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The Use of Psychotropic Medications in Pregnancy and the Postpartum

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1 The Use of Psychotropic Medications in Pregnancy and the Postpartum
Stephanie Berg, MD Medical Director The Women’s Emotional Health Center At Midlands Psychiatry 125 Alpine Circle Columbia, SC 29223 September 29, 2010

2 Disclaimer I have nothing to disclose
All discussion of medications is off label as no medications are FDA approved in pregnancy

3 Objectives Introduction Antidepressant medications
Pregnancy Breastfeeding Mood stabilizer medications Antipsychotic medications Antianxiety medications

4 The Women’s Emotional Health Center at Midlands Psychiatric Service, LLC 125 Alpine Circle Columbia, South Carolina (803)

5 Who we are Stephanie Berg, MD Psychiatrist
Primary focus is psychiatric medication management and diagnosis of mental health difficulties in women

6 Particular interests Mood disorders in pregnancy
Mood disorders in the postpartum period Psychiatric aspects of chronic pelvic pain Eating disorders Mood changes with menopause Mood changes with premenstrual disorders Mood disorders in victims of interpersonal violence

7 Who we are Kelly Helms, LISW-CP Clinical Social Worker
Primary focus is EMDR as well as individual and family therapy for women, infants, and children

8 Particular Interests Trauma recovery therapy Perinatal mood disorders
EMDR (Eye Movement Desensitization and Reprocessing) For women with history of Assault Post-traumatic stress disorder Anxiety disorder Abuse history Perinatal mood disorders Individual and couple counseling for difficulties with intimacy

9 Particular Interests Parental counseling of families planning for adoption Parenting skills in the mother of newborns through toddler age children Therapy for women struggling with infertility and pregnancy loss

10 Perinatal Psychiatric Disorders
Pregnancy Depression Postpartum Blues Postpartum Depression Postpartum Psychosis Postpartum Obsessive-Compulsive Disorder Exacerbation of other illness

11 Antidepressant medications
SSRIs Fluoxetine (Prozac) Sertraline (Zoloft) Paroxetine (Paxil) Fluvoxamine (Luvox) Citalopram (Celexa) Escitalopram (Lexapro) SNRIs Venlafaxine (Effexor) Duloxetine (Cymbalta) Desvenlafaxine (Pristiq)

12 Antidepressant medications
Other Wellbutrin (Bupropion) Norepinephrine and dopamine Trazodone Mirtazapine (Remeron) Tricyclic Antidepressants Amitriptyline (Elavil) Nortriptyline (Pamelor) Imipramine (Tofranil) Clomipramine (Anafranil) MAOIs Phenylzine (Nardil) Tranylcypromine (Parnate)

13 Perinatal mood disorder treatment scenarios

14 Treating MDD in Pregnancy: The Ideal Situation
Ms. J has a long history of recurrent depression. She is currently stable on sertraline (Zoloft). She would like to become pregnant. What should she do?

15 Versus Ms. J has had a difficult time becoming pregnant. She is not taking psychiatric medications. Two months after finding out she is pregnant, she notices she feels down and is unsure if she evens wants to continue the pregnancy. What should she do?

16 Versus Ms. J has a long history of depression and just found out she is pregnant. She is currently taking fluoxetine (Prozac). What should she do?

17 Major Depressive Episode
At least 2 weeks Sad Interest Guilt Energy Concentration Appetite Feeling restless or slowed Sleep Suicidality

18 Depression in pregnancy is common
First trimester 7 % Second trimester 13 % Third trimester 12 % Up to 30% in low-income populations

19 Detection of Perinatal Depression
Edinburgh Postnatal Depression Scale (EPDS) Can be used during pregnancy and postpartum 10-item, self-administered Easy to score Score of at least indicates depression Validated in at least 12 languages


21 Depression in Pregnancy
Risks of untreated depression Preeclampsia Placenta abnormalities Low birth weight Preterm labor Developmental delay

22 Depression in Pregnancy
Risks of untreated depression Poor follow up with OB appointments Malnutrition, less likely to take folate More likely to smoke, use alcohol, or other substances Greater likelihood to develop post partum depression Bonari et al (2004) Can Fam Physician 49;11:

23 Postpartum Depression
Previous Condition Risk of PPD Major depressive disorder 24 % Depression in pregnancy 35 % Previous PPD 50 %

