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Presentation1.pptx
1. Teratogenicity of
Psychotropic Drugs
By Dr. Divya Salwan, Chairperson Dr. Manasa Ram
Teratogenicity of
Psychotropic Drugs
By Dr. Divya Salwan , Chairperson Dr. Manasa Ram
2. NEED FOR STUDY
• Mental illness in the mother is not a benign event & may itself pose significant risks to both
mother & child, simply discontinuing or avoiding medication use during pregnancy may not be
possible. Therefore, prenatal exposure to psychotropic drugs is a major public health concern.
• Adverse outcomes due to drug exposure.
• Globally, maternal mental health problems are considered as a major public health challenge ,
which requires a stronger focus on mental health services that will benefit both mother and child.
• To make well-informed decisions and understanding the risks associated with the use of
psychotropic medications during pregnancy
3. • Would a physician tell a pregnant
woman with epilepsy, ‘Stop your meds
and ride out the seizures until you
deliver’?
• Are the medications of pregnant
women with mental illness somehow
more “optional”?
4. GUIDING PRINCIPLES
• Minimize exposures both to the untreated illness and to psychotropics.
• The medication to which a mother had response in the past is often the best choice.
• Psychotropic transfer to the baby via lactation is much lower than placental transfer .
• If fetal exposure to a particular psychotropic has already occurred, continue same during lactation
rather than switching to one with theoretically lower exposure.
• If the drug was started postpartum, observation of the infant’s behavior before the mother is
treated , aids to avoid misinterpreting/misdiagnosing typical behavior as potentially drug related.
5. MATERNAL-FOETAL DRUG TRANSFER
Dependson:
D.C. Dutta, Text book of obstetrics 4th edition ,
•Serumalbumin
•Uteroplacental bloodflow
• Placental surface area
•Thickness ofplacental membrane
•Molecular weight
•Concentration offree drugs
•Lipidsolubility (drug factor )
• Moretransfer ofdrugs atterm
6. When to start pharmacotherapy ?
• Pharmacotherapy is an important modality for
women with illness unresponsive to alternative
treatments.
• The psychiatrist plays an important role in
supporting the patient to make an informed
decision and in providing education to and
fostering communication with the obstetrician
and pediatrician
9. TERATOGENICITY
• Capacity of a drug to cause foetal abnormalities
when administered to the pregnant mother.
• Teratogenicity testing came into being since the
thalodimide tragedy of 1961.
• Drugs can effect the foetus at 3 stages :
- Fertilization and implantation (conception to 17
days )
- Organogenesis (Most Vulnerable Period) 18 to 55
days of gestation
- Growth and development (56 days onwards)
10.
11. CHARACTERISTICS OF A TERATOGEN
• A True teratogen is associated with a consistent birth defect across studies
• The association must be plausible
• Proven exposure to agent at critical times in prenatal development.
• Proof that the agent acts on the embryo or fetus directly or indirectly.
• Rare environmental exposure a/w rare defect, with atleast 3 reported cases-
easiest if defect is rare
12. TERATOGENICITY AND OTHER EFFECTS
For each psychotropic class , the available evidence is summarized in order of reproductive
domain:
• Congenital teratogenicity
• Late gestation effects
• Neonatal withdrawal/toxicity
• Developmental(neurobehavioral) teratogenicity
• Lactation
13. PHARMACOLOGIC RISKS DURING PREGNANCY
1ST Trimester- Morphologic risk
• <2 weeks No maternal/ fetal exposure
• 1-5 weeks Neural Tube Development
• 3-8 weeks Cardiac
• 6-9 weeks Lip and Palate
2nd-3rd Trimester
• Behavioral/ functional risks
• Neonatal effects (toxicity/withdrawal)
• Preterm labor
• Maternal side effects
14. ● Regular scanning at around 18-21 weeks helps in detecting the congenital anomalies
(Antonsson et al, 2008).
● Cardiac lesions could be detected with more success if liaised with fetal cardiologist.
MRI scan could be another complementary investigations in this regard
(Antonsson et al, 2008).
● Therapeutic drug monitoring (TDM) during pregnancy ensures an adequate drug
dose to achieve the desired benefits while avoiding excessive fetal accumulation for
drugs (Lindsay et al, 2006)
Measures toreduce/detect the congenital anomalies inthe fetus
17. CATEGORY DEFINITION DRUGS
A No fetal risks in controlled human studies. Iron
B No fetal risk in animal studies but no controlled human studies.
Hence Minimal evidence of risk
Paracetamol, Bupropion,
Clozapine , Zolpidem
C Adverse fetal effects in animals and no human data
available.Hence Caution in use
Haloperidol, Chlorpromazine
Duloxetine, fluoxetine, fluvoxamine
Escitalopram, Dothiapin,
Lamotrigine, Topiramate
D Human fetal risk is seen (may be used in life threatening
situation)
Lithium, Carbemezepine,
Paroxetine
X Contraindicated. Proved fetal risk in humans (no indication Valproate, Flurazepam
US FOODAND DRUG ADMINISTRATION PREGNANCY CATEGORIES
18. TheProblemwithLetters
• Pregnancy letter category system was overly simplistic
• Misinterpreted as a grading system
• A drug with adverse information in animals could be
labeled as the same category as a drug with no animal
information
– Example: Pregnancy Category C
– Animal reproduction studies have shown an adverse effect on the
fetus, there are no AWC studies in humans, BUT the benefits from
the use of the drug in pregnant women may be acceptable despite
its potential risks
– Studies in pregnant women and animals are not available
19. • Provide the prescriber with relevant information for critical decision-making
when treating pregnant or lactating women
• More complete statement of the known risks based on the available data
• Considerations of medical/disease factors
• Animal data put in context of human exposure
• Human data added when available
• Explicitly states when no data are available
ReasonstodevelopPLLR (PREGNANCY&LACTATIONLABELLINGRULE)
20. • Effective date June 30, 2015.
• Prescription drugs approved on or after June 30,
2001 have additional content and formatting
requirements
PLLR
22. PREGNANCY Pregnancy exposure registry
Risk summary
Clinical considerations
Data
Dosing ,potential fetal risk , info about
pregnancy registries
Always required , even if no data
Can be omitted if no data
Can be omitted if no data
LACTATION
(replaces the earlier
nursing mothers
section)
Risk summary
Clinical considerations
Data
Drugs that should not be used during
lactation , human or animal data about
drug metabolites in milk , risk vs benefit
section ,timing of feeding.
