Antidepressants During Pregnancy and Breastfeeding

A MEDLINE Search by, Ivan Goldberg, MD

1: Am J Psychiatry. 1996 May;153(5):592-606.

Comment in:
Am J Psychiatry. 1997 May;154(5):718-9.

Pharmacologic management of psychiatric illness during pregnancy: dilemmas and

Altshuler LL, Cohen L, Szuba MP, Burt VK, Gitlin M, Mintz J.

UCLA Neuropsychiatric Hospital, USA.

OBJECTIVE: Given concerns about use of psychotropic medication during pregnancy,
the authors reviewed the literature regarding the effects of prenatal exposure
to psychotropic medications on fetal outcome. METHOD: A MEDLINE search of all
articles written in English from 1966 to 1995 was performed to review
information on the effects of psychotropic drug use during pregnancy on fetal
outcome. Where sufficient data were available and when methodologically
appropriate, meta-analyses were performed to assess risk of fetal exposure by
psychotropic medication class. RESULTS: Three primary effects are associated
with medication use during pregnancy: 1) teratogenicity, 2) perinatal syndromes
(neonatal toxicity), and 3) postnatal behavioral sequelae. For many drug classes
there are substantial data regarding risk for teratogenicity. Tricyclic
antidepressants do not seem to confer increased risk for organ dysgenesis. The
available data indicate that first-trimester exposure to low-potency
phenothiazines, lithium, certain anticonvulsants, and benzodiazepines may
increase the relative risk for congenital anomalies. However, the absolute risk
of congenital malformations following prenatal exposure to most psychotropics is
low. CONCLUSION: Exposure to certain psychotropic drugs in utero may increase
the risk for some specific congenital anomalies, but the rate of occurrence of
these anomalies even with the increased risk remains low. Use of psychotropic
medications during pregnancy is appropriate in many clinical situations and
should include thoughtful weighing of risk of prenatal exposure versus risk of
relapse following drug discontinuation. The authors present disorder-based
guidelines for psychotropic drug use during pregnancy and for psychiatrically
ill women who wish to conceive.

Publication Types:

PMID: 8615404 [PubMed – indexed for MEDLINE]


2: Isr J Psychiatry Relat Sci. 2000;37(3):205-22.

The use of psychiatric drugs in pregnancy and lactation.

Arnon J, Shechtman S, Ornoy A.

Dept. of Anatomy and Cell Biology, Hebrew University, Hadassah Medical School,
Jerusalem, Israel.

To help determine which drugs can be used with relative safety during pregnancy,
we reviewed the literature on the possible teratogenic, perinatal, behavioral or
developmental effects of the various groups of commonly used psychiatric drugs,
and their effects on lactation. Tricyclic antidepressants, fluoxetine,
phenothiazines, and most benzodiazepines are not considered to be teratogenic
and may be used during pregnancy. All anti-epileptic drugs seem to have an
embryotoxic and teratogenic potential and we recommend, if possible, avoiding
these drugs. Lithium administration during the first trimester of pregnancy
increases the risk of cardiac malformations, but the risk is not as high as
originally reported. Therefore lithium may be continued whenever it seems to be
the “drug of choice” if fetal echocardiography and ultrasonography are
performed. There is a lack of information on the teratogenic effect of the newer
drugs, and in spite of the fact that similar “older” drugs do not seem to
adversely affect the fetus, they should be used with care. Although the data on
the development of children following in-utero exposure to psychiatric drugs is
limited, there seems to be no evidence of any long-term adverse effects on the
development of children exposed to most psychotropic medications. However,
children exposed in utero to anti-epileptic drugs may exhibit long-term
developmental problems. Most of the drugs are detected in breast milk only at
low concentrations. In nursing women taking these drugs, breastfeeding is
possible. The infant should be carefully monitored for any clinical side effects
and whenever observed, nursing should be discontinued. In light of our knowledge
today, there seems to be only rarely an indication for pregnancy interruption
following maternal exposure to psychiatric drugs during pregnancy.

Publication Types:
Review, Tutorial

PMID: 11084808 [PubMed – indexed for MEDLINE]


3: Aust N Z J Psychiatry. 1998 Dec;32(6):778-84.

Use of psychotropic medications in breast-feeding women: acute and prophylactic

Austin MP, Mitchell PB.