24 Depression in pregnancy goes untreated
Less than 1/3 of women receive treatment for depression during pregnancy Who does get treatment? History of depression History of psychiatric treatment Depression severity Flynn et al. 2006

25 What happens to the untreated?
Cohen et al. 2006 High relapse risk Looked at 201 early pregnant euthymic women on antidepressants (AD) N = 82 maintained AD Relapse rate = 26% (n = 21) N = 65 discontinued AD Relapse rate = 68% (n = 44) 90% of relapses occurred by 2nd trimester <16 weeks pregnant, relapse by EPDS and SCID Those who continue through pregnancy do somewhat better than those who restart during pregnancy, but it does suggests you might be able to get through the first trimester…

26 Depression in Pregnancy
Li et al – 2008 Human Reproduction 791 women interviewed in early pregnancy Women with depression had twice the risk of preterm delivery Related to Low educational level History of fertility difficulties Obesity Stressful life events Antidepressants did not contribute to preterm labor

27 Why? Stress hormones? HPA axis hyperactivity
Increased placental release of CRH Prenatal cortisol elevations Catecholamines ACTH, cytokines Altered excretion of vasoactive hormones Altered neuroendocrine transmitters

28 An individual decision that’s made on a case by case basis!
Medication Choice An individual decision that’s made on a case by case basis!

29 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 (and eventually you may need to up the dose) Can alternative allow us to avoid med or use lower dose?

30 General Guidelines Document Document Document
“I have explained the risks, benefits, and alternatives of psychiatric medications in pregnancy. Ms. X (and her partner) have given consent.”

31 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

32 FDA labels Patients read them They will change They will be changing
Standard information on background rates Fetal risk data Clinical considerations Registry information 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

33 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

34 Treating Depression in Pregnancy
Think Sertraline (Zoloft)

35 FDA categories of Antidepressants in Pregnancy as of 9/24/10
Medication Pregnancy Category Lactation Risk Fluoxetine C Safety Unknown Paroxetine D Safe Sertraline Citalopram Escitalopram Bupropion Possibly Unsafe Venlafaxine Nortriptyline Probably Safe Amitriptyline Mirtazapine Trazodone 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

36 Pregnancy factors that may increase medication concentrations
Reduced gastrointestinal motility Absorption changes for some medications Reduced fecal elimination Serum proteins lower May result in higher ‘free’ drug concentrations Women get constipated, morning sickness

37 Pregnancy factors that may decrease medication 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 To appreciate some of the data that I’ll share on anti D in pg, some background info…

38 Pregnancy factors that may decrease medication concentration
Nausea and vomiting Reduced absorption Increased liver metabolism May result in increased elimination of certain medications

39 Decrease in blood levels
Sit et al 2008 N = 11 Citalopram, escitalopram, sertraline Blood level decreases at 20 weeks Increases after delivery Normalizes by 12 weeks after delivery

40 Antidepressant Blood Levels and Pregnancy
Prepregnancy Conception 20 weeks Delivery Postpartum Adapted from Sit et al 2008

41 Risk of Gestational HTn with SSRIs
Toh et al 2009 AJP n = 5731 registry women without known HTn and with healthy babies Increased risk of HTn with SSRIs overall 9% vs 19.1 % Increased risk of HTn with SSRIs after the first trimester 13.1% vs. 26.1% Increased risk of preeclampsia 2.4% vs. 3.7% vs. 15.2%

42 What should we be concerned about?
Organ malformation (teratogenicity) Miscarriage is worst outcome of this Neonatal Adaptation Physical and behavioral symptoms noted shortly after birth Related to drug use near time of birth Limited duration Long term behavioral abnormalities

43 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

44 Medication Background
Women usually find out when already 5-7 weeks gestation Therefore, may want to keep same medication if it’s working A couple of those helpful hints… It will be around for a while…though metabolism does change during pregnancy…

45 Risk of miscarriage Increased slightly with SSRIs
1.45 relative risk of miscarriage Within normal population rates Bupropion (Chun-Fai-Chen 2005) N = 136 Higher rate of spontaneous abortions 15.4 % vs. 6.7 % 12.4 % other antidepressants

46 Antidepressants During Pregnancy
SSRI complications Congenital anomalies Persistent Pulmonary Hypertension of the Newborn Neonatal adaptation syndrome