FEMALES AND MALES
OF REPRODUCTIVE
POTENTIAL
Pregnancy testing
Contraception
Infertility
Relevant information about pregnancy
testing , contraception during and after
drug therapy.
Effect on fertility and potential chance
of miscarriage.
NEWFDACLASSIFICATION–SECTIONSANDSUBSECTIONS
24. CASE VIGNETTE
A 25-year-old female presents with a history of recurrent depressive disorder and has been taking
fluoxetine 20 mg/day. She has come with history of 2 months’ amenorrhea with urine pregnancy
test being positive. She has been reporting decreased sleep and feels anxious about being on
medication and its effects on the infant. She wants to know whether she can stop medication. What
would be the appropriate advice?
25. • The effects of antidepressants on the fetus can be broadly classified as teratogenic risks, perinatal toxicity and
effects on the neurobehavioral development of neonates. Most of the retrospective studies which have studied
SSRIs in general have shown no difference in the occurrence of major malformations when compared to
general population (2%-4%) except for paroxetine.
• Among the four prospective studies, only one study has found a possible association between cardiovascular
anomalies and the first-trimester exposure to fluoxetine. Hence, when it comes to major malformations, the
occurrence is similar to that in the general population.
• Fluoxetine has been associated with perinatal adverse effects. Cardiac arrhythmias and low birth weight have
been reported. Two studies which have looked at perinatal outcomes have reported increased risk of premature
delivery and poor neonatal adaptation with neonatal withdrawal symptoms. Most of the adverse effects were
self limiting. When it comes to long-term neurodevelopmental effects, the results are inconclusive.
• However it is clear that the research suggesting a lack of adverse events on infants’ neurocognitive development is
much larger and methodologically better conducted than the studies showing possible unwanted cognitive and
behavioral effects. Considering the available information about the safety of the drug the risks and benefits of
antidepressant use, an informed decision needs to be taken.
26. SSRI’S(SELECTIVESEROTONINREUPTAKEINHIBITORS)
• No confirmed teratogen, in 1st trimester exposure.
• Placental transfer ----- CITALOPRAM > FLUOXETINE > SERTRALINE >
• Paroxetine with Cardiac Septal Defects resulted in FDA label change to category D in 2005
• Possible link b/w late pregnancy (after 20 wks of gestation) exposure to SRI’s & Persistent
Pulmonary Hypertension (PPHN) d/t platelet serotonin levels resulted in FDA label changes
warning of risk in 2006, which was then revoked in 2011.
• BUT current information, therefore doesnot support SRI discontinuation on the basis of PPHN
risk
CITALOPRAM > FLUOXETINE > SERTRALINE > PAROXETINE
27. PERINATAL COMPLICATIONS OF ANTIDEPRESSANTS
● Lower gestational age with unfavourable effects on birth weight and APGAR scores
(Simon et al, 2002; Lennestål R et al 2007; Davis et al,2007, Suri et al, 2007).
● Increased risk of spontaneous abortions (Hemels et al, 2005, Rahimi et al., 2006).
● However, retrospective cohort study found no evidence of major increase in risks of
adverse obstetrical or neonatal outcomes (Pearson et al,2007)
28. SSRI’S
• Antidep exposure in late pregnancy has been significantly a/w lower gestational age &
lower APGAR scores at 1,5 mints
• SRI exposure was a/w---- Lower Infant Birth Weight (only when maternal psych status was
unaccounted for)
• The extent to which depression is a/w Preterm birth from SRI’s remains to be studied
further
• No impact of SRIs or TCAs on temperament, mood, arousability, activity level,
distractibility, global IQ or language development in children followed to 7 yrs of age.
• More recent studies finds no association between SRI exposure and ASD but a possible
relationship with ADHD (OR = 1.8).
29. Neonatal Adaptation Syndrome
● Consists of features like Respiratory difficulty, hypoglycemia, hypertonia, jitteriness, irritability
vomiting, seizures & sleep disturbances.
• NAS affect 30 % of late pregnancy, SSRI-exposed newborns & substantially more preterm infants .
● Syndrome is time limited with greatest incidence in the first 48 hours post birth, but potentially extending to
2wks.
SSRI’S
30. • The only prospective study to be shown congenital
malformations like Omphalocele, Craniosynostosis
was with paroxetine (5.1%), cardiovascular
malformations (VSD,ASD) (1.9%);
• Fluoxetine was not associated with major
malformation. (Diav-Citrin et al., 2005).
ProspectiveStudies(SSRI’S)
31. • Fluoxetine excreted in human milk- No
detrimental effects in infant noted
• No detectable fluoxamine present in infants -
use is safe during breast feeding
Prospective Studies (SSRI’S)
32. Prospective studies (SSRI’S)
• Though, Paroxetine levels in maternal milk fluctuate, safety profile during lactation is
elucidated in prospective trial.
• Mothers taking sertraline can breastfeed without any effect on the infant (Gentile et al,
2012).
• No statistically significant adverse affects noted in infants with citalopram.
33. BREASTFEEDING
• Sertraline & Paroxetine –LARGEST EVIDENCE BASED USE in breastfeeding
RID from breastmilk less than 2% of adjusted maternal dose
• Citalopram, Fluoxetine, Venlafaxine more commonly a/w infant concentration more
than 10% of adjusted maternal dose
• There have been isolated case reports of elevated infant levels and toxicity with
breastfeeding mothers taking Doxepin or fluoxetine
SSRI’S
34. • Fluoxetine, breast-fed infants of fluoxetine-treated mothers
gained less wt. after birth.
Colic was reported
Full-term neonatal cytochrome P450 activity decreases
• Taking medication immediately after breast-feeding minimizes the amount present
in milk and maximizes clearance before the next feeding.
● Duloxetine is a newer SNRI
● Proved to be efficacious in MDD, GAD & fibromyalgia.
doesn’t confer any disproportionate adverse pregnancy outcomes
Estimated infant dose through breast milk is low and estimated at 0.14 percent of the
maternal dose.
BREASTFEEDING
SSRI’S
36. (Ahmed SM, Moukaddam N, Worley AV, Patel KR, Shah A, et al. (2016) Teratogenic
Potential of Commonly Prescribed Psychotropic Drugs. Med J Obstet Gynecol 4(4): 1091)
• Paroxetine has been shown to cause cardiac anomalies, especially atrial and ventricular
septal defects (Ahmed SM et al).