Department of Liaison Psychiatry, Prince of Wales Hospital, Randwick, NSW,

OBJECTIVES: The postnatal period is a time of increased onset and relapse of
mental illness. It poses a clinical dilemma, as many mothers requiring
medication acutely or prophylactically will also choose to breast feed. The
present paper first reviews the safety of psychotropes in breast-fed infants and
the usefulness of prophylaxis for women at risk of postpartum affective relapse
and, second, provides guidelines in the use of psychotropic drugs in
breast-feeding women. METHODS: A Medline review was conducted reviewing all
papers published during the period 1993-1998 (and their associated
bibliographies) on the use of psychotropes in breast-feeding women and the
prophylactic usefulness of medications in women at risk of affective postpartum
relapse. RESULTS: Findings are based on case reports and small, mostly
uncontrolled studies. Both tricyclic antidepressants (TCA) and specific
serotonin re-uptake inhibitors (SSRIs) appear to be relatively safe in breast
feeding. Antidepressants commenced in the early postpartum period may reduce
depressive relapse. While prophylactic lithium appears to significantly reduce
relapse of affective psychosis in the puerperium, there have been no studies of
the anticonvulsants in the puerperium. Finally, high dose antipsychotics should
be avoided, as they may be associated with long-term adverse sequelae in the
infant. CONCLUSIONS: On the basis of current knowledge, the use of SSRIs, TCA,
carbamazepine, sodium valproate and short-acting benzodiazepines in breast
feeding is relatively safe. If lithium is to be used, close collaboration with a
paediatrician is essential. The long-term risks of antipsychotics, especially at
high doses, remain to be clarified. Before a decision can be made, the
risk-benefit ratio must be clearly outlined and discussed with the mother and
her partner.

Publication Types:
Review, Tutorial

PMID: 10084341 [PubMed – indexed for MEDLINE]


4: Med J Aust. 1998 Oct 19;169(8):428-31.

Psychotropic medications in pregnant women: treatment dilemmas.

Austin MP, Mitchell PB.

Prince of Wales Hospital, Sydney, NSW.

OBJECTIVES: To review the evidence from all studies of adverse effects on infant
outcome of psychotropic medications taken during pregnancy. DATA SOURCES:
MEDLINE January 1976-February 1998, EMBASE 1976-February 1998, and
bibliographies of retrieved articles. STUDY SELECTION AND DATA EXTRACTION: All
studies focusing on adverse effects associated with psychotropic drug use during
pregnancy, with a particular focus on prospective controlled studies. OUTCOME
CRITERIA: Congenital anomalies, perinatal complications and neurobehavioural
sequelae. DATA SYNTHESIS: 23 studies were identified, nine of which were
prospective controlled studies: five involving antidepressants (tricyclic
antidepressants [TCAs] and selective serotonin reuptake inhibitors [SSRIs]), one
each involving lithium and carbamazepine, and two involving benzodiazepines. As
statistical synthesis was not possible given the heterogeneity of outcome
criteria, a qualitative review is provided. Neither the SSRIs nor the TCAs
appear to cause major congenital anomalies, but both may be associated with a
small increased risk of minor anomalies, prematurity and neonatal complications.
Benzodiazepines, lithium, anticonvulsants and chlorpromazine do lead to an
increased rate of congenital anomalies as well as neonatal problems. Studies of
longer-term neurobehavioural sequelae of psychotropic medications are very
limited, but at present do not indicate any adverse effects. CONCLUSIONS: While
some psychotropes are associated with congenital anomalies and perinatal
complications, mental illness per se may also be associated with an adverse
outcome in the infant. Clearly, the risks to both mother and infant need to be
carefully weighed and discussed with the parents.

Publication Types:
Review, Tutorial

PMID: 9830392 [PubMed – indexed for MEDLINE]


5: J Clin Psychiatry. 2002 Oct;63(10):910-1.

Serum bupropion levels in 2 breastfeeding mother-infant pairs.

Baab SW, Peindl KS, Piontek CM, Wisner KL.

Frances Payne Bolton School of Nursing, Case Western Reserve University School
of Medicine, Cleveland, Ohio 44106, USA.