47 SSRIs and NEJM – article #1
Alwan et al, 2007 N = 9622 with major birth defects N = 4062 without birth defects No overall congenital heart defects As a group, increased risk of Anencephaly (OR 2.4) Baseline rate 20:100,000 Craniosynostosis (OR 2.5) Baseline rate 5:10,000 Omphalocele (OR 2.8) Baseline rate 1:10,000

48 SSRIs and NEJM – article #2
Louik et al, 2007 N = 9849 infants with birth defects N = 5860 infants without birth defects No overall birth defects for SSRIs as a group Sertraline omphalocele (OR 5.7) Septal defects (OR 2.0) Paroxetine Right ventricular outflow tract obstruction defects (OR 3.3)

49 Pedersen et al 2009 BMJ n = 493,113 SSRIs overall increase risk of septal defects (OR 1.99) Sertraline 3.25 Citalopram 2.52 Fluoxetine 1.34 Multiple SSRIs 4.70 Risk increases 0.5% to 0.9%

50 Paroxetine Has FDA warning against using in first trimester due to increased risk of cardiac defects

51 Paroxetine Berard 2007 Looked at paroxetine vs. other ADs 1403 women
101 with major malformations 24 of these were cardiac Paroxetine OR = 1.38 vs. other 0.89 Not significant However OR = 2.25 when paroxetine dose > 25mg daily Berard 2007

52 Paroxetine Einarson et al. 2008
N = 3235 infants Cardiac malformations Paroxetine group 0.7% Unexposed group 0.7% Paxil is not associated with heart defects in this group

53 Neonatal Adaptation Syndrome
Moses-Kolko EL et al, 2005 JAMA Meta analysis N = 18 cases and n = 9 cohort studies SRI late exposure RR: 3.0 FLX and PXT exposure for most Peak of 3 days for term, 5 days for premies

54 Neonatal Adaptation Syndrome
Cohort study (n = 120), included venlafaxine Neonatal abstinence syndrome occurs in 30% of neonates exposed to SRIs in utero Monitor for 48 hours after birth Levinson-Castiel R (2006) Arch Pediatr Adolesc Med 160:

55 Neonatal Adaptation Syndrome
Tremors Increased muscle tone Feeding difficulties Irritability Respiratory problems Increased reflexes Increased crying Sleep changes Seizures Moses-Kolko EL et al (2005) JAMA 293:

56 SSRIs and Persistent Pulmonary Hypertension
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: ) 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:

57 QT Interval Prolongation with SSRIs
Dubnov-Raz et al. 2008 52 SSRI exposed, 52 gestation matched babies Mean QTc 409±42 vs. 392±29 ms, (p<0.05) 10% in SSRI group >460 ms 0 controls ALL normalized in subsequent EKGs It’s always something new…(story of being at Marce, pts coming in with questions they saw on the news..) Blinded peds cardiologist read the EKGs. Risk for clinical events and arrhythmias remains to be seen…

58 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 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:

59 Tricyclics in pregnancy
The studies are conflicting Fetal tachycardia? One case report Neonatal symptoms Tachypnea Tachycardia Cyanosis Irritability Hypertonia Clonus Spasm ACOG 2007

60 MAOIs Not recommended in pregnancy
Can be dangerous with medications used around the time of delivery

61 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

62 Electroconvulsive Therapy
Safe with anesthesia, muscle relaxants Electrical impulse to scalp Induces 30 second seizure Side effects Memory loss Usually resolves by 6 months Muscle soreness Headache Nausea

63 ECT in Pregnancy Miller 1994 Literature review
N = 300 cases reports from

64 ECT in Pregnancy Risks Fetal cardiac arrhythmia (1.7%)
Vaginal bleeding (1.7%) Uterine contractions (0.67%) Abdominal pain (1%) Premature labor (1.3%) Miscarriage (1.7%) Neonatal death (1%) Respiratory distress (0.3%) Teratogenicity (1.7%) Miller 1994

65 ECT in Pregnancy Procedural risks Pulmonary aspiration
Aortocaval compression Elevate the right hip Fetal hypoxia Oxygenate the woman well Slower recovery from muscle relaxant (theoretical) Miller 1994

