Principles of Teratology;Principles of Teratology;Treating The MotherTreating The Mother--Protecting the UnbornProtecting the Unborn

Gideon Koren MD, FRCPC, FACMT Gideon Koren MD, FRCPC, FACMT Motherisk ProgramMotherisk Program

and Ivey Chair in Molecular Toxicologyand Ivey Chair in Molecular Toxicology

Motherisk:1985Motherisk:1985--20102010

65 trainees from 35 countries65 trainees from 35 countriesMotherisk Services initiated by our Motherisk Services initiated by our trainees:trainees:Australia Australia Soon to startSoon to start::Israel Hong KongIsrael Hong KongBrazil India Brazil India Italy Sweden Italy Sweden CanadaCanadaJapanJapanSouth KoreaSouth Korea

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Monthly columns:Monthly columns:Canadian Family Physician Canadian Family Physician Can. J. Obstet. GynaecolCan. J. Obstet. Gynaecol

MotheriskMotherisk--Selected FacultySelected Faculty

Shinya ItoShinya Ito MD, FRCPC: Drugs in MD, FRCPC: Drugs in breastfeedingbreastfeedingIrena NulmanIrena Nulman MD, FRCPC: Long MD, FRCPC: Long term neurodevelopmentterm neurodevelopmentJoanne RovetJoanne Rovet PhD: FASDPhD: FASDTom EinarsonTom Einarson PhD: Meta analysisPhD: Meta analysisBuhshan KapurBuhshan Kapur PhD: Toxicology PhD: Toxicology analysisanalysis

Drugs in PregnancyDrugs in Pregnancy--The issuesThe issuesOnly half of all pregnancies are plannedOnly half of all pregnancies are plannedMany women need medications for Many women need medications for pregnancy induced conditions (e.g. pregnancy induced conditions (e.g. Morning Sickness), chronic conditions Morning Sickness), chronic conditions (e.g. Epilepsy), intercurrent conditions (e.g. Epilepsy), intercurrent conditions (Allergies)(Allergies)Women work with chemicals, exposed to Women work with chemicals, exposed to radiation and use illicit drugsradiation and use illicit drugsDuring embryogenesisDuring embryogenesis--drugs &chemicals drugs &chemicals may adversely affect development may adversely affect development

Situational AnalysisSituational Analysis

A) Anxiety of birth defects:A) Anxiety of birth defects:Leads women not to take medications Leads women not to take medications during pregnancy& lactation.during pregnancy& lactation.Leads pharmaceutical companies not to Leads pharmaceutical companies not to develop drugs for pregnant &lactating develop drugs for pregnant &lactating women.women.B) Women are not treated appropriately B) Women are not treated appropriately even after first trimester, or for life even after first trimester, or for life threatening conditionsthreatening conditions

Perception of Teratogenic Risk(1)Perception of Teratogenic Risk(1)

Even when exposed to non Even when exposed to non teratogenic drugsteratogenic drugs--women assign women assign 25% teratogenic risk (Am J Obstet 25% teratogenic risk (Am J Obstet Gynecol 1989)Gynecol 1989)

EvidenceEvidence--based counseling can based counseling can prevent unnecessary pregnancy prevent unnecessary pregnancy terminations (Teratology 1990)terminations (Teratology 1990)

Perception of Teratogenic Risk(2)Perception of Teratogenic Risk(2)

Following the Chernobyl disasterFollowing the Chernobyl disaster--half half of all pregnancies in Athens were of all pregnancies in Athens were terminated (Trichopoulos, BMJ, terminated (Trichopoulos, BMJ, 1987)1987)

Women exposed to diagnostic Women exposed to diagnostic radiation assign major teratogenic radiation assign major teratogenic risk (Bentur, Teratology, 1991)risk (Bentur, Teratology, 1991)

Misperception and Pregnancy Misperception and Pregnancy TerminationsTerminations

Loebstein et al(Antimicrob Agent Chemother Loebstein et al(Antimicrob Agent Chemother 1998):1998):9/200 women on 9/200 women on quinolonesquinolones terminated terminated pregnancy vs.2/200 controls[RR 4.5(95%CI .98pregnancy vs.2/200 controls[RR 4.5(95%CI .98--20.6)]20.6)]