• Among SSRIs, sertraline and citalopram are usually the first line agents, as they have
little or no teratogenic potential and safe for use during lactation as well . Escitalopram
and fluvoxamine are relatively studied less for their effects during pregnancy and are thus
not prescribed routinely.
37. • The overall conclusion appears to be that prenatal exposure to either maternal
depression or AD drugs carries at least short-term risks to the developing fetus
• But there is not enough research on the long-term cognitive deficits and behavioural
development, so existing information is simply too limited to accurately and fully
determine risk.
• A recent population-based case control study reported a connection between ASD and prenatal AD
exposure. Specifically, maternal SRI exposure during the year before delivery, and especially
during the first trimester, was associated with twice the risk of an ASD diagnosis of the exposed
child.
38. • NCBI study showed women who discontinued AD medication during pregnancy were more likely to
experience a relapse than women who continued medication use.
• Neonates exposed late in the 3rd trimester have developed complications requiring prolonged
hospitalization, respiratory support, and tube feeding.
• Paroxetine has been shown to cause cardiac anomalies, especially atrial and ventricular septal defects
(Ahmed SM et al).
• Among SSRIs, sertraline and citalopram are usually the first line agents, as they have little or no
teratogenic potential and safe for use during lactation as well .
• Escitalopram and fluvoxamine are relatively studied less for their effects during pregnancy and are
thus not prescribed routinely.
40. ● No evidence of increased incidence of Congenital malformations .
● Majority of exposures have been to Clomipramine
(QT Prolongation ,Torsades de pointes- single case)
● Increased likelihood of
Preterm Birth
LBW
PPHN
Cardiac Septal Defects
• Well known to produce Neonatal Withdrawal effects during first few hrs/days-
dyspnea, lethargy , Colic, Irritability , hypo/hypertension ,Tremors
TRICYCLICANTIDEPRESSANTS(TCA’S)
41. • Secondary TCAs (Nortriptyline, Desipramine) may be preferred in pregnancy
based upon fewer hypotensive and anticholinergic effects.
• A Poor Neonatal Adaptation Syndrome has been described including
anticholinergic symptms of Urinary retention and Bowel obstruction
• Anafranil (clomipramine) is not recommended
● Risk Cat-C
● Crosses the placenta
TCA’S
42. BREASTFEEDING
● Moderate amounts seen in breast milk doxepin reported to cause resp. depression &
sedation in infants of breast feeding mothers .
● Nortriptyline has been studied the most as a rx for breastfeeding mothers
● Discontinuation of drug or bottle feed recommended
● Infants serum level range from undetectable to low .
● Adverse effect has not been reported in infants exposed to amitryptiline,
nortryptiline, clomipramine, imipramine, dothepin.
TCA’s
44. Contraindicated in pregnancy for following various reasons -
Growth retardation
Pregnancy-induced hypertension exacebration
Placental hypoperfusion
Serious fetal consequences
● If premature labor occurs, tocolysis with β-mimetics may not be possible because of potential
interaction with the MAOIs.
● Anesthetic management in labor may be complicated by the relative contraindication of
opioids in patients taking MAOIs.
● If pregnancy occurs while the patient is taking MAOIs, the drug should be discontinued.
● Guidelines have been suggested for appropriate obstetrical anesthesia and analgesia for women
treated with MAOIs.
MONOAMINEOXIDASEINHIBITORS(MAO’S)
45. • Phenelzine may increase fetal/pup mortality in rats.
• There is little information on the effects of exposure to tranylcypromine or isocarboxazid in animals.
• Exposure to selegiline at many times the MRHD ( max recommended human dose) increased the risk
for Major malformations (delayed ossification) and decreased fetal weight.
• There are no adequate and well controlled studies in pregnant women.
46. ● Bupropion’s dopaminergicmechanism ofaction & roleinsmokingcessation
give it an important place in the treatment
● Inconsistent findings about incidence of cardiac
malformations attributable to 1st trimester bupropion
exposure
● Increased risk of ventricularseptaldefectsandleftoutflow tractheart
defects.
• The estimated infant dose through breast milk is estimated at
5.7 % of the maternal dose.
BUPROPION (NDRI)
47. ● Mirtazapine is a novel antidepressant with noradrenergicandselectiveserotonin effects.
● There is rapid alleviation of hyperemesisgravidarumd/t serotonin 3 receptor blockade.
● Treatment benefits were obtained at doses of 7.5 to 45mg/day , in some cases it was administered
initially through I/V fluids & treatment course was concluded after 10 days.
● In a study of 1st trimester mirtazapine exposure, there were no increased rate of malformations ,
Similar rates of spontaneous abortion and preterm birth compared to pregnancies with other
antidepressant exposures.
● Estimated infant dose through breast milk is 1.8 to 4.4 % of the maternal dose.
MIRTAZAPINE (NASSA)
48. Prospective studies ( Mirtazapine, bupropion,venlafaxine)
• No adverse events reported infants with maternal mirtazapine intake during
lactation.
● Not enough data on venlafaxine, bupropion, escitalopram. (Gentile et al)
● A recent analysis of the available studies of antidepressants revealed that
sertraline, paroxetine, and nortriptyline are the least likely to lead to
accumulation in the infant (Weissman et al.).
BREAST FEEDING
50. ANTIPSYCHOTICS
• Minimal risk of teratogenicity
• Low-potency antipsychotics (chlorpromazine), there was a 0.4 percent increased risk of
malformations.
• High-potency antipsychotic (Haloperidol) was not associated with increased risks of
malformations/ limb defects.
• Preterm birth and SGA births , more common with FGA than SGA exposure
• FGA use in 2nd and 3rd trimester is a/w increased rates of - Perinatal complications
- LBW
- Transient Perinatal Syndromes
(motor restlessness, tremor, hypertonicity, abnormal movements, difficulty with feeding, and possible neonatal
jaundice & functional bowel obstruction)
51. • General FDA warning: 3rd trimester exposure increases risk for neonatal extrapyramidal and/or withdrawal
symptoms (EPS), including reports of agitation, hyper/hypotonia, tremor, somnolence, respiratory distress and
feeding problems. Severity varies from self-limited symptoms to intensive care unit support and prolonged
hospitalization
• No teratogenic effects or fetal toxicity have been observed in animal studies involving exposure to clozapine or
lurasidone.