66 ECT in Pregnancy Modifications in Procedure
Pelvic exam in pre-ECT workup Uterine monitoring if the patient can not reliably identify contractions Rehydrate Take measures to prevent aspiration Fetal cardiac monitoring Consider intubating if beyond first trimester Due to risk of aspiration Miller 1994

67 ECT in Postpartum Medications with minimal risk to breastfeeding infant Monitor mother’s memory and ability to care for child Rabheru 2001

68 Non pharmacological treatments
Decrease caffeine, nicotine, alcohol Improve sleep Increase relaxation Psychotherapy Interpersonal Cognitive Behavioral Support groups Education Marital counseling Decrease psychosocial stressors Communicate with obstetrical team

69 Postpartum Mood Disorders

70 Postpartum Depression
Two weeks after Ms. J’s son is born, she begins to feel depressed. Even though she is continually exhausted, she has trouble falling asleep when her baby sleeps. She has repetitive thoughts of her baby falling out the window but these thoughts scare her and she states she would never act on it.

71 Postpartum Psychiatric Disorders
Incidence Time Course Clinical Features Postpartum Blues 70 – 80 % Within first week and ends by 14 days Tearfulness Anxiety Insomnia Mood Instability Postpartum Depression 10 % Within first month and can last for a year Depression Guilt Fear of harm to baby Obsessions Postpartum Psychosis 0.1 – 0.2 % Within first month Disorientation Confusion Delusions Hallucinations Rapid Mood Cycling

72 Postpartum Depression
Later onset than Postpartum Blues Places child at risk down the road Lower self-esteem More acting out Nursing infants gain less weight Duration of mother’s episode correlated with degree of impairment in child

73 Postpartum Depression
Symptoms Depression, crying Inability to sleep when the baby sleeps Intrusive thoughts Thoughts of hurting the baby Thoughts of hurting self Suicidal thoughts Loss of appetite Lack of interest in the baby Anxiety and panic attacks

74 Postpartum Depression
Previous Condition Risk of PPD Major depressive disorder 24 % Depression in pregnancy 35 % Previous PPD 50 %

75 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

76 Medications in breastfeeding
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

77 SSRIs with Breastfeeding
Monitor baby’s behavior with any medication Half life may be extended in infant Case reports of severe colic, fussiness, crying, poor weight gain

78 Half Lives of Antidepressants
Fluoxetine 2-3 days Citalopram 34 hours Escitalopram 30 hours Sertraline 29 hours Paroxetine 24 hours Bupropion 12 hours Duloxetine Venlafaxine 5 hours (metabolite = 11 hours)

79 Pharmacotherapy in Infants
Approximate clearance values at different ages Post-conceptual age Clearance of drug (compared with adults) 24-28 weeks 5% 28-34 weeks 10% 34-40 weeks 33% 40-44 weeks 50% 44-68 weeks 66% 68 weeks 100% Sometimes this info and being able to share it with women can impact a woman’s decision to start medication or have a dose increase From 05/14/04

80 Antidepressants and Breastfeeding
N = 78 breastfed infants of mothers taking antidepressants Mothers mood assessed at 6, 12, and 18 months Results No difference in child weights with population norms Infants of mothers with MDD relapse (> 2 months duration) weighed less than those with euthmymic mothers and those with a relapse < 2 months (p = 0.002) Hendrick et al (2003) J Clin Psychiatry 64:

81 Antidepressants and Breastfeeding
Weissman 2004 57 studies, n= 337 cases, n = 238 infants Looked at maternal plasma, breast milk, infant levels No detectable levels in infant Nortriptyline Paroxetine Sertraline Increased levels Citalopram 17 % of the cases Fluoxetine 22 % of the cases

82 Antidepressants and Breastfeeding
Paroxetine (Stowe 2000) N = 16 pairs Level of paroxetine increased in hindmilk No level found in infants Sertraline (Stowe 2005) N = 11 Levels of sertraline in 3 infants Levels of desmethylsertraline in 6 infants

83 Antidepressants in Breastfeeding
Tricyclic antidepressants OK Not doxepin though

84 Postpartum Depression – Treatment
Check thyroid function Increase support Psychotherapy Interpersonal Psychotherapy Phototherapy ECT

85 Treating Bipolar Disorder in Pregnancy
My patient delivers the baby, breastfeeds without problem, and the baby does fine. Six months later, she has a manic episode. She recovers and decides it’s time to have another child. At our next appointment, she asks about medication for her bipolar disorder during pregnancy and breastfeeding. What do you tell her?

