(and eventually you may need to up the dose) Can alternative allow us to avoid med or use lower dose?
Why should you know this…your patients will read it..the good news? The FDA is going to change its labelling to include registry information, standard information on background rates
Paxil- OR 2.08 for congenital malformations – VSD – retrospective 3581 Swedish registry study – 4 % paxil major congenital anom vs 2 % with other AD 6.1 OR for PPH
Women get constipated, morning sickness
To appreciate some of the data that I’ll share on anti D in pg, some background info…
A couple of those helpful hints… It will be around for a while…though metabolism does change during pregnancy…
Drugs in pregnancy&lactation
WALID SARHAN F.R.C.Psych
US FDA pregnancy drug labeling categoriesA -Adequate, well-controlled studies in pregnantwomen have not shown an increased risk of fetalabnormalities to the fetus in any trimester ofpregnancy..
B Animal studies have revealed no evidence ofharm to the fetus; however, there are no adequateand well-controlled studies in pregnant women.OrAnimal studies have shown an adverse effect, butadequate and well-controlled studies in pregnantwomen have failed to demonstrate a risk to the fetusin any trimester
C Animal studies have shown an adverseeffect andthere are no adequate and well-controlledstudies in pregnant women.OrNo animal studies have been conducted andthere are no adequate and well-controlledstudies in pregnant women.
D Adequate well-controlled or observational studiesin pregnant women have demonstrated a risk to thefetus. However, the benefits of therapy mayoutweigh the potential risk. For example, the drugmay be acceptable if needed in a life-threateningsituation or serious disease for which safer drugscannot be used or are ineffective.
X Adequate well-controlled or observational studiesin animals or pregnant women have demonstratedpositive evidence of fetal abnormalities or risks. Theuse of the product is contraindicated in women whoare or may become pregnant.
Medication Choice An individual decision that’s made on a case by case basis!
Medication choices Pre-conception taper Stop medications entirely Stop and restart if symptoms Stop and restart after 1st trimester Continue through pregnancy Decrease dose Reduce or discontinue in late pregnancy Transition to psychotherapy
General guidelines Treat a woman as if she could become pregnant at any time… Up to 80% of pregnancies are unanticipated Document use of birth control Encourage use of folic acid and multivitamin
FDA labels Patients read them They will change They will be changing Standard information on background rates Fetal risk data Clinical considerations Registry information
FDA Classifications Most psychotropics are C None are A No antidepressants are FDA approved for pregnancy No drug is “safe” No good randomized, placebo- controlled studies Most studies are retrospective, case reports, and registry data
FDA categories of Antidepressants in Pregnancy as of9/24/10 Medication Pregnancy Category Lactation RiskFluoxetine C Safety UnknownParoxetine D SafeSertraline C SafeCitalopram C Safety UnknownEscitalopram C Safety UnknownBupropion C Possibly UnsafeVenlafaxine C Safety UnknownNortriptyline D Probably SafeAmitriptyline C Probably SafeMirtazapine C Safety UnknownTrazodone C Probably Safe
Pregnancy factors that may increasemedication concentrations Reduced gastrointestinal motility Absorption changes for some medications Reduced fecal elimination Serum proteins lower May result in higher ‘free’ drug concentrations
Pregnancy factors that may decreasemedication concentration Total blood volume increases 30 – 40% 2nd and 3rd trimesters extravascular volume increases ○ Results in lower plasma levels of meds Increased kidney plasma flow 30% GFR increased by 50% ○ Renal excreted drugs have faster elimination
Pregnancy factors that may decreasemedication concentration Nausea and vomiting Reduced absorption Increased liver metabolism May result in increased elimination of certain medications
Antidepressant Blood Levels and PregnancyPrepregnancy Conception 20 weeks Delivery Postpartum Adapted from Sit et al 2008
What should we be concerned about? 1. Organ malformation (teratogenicity) ○ Miscarriage is worst outcome of this 2. Neonatal Adaptation ○ Physical and behavioral symptoms noted shortly after birth Related to drug use near time of birth Limited duration A Long term behavioral abnormalities
Medication Background Incidence of major birth defects in US is 2 to 4% 65 – 70% of unknown cause 2 – 4% medication related Period of maximum vulnerability for birth defects of the nervous system is 14 – 35 days post conception
Medication Background Women usually find out when already 5-7 weeks gestation Therefore, may want to keep same medication if it’s working
Antidepressants During Pregnancy SSRI complications Congenital anomalies Persistent Pulmonary Hypertension of the Newborn Neonatal adaptation syndrome
SSRIs DURING PREGNANCY AND RISK OFPERSISTENT PULMONARY HYPERTENSION INTHE NEWBORN: population based cohort studyfrom the five Norodic countries The risk of persistent pulmonary hypertension of the newborn is low, but use of SSRIs in late pregnancy increases that risk more than twofold . The increase risk seems to be a class effect BMJ .2011JAN 12,:d8012.doi:10.1136/bmj
Paroxetine Has FDA warning against using in first trimester due to increased risk of cardiac defects
Neonatal AdaptationSyndrome Cohort study (n = 120), included venlafaxine Neonatal abstinence syndrome occurs in 30% of neonates exposed to SRIs in utero Monitor for 48 hours after birthLevinson-Castiel R (2006) Arch Pediatr Adolesc Med 160:173-176.