• At doses >MRHD: Ziprasidone caused cardiovascular malformations, Quetiapine—lower fetal weights and
delays in skeletal ossification.
• Aripripazole–increased fetal/pup death, lower birth weight, and skeletal abnormalities.
• At >MRHD asenapine—lower pup weights and pup mortality.
• Ziprasidone—developmental delays and neurobehavioral impairment. There are no adequate and well-
controlled studies in pregnant women.
• Olanzapine has been associated with adverse pregnancy outcomes, including neonatal death due to
cardiovascular defect, and abortion (3 therapeutic, 1 spontaneous).
52. BREASTFEEDING
● The estimated infant dose through breast milk is estimated at 3% of the maternal dose
● Reports of drowsinessin the infant.
● There is no evidence of long-term effects on behavioral functioning or IQ up to age 4 years in children.
• One study found that in utero exposure was associated with a nearly 4-fold increased rate of abnormal
psychomotor development at 7 to 10 months of age
• Lower-potency FGAs greater risk of hypotension
• Higher-potency FGAs risk for extrapyramidal symptoms.
• Intermediate-potency Perphenazineconstitute a useful compromise (Neonatal
Jaundice has been reported with phenothiazines )
1st Generation antipsychotics (FGA)
53. ● Pregnancy risk Cat-C
● Reports of extrapyramidal symptoms jaundice
hyperreflexia/hyporeflexia have been reported .
● Reports of limb deformity have also been reported
● Hence To be avoided in 1st trimester
● Drug is present in breast milk.
● Recommended to discontinue drug or bottle feed
HALOPERIDOL
54. ● No difference in malformation rates, unlikely to be major teratogen
● Placental passage
Olanzapine>Risperidone> Quetiapine
LBW & higher NICU admissions a/w small increased risk in overall malformation
Large HC with Microsomia
● SGA causes
increases in maternal weight gain,
increased risk of Neural tube defects in exposed infants
increased risk of Gestational diabetes
Large-for-gestational age infants
increased risk for C-section delivery
2ND Gen Antipsychotics ( SGA )
Olanzapine>Risperidone>Quetiapine
55. Clozapine
• Should be used with caution as, it may cause Gestational Diabetes, Neonatal Seizures
• SGAs confer less risk for extrapyramidal side effects in the mother
• In a study of 142 pregnancies of largely SGAs,
•
SGA dose 1
Gestational age at birth
● Higher rates of respiratory distress were reported when SGAs were combined with mood
stabilizers.
● Intake of SGA through milk leads to 0.1 to 10 percent maternal dose.
2ND Gen Antipsychotics (SGA)
∝
56. ● SGA +SSRI = Cardiac septal defects
● SGA + MOOD STABILISERS = Increased rates of Respiratory distress
● In SGA exposed 6 month old infants & in mothers with increased severity of maternal
psychiatry history = Lower psychomotor scores on posture, tone reflexes, and motor skills
● psychiatric history.
● There are no data yet available on long-term neurodevelopment of infants with in utero
SGA exposure.
2ND Gen Antipsychotics( SGA )
57. ● Olanzapine relatively safe with respect to congenital
malformation,.
● There is no clustering of congenital malformations.
● Reports of increase in the risk of gestational diabetes.
● Unknown if secreted in human breast milk
● Relatively safe to breast feed- infant to be monitored
OLANZAPINE
58. ● Pregnancy risk Cat-C
● Early findings of infants exposed to risperidone in utero do
not show adverse consequences
● Hyper-prolactinemia effect in foetus not known
● Preferred over mood stabilizers
RISPERIDONE
59. TERATOGEN
ICITY
OBSTETRIC
OUTCOME
LONG TERM
BEHAVIORA
L SEQUELAE
POSTNATAL
SYNDROME
REMARKS
ZIPRASIDON
E
Renal and
cardiac
malformatio
ns in
animals
Still births in
animals
Delayed
developmen
t
No data No human
studies
Best avoided
ARPIPRAZOL
E
Delayed
skeletal
ossification
in animals
LBW in
animals
No data No data No human
studies.
Best avoided
QUETIAPINE Delayed
skeletal
LBW No data No data Best avoided
Placental passage of antipsychotics ----
OLANZAPINE > HALOPERIDOL > RISPERIDONE > QUITIAPINE
In 1ST & 2nd trimester --- Teratogenicity
In 3rd trimester ----- Neonatal Toxicity and withdrawal
EPS is more likely to be caused be FGA > Risperidone > SGA
61. ● FDA pregnancy Cat-D
● Acc to International register on li babies- 11% risk of
major malformations.
● Teratogenic risk 4- 12 %
● Lithium completely equilibrates across the placenta.
● NICE recommends the use of mood stabilising
antipsychotics as a preferable alternative to
continuation with a mood stabiliser
LITHIUM
62. ● Major Anomaly in First trimester - increased risk of a serious congenital
heart defect known as Ebstein’sanomaly, which occurs in approximately 1 out
of 1000 live births.
LITHIUM
63. ● Other ANOMALIES are --
Polyhydromnios
Thyroid abnormalities
Sick sinus syndrome
Floppy baby syndrome
LITHIUM
64. ● The period of maximum risk to the foetus is 2 – 6 weeks after conception.
● The risk of atrial and ventricular septal defects may also be increased
● Anomaly scan at 16- 20 wks.
● NICE recommends Li plasma levels monitoring every 4 weeks until 36 wks &
weekly thereafter
● High doses are required d/t inc GFR with inc plasma volume
● Withholding mat. Li therapy for 24 to 48 hrs prior to delivery is suggested & plasma
levels checked 12 hours after her last dose
LITHIUM
65. ● Lithium has also been associated with perinatal toxicity
Neonatal signs of Li Toxicity------
Muscle flaccidity /Hypotonia
Inhibition of normal neonatal reflexes
Neonatal Goitre
Lethargy and Cyanosis
CVS effects—Atrial flutter,TR ,CHF
LITHIUM
66. LITHIUM
• For women with severe bipolar illness, the risk of recurrence during pregnancy may
overshadow the relatively small risk of Ebstein’s anomaly, then maintenance lithium
therapy during pregnancy may be the most appropriate course.
• On the other hand, for women with significant periods of euthymia and few past mood
episodes, slowly tapering off lithium & reintroducing lithium after the 1st trimester may
decrease the risk of relapse during the postpartum
67. Breastfeeding
● AAP (American academy of pediatrics ) recommends lithium usage in nursing
mothers with caution.