86 Mood Stabilizer Medications
Lithium (Lithobid) Valproic Acid (Valproate, Depakote, Depakene) Carbamazepine (Tegretol, Equitro) Lamotrigine (Lamictal) Topiramate (Topamax) Atypical antipsychotics Risperidone (Risperdal) Olanzapine (Zyprexa) Quetiapine (Seroquel) Ziprasidone (Geodon) Aripiprazole (Abilify)

87 Risk of Relapse of Bipolar Disorder in Pregnancy
Viguera 2007 N = 89 pregnant women with BPAD I or II Continue medications - 37% relapse Discontinue medications - 85% relapse (RR = 2.3, p < 0.001)

88 Postpartum Psychosis Believed to be related to bipolar disorder
History of Bipolar Disorder leads to 35% risk postpartum psychosis 60 % risk of recurrent affective illness after Postpartum psychotic episode Significant danger to child Risk of abuse, neglect, infanticide, suicide HOSPITALIZE

89 Anticonvulsants – Summary as of 9/24/10
Drug FDA Fetal Risk Summary Lithium D Ebstein’s anomaly, “floppy baby” syndrome reported CBZ FHS, NTD, neurodevelopment effects? VPA Major and minor congenital abnormalities, intrauterine growth retardation, hyperbilirubinemia, hepatotoxicity, transient hyperglycemia, neural tube defects (day 17 – 30) Topiramate C Lamotrigine Unsafe with breastfeeding Gabapentin 4 reports of normal pregnancy, 1 report of respiratory distress

90 Lithium in Pregnancy Animal Studies - Teratogenic at high doses
Lithium Register 1980 (N = 225 1st trimester exposures) 11.1% malformation rate 8% CV malformations Ebstein’s anomaly = 1% (400 X normal)

91 Lithium in Pregnancy Two cohort studies and four case control studies
Association between Ebstein’s anomaly and Lithium 1st trimester exposure More recent estimate at x general population Baseline risk = 1:20,000 (0.005%) Lithium risk = 1:1,000 (0.1%) Thus, although risk is higher with lithium, overall absolute risk relatively small

92 Ebstein’s Anomaly

93 Lithium Neonatal toxicity Neurobehavioral
“floppy baby”: cyanosis, hypertonicity Neurobehavioral 5 year follow-up study (n = 60) – 2nd and 3rd trimester exposure Parents given questionnaires Exposed children compared with non-exposed siblings No significant differences in developmental anomalies between groups

94 Lithium in Pregnancy May require higher doses to achieve pre pregnancy therapeutic levels Increased volume of distribution Increased renal plasma flow, increased renal clearance Stop Lithium 1 to 2 days before planned delivery As soon as labor starts Newport 2005

95 Lithium in Pregnancy Evaluate need for Li prophylaxis
Gradually taper or stop before pregnancy if Single episodes of affective illness Long periods between affective episodes Restart Li in 2nd or 3rd trimester only if needed If Li d/c is a risk then d/c Li during embryogenesis Restart Li if deterioration occurs Use Li during pregnancy if needed

96 Lithium in Pregnancy Newport et al 2005 Lithium Guidelines
Monitor Li Closely Check [Li] weekly (at least monthly in first Trimester) avoid salt restriction and diuretics Stop Li with delivery 24-48 hours before planned induction or c-section At onset of labor Restart at pre-pregnancy dose after delivery

97 Lithium and Breastfeeding
Breast milk [Li] = % mother serum [Li] Cyanosis,  muscle tone, T-wave changes Not a good idea

98 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:

99 Anticonvulsants Teratogenicity – 1st trimester Neural Tube Defects
0.5% - 1% risk for carbamazepine 1% - 9% risk for valproate 0.03% general population Risk may be dose related, increased with multiple AED use, and associated with higher maternal plasma conc. Orofacial Clefts Minor malformations Rotated ears, depressed nasal bridge, short nose, elongated upper lip, fingernail hypoplasia

100 Anticonvulsants Neurobehavioral effects Data conflicting
Studies failed to show adverse effects on IQ in children with prenatal exposure to carbamazepine Finnish study (n = 148 v. 105 controls) Evaluated at 5.5 yrs post perinatal exposure Verbal and non-verbal intelligence scores significantly lower in study group children than controls. (p = 0.03)