Bar Oz et al(In Press):Bar Oz et al(In Press):First trimester First trimester MMR vaccineMMR vaccine7/94 vs 0/95 terminations(p=.007)7/94 vs 0/95 terminations(p=.007)

Cohen Kerem et al(2004): 7/198 Cohen Kerem et al(2004): 7/198 diagnostic diagnostic radiationradiation terminated vs. 0/198 controls (p<.04)terminated vs. 0/198 controls (p<.04)

ShepardShepard’’s Principles of s Principles of TeratologyTeratology

The agent must be present during The agent must be present during the critical periods of developmentthe critical periods of developmentExperimental models corroborating Experimental models corroborating the findings (i.e biological the findings (i.e biological plausibility)plausibility)Acts directly on the embryoActs directly on the embryo-- fetus or fetus or on the placentaon the placenta

Case 1Case 1

25 y.o. aboriginal woman, northern 25 y.o. aboriginal woman, northern reservereserveDiagnosed with Gestational Diabetes Diagnosed with Gestational Diabetes at 24 wk gestationat 24 wk gestationInstructed to start insulin therapyInstructed to start insulin therapy2 d later the nurse finds out she is 2 d later the nurse finds out she is reluctant to start insulin injectionsreluctant to start insulin injections????????????/????????????/

Gestational DiabetesGestational Diabetes

Affects up to 10% of pregnant Affects up to 10% of pregnant womenwomenGlucose intolerance in third trimesterGlucose intolerance in third trimesterStrong predictor of later Type 2 Strong predictor of later Type 2 diabetesdiabetesResults in higher rates of pre Results in higher rates of pre eclampsia, fetal distress, eclampsia, fetal distress, macrosomia, neonatal hypoglycemiamacrosomia, neonatal hypoglycemiaManaged by dietManaged by diet--insulin (if needed)insulin (if needed)

GlyburideGlyburideFearFear:oral hypoglycemics cross placenta:oral hypoglycemics cross placenta--neonatal neonatal hypoglycemiahypoglycemia

Elliott (Am J Obstet Gynecol 1994):Glyburide Elliott (Am J Obstet Gynecol 1994):Glyburide does not cross the placenta in perfusion studies.does not cross the placenta in perfusion studies.

Langer et al (NEJM 2001): Langer et al (NEJM 2001): Glyburide as effective and safe as insulinGlyburide as effective and safe as insulinUndetectable umbilical cord levels with therapeutic Undetectable umbilical cord levels with therapeutic

maternal levels(50maternal levels(50--150ng/ml)150ng/ml)

MechanismsMechanisms: high protein binding(99.8%), : high protein binding(99.8%), short T1/2(2short T1/2(2--6 hr), BCRP transporter substrate.6 hr), BCRP transporter substrate.

Perfusion SystemPerfusion System

Maternal Vein

Maternal Artery

FetalVein

Fetal Artery

MaternalPump

FetalPump

= Sampling Port

Maternal Perfusate

Fetal Perfusate

95% N25% CO2

95% O25% CO2

Fetal Safety of GlyburideFetal Safety of Glyburide

Meta analysis( Motherisk 2006)Meta analysis( Motherisk 2006)--glyburide glyburide vs insulinvs insulinMacrosomiaMacrosomia-- OR1.04(.74OR1.04(.74--1.45)1.45)Birth weight: WMD 17g(Birth weight: WMD 17g(--4444--80)80)Gestational age: WMD 0(Gestational age: WMD 0(--.28.28--.27).27)Neonatal hypoglycemia OR 1.33(.99Neonatal hypoglycemia OR 1.33(.99--1.79)1.79)In LangerIn Langer’’s study:18/201 vs. 12/203s study:18/201 vs. 12/203(OR 1.57(.73(OR 1.57(.73--3.34) 3.34)