● Li concentration in breast milk 24-72% - lithium is soluble in breast milk.
● Lithium can quickly accumulate in the nursing infant and lead to levels exceeding
50% of the maternal level.
● Given this risk of lithium toxicity in the nursing infant, breastfeeding while on
lithium is generally not recommended
LITHIUM
68. ● Pregnancy CAT-X (contraindicated )
● Use during first trimester may raise the risk of neural tube
defects or other congenital anomalies.
● 1 – 5 % particularly spina bifida.
● other potential teratogenic effects- facial dysmorphism ,
congenital cardiac defects , limb reduction defects.
VALPROATE
71. ● If the drug is continued, monitor clotting parameters and perform tests to detect birth
defects.
● Consider vitamin k during the last 6 weeks of pregnancy to reduce the risk of
bleeding.
● Valproate should generally be discontinued before anticipated pregnancy.
VALPROATE
72. ● Given the risk of relapse in the postpartum period , valproate should generally
be restarted immediately after delivery if patient is unmedicated during
pregnancy.
● Low dose monotherapy is recommended
● NICE guidelines recommends the dose of valproate should be limited to 1000
mg / day.
VALPROATE
73. ● Drug is found in breast milk ,but generally considered safe to breast feed
● If infants shows signs of irritability or sedation, drug may need to be discontinued.
● Valproate safer than lithium in post partum period
● Valproate has been associated with infant anaemia and thrombocytopenia
VALPROATE
Breast feeding
74. CARBAMAZEPINE
• CAT-D
• First trimester - risk of neural tube defects or other congenital anomalies . 0.5-1%
• If the drug is continued , perform tests to detect birth defects.
• Start on folate 1 gm/day early in pregnancy to reduce risk of neural tube defects.
75. CARBAMAZEPINE
• CAT-D
• First trimester - risk of neural tube defects or other congenital anomalies (0.5-1%)
• If the drug is continued , perform tests to detect birth defects.
• Start on folate 1 gm/day early in pregnancy to reduce risk of neural tube defects.
76. ● CBZ should be discontinued before anticipated pregnancy.
● It is a competitive inhibitor of prothrombin precursors and may increase
the risk of neonatal hemorrhage.
● Use of carbamazepine in third trimester may necessitate maternal
vitamin k.
● To be given to mother 20mg of vit k/ day & 1mg after birth to neonate.
● Mild facial abnormalities & others finger nail hypoplasia have
been reported
CARBAMAZEPINE
77. Breast feeding
● Drug is found in breast milk
● Recommended to discontinue drug or bottle feed
● If continued –infant to be monitored for adverse effects.
● If infants show signs of irritability or sedation , drug may need to be
discontinued.
CARBAMAZEPINE
78. • Carbamazepine has been associated with transient hepatic dysfunction
● Some cases of neonatal seizures , respiratory depression , vomiting & diarrhea
have been reported in infants.
● Atypical antipsychotics and anticonvulsants such as valproate may be safer
than carbamazepine during the post partum period when breast feeding.
CARBAMAZEPINE
79. +
● Highly effective mood stabilizer, particularly for bipolar depression.
● According to the manufacturer-sponsored Lamotrigine Pregnancy Registry and other
published studies (Cunnington and Tennis 2005), there appeared to be no increased risk of
congenital defects above the baseline risk with lamotrigine monotherapy
● However, when combined with valproic acid in pregnancy, the risk estimate was found
to be elevated to above 10%.
LAMOTRIGINE
80. ● The North American Antiepileptic Drug Pregnancy Registry recently found that infants
who are exposed to lamotrigine monotherapy during pregnancy have a much higher risk
of oral cleft defects.
● Even if future prospective studies confirm this association between first trimester
lamotrigine use and oral cleft lip and palate, the overall risk appears to be low and may be
overshadowed by the high risk of recurrent illness in some women with bipolar disorder.
● NICE Suggests that lamotrigine should not be routinely prescribed in pregnancy.
LAMOTRIGINE
81. BREASTFEEDING
● Lamotrigine is excreted in breast milk , infant serum levels range from 18% to 50% of
maternal serum levels
● Study done showed no change of electrolyte and hepatic profile , no rash , few had
thrombocytosis
● Because of theoretical risk of life threatening rashes its advisable to avoid lamotrigine
LAMOTRIGINE
82. ● Gabapentin
● Oxcarbazepine
● Topiramate
They have limited reproductive safety data to
guide their use in pregnancy.
NEWER ANTICONVULSANTS
83. Gabapentin
● Risk cat C
● Lack of convincing efficacy for treatment of bipolar disorder suggests risk
benefit ratio in favour of discontinuing gabapentin during pregnancy.
● Gabapentin should generally be avoided before anticipated pregnancy.
84. Oxcarbazepine
● Risk category C
● Oxcarbazepine is structurally similar to carbamazepine
● Use during first trimester may raise the risk of of Neural tube defects or other
congenital anomalies.
NEWER ANTICONVULSANTS
85. Topiramate
● Category C
● Hypospadias has occurred in some male infants whose mother took topiramate in
pregnancy
NEWER ANTICONVULSANTS
86. • There are no adequate and well-controlled studies in pregnant women.
• Lithium may cause Ebstein’s anomaly.
• Carbamazepine is associated with risk to the fetus, including congenital malformations (spinal bifida), and
developmental delays.
• Valproate may produce congenital malformations (e.g., neural tube defects) at a rate higher than other
antiepileptic drugs; other complications include neonatal hepatic failure and hypoglycemia; long-term effects
include low IQ and a greater risk for autism spectrum disorder in children. Valproate should not be used to
treat women with epilepsy who are pregnant or who plan to become pregnant.
• If a woman becomes pregnant while taking trimethadione, termination of the pregnancy should be
considered. Trimethadione and phenytoin may be associated with a neonatal coagulation defect that may
cause bleeding during the early neonatal period (prophylactic Vitamin K may be indicated).
• Prenatal exposure to phenytoin is associated with a greater risk of neuroblastoma.
• Risk of use of this class of medications appears particularly high in the 1st trimester. However, abrupt
discontinuation of antiepileptic drugs in mothers who use them to prevent major seizures should be avoided
Mood stabilisers summary
88. ● Studies of benzodiazepines use during pregnancy have been contradictory and
controversial.
● Benzodiazepine use during pregnancy has been a/w case reports of perinatal
toxicity, including temperature dysregulation, apnea, depressed APGAR
scores, hypotonia, and poor feeding.
BENZODIAZEPINES
89. ● Early studies revealed an elevated risk of oral cleft palate defects compared to
the baseline risk in the general population.
● However, more recent studies have shown that the overall risk of cleft lip and
palate with benzodiazepine use in pregnancy is likely quite low (Iqbal et al.
2002, Lin et al. 2004).
BENZODIAZEPINES
90. ● Benzodiazepines have been associated with pylrostenosis and alimentary tract
atresia
● There is an association between benzodiazepine use and low birth weight
babies.
● Cases of severe neonatal respiratory depression have been reported when Zolpidem
was used at the end of pregnancy, especially when taken with other CNS-depressants
BENZODIAZEPINES
91. ● Diazepam is excreted in breast milk
● Infants serum level vary from undetectable to around 14% of the maternal
serum levels.
● Lorazepam , tenezepam and clonazepam are excreted in small amounts .
● Infants exposed to benzodiazepines should be monitored for CNS depression
and apnoea.
BENZODIAZEPINES ( Breast feeding )
92. • All three are excreted into breast milk in small amounts.
• No adverse effects were noted in exposed infants.
• The manufacturers of zopiclone, zolpidem and zaleplon advise against their use in breast
feeding.
Zopiclone, zolpidem and zaleplon
93. BZD’S TERATOGENICITY OBSTETRC
PROBLEMS
LONG
TERM
NEONATAL
EFFECTS
CONCLUSION
Alprazola
m
PDA, craniofacial
malformations,
pyloricstenosis,
cryptorchidism
No data No data Low
apgar,respiratory
difficulty,jaundice
,hypothermia
Best avoided
Lorazepa
m
Anal atresia No data No data Same as above Best avoided
Clonazpam Congenital HD
Uteropelvic junction
anomalies
No data No data apnea, cyanosis,
hypotonia,
breathing,CNS
depression.
Best avoided
Diazepam Rare cases of cleft lip
and cleft palate
No data No data No significant risks
found
Can be used if
absolutely
necessary
95. ● Psychoanaleptics are psychostimulators which enhance the activity of the CNS.
● The methylxanthines caffeine and theobromine belong to the group of psychoanaleptics.
● The most frequently used analeptics are derivatives of phenylethylamine
● The prototype of this group is amphetamine.
● These drugs are related to the sympathomimetics, enhance mental performance, and repeated use can
lead to addiction.
● Drugs such as amfetaminil, fenethylline, and Methylphenidate and Modafinil
belong to this group
● Sodium oxybate used for narcolepsy with cataplexy
● Pemoline, an oxazolidine, used for attention deficit disorder.
PSYCHOANALEPTICS
96. .
● Acc to Pottegård et al (2014)- no statistically significant increase in major malformations or
cardiac malformations was observed with methylphenidate
● There is one published case report on modafinil exposure during pregnancy which was followed
by the birth of a healthy child (Williams 2008).
• Wajnberg (2011) found no differences compared to a control group in gestational age and birth
weight or the rate of miscarriage. With their increasing use into adulthood for attention deficit
disorder, more exposures in pregnancy are likely to occur.
Recommendation. If stimulants are used during pregnancy, the expected benefit which outweighs
the risk should be documented. The most data are available for methylphenidate
98. ● During pregnancy, anti-Parkinson drugs play a role for restless legs syndrome (RLS).
● This syndrome is related to parity, and its symptoms may worsen during pregnancy.
● Treatment with levodopa or dopamine agonists is the first-line therapy for RLS;
however, there are limited data on treatment in pregnancy. No major birth defects were
found, only minor anomalies in three infants.
● Amantadine is used as an anti- Parkinson drug & is effective as a virus static against
influenza-A viruses. In humans, malformations have been identified in case series &
individual case reports, (Greer 2010).
● Reports on levodopa (L-dopa) in combination with benserazide or carbidopa do not
indicate any prenatal toxicity (e.g. Dostal 2013).
● Case series on pramipexol, provides no indication of teratogenic effects.
● Ropinirole and rotigotine ( Dostal 2013),no major birth defects found
ANTIPARKINSONDRUGS&RESTLESSLEGSYNDROME
99. ● .
● If necessary, levodopa rx may be considered as an alternative to cabergoline, which has substantially more data
for use in pregnancy.
● Other than the dopamine-agonist-acting ergotamine derivatives, which are used as medication for Parkinson’s
Disease are- bromocriptine, cabergoline, α-dihydroergocryptine, lisuride and pergolide. Some of these
drugs are used by women in reproductive age for prolactinomas and associated fertility disorders.
● Anti-Parkinson drugs, which are used for treatment of EPS induced by antipsychotics are: biperiden,
benzatropine, bornaprine, budipin, metixen, piribedil, pridinol, procyclidine, tetrabenazine
● For hyperkinetic movement disorders tiapride & trihexyphenidyl as well as the monoaminoxidase-B-
inhibitors (MAO-B-inhibitors) selegiline & rasagiline.
With the exception of the older ergotamine derivatives, there is minimal experience with most of
these drugs
ANTIPARKINSONDRUGS
100. Recommendation-Treatment with anti-Parkinson drugs may be
necessary during pregnancy; for example, in the context of therapy for
a prolactinoma with ergotamine-derivatives or for extrapyramidal side-
effects of an antipsychotic treatment.
With marked restless-legs symptoms, cabergoline or levodopa are
reasonable choices.
ANTIPARKINSONDRUGS
102. • Thomas Hales’Medicationsand Mothers Milk(2014) now in its 16th edition, has
emerged as the standard reference for lactation safety ratings.
• Hale also used a five-category system, rating medications from L1 (Safest) to L5
(contraindicated).
• Relative infant dose (RID): It is calculated by dividing the totaldaily ingestion of a
medication by an exclusively breastfeed infant (mg/kg infant body weight) by the
mother’s daily dose of the medication. Hale advises that a RID of less than
10% can be considered safe.
MEDICATIONSAFETYPROFILES
105. ● MOST WOMEN ON MEDS CAN
BREASTFEED!!!!!
● Risk of child dying from diarrhoea,
respiratory disease, malnutrition higher than
medication side effects
● Breastfeeding, bedsharing mothers get more
sleep
● Case by case basis
106. ● Antidepressants – generally safe
● Antipsychotics
Infant sedation
Neonatal EPSE
• Mood stabilisers
All present problems
Consider risk benefit carefully
● Lithium
Maternal hydration important
• Anticonvulsant class
Rashes
107. ● Sulpiride, (not approved by US FDA during lactation, but still in use in other countries
including Asia)
● Antipsychotic with theoretical mood elevation properties at low doses
● Side effect of increasing milk supply
● Sedating
● NOT an effective antidepressant
EGLONYL
110. ANTIDEPRESSANTS ANTIPSYCHOTICS
LITHIUM &
OTHER
ANTIMANICS
BZDS &
ZOPICLONE
PSYCHOAN
ALEPTICS
ANTIPARKIN
DRUGS
RX
OF
CHOICE
Psychoth , Light th. &
Acupucture
SERTRALINE
PAROXETINE ,CITALO
AMITRIPTYLINE
NORTRIPTYLINE
(TCAS)
Both typical &
Atypicals can be used
FLUPENTIXOL,PHENAZI
NE HALOPERIDOL
QUITIAPINE,OLANZPIN
E
Li can be
permitted with
monitoring of
infant.
OLANZAPINE
QUITIAPINE
DIPHENHYDRAMINE
(antihistaminic),
LORMETAZEPAM
/TEMAZEPAM
OXAZEPAM,
DIAZEPAM,
ZOPICLONE-Tolerabl
MIDAZOLAM
HYDROXYZINE
Only if
urgently
required
on CASE BY
CASE BASIS
BIPERIDEN ,
BROMOCRIPTINE
&
CARBEGOLINE
TOLERABLE
TO BE
AVOIDED
DOXEPIIN &
FLUOXETINE
All others VALPROIC ACID,
LAMTRGNE,
ASENAPINE
All others Should be
avoided
All others
STABLE
ADJUSTMEN
T
Should not be changed Should not be changed Should not be
changed
Should not be changed Should not
be changed
Should not be
changed
GOAL Low dose
Monotherapy
Case by case basis
-- -- -- -- --
NON-
EXPLAIND
SYMPTMS
More likely d/t Prenatal
Medictn rather than to
medictn in milk
-- -- -- -- --
Recommendations inBreastfeeding
111. • Whenever possible, pregnant patients should be treated with nonpharmacological approaches.
• If psychopharmacological treatment is necessary, the choice of medication should be guided primarily by its
safety data.
• In deciding on the course of treatment, the clinician and patient should engage in a careful risk–benefit
discussion before any medications initiated.
● Important issues to be kept in mind include -Folate supplementation in all women in the reproductive age
group and Planning pregnancies to minimize foetal exposure
• Risks and benefits may change over the course of treatment and should therefore be re-examined periodically.
• Women with mood and anxiety disorders require close monitoring following delivery as they are at risk of
experiencing a post partum relapse or exacerbation of the illness.
• For medications lacking safety data in breast-feeding,- General estimates of the infant’s likely exposure can be
made from the medication’s pharmacokinetic parameters & from blood levels of medication in the infant.
CONCLUSION
112. ● ACOG.Obesityinpregnancy.http://www.acog.org/Resources_And_PublicationCommittee_Opinions/Committee_on_Obstetric_Pra
ctice/Obesity_in_Pregnancy, 2013.
● Aichhorn W, Yazdi K, Kralovec K et al. Olanzapine plasma concentration in a newborn. J Psychopharmacol 2008; 22: 923–4.
● Alwan S, Reefhuis J, Botto LD et al. Maternal use of bupropion and risk for congenital heart defects. Am J Obstet Gynecol 2010;
203: 52–6.
● Alwan S, Reefhuis J, Rasmussen SA et al. National Birth Defects Prevention Study: Use of selective serotonin-reuptake inhibitors in
pregnancy and the risk of birth defects. N Engl J Med 2007; 356: 2684–92.
● Alwan S, Reefhuis J, Rasmussen SA et al. National Birth Defects Prevention Study: Patterns of antidepressant medication use
among pregnant women in a United States population. J Clin Pharmacol 2011; 51: 264–70.
● Anderson IM. Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. J
Affect Disord 2000; 58: 19–36.
● Andrade SE, McPhillips H, Loren D et al. Antidepressant medication use and risk of persistent pulmonary hypertension of the
newborn. Pharmacoepidemiol Drug Saf 2009; 18: 246–52.
IMPORTANTSOURCES
• Kaplan and Sadock's Comprehensive Textbook of Psychiatry 11th edition.
• The Maudsley Prescribing Guidelines in Psychiatry, 13th edition.
• Drugs During Pregnancy and Lactation ;Treatment Options and Risk Assessment 3rd edition.
• Psychiatric Disorders in Pregnancy and the Postpartum, Principles and treatment;edited by Victoria Hendrick MD; OliveView-UCLA
Medical centre Sylmar CA.
113. CONTENTS
OF
THIS
TEMPLATE
• Draft Guidance for Industry: Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription Drug and Biological
Products — Content and Format http://www.fda.gov/downloads/drugs/guidancecomplianc
eregulatoryinformation/guidances/ucm425398.pdf
• Pregnancy and Lactation Labeling Final Rule http://www.fda.gov/Drugs/DevelopmentApprovalProcess/
DevelopmentResources/Labeling/ucm093307.htm
• Physician’s Labeling Rule Requirements for Prescribing Information http://www.fda.gov/Drugs/GuidanceComplianceRegulatory
Information/LawsActsandRules/ucm084159
IMPORTANTSOURCES
• Bergink V, Bouvy PF, Vervoort JS et al. Prevention of postpartum psychosis and mania in women at high risk. Am J Psychiatry
2012; 169: 609–15.
• Blencowe H, Cousens S, Modell B et al. Folic acid to reduce neonatal mortality from neural tube disorders. Int J Epidemiol 2010;
39: i110–21.
• Bodén R, Lundgren M, Brandt L et al. Antipsychotics during pregnancy: relation to fetal and maternal metabolic effects. Arch Gen
Psychiat 2012a; 69: 715–21.
• Bodén R, Lundgren M, Brandt L et al. Risks of adverse pregnancy and birth outcomes in women treated or not treated with mood
stabilisers for bipolar disorder: population based cohort study. BMJ 2012b; 345: e7085.
• Dostal M, Weber-Schoendorfer C, Sobesky J, Schaefer C. Pregnancy outcome following use of levodopa, pramipexole, ropinirole and
rotigotine for restless legs syndrome during pregnancy: a case series. Eur J Neurol 2013; 20: 1241–6.
• Dubnov-Raz G, Juurlink DN, Fogelman R et al. Antenatal use of selective serotonin-reuptake inhibitors and QT interval prolongation
in newborns. Pediatrics 2008; 122: e710–5.
• Duijvestijn YCM, Kalmeijer MD, Passier ALM et al. Neonatal intraventricular haemorrhage associated with maternal use of
paroxetine. Br J Clin Pharmacol 2003; 56: 581–2.
• Dunkel Schetter C, Tanner L. Anxiety, depression and stress in pregnancy: implications for mothers, children, research, and practice.
Curr Opin Psychiatry 2012; 20: 141–8
114. • Weissman, M. M. and Jensen, P. (2002) What research suggests for depressed women with children. J. Clin. Psychiatry 63, 641–647.
• Stevens, J. R. (2002) Schizophrenia: reproductive hormones and the brain. Am. J.Psychiatry 159, 713–719.
• Suppes, T., Dennehy, E. B., and Gibbons, E. W. (2000) The longitudinal course ofbipolar disorder. J. Clin. Psychiatry 61 Suppl 9, 23–30.
• Altshuler, L. L., Hendrick, V., and Cohen L. (1998) Course of mood and anxietydisorders during pregnancy and the postpartum period. J. Clin. Psychiatry 59, 29–
33.
• Creasy, R. K. and Resnik, R. (1994) Maternal-Fetal Medicine: Principles and Practice, 3rd ed. Philadelphia, WB Saunders, pp. 96–97.
• Hernandez-Diaz, S., Werler, M. M., Walker, A. M., et al. (2000) Folic acidantagonists during pregnancy and the risk of birth defects. N. Engl. J. Med. 343,1608–
1614.
• Kessler, R. C., McGonagle, K. A., Zhao, S., et al. (1994) Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: results from
the National Comorbidity Survey. Arch. Gen. Psychiatry 51, 8–19.
• Tardieu, S., Micallef, J., Gentile, S., et al. (2003) Weight gain profiles of new antipsychotics:public health consequences. Obes. Rev. 4,129–138.
• Koren, G, Cohn, T., Chitayat D., et al. (2002) Use of atypical antipsychotics during pregnancy and the risk of neural tube defects in infants. Am. J. Psychiatry
159,136–137.
• Moos, M. K. (2003) Unintended pregnancies: a call for nursing action. MCN Am.J. Matern. Child Nurs. 28, 24–30.
• Coverdale, J., Aruffo, J., and Grunebaum, H. (1992) Developing family planning services for female chronic mentally ill outpatients. Hosp.
Commun. Psychiatry 43, 475–478.
• Altshuler, L. L. and Hendrick, V. (1996) Pregnancy and psychotropic medication:changes in blood levels. J. Clin. Psychopharmacol. 16,78–80.
• Schwartz, J. B. (2003) The influence of sex on pharmacokinetics. Clin. Pharmacokinet. 42, 107–121.
• Meibohm, B., Beierle, I., and Derendorf, H. (2002) How important are gender differences in pharmacokinetics? Clin. Pharmacokinet.41,329-342.
• Hagg, S., Spigset, O., and Dahlqvist, R. (2001) Influence of gender and oral contraceptives on CYP2D6 and CYP2C19 activity in healthy
volunteers. Br. J. Clin.Pharmacol. 51, 169–173.
• Wadelius, M., Darj, E., Frenne, G., et al (1997) Induction of CYP2D6 in pregnancy.Clin. Pharmacol. Ther. 62, 400–407.
IMPORTANTSOURCES
115. • Zaigler, M., Rietbrock, S., Szymanski, J., et al (2000) Variation of CYP1A2-dependent caffeine metabolism during menstrual cycle in healthy women. Int. J.Clin.
Pharmacol. Ther. 38, 235–244.
• McCune, J. S., Lindley, C., Decker, J. L., et al (2001) Lack of gender differences and large intrasubject variability in cytochrome P450 activity measured by
phenotyping with dextromethorphan. J Clin. Pharmacol. 41, 723–731
• Costei, A. M., Kozer, E., Ho, T., et al. (2002) Perinatal outcome following third trimester exposure to paroxetine. Arch. Pediatr. Adolesc. Med. 156, 1129–1132
• Cohen, L. S., Heller, V. L., Bailey, J. W., et al. (2000) Birth outcomes following
• prenatal exposure to fluoxetine. Biol. Psychiatry 48, 996–1000.
• Swortfiguer, D., Cissoko, H., Giraudeau, B., et al (2005) Neonatal consequences of benzodiazepines used during the last month of pregnancy. Arch. Pediatr.
[Epubahead of print]
• Miller, L. J. (2002) Postpartum depression. JAMA 287:762–765.
• Grace, S. L., Evindar, A., and Stewart D. E. (2003) The effect of postpartumdepression on child cognitive development and behavior: a review and critical
analysis of the literature. Arch. Women Ment. Health 6, 263–274.
• Howard, L., Hoffbrand, S., Henshaw, C., et al. (2005) Antidepressant prevention of postnatal depression. Cochrane Database Syst. Rev. 2, CD004363.
• Abernathy, D. R., Greenblatt, D. R., Divoll M., et al. (1982) Impairment of diazepam metabolism by low-dose estrogen-containing oral-contraceptive steroids.
N.Engl. J. Med. 306, 791–792.
• Abernathy, D. R., Greenblatt, D. J., and Shader, R. I. (1984) Imipramine disposition in users of oral contraceptive steroids. Clin. Pharmacol. Ther. 35, 792–797.
• Sabers, A., Buchholt, J. M., Uldall, P., and Hansen, E. L. (2001) Lamotrigine plasma levels reduced by oral contraceptives. Epilepsy Res. 47, 151–154.
• Doose, D. R., Wang, S. S., Padmanabhan, M., et al. (2003) Effect of topiramate or carbamazepine on the pharmacokinetics of an oral contraceptive containing
norethindrone and ethinyl estradiol in healthy obese and nonobese female subjects.Epilepsia 44, 540–549.
• Hendrick, V., Stowe Z. N., Altshuler, L. L., et al.(2001) Fluoxetine and norfluoxetine concentrations in nursing infants and breast milk. Biol. Psychiatry 50, 775–
782.
IMPORTANTSOURCES