101 Valproic Acid Intrauterine growth retardation Developmental delay
Neonatal toxicity HR decelerations Withdrawal symptoms Irritability, feeding problems, abnormal tone Liver toxicity Hypoglycemia Yonkers 2004

102 Valproic Acid Increased glucoronidation in pregnancy In lactation
Lower VPA levels In lactation Breast milk / infants < 1% - 10% concentration Thrombocytopenic purpura Anemia Generally felt to be reasonable Yonkers 2004, Gentile 2006

103 Carbamazepine Craniofacial defects (11%) Fingernail hypoplasia (26%)
Developmental delay (20%) Don’t forget neural tube defects (0.5% to 1%) Intrauterine growth retardation Transient cholestatic hepatitis Urinary tract abnormalities Cardiovascular abnormalities Fetal Vitamin K deficiency Take 20mg daily oral Vitamin K Pediatric dose of Vitamin K 1mg IM Yonkers 2004

104 Carbamazepine in Breastfeeding
“Probably safe” Possible effects Transient cholestatic hepatitis hyperbilirubinemia

105 Lamotrigine in Pregnancy
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: , 2004

106 Lamotrigine Pharmacokinetics
Pennell et al. Neurology; 62: , 2004

107 Lamotrigine Pharmacokinetics

108 Lamotrigine in Pregnancy
Cunnington (2004) N = 414 Lamotrigine 2.9 % Major Congenital Malformations monotherapy 12.5 % MCM when polytherapy with VPA No specific pattern Concerns Poor neonatal adaptation thrombocytopenia

109 Antipsychotics in Pregnancy as of 9/24/10
Drug FDA Fetal risk summary Haldol C Chlorpromazine Aripiprazole Olanzapine Seroquel Risperidone Clozapine B Geodon

110 Antipsychotics in Pregnancy
Risperidone 300 cases in pregnancy – probably OK Breastfeeding Data is conflicting on whether level present in infants Olanzapine Lilly registry No increased risk of complications Metabolic problems Lower birth weight Low levels in breastmilk but some adverse effects Cardiac problems, jaundice, lethargy, poor suckling, sleep problems, EPS, transient neurodevelopmental delay Gentile 2006

111 Antipsychotics in Pregnancy
Quetiapine 8 cases of congenital anomalies out of 487 reports Low levels in breastmilk without difficulties

112 Treating Anxiety in Pregnancy
I have a patient with bad panic disorder and I can’t seem to get her off her benzodiazepines. Now she is pregnant. What do I do?

113 Benzodiazepines Teratogenicity Oral clefts Clonazepam
General population = 0.06% (6:10,000) 3 studies (diazepam): odds ratio = 2.4 (CI: 1.4 – 4.03) 1 study (alprazolam): risk increased to 0.7% (7:1000) Controversy over risk Clonazepam Animal studies show low to no risk Case reports in women with no adverse effects

114 Benzodiazepines Neonatal effects 3rd trimester or parturition exposure
Sedation, muscular hypotonicity, failure to feed, impaired temperature regulation, apnea, and low Apgar scores. Withdrawal signs: hypertonia, restlessness, irritability, seizures, inconsolable crying, tremors, etc. Can appear after delivery to 3 weeks after birth May last several months

115 Benzodiazepines Behavioral effects
Impaired learning and memory, absence of startle reflexes, other sustained/subtle behavior Data is conflicting

116 BZD and Pregnancy as of 9/24/10
Drug FDA Fetal risk summary Alprazolam D Reports are conflicting. Cleft plate risk increased to 7/ Withdrawal after in utero exposure reported (crying/restlessness) Clonazepam Little data on teratogenicity. Newborn toxicity noted (apnea, cyanosis, lethargy, and hypotonia). Diazepam 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.

117 Benzodiazepines and Pregnancy
Generally, if must use BZs in pregnancy, stick with ones that are short acting and don’t have metabolites, e.g. lorazepam

118 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

119 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

120 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

121 Perinatal Mood Disorders
Questions ?

122 Resources www.
Yonkers et al, 2009 APA and ACOG Consensus Statement, General Hospital Psychiatry and Obstetrics and Gynecology

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