Neonatal Adaptation Syndrome Tremors Increased muscle tone Feeding difficulties Irritability Respiratory problems Increased reflexes Increased crying Sleep changes SeizuresMoses-Kolko EL et al (2005) JAMA 293: 2372-2382
SSRIs and Persistent PulmonaryHypertension N = 377 women with PPHN infants N = 836 matched controls Blinded nurses interviews N = 14 PPHN infants exposed to SSRI after 20 weeks gestation (n = 6 for controls) OR = 6.1 (95% CI: 2.2-16.8) Use of SSRI before 20 weeks or use of non-SSRI at any time during pregnancy not associated with PPHN Risk increases from 2/1000 to 6/1000 Chambers CD et al (2006). NEJM 354;6: 579-587.
SSRI Long Term Effects Prospective cohort study TCA (n = 46), FLX (n = 40), No MDD (n = 36) Children’s IQ, language, development, temperament assessed and compared ○ Ages 15 -71 months No differences between groups IQ negatively associated with duration of depression Language negative associated with # MDD episodes after delivery Nulman et al (2002) AJP 159: 1889-1895.
Tricyclics in pregnancy The studies are conflicting Fetal tachycardia? One case report Neonatal symptoms Tachypnea Tachycardia Cyanosis Irritability Hypertonia Clonus Spasm ACOG 2007
Electroconvulsive Therapy Safe and effective treatment 70% of patients who have not responded to medications respond well to ECT Effective for major depressive episode ○ Especially with psychosis or melancholic features Effective for manic episode Effective for acute schizophrenia episode?
Non pharmacologicaltreatments Decrease caffeine, nicotine, alcohol Improve sleep Increase relaxation Psychotherapy Interpersonal Cognitive Behavioral Support groups Education Marital counseling Decrease psychosocial stressors Communicate with obstetrical team
Breastfeeding Most medications excreted into breast milk Amount infant receives is based on mother milk:plasma ratio and amount of breast milk received Most important determinant of drug penetration is mother’s plasma levels Drug levels in breastmilk are less than what crosses the placenta
Medications inbreastfeeding Avoid long half life or sustained release medications Schedule medication dosing immediately after feeding or right before long rest period Advise mother to monitor for oversedation, especially with cosleeping
Anticonvulsants – SummaryDrug FDA Fetal Risk SummaryLithium D Ebstein’s anomaly, “floppy baby” syndrome reportedCBZ D FHS, NTD, neurodevelopment effects?VPA D Major and minor congenital abnormalities, intrauterine growth retardation, hyperbilirubinemia, hepatotoxicity, transient hyperglycemia, neural tube defects (day 17 – 30)Topiramate CLamotrigine C Unsafe with breastfeedingGabapentin C 4 reports of normal pregnancy, 1 report of respiratory distress
Lithium andBreastfeeding Breast Feeding Breast milk [Li] = 30-100% mother serum [Li] Cyanosis, ⇓ muscle tone, T-wave changes Not a good idea
Anticonvulsants All studies done in women receiving anticonvulsants for epilepsy None in women with primary psychiatric disorder Women with epilepsy bear more children with malformations ○ 3.5 % Morrow J et al (2006) J Neurol Neurosurg Psychiatry 77: 193-198.
Lamotrigine inPregnancy N = 14 pregnant women LTG monotherapy LTG metabolism increases during pregnancy ○ % in relative clearance (dose in mg/weight in kg/serum conc in mg/L) 1st trimester = 118% higher 2nd trimester = 171% higher 3rd trimester = 208% higher Postpartum = 4% higher Pennell et al. Neurology; 62: 292-295, 2004
Antipsychotics in PregnancyDrug FDA Fetal risk summaryHaldol CChlorpromazine CAripiprazole COlanzapine CSeroquel CRisperidone CClozapine BZELDOX C
Benzodiazepines Behavioral effects Impaired learning and memory, absence of startle reflexes, other sustained/subtle behavior Data is conflicting
BZD and PregnancyDrug FDA Fetal risk summaryAlprazolam D Reports are conflicting. Cleft plate risk increased to 7/1000. Withdrawal after in utero exposure reported (crying/restlessness)Clonazepam D Little data on teratogenicity. Newborn toxicity noted (apnea, cyanosis, lethargy, and hypotonia).Diazepam D Accumulates in fetus 1-3x mother. T1/2 prolonged. Increased risk of cleft palate. Floppy infant syndrome and withdrawal possibility.Triazolam X Little data available, but similar to other BDZ.
Benzodiazepines andPregnancyGenerally, if must use BZs in pregnancy, stick with ones that are short acting and don’t have metabolites, e.g. lorazepam
NEROLEPTICS Typical neuroleptics: Haldol ,clopixol atypical neuroleptics: Risperidone, Olanzapine ,Seroquel Careful in choice in pregnancy and lactation for the side effects. Sedation with Seroquel. Weight gain with olanzapine. Risperidone could be a good choice in pregnancy and lactation.
Take Home Points Depression in pregnancy is common Untreated depression in pregnancy carries risks for both the mother and the child No antidepressants are FDA approved in pregnancy But sertraline is generally agreed to be “safest” Must weigh risks and benefits with the mother (and partner) on an individual basis
Take Home Points SSRIs may be associated with septal defects, PPHN, and a neonatal syndrome. SSRIs are “safe” in breastfeeding Sertraline and paroxetine probably safest ECT is safe with pregnancy and breastfeeding
Take Home Points Lithium is moderately safe in pregnancy?? but not with breastfeeding Carbamazapine and Valproic Acid are not safe in pregnancy but moderately safe with breastfeeding Lamotrigine and the atypical antipsychotics seem to be relatively safe in pregnancy but need more data Benzodiazepines are associated with clefting
Resources www. Motherisk.org http://www.womensmentalhealth.org http://www.emorywomensprogram.org www.postpartumprogress.typepad.com Yonkers et al, 2009 APA and ACOG Consensus Statement, General Hospital Psychiatry and Obstetrics and Gynecology