Case 2Case 211 days full term baby 11 days full term baby Appeared not to feed well, dusky colorAppeared not to feed well, dusky colorAt 10dAt 10d-- pediatric assessment pediatric assessment ““gained his birth gained his birth weightweight””Day 11Day 11-- not feeding, sleepingnot feeding, sleepingFound dead Found dead PM: negativePM: negativeMorphine in blood: 80ng/mlMorphine in blood: 80ng/mlMom prescribed codeine as Tylenol 3 for Mom prescribed codeine as Tylenol 3 for episiotomyepisiotomyTook the drug throughoutTook the drug throughout

Case 2Case 2--contcont’’dd

Mother and grandmother: Ultra rapid Mother and grandmother: Ultra rapid metabolizers of P450 2D6metabolizers of P450 2D6Stored milk: 80ng/ml of morphineStored milk: 80ng/ml of morphineLevels described in literature: up to Levels described in literature: up to 5ng/ml5ng/ml

Lancet, Aug 18,2005Lancet, Aug 18,2005

Codeine Use During Breastfeeding Codeine Use During Breastfeeding in Canadain Canada

~ ~ 129,000129,000 Canadian breastfeeding Canadian breastfeeding mothers per year are prescribed mothers per year are prescribed codeine postcodeine post--partum partum

-- 340,000 births per year340,000 births per year-- 73% breastfed73% breastfed-- 52% caesarian sections52% caesarian sections

Codeine is compatible with Codeine is compatible with breastfeedingbreastfeedingLast updated in 2001Last updated in 2001Based on three reports in which Based on three reports in which breast milk levels were measured breast milk levels were measured and found to be low and found to be low

Codeine MetabolismCodeine Metabolism

MorphineMorphine

UGT1A1UGT2B7

CYP3A4

Norcodeine

Morphine 3-glucuronide

KidneyLiver

Opioid Opioid activity in activity in

brainbrain

CodeineCodeine

CYP2D6

Morphine Morphine 66--glucuronideglucuronide

UGT2B7

Codeine 6-glucuronide

Norcodeine 6-glucuronide

171 mothers interviewed

CNS Depressionin infant

No CNS Depression

Maternal DNA Genotype CYP2D6

Genotype UGT2B7

ResultsResults

17 55

AsymptomaticSymptomatic

99 mothers excludeddid not take codeine, cough syrup, other CNS

meds

ResultsResults

17 (24%) infants exhibited CNS 17 (24%) infants exhibited CNS depressiondepression–– Major decrease in alertness during codeine Major decrease in alertness during codeine

compared to period without codeinecompared to period without codeine

Good concordance between maternal and Good concordance between maternal and infant CNS depressioninfant CNS depression–– 71% infant and mother CNS depressed71% infant and mother CNS depressed–– 10% mother only CNS depressed 10% mother only CNS depressed

Codeine dosingCodeine dosing

Mothers of symptomatics

Mothers of asymptomatics

P-value

Total codeine dose (mg/kg/d)

1.62 (0.79)

range: *0.63-3.64

1.02 (0.54)

range: 0.18-2.7

0.004

Codeine duration (d) 7 (1-180) 4 (1-180) 0.49

Statistically significant p<0.05

(n = 17) (n = 55)

median (min-max)

mean (SD)

* 0.63 mg/kg/d = 44 mg in a 70 kg woman= 1.5 tab Tylenol 3 = 3 tab Tylenol 2

Genotype Symptomatic Asymptomatic

2D6 UM andUGT2B7*2/*2

2/17 (11.8%)

0/55 (0%)

Genotype Symptomatic Population P-value Odds Ratio

2D6 UM andUGT2B7 *2/*2

11.8% 1-2% <0.001 7.84

Genotype Results

FDA Public Health AdvisoryUse of Codeine By Some Breastfeeding Mothers May Lead To

Life-Threatening Side Effects In Nursing Babies

August 17, 2007

Case 3Case 3Codeine Pharmacogenetics in ToddlersCodeine Pharmacogenetics in Toddlers

A 2 yr male toddler with Obstructive A 2 yr male toddler with Obstructive Sleep ApneaSleep ApneaOtherwise healthyOtherwise healthyUnderwent tonsillectomy as Underwent tonsillectomy as outpatientoutpatientWas released home in the afternoonWas released home in the afternoonReceived syrup codeine10Received syrup codeine10--12.5mg 12.5mg po q4po q4--q6 prnq6 prnWas found dead next morningWas found dead next morning

Case 3Case 3--contcont’’dd

Femoral bloodFemoral blood--32ng/ml morphine32ng/ml morphineCYP2D6 genotyping: CYP2D6 genotyping: Functional duplications of 2D6 allelesFunctional duplications of 2D6 allelesUM phenotypeUM phenotypePresently;Presently; No genetic testing is No genetic testing is donedoneIn 15In 15--20% cases20% cases--no reversal of sleep no reversal of sleep apnea after surgeryapnea after surgery

NEJM 2009NEJM 2009

Case 4Case 4

A 29y.o. G2P1 woman, 4 wk A 29y.o. G2P1 woman, 4 wk gestationgestationVery severe morning sickness in Very severe morning sickness in previous pregnancy (dehydration, previous pregnancy (dehydration, repeated hospitalizations)repeated hospitalizations)Very concerned now about a repeat Very concerned now about a repeat of a similar experienceof a similar experience

Nausea and Vomiting of Pregnancy Nausea and Vomiting of Pregnancy (NVP)(NVP)

* NVP affects 80% of pregnant women* NVP affects 80% of pregnant women*Bendectin (doxylamine*Bendectin (doxylamine--pyridoxine) was pyridoxine) was

used by 40% pregnant American women used by 40% pregnant American women in 1978in 1978

*Due to litigations*Due to litigations--drug removed in 1983 drug removed in 1983 despite scientific/FDA supportdespite scientific/FDA support

*2*2--3 fold increase in hospitalization rates for 3 fold increase in hospitalization rates for NVP in USANVP in USA

In Canada: Diclectin use is increasingIn Canada: Diclectin use is increasing--Temporal decrease in hospitalizationsTemporal decrease in hospitalizations

U.S.A. Temporal Trends for U.S.A. Temporal Trends for Limb Reduction Deformities, Bendectin Sales, Limb Reduction Deformities, Bendectin Sales, and Hospitalizations for NVPand Hospitalizations for NVP

Rate of Hospitalization in CanadaRate of Hospitalization in Canada

Case 5Case 5

32y.o woman with depression32y.o woman with depressionWell balanced on venlafaxin (effexor)Well balanced on venlafaxin (effexor)At 4 wk gestation: told by her At 4 wk gestation: told by her pharmacist that the drug may not be pharmacist that the drug may not be safe for the baby in pregnancy, and safe for the baby in pregnancy, and post partumpost partumShe d/c her medication and her She d/c her medication and her depression symptoms re appeardepression symptoms re appear

Depression in PregnancyDepression in Pregnancy*Affects up to 20% of pregnant women*Affects up to 20% of pregnant women

* SSRI appear safe(both dyspmorphology * SSRI appear safe(both dyspmorphology &neurobehavior)&neurobehavior)

(Nulman et al 1996, 2002)(Nulman et al 1996, 2002)

•• Neonatal Discontinuation SyndromeNeonatal Discontinuation Syndrome

•• Women commonly D/C therapy; high morbidity Women commonly D/C therapy; high morbidity (Einarson et al 2001)(Einarson et al 2001)

* Those treated* Those treated--very low average doses (Nulman very low average doses (Nulman 2003)2003)

AntidepressantsAntidepressants--Malformation Malformation Rates (1)Rates (1)

After 15 yrs of reassuring dataAfter 15 yrs of reassuring data--recent reports of excess cardiac recent reports of excess cardiac malformations, mostly with malformations, mostly with paroxetineparoxetineLed FDA & Health Canada to add Led FDA & Health Canada to add warnings to labelwarnings to labelThe studies are contradictoryThe studies are contradictoryRecent meta analysisRecent meta analysis--no increased no increased riskrisk