BACKGROUND: These are the first reported data on bupropion and hydroxybupropion
levels in infants whose treated mothers were breastfeeding. The information will
assist physicians and parents in the risk-benefit decision-making process for
bupropion treatment during breastfeeding. METHOD: Serum samples were obtained by
venipuncture from 2 mother-infant pairs. The serum was assayed for levels of
bupropion and its most active metabolite, hydroxybupropion. RESULTS: Neither
infant had quantifiable serum levels of bupropion or its metabolite at steady
state. Neither infant had medical problems during the time of maternal therapy.
CONCLUSION: We recommend obtaining and publishing additional serum level
findings for breastfeeding mother-infant pairs since data for bupropion are
favorable but limited.

PMID: 12416600 [PubMed – indexed for MEDLINE]


6: Harv Rev Psychiatry. 1996 Sep-Oct;4(3):117-25.

Selective serotonin-reuptake inhibitors in pregnancy and lactation.

Baum AL, Misri S.

Fairfax Hospital, Georgetown University, Falls Church, Va., USA.

We explore the effects on the developing fetus and neonate of selective
serotonin-reuptake inhibitors (SSRIs) during pregnancy and lactation, reviewing
the relevant animal and human studies published in English from 1976 to the
present. Medline was used to search the terms SSRI, fluoxetine, pregnancy,
lactation, and teratogenesis. Animal studies were inconclusive: some found that
fetal exposure to high doses of fluoxetine produced no congenital anomalies,
while others linked the drug to abnormalities such as craniofacial
malformations, alterations in serotonergic neurotransmitter systems,
birth-related hematomas, and inhibition of the milk-ejection reflex. Human
investigations indicated no relationship between in utero exposure to fluoxetine
and teratogenic effects, although data are limited, and none have been collected
regarding behavioral teratogenesis. However, we found a suggestion of an
increased rate of miscarriage, an association with infants large for gestational
age, one reported case of perinatal toxicity, and one case of an infant who was
colicky while receiving breast milk from a mother taking fluoxetine. Based on
these data, controlled prospective studies of exposure to SSRIs during pregnancy
and lactation are needed, as is long-term evaluation for behavioral
teratogenesis and enduring cognitive effects. Data are lacking on drug levels in
breast milk and neonatal serum. Neonatal toxicity and the effect of SSRIs on
labor and delivery, the mother-infant interaction, and lactation also merit
further study. Clinically, a conservative approach is encouraged, minimizing the
use of SSRIs in pregnancy, avoiding such drugs during the first trimester,
tapering them prior to delivery, and discouraging breast-feeding during their

Publication Types:
Review, Tutorial

PMID: 9384984 [PubMed – indexed for MEDLINE]


7: Prim. Care Update Ob Gyns. 2000 May 1;7(3):113-117.

When and how to use mood stabilizers during breastfeeding.

Chaudron LH.

William S Middleton Memorial Veteran’s Administration Hospital and University of
Wisconsin Medical School, Madison, Wisconsin, USA

For many women with bipolar disorder, treatment with mood stabilizers is
indicated to decrease the risk of a recurrence of depression, mania, or
psychosis during the postpartum period. Because breastfeeding during this time
exposes infants to these medications, a risk-benefit analysis is crucial for the
mother and her physician when deciding whether to breastfeed. This article
reviews the risks and benefits to mothers and nursing infants with regard to
untreated mental illness, breastfeeding, and medication exposure during
breastfeeding. Reports of breast milk and infant serum drug concentrations are
summarized. Adverse events reported with lithium, valproate, and carbamazepine
are also described. The current available data and their limitations are further
summarized to allow physicians to assess more accurately the risks and benefits
of the use of mood stabilizers during breastfeeding. Finally, a list of
practical recommendations is provided.

PMID: 10840214 [PubMed – as supplied by publisher]


8: J Clin Psychiatry. 2000 Feb;61(2):79-90.

Mood stabilizers during breastfeeding: a review.

Chaudron LH, Jefferson JW.

William S. Middleton Memorial Veterans Affairs Hospital and the University of
Wisconsin Medical School, USA.

BACKGROUND: The postpartum period is an exceptionally high-risk time for
recurrence of depression, mania, or psychosis for women with bipolar disorder.
Puerperal prophylaxis with mood stabilizers decreases this risk. To allow
patients and clinicians to make informed decisions about mood-stabilizer use
during breastfeeding, there is a need for a critical review and analysis of the
data. DATA SOURCES: A search of MEDLINE (1966-1998) and the Lithium Database,
Madison Institute of Medicine, was conducted to obtain articles about lithium,
valproate, carbamazepine, gabapentin, or lamotrigine use during lactation.
Search terms used were pregnancy, teratogenesis, breastfeeding, lactation,
breast milk levels and lithium, anticonvulsants, mood stabilizers. No other
search restrictions were used. Unpublished data on gabapentin and lamotrigine
were provided by the manufacturers. RESULTS: The search revealed 11 cases of
lithium use during breastfeeding, 8 of which reported infant serum levels. Two
cases reported symptoms consistent with lithium toxicity in the infants.
Thirty-nine cases of valproate use during breastfeeding were found, 8 of which
reported infant serum levels. There was 1 report of thrombocytopenia and anemia
in an infant. Fifty cases of carbamazepine use during breastfeeding were found,
10 of which reported infant serum levels. Two infants experienced hepatic
dysfunction. One unpublished study of gabapentin in breast milk was found. Three
reports of lamotrigine use during breastfeeding were found. DISCUSSION:
Available information remains limited to uncontrolled studies and case reports.
Carbamazepine and valproate, but not lithium, have generally been considered
compatible with breastfeeding. The overall paucity of data, data confounded by
polypharmacy and infant age differences, and adverse reactions reported with all
established mood stabilizers dictate a reassessment of these recommendations. We
propose that a woman’s historical response to medication and the clinical
circumstances be the primary considerations when choosing a mood stabilizer
during breastfeeding, rather than strict adherence to categorical assignments.

Publication Types:
Review, Tutorial

PMID: 10732654 [PubMed – indexed for MEDLINE]


9: Drug Saf. 1997 Aug;17(2):127-42.

A guide to the safety of CNS-active agents during breastfeeding.

Chisholm CA, Kuller JA.

Department of Obstetrics and Gynecology, University of Virginia Health Sciences
Center, Charlottesville, USA.

For most agents with CNS activity, there are limited data regarding their safety
in breastfeeding. Any decision to institute treatment for a neurological or
psychiatric disorder must weigh the benefits of maternal treatment against the
potential harm to the breastfeeding mother of withholding medication which may
improve her illness. For the neonate, one must balance the risk of medication
exposure against the benefit of receiving breast milk. Most tricyclic
antidepressants can be used in lactating women. Because of the limited data,
selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors should only
be used with due consideration of the potential adverse effects. Breastfeeding
is best avoided by women who require lithium therapy, because of both the
immature excretory systems in the infant and relatively high doses received by
the infant. There is little information about the safety of antipsychotic
medications in breastfeeding. Concerns include toxicity and abnormal
neurological development in the infant. These agents may be used with caution.
Most agents which cause depression of the CNS, including opiates and sedatives,
can be used in small doses and for short courses in breastfeeding mothers. Most
anticonvulsants can be used in lactating women. Reference texts and consultation
with experts are useful adjuncts to discussion of the risks and benefits of
therapy with the patient. The scope of this review is limited to drugs with
therapeutic uses, thus drugs of abuse are not discussed, nor are caffeine and
alcohol (ethanol).

Publication Types:
Review, Tutorial

PMID: 9285203 [PubMed – indexed for MEDLINE]


10: J Clin Psychiatry. 1998;59 Suppl 2:18-28.

Psychotropic drug use during pregnancy: weighing the risks.

Cohen LS, Rosenbaum JF.

Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.

Although psychotropic drugs have not been tested or approved by the Food and
Drug Administration for use during pregnancy, some women continue to take these
medications while they are pregnant, particularly since mood and anxiety
disorders cluster in women during childbearing years. The relative risks and
benefits of drug therapy for these women must be weighed with each patient and
treatment limited to those situations in which risks to mother and fetus from
the disorder are presumed to exceed the risk of drug treatment. Risks of
psychotropic drug use during pregnancy include teratogenic effects, direct
neonatal toxicity, and the potential for longer term neurobehavioral sequelae.
Of growing concern is the risk of untreated psychiatric disorder as it may
potentially affect fetoplacental integrity and fetal central nervous system
development. Coordination of care with the patient, her husband or partner, and
the obstetrician is essential, as is careful medical record documentation when
treating pregnant patients with psychiatric disorders.

Publication Types:
Review, Tutorial

PMID: 9559756 [PubMed – indexed for MEDLINE]


11: Rev Med Brux. 2001 Sep;22(4):A264-6.

[Neuropsychiatric drugs during pregnancy] [Article in French]

Doehaerd S.

Service de Psychiatrie, C.H. F. Rabelais, Site Cesar De Paepe 2000, U.L.B.

As studies concerning the innocuousness of neuropsychiatic drugs during
pregnancy are sometimes contradictory and difficult to interpret, the guiding
line to follow is that the risk incurred by the foetus must be inferior to that
of an untreated maternal pathology. Categories such as “anticonvulsivants”,
benzodiazepins or lithium may increase, particularly during the first term, the
risk of some malformations. IMAOs and psychostimulants are to be avoided. As for
antidepressants, some SSRIs such as fluotexin or citalopram will be preferred as
far as possible. Neuroleptics will only be continued in case of major
depressions and in small quantities. Exposure to some categories of drugs in the
third term will mainly lead to neonatal symptoms. Finally, the importance of
psychological or psychiatric support must be stressed throughout pregnancy.

PMID: 11680186 [PubMed – indexed for MEDLINE]


12: Am J Psychiatry. 2001 Oct;158(10):1728-30.

Pregnancy outcome following gestational exposure to venlafaxine: a multicenter
prospective controlled study.

Einarson A, Fatoye B, Sarkar M, Lavigne SV, Brochu J, Chambers C, Mastroiacovo
P, Addis A, Matsui D, Schuler L, Einarson TR, Koren G.

The Motherisk Program, The Hospital for Sick Children, University of Toronto,
Ontario, Canada.

OBJECTIVE: Because there are no studies available on the safety of venlafaxine
during pregnancy, the authors’ goal in this study was to determine whether
venlafaxine increases the risk for major malformations. METHOD: Data on 150
women exposed to venlafaxine during pregnancy in seven pregnancy counseling
centers were compared with data from studies of pregnant women who 1) received
selective serotonin reuptake inhibitor antidepressants (SSRIs) (N=150) and 2)
who received nonteratogenic drugs (N=150). RESULTS: Among the 150 women who were
exposed to venlafaxine during pregnancy, 125 had live births, 18 had spontaneous
abortions, and seven had therapeutic abortions; two of the babies had major
malformations. There were no significant differences between these women and the
two comparison groups on any of the measures analyzed. CONCLUSIONS: These
results suggest that the use of venlafaxine during pregnancy does not increase
the rates of major malformations above the baseline rate of 1%-3%.

Publication Types:
Multicenter Study

PMID: 11579012 [PubMed – indexed for MEDLINE]


13: Acta Psychiatr Scand Suppl. 2000;403:26-34.

Tricyclic antidepressants and selective serotonin reuptake inhibitors: use
during pregnancy, in children/adolescents and in the elderly.

Emslie G, Judge R.

The University of Texas, Southwestern Medical Center at Dallas, USA.

OBJECTIVE: Depressive disorders can occur at any point in the lifespan. One way
of differentiating antidepressants is by examining their efficacy and safety in
the special patient populations that exist along the lifespan. Thus, we examine
clinical data that is available regarding the use of selective serotonin
reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) at three
distinct points in the lifespan: childhood and adolescence, pregnancy and late
adulthood. METHOD: Literature regarding the use of antidepressants in children
and adolescents, pregnancy and the elderly was reviewed. RESULTS: Clinical data
suggest that SSRIs should be first line treatment in children and adolescents as
TCAs have questionable efficacy and definite safety issues. Similarly, although
TCAs and SSRIs show equivalent efficacy in elderly patients, the safety profile
of the SSRIs makes them a more prudent choice in this population. Finally,
although there is no definitive data that contraindicates the use of a
particular antidepressant in pregnancy, the bulk of reassuring pregnancy outcome
data exists for the SSRIs, specifically for fluoxetine. CONCLUSION: Although no
single antidepressant can ever be recommended for every patient, SSRIs should be
considered the first-line choice in the treatment of depression in special
patient populations.

Publication Types:
Review, Tutorial

PMID: 11019932 [PubMed – indexed for MEDLINE]


14: Am J Psychiatry. 2001 Oct;158(10):1631-7.

Comment in:
Am J Psychiatry. