally exposed to SSRIs scored lower on the psychomotorindexes of the Bayley Scales of Infant Development test and lower on themotor quality factor of the Bayley Behavioral Rating Scale. The authorssuggest that subtle motor developmental delays may be one of the sideeffects of prenatal SSRI exposure. In another recent study, Zeskind andStephens (2004) used a systematic prospective study to investigate theprenatal effects of SSRIs on newborn neurobehaviour. They found thatinfants were hyperactive, tremulous and had behavioural state abnormalities. The aforementioned human studies demonstrate that gestational exposure toSSRIs cause behavioural abnormalities in infants and possibly in laterchildhood. Studies in which animals were prenatally exposed to SSRIs alsoshow minimal cognitive deficits. For example, Vorhees et al. (1994) foundthat prenatal fluoxetine found no effects on locomotor activity, behaviourparadigms or cognitive performance. Similarly, Coleman, Christensen,Gonzalez and Rayburn (1999) administered paroxetine prenatally to mice. The authors found no major behavioural effects of exposed mice. However,they did find that male mice were more aggressive and vocal at various times,which may suggest heightened anxiety.
Adverse effects of prenatal antidepressant exposure on the fetus may besecondary to effects of drugs. Both TCA and SSRIs are known to causeneonatal withdrawal symptoms when these drugs are used during the thirdtrimester of pregnancy and especially nearing delivery. Symptomsassociated with antidepressant withdrawal are collectively called neonatalwithdrawal syndrome or neonatal discontinuation (Haddad, 2001; Lee et al.,2000). Withdrawal symptoms associated with prenatal antidepressantsinclude: irritability, tremulousness, diarrhoea, poor feeding, respiratorydistress and seizures (convulsions). These symptoms can occur in patients
taking therapeutic or larger doses. Withdrawal can begin in as little as 72hours post-partum and last for several days (Lee et al., 2000). Chambers etal. (1996) investigated birth outcomes after administration of fluoxetineduring each of the three trimesters. Infants exposed during the third trimesterhad significantly increased risk of premature delivery and admission tospecial care nurseries as compared to those exposed during the first twotrimesters. Infants exposed late in gestation also had lower birth weights andwere generally shorter in length. Most importantly, infants showed neonatalwithdrawal symptoms including respiratory difficulties, cyanosis on feedingand jitteriness. In a recent case study of 5 women, Nordeng, Lindemann,Perminov and Reikvam (2001) investigated neonatal withdrawal symptomsin women taking other SSRIs (paroxetine, citalopram and fluoxetine) takenas monotherapy within the therapeutic dose. Neonatal withdrawal symptomsincluded irritability, constant crying, shivering, increased tonus, eating andsleeping difficulties and convulsions. The authors found that symptomsstarted as early as delivery and lasted for up to one month. In all these cases,APGAR scores were between 8 and 9 after 1 minute.
In another recent study, Laine et al. (2003) used a prospective controlledstudy of 20 mothers taking either fluoxetine or citalopram during the thirdtrimester. The authors measured neonatal withdrawal symptoms, using theterm serotonergic symptoms, and measured levels of monoamines in theumbilical cord. Compared to control infants, those exposed to SSRIs hadprogressively lower Apgar scores at 1, 5 and 15 minutes, becomingsignificant only at 15 minutes. SSRI exposed infants also had a significant 4-fold increase in serotonin symptoms versus controls occurring in the first 4days of life. These symptoms include myoclonus, restlessness, tremor,shivering, hyperreflexia, incoordination, and rigidity. Measuring the levels ofmonoamines in the umbilical vein, the authors found that serotonin (5-HT)and its metabolite (5-HIAA), dopamine metabolite (HVA), and noradrenalinwere all significantly reduced. In another study by Costei, Kozer, Ho, Ito andKoren (2002), 55 neonates exposed to paroxetine in the third trimester wereexamined for withdrawal symptoms. The authors found a significant increasein respiratory distress, hypoglycemia, and jaundice when compared toneonates exposed in the first two trimesters or unexposed neonates. Theauthors found that the discontinuation syndrome began shortly after birth andlasted for up to 1 month. Simon et al. (2002) investigated the perinatal effectsof antidepressant use. They found that SSRI but not TCA exposure caused asignificant decrease in Apgar scores at 5 minutes. Using different analysis ofthe Apgar data the authors looked at the number of infants who scored lessthan 5 at 1 minute and less than 7 at 5 minutes. They found that more SSRIexposed infants scored less than 5 and less than 7 at 1 and 5 minutes,
EFFECTS OF PSYCHOTROPIC DRUGS ON THE FETUS
respectively. Further, the authors investigated the effect of time of exposureof SSRI on Apgar scores. They found that third trimester exposure yieldedsignificant decreases in Apgar at both 1 and 5 minutes. Interestingly, thedifferences at 1 and 5 minutes were 0.83 and 0.47, respectively out ofpossible 10. The authors of this paper also investigated developmental delays. Although they found no significant differences, their data does showincreased motor delay in SSRI exposed group, and also increased seizureoccurrence in both SSRI and TCA exposed groups.
It would be informative to analyze the relationship between those exposedduring the third trimester that had low Apgar scores and their risk of havingdevelopmental delays or seizure disorders. This idea is reiterated in the studyof mental retardation etiology published by Stromme (2000). The authordescribes analysis of Norwegian children displaying mental retardation andthe prenatal/perinatal factors that may contribute to etiology. Decreasedbirth weight and Apgar scores between 3 - 6 at 1 and 5 minutes wereassociated with increased risk of mental retardation. Similarly, Krebs,Langhoff-Roos and Thorngren-Jerneck (2001) used a population-basedfollow-up of children with low Apgar scores. The authors found thatchildren with Apgar scores below 7 at 5 minutes had significantly morespeech/language deficits.
Although low Apgar scores predispose infants to motor and cognitivedevelopmental delays, it should be noted that low and extremely low Apgarscores were investigated in the aforementioned articles. Most authors did notdistinguish the important levels 6 - 8. This level may be critical for futuredevelopment especially considered with other neonatal withdrawalsymptoms. Further, it would seem that 0.5 - 1 full point decrements in Apgarscores would make a large difference and should be scrutinized. Perhapsthese studies did not have the proper sensitivity in protocols to discriminatesmall differences in Apgar scores. It would be crucial for future studies tofocus on perinatal events, such as those that cause Apgar scores and neonatalwithdrawal symptoms. Protocols should be set in place to clearly label allsymptoms and characteristics of the neonate so that future follow-up studiescould properly describe cognitive and neurodevelopmental milestones withgreater accuracy. Anxiolytics
Benzodiazepines are one of the most frequently used drugs to treat anxiety,and among the most commonly prescribed drug to women (Iqbal, Sobhan &Ryals, 2002). Benzodiazepines (BZD) exert their main function by acting on
the gamma-amino butyric receptor A (GABA A receptor) in the brain(GABA is an inhibitory neurotransmitter). Apart from being used to treatvarious anxiety disorders, benzodiazepines are also used for sedation, lightanaesthesia during surgery, anticonvulsants, muscle relaxants, and insomnia. According to Koren (2001), 2% of pregnant women may be on BZD. Considering that half of all pregnancies are unplanned, there must be a strictconcordance about the long-term effects of BZD use during pregnancy. Theteratogencity of BZD remains a controversial topic among prenatal drugexposure. A recent meta-analysis by Koren (2001) showed that there was norisk of major congenital malformations associated with BZD use. However,when the analysis was done on case studies alone, the authors found asignificant increase in risk of major malformation or cleft palate/lip.
Several studies have suggested that prenatal exposure to BZD may producethe "benzodiazepine syndrome" (Gilstrap & Little, 1998; Iqbal et al., 2002). This syndrome consists of facial dysmorphism (slanted eyes and epicanthalfolds), hypotonia and delayed motor development, polycystic kidney, sub-mucous clef hard palate, microcephaly, varying degrees of mentalretardation, convulsions, and neonate abstinence syndrome. The hypothesisoriginally posited by Laegreid, Olegard, Walstrom and Conradi (1989)likens the characteristics of benzodiazepine syndrome to fetal alcoholsyndrome. Although the publication was based on case studies, the authorsmeasured blood levels of BZD and confirmed that elevated levels wereobvious after regular therapeutic usage of BZD. The same authors followedup various infants prenatally exposed to BZD to assess their neuro-cognitivedevelopment. Laegrid (1990) followed up children prenatally exposed toBZD and highlighted the following characteristics: microcephaly (n = 2),severe mental retardation (n = 2), mild mental retardation (n = 5) and normalintelligence (n = 1). In a prospective study, Laegreid, Hagberg, andLundberg (1992a) followed 17 children prenatally exposed to therapeuticdoses BZD as the only psychotropic drug and compared to childrenunexposed to any psychotropic drug. The authors found that BZD exposedchildren deviated in neurodevelopmental tests. Gross motor and fine motordevelopment was delayed at 6 and 10 months follow-up. At 18 monthsfollow-up fine motor control was still delayed and children had muscle tonedeficits compared to the control group. The same group of children werefollowed up for cognitive testing in another study (Viggedal, Hagberg,Laegrid & Aronsoon, 1993). The authors used the Griffith's DevelopmentalScale which measures Locomotor, Hearing and Speech, Eye and HandCoordination, Performance, Practical Reasoning, and Personal-Social. Theyfound that BZD exposed children consistently scored lower on the generalquotient (G.Q.) at 10 and 18 months.
EFFECTS OF PSYCHOTROPIC DRUGS ON THE FETUS
In another study, Laegreid, Hagberg and Lundberg (1992b) hypothesizedthat the effects of prenatal BZD use on neurological development mightstem from drug intoxication and neonatal withdrawal symptoms. Indeed, theauthors found infants exposed to BZD had lower birth weights, shorter birthlength, and had significantly more perinatal complications than theirunexposed control groups. Neonatal withdrawal symptoms after BZDexposure are well documented for variety of BZD drugs (Gilstrap & Little,1998; Iqbal et al., 2002). Neonatal withdrawal symptoms included: lowApgar scores, hypertonia, irritability, abnormal sleep patterns, constantcrying, tremors, myoclonus, bradycardia, cyanosis, suckling difficulties,apnea, feeding aspirations, diarrhea, vomiting, and growth retardation. When diazepam and other BZDs are administered close to delivery, theneonates are given the label "floppy infant syndrome." The characteristics ofthis syndrome include withdrawal symptoms (mentioned above),hypothermia, lethargy, respiratory problems and feeding difficulties. Although the authors claim that infants recover without long-lasting effects,it is likely that these withdrawal symptoms could cause some types of neuro-cognitive developmental delays.
Animal studies also show immediate and long lasting effects of prenatalBZD exposure. Rats prenatally exposed to diazepam had significant deficitsin acquisition and retention of spatial discrimination task (Jaiswal &Bhattacharya, 1993). Alprazolam, another commonly used BZD givenprenatally to either mice (Christensen, Gonzalez & Rayburn, 2003) or rats(Jaiswal, 2002) produces significant increases in anxiety in offspring whentested as juveniles or adults. Because BZD acts by activating GABAAreceptors, it is suspected that increased anxiety is indicative of GABAAreceptor desensitization. Indeed, Nicosia et al. (2003) found that male ratshad long lasting behavioural deficits and were hypersensitive to convulsantssuch as pentylenetetrazol (GABAA antagonist). In contrast, female ratsshowed increased resistance to seizures. The complex nature of prenatalBZD exposure on cognitive and behaviour seems to depend on gender, atleast in animals.
Human fetuses should be sensitive to BZD throughout fetal developmentsince the density of GABA A receptors is continually increasing, and animalstudies have shown that chronic BZD use reduces the number and density ofGABA A receptors in the brain. Using aborted fetal brains, Reichelt et al. (1991) found that receptors appeared in the human brain as early as 8th weekof gestation. The density of GABA A receptors steadily increased throughoutthe gestational period. In another study, Hebebrand et al. (1988) found thatGABA A receptor density steeply increased in the whole brain between 8
and 11 weeks of gestation, and in the frontal cortex receptor density increasedbetween 12 and 26 weeks of gestation. Livezey, Marczynski and Isaac (1986a,b) found that prenatal diazepam caused chronic anxiety in the adult rat and catoffspring and that this was related to a reduced number of receptors in thebrain. These effects, if true in human cases, may explain the long termbehavioural and cognitive effects often observed in prenatal BZD exposure.
Around 0.5 - 1% of all pregnancies occur to women with some form ofepilepsy (Gilstrap & Little, 1998). In these cases, the patients do not have achoice about the prenatal exposure to drugs because anti-epileptic drugs(AED) are essential to daily living (Dean et al., 2002). Use of AED duringpregnancy increases the risk of congenital malformation about 2 to 3 fold. Theexact mechanisms by which these occur depend on the type of AED. Theincreased malformation has been shown not to be related to the maternalepilepsy per se, but rather to the AED. Epileptic mothers not using AEDgenerally have the same rate of malformations as non-epileptic mothers. Further, epileptic mothers using AED have just as high a malformation rate asnon-epileptic mothers using AED as mood stabilizers (Meador, 2002). Olderanticonvulsants are known teratogens, and although newer AED may havebetter pharmacokinetic profiles, their effects on pregnancy are still unknown.
Some of the older AED with known profiles of teratogenicity includephenytoin, carbamazepine, and valproate. Phenytoin has been used for morethan 50 years as an AED and has been one of the most commonly prescribedanticonvulsant. The effects of phenytoin on the fetus have been termed fetalhydantoin syndrome because of characteristic malformations that occur. Some of the congenital malformations include cleft lip/palate and othercraniofacial anomalies, limb defects, and some learning deficiencies. In afew studies it was found that children exposed to phenytoin prenatally had10-point decrease in I.Q., although this was not considered mentally retarded(Gilstrap & Little, 1998). In a recent review by Meador (2002) studies onprenatal AED show that phenytoin has adverse effects on neurobehaviouraldevelopment. Various animal studies also show similar trends. For example,prenatal phenytoin exposure in rats caused long term spatial (Morris andradial arm maze) and working memory (delayed non-matching to sample)deficits in the offspring (Tsutsumi, Akaike, Ohno & Kato, 1998). Schilling,Inman, Medford, Moran and Vorhees (1999) extended the findings to includedeficits in reference memory based spatial learning deficits using cuedplatform learning and spatial discrimination tests.
EFFECTS OF PSYCHOTROPIC DRUGS ON THE FETUS
Using carbamazepine prenatally results in consequences similar to those ofphenytoin. Craniofacial, limb anomalies, learning disabilities and neuraltube defects have been summarized as the fetal carbamazepine syndrome. Inone study verbal I.Q. was reduced by 10 points (Meador, 2002). However,in a recent study Gaily et al. (2004) found no difference in verbal and non-verbal I.Q. scores of children prenatally exposed to carbamazepine. Usingvalproate prenatally increases the risk for neural tube defects, variouscraniofacial malformations and congenital heart defects, but no cognitivedysfunction (Gilstrap & Little, 1998). However, Koch et al. (1996) foundthat valproate caused immediate neonatal withdrawal symptoms such ashyperexcitability causing neurological deficits. When examined 6 yearslater, the children continued to have long-term neurological dysfunctions. Ina recent clinical study of 57 children prenatally exposed to AED, around77% of children had developmental delay, most cases (80%) having hadprenatal exposure to valproate alone or in combination with another AED(Moore et al., 2000).
In the aforementioned study by Moore et al. (2000), the effects of prenatalAED exposure were not differentiated by type of drug, but rather grouped ina clinical diagnosis of fetal anticonvulsant syndrome. Interestingly theauthors found that 44 of 57 (77%) had learning difficulties, 81% had speechdelay, 60% gross motor delay and 42% fine motor delay. Interestingly, of theschool aged children, 74% were enrolled in special education or receivinglearning support. Considering behavioural problems, 81% of cases reportedsome type of behavioural dysfunction. Of these, 60% had some autisticfeatures, 39 % had hyperactivity, but only a few were actually diagnosedwith autism or Asperger syndrome. Although the authors report 19% birthincidence of neonatal withdrawal (including seizures and jitteriness), thiswas not discussed at length or compared to the current neurodevelopmentprofile. Furthermore, the authors failed to separate the data based onparticular AED exposure, which would have been more informativeconsidering mechanistic differences amongst the drugs. Nevertheless, thisstudy is one of the pioneering case studies investigating the long termneurodevelopmental profiles of prenatal AED exposure.
In a recent comprehensive paper, Dean et al. (2002) used a retrospectivestudy to investigate the neonatal effects and long-term consequences ofprenatal AED exposure. Based on hospital records they found significantneonatal withdrawal symptoms after exposure to valproate and phenytoinand polytherapy (more than one drug). Neonatal withdrawal was defined ashaving the following: jitteriness, hypotonia, seizures, apnoeic episodes,hypoglycemia and feeding disorder. The authors further investigated
prenatal exposure on developmental delays and found significant adverseoutcomes after treatment with carbamazepine, valproate, phenytoin orpolytherapy. In all cases, speech delay was the most common developmentaldisability. When looking at behavioural disorders (autism spectrum, ADHD)associated with normal development, the authors found significant effectsafter exposure to carbamazepine, valproate and polytherapy. Although theauthors did not find a link between neonatal withdrawal symptoms andcognitive dysfunction, this study is one of the first, and does not rule out apossible link. How Drugs Exert Teratogenic Effects
As pharmaceutical companies design drugs to become more permeable tothe blood brain barrier, they will inevitably cross the placenta and enter thefetal brain as well. Highly prescribed drugs such as fluoxetine and diazepamhave been investigated and researched thoroughly. Although their safetyprofile shows little or no risk for major congenital malformations (Gilstrap& Little, 1998), their effects on neuro-cognitive development is far frombeing completely understood. Antidepressants, anxiolytics and antiepilepticsact on neurotransmitter systems that are being shaped as early as the 5th and8th week of gestation for serotonin and GABA, respectively (Herlenius &Lagercrantz, 2001).
The effects of drugs on cognitive and neuro-development can occur via twomain pathways. First, drug specific actions on the developing brain alterbrain neurotransmitter levels, change receptor levels and ultimately alterbrain circuitry. For example, Cabrera-Vera and Battaglia (1998) found thatprenatal exposure to fluoxetine changed the levels of serotonin reuptake inprepubescent age. In various limbic regions such as the hippocampus andamygdala, which are vital for learning and emotions, reuptake channels wereupregulated. In contrast, Montero, de Caballos and Del Rio (1990) foundthat various antidepressants, including fluoxetine, downregulated thereuptake channel in the cerebral cortex of the rat that lasted until adulthood. These data suggest that various molecular changes occurring in the brainafter prenatal drug exposure may have functional consequences in later life.
The second pathway of prenatal drug exposure on cognitive neuro-development is via perinatal complications. All of the antidepressants,anxiolytics and antiepileptics mentioned above caused some form ofneonatal withdrawal symptoms even when parental exposure was within thetherapeutic dose. The most common neonatal withdrawal symptomsincluded a motor component, displaying as jitteriness, tremors, irritability,
EFFECTS OF PSYCHOTROPIC DRUGS ON THE FETUS
hypo/hypertonus, and hyperreflexia. The exact consequence of these motormanifestations is unknown but it is likely to have some gross/fine motordevelopmental delay as been shown for prenatal exposure of BZD (Laegridet al., 1992) and antiepileptic drugs (Moore et al., 2000). However, in allthree drug classes, convulsions and seizures seem to be some of the moresevere neonatal withdrawal symptom. It is possible that infants may haveminor convulsions (such as cyclonic jerks), which may not be identified butinstead classified as a motor manifestation (jitteriness, tremor etc.). Thesituation is further complicated because neonatal withdrawal symptoms maybecome apparent several days post-partum and can last up to one month. Thus, parents who take their newborns home one day post-partum may notbe aware or attentive to possible neonatal withdrawal symptoms. In somecases, parents will return to the hospital and admit the infant to the hospitalfor these symptoms. The lag in treatment and lack of constant supervisionduring those few critical days post-partum may have unknownconsequences on fetal development.
Withdrawal symptoms can include cyanosis, apnea, respiratory and sleepdifficulties. It is very probable that these processes contribute to low Apgarscores. Holst et al. (1989) assessed the neonatal risk factors associated withhandicap (developmental disability) in later life. The authors found thatintrapartum asphyxia was a strong predictor of developmental disabilities inchildhood. The authors described asphyxia as Apgar scores of less than 7 at1 minute and less than 10 at 10 minutes. Many of the neonates prenatallyexposed to SSRIs or BZD in third trimester all had reduced Apgar scores ascompared to unexposed children, which may have put them at risk fordevelopmental disabilities in later life. The authors also describe low birthweight and early gestation as a strong predictor of delays in development. Inthe study by Chambers et al. (1996), neonates exposed to SSRIs during thirdtrimester have increased risk of premature delivery and lower birth weights. Similar results have been shown for prenatal exposure to BZD (Laegrid etal., 1992).
Although mental illnesses and epilepsy cannot be ignored and untreatedespecially in pregnant women, some caution should be exercised. Closemonitoring of drug dosages and blood levels of metabolites should indicatethat therapeutic doses are maintained. Further, psychotropic drugs given topregnant women should be given according to their pharmacokineticprofiles. For example, drugs with longer half-lives and active metabolites
are preferred to those with longer half-lives and no active metabolites (Iqbalet al., 2002). Drugs with shorter half-lives will be excreted at a faster rateand are more likely to produce withdrawal symptoms. Active metabolitesprolong the effect of the drug in the brain and thus minimize the risk ofwithdrawal symptoms post-partum. Withdrawal symptoms can be reducedby reducing the tapering the mother off the drug near time of delivery. However, caution should be exercised that the mother's mental illness doesnot relapse. Until more is known about the effects of these drugs on theneonates, unnecessary usage of psychotropic drugs should be eliminated orreduced dramatically and supplemented with psychiatric therapy. References
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