AntidepressantsAntidepressants--Malformations(2)Malformations(2)

Motherisk(2008): over 1000 Motherisk(2008): over 1000 prospectively collected paroxetine prospectively collected paroxetine casescases-- 0.7% cardiac malformations, 0.7% cardiac malformations, similar to the control group, and to similar to the control group, and to literature (literature (Am J PsychiatrAm J Psychiatr))Admin database studies: chance of Admin database studies: chance of detection biasdetection bias--depressed women depressed women more likely to see physicians and more likely to see physicians and having children examinedhaving children examined

““Cold Turkey SyndromeCold Turkey Syndrome””Many women discontinue SSRI/SNRI in Many women discontinue SSRI/SNRI in pregnancy due to concerns and misinformationpregnancy due to concerns and misinformationMany women receive small, ineffective dosesMany women receive small, ineffective dosesD/C treatment: increased risk of morbidity, D/C treatment: increased risk of morbidity, depression, hospitalization, drug abuse depression, hospitalization, drug abuse Discontinuation syndrome in adultsDiscontinuation syndrome in adults--well well characterizedcharacterizedDepression in late pregnancyDepression in late pregnancy--the strongest the strongest predictor for postpartum depressionpredictor for postpartum depression

Poor Neonatal Adaptation Poor Neonatal Adaptation SyndromeSyndrome

1010--30% of exposed babies30% of exposed babies--jittery, jittery, unconsolable, tremor, diarrhea, unconsolable, tremor, diarrhea, respiratory distressrespiratory distress——resolved resolved spontaneously within 3spontaneously within 3--5 days5 daysMostly discontinuation syndromeMostly discontinuation syndromeRarelyRarely--dopaminergic syndrome dopaminergic syndrome ((Knoppert, TDM 2006)Knoppert, TDM 2006)Treatment with an SSRI?Treatment with an SSRI?Indication for neonatal TDMIndication for neonatal TDM

Persistent Pulmonary Hypertension Persistent Pulmonary Hypertension of the Newborn of the Newborn

Increased OR of SSRIs in cases of PPHNIncreased OR of SSRIs in cases of PPHNNo case of SSRINo case of SSRI--PPHN death in series PPHN death in series Attributable risk: less than 1% of SSRI Attributable risk: less than 1% of SSRI exposure (exposure (Chambers, NEJM, 2006)Chambers, NEJM, 2006)

Produced in rats with fluoxetine (Produced in rats with fluoxetine (Bialek, Bialek, 2008)2008)

This may be a mechanism for the This may be a mechanism for the respiratory distressrespiratory distress

AntidepressantsAntidepressants--Neurobehavioral Neurobehavioral EffectsEffects

Nulman(1996): IQ, language, behaviorsNulman(1996): IQ, language, behaviors--similar among prozac, tricyclicsimilar among prozac, tricyclic--exposed exposed and controls (and controls (NEJMNEJM))Nulman(2001): Maternal depressive Nulman(2001): Maternal depressive syndromes, and not medications, affect syndromes, and not medications, affect adversely child achievementsadversely child achievementsCorroborated by recent studies with other Corroborated by recent studies with other SSRIsSSRIs--New Motherisk study with VenlafaxineNew Motherisk study with Venlafaxine

AntidepressantsAntidepressants--BreastfeedingBreastfeeding

Normalized dose (per Kg) of SSRIsNormalized dose (per Kg) of SSRIs--SNRIs in milk: <5% of maternal SNRIs in milk: <5% of maternal dosedoseSuggestion of lower postnatal growth Suggestion of lower postnatal growth raterate-- probably correlate with probably correlate with maternal depressive symptomsmaternal depressive symptomsSSRIs in milk may partially mitigate SSRIs in milk may partially mitigate neonatal withdrawalneonatal withdrawal

Case 6Case 6

A neonate born with Apgar 2 (1 min) A neonate born with Apgar 2 (1 min) after Placental Abruptionafter Placental AbruptionTremolous, seizures, intracranial Tremolous, seizures, intracranial bleedingbleedingMother denies any illness or drug useMother denies any illness or drug useNeonatal urine Neonatal urine ––negative for drugs of negative for drugs of abuseabuseNeonatal hairNeonatal hair-- highly positive for highly positive for cocaine and benzoylegconinecocaine and benzoylegconine

Physiology of the Hair ShaftPhysiology of the Hair Shaft

Prevalence of In Utero Exposure to Prevalence of In Utero Exposure to Cocaine in Toronto (1990Cocaine in Toronto (1990--1)1)

a random study of 600 casesa random study of 600 cases

37/600 babies positive for cocaine37/600 babies positive for cocaine34 in hair test34 in hair test9 urine test9 urine test7 maternal interviews7 maternal interviewsWithout hair testWithout hair test--75% of cases 75% of cases would have been missedwould have been missedNeonatal hairNeonatal hair--last 3 mo. of last 3 mo. of pregnancy= evidence of maternal pregnancy= evidence of maternal addictionaddiction

Major Medicinal TeratogensMajor Medicinal Teratogens(1)(1)

AntiepilepticsAntiepilepticsCarbamazepineCarbamazepine--NTD(1%)NTD(1%)ValproateValproate--NTD(2%);other NTD(2%);other malformations (Holmes 2003)malformations (Holmes 2003)Phenytoin: Fetal Hydantoin Syndrome(10Phenytoin: Fetal Hydantoin Syndrome(10--15%?)15%?)

ACE inhibitorsACE inhibitors: renal insuffuciency, hypocalvaria: renal insuffuciency, hypocalvaria

LithiumLithium--EbsteinEbstein’’s anomaly(1/5000)s anomaly(1/5000)

CoumadinCoumadin--Fetal Warfarin SundromeFetal Warfarin Sundrome

Major Human TeratogensMajor Human TeratogensIsotretinoinIsotretinoin; 50% malformation rate; 50% malformation rateSMART program to prevent fetal SMART program to prevent fetal exposureexposure--fetuses still exposedfetuses still exposedLeflunamideLeflunamide--Human levels teratogenic in Human levels teratogenic in animals; prospective study (n=40) still animals; prospective study (n=40) still negativenegativeThalidomideThalidomide--for leprosy, HIV, Drug vs for leprosy, HIV, Drug vs HostHostMisoprostolMisoprostol-- Moebius sequence; high Moebius sequence; high attributable risk, very low overall risk.attributable risk, very low overall risk.

Labeling(1)Labeling(1)

Prozac product Prozac product monograph(2004monograph(2004): ): ““Safe use in Safe use in pregnancy has not been established. pregnancy has not been established. Therefore, it should not be Therefore, it should not be administered to women od administered to women od childbearing age unless, in the childbearing age unless, in the opinion of the treating physician, the opinion of the treating physician, the expected benefits to the patient expected benefits to the patient markedly outweight the possible markedly outweight the possible hazards to the child or fetushazards to the child or fetus””..

Labeling(2)Labeling(2)Scientific reality:Scientific reality:Till Dec. 2003:Till Dec. 2003:

6 dysmorphology studies6 dysmorphology studies

3 neurodevelopmental studies3 neurodevelopmental studies

One meta analysisOne meta analysis

All showing apparent safetyAll showing apparent safety

ConclusionsConclusions

Pregnant and lactating women are Pregnant and lactating women are commonly orphaned from the commonly orphaned from the benefits of drug therapy, even when benefits of drug therapy, even when solid data on safety/effectiveness solid data on safety/effectiveness exist.exist.Change labeling systemChange labeling systemAllow evidenceAllow evidence--based counselingbased counselingAlways consider the risk of untreated Always consider the risk of untreated maternal conditionmaternal condition

Case 5Case 5

A 39 y.o G1P0 woman has A 39 y.o G1P0 woman has hypertension treated successfully hypertension treated successfully with an ACE inhibitorwith an ACE inhibitorShe sees her doctor at 4 wks She sees her doctor at 4 wks gestationgestationHe refers her to MotheriskHe refers her to MotheriskWe recommend to d/c ACE inhibitor We recommend to d/c ACE inhibitor due to potential risk of fetal renal due to potential risk of fetal renal damage anf hypocalvariadamage anf hypocalvaria

Fetal Safety of Antihypertensive Fetal Safety of Antihypertensive Drugs (1)Drugs (1)

Hypertensive disorders in :5% of all Hypertensive disorders in :5% of all pregnanciespregnanciesMany of these women require Many of these women require medicationsmedicationsACE InhibitorsACE Inhibitors: fetal/neonatal renal : fetal/neonatal renal insufficiency, hypocalvaria; insufficiency, hypocalvaria; inconclusive evidence of first inconclusive evidence of first trimester embryopathytrimester embryopathy

Antihypertensive Drugs(2)Antihypertensive Drugs(2)

Ca++ channel blockersCa++ channel blockers: : incomplete but reassuring dataincomplete but reassuring dataBeta blockersBeta blockers: a trend toward IUGR : a trend toward IUGR (atenolol more than the other?)(atenolol more than the other?)DiureticsDiuretics:theoretical concerns :theoretical concerns around decreased uterine blood flowaround decreased uterine blood flow--not proven by a meta analysisnot proven by a meta analysis

Drugs of Choice in PregnancyDrugs of Choice in Pregnancy

Methyl DopaMethyl Dopa: no apparent risk of : no apparent risk of adverse perinatal outcomesadverse perinatal outcomesOne neurodevelopmental study to One neurodevelopmental study to 7.5 yr of age: children developed 7.5 yr of age: children developed similar to controlssimilar to controlsLabetalol: Labetalol: no evidence of IUGRno evidence of IUGRNo study on neurodevelopmentNo study on neurodevelopment

Motherisk study (1)Motherisk study (1)

Prospective cohort, controlledProspective cohort, controlledChildren born 1996Children born 1996--20012001Labetalol (n=32)Labetalol (n=32)Methyldopa (n=25)Methyldopa (n=25)Controls (n=53)Controls (n=53)

Motherisk studyMotherisk studyOutcome measures: Outcome measures: Child verbal, performance, and full scale Child verbal, performance, and full scale IQIQAttentionAttentionEE xecutive processingxecutive processingLanguageLanguageMemoryMemoryLearningLearningMaternal IQMaternal IQ--confounderconfounderSESSES--confounderconfounder

Results(1)Results(1)

Mothers with hypertensionMothers with hypertension--olderolderNo differences in alcohol, cigarettes, No differences in alcohol, cigarettes, SESSESMothers in methyldopa treated for Mothers in methyldopa treated for longer periods in pregnancy(27.6+/longer periods in pregnancy(27.6+/--12.7 vs. 198.8+/12.7 vs. 198.8+/--14.2 wk)14.2 wk)Methyldopa: trends toward lower Methyldopa: trends toward lower maternal IQmaternal IQ

Results(2)Results(2)

Prematurity ratesPrematurity rates::LBTLBT--28%28%MetMet--20%20%ControlsControls--4%4%

Results(3)Results(3)

LBT NTCLBT NTCVerbal IQ 110+/Verbal IQ 110+/--8 112+/8 112+/--1111

Perfor. IQ 105+/Perfor. IQ 105+/--8 109+/8 109+/--1212

FSIQ 112+/11 105+/FSIQ 112+/11 105+/--1111

Resluts(4)Resluts(4)Methyldopa scoresMethyldopa scoreslower than controls for FSIQ (105+/lower than controls for FSIQ (105+/-- 12) 12) vs 112+/vs 112+/--11) and11) andPerf.IQ (109+/Perf.IQ (109+/--12 VS 99+/12 VS 99+/--16)16)

Multivariate analysisMultivariate analysis: : Groups, maternal FIQ, age at testing, Groups, maternal FIQ, age at testing, maternal age:maternal age:METMET--significant predictor of lower significant predictor of lower child FIQchild FIQNo differences in other achievementsNo differences in other achievements

ConclusionsConclusions

Labetalol is not associated with Labetalol is not associated with neuro developmental deficitsneuro developmental deficitsMethyldopa may be associated with Methyldopa may be associated with lower FIQlower FIQ

Late Pregnancy; Pharmacokinetic Late Pregnancy; Pharmacokinetic ChangesChanges

Dempsy & Benowitz(2002):Increased Dempsy & Benowitz(2002):Increased nicotine clearence ratenicotine clearence rateHeikkinen(2003): Increased fluoxetine Heikkinen(2003): Increased fluoxetine apparent clearance rateapparent clearance rateIncreased clearance rate of digoxin, Increased clearance rate of digoxin, lithiumlithiumIncreased hepatic blood flow, GFR, lower Increased hepatic blood flow, GFR, lower protein binding, lower compliance rateprotein binding, lower compliance rateNEED FOR HIGHER DOSESNEED FOR HIGHER DOSES

Critical CareCritical Care--Issues (1)Issues (1)Diagnostic RadiationDiagnostic Radiation-- use lead apron for non use lead apron for non abdominal proceduresabdominal proceduresEssential abdominal proceduresEssential abdominal procedures-- should go aheadshould go aheadAverage Fetal ExposureAverage Fetal Exposure::Lumbosacral spine:150Lumbosacral spine:150--500mR500mRUpper GI: 245mRUpper GI: 245mRBarium Enema: 700Barium Enema: 700--1500mR1500mRIVP: 800IVP: 800--1400mR1400mRAbdominal CT: 640mRAbdominal CT: 640mRLumbar Spine: 2500mR Lumbar Spine: 2500mR

Critical CareCritical Care-- Issues (2)Issues (2)

Main AntimicrobialsMain Antimicrobials-- not teratogenicnot teratogenicPenicillins Penicillins CephalosporinsCephalosporinsAminoglycosidesAminoglycosidesSulfonamidesSulfonamides--anti folatesanti folates--NTDNTDQuinolonesQuinolones-- safe in humanssafe in humans

Critical CareCritical Care--Issues (3)Issues (3)

SympatomimeticsSympatomimetics-- not teratogenic in not teratogenic in humanshumansBronchodilatorsBronchodilators--non teratogenicnon teratogenicMaternal Maternal ––Fetal Conflict: Fetal Conflict: maternal maternal well being must prevailwell being must prevailEnsure the family is well informedEnsure the family is well informedEnsure a perinatologist is on the Ensure a perinatologist is on the teamteam

Fetal Safety of MetforminFetal Safety of MetforminMotherisk meta analysisMotherisk meta analysis1% malformation rate in metformin1% malformation rate in metformin7% among disease matched controls7% among disease matched controls

(p<0.01)(p<0.01)Potential protective effectPotential protective effectPossibly because of improvement in insulin Possibly because of improvement in insulin

resistance and in androgen statusresistance and in androgen status

Use of metformin throughout pregnancy for Use of metformin throughout pregnancy for maternal diabetesmaternal diabetes-- appears safe appears safe (NEJM 2009)(NEJM 2009)

Fetal Safety of Oral HypoglycemicsFetal Safety of Oral Hypoglycemics

Motherisk Meta analysis (Can J Clin Motherisk Meta analysis (Can J Clin Pharmacol 2003;10:179Pharmacol 2003;10:179--83)83)10 studies10 studies471 exposed;1,344 controls471 exposed;1,344 controlsMajor malformations: OR 1.05 (.65Major malformations: OR 1.05 (.65--1.7)1.7)Neonatal death: OR1.16(.67Neonatal death: OR1.16(.67--2)2)

Back to Case 4Back to Case 4

Pre emptive use of antinauseants can Pre emptive use of antinauseants can mitigate the risk of reoccurence( mitigate the risk of reoccurence( J J Obst Gynaecol 2006)Obst Gynaecol 2006)

G.E. Reflux increases the severity of G.E. Reflux increases the severity of NVPNVPTreatment of reflux symptoms Treatment of reflux symptoms improves NVP symptoms( improves NVP symptoms( Motherisk, Motherisk, 2008)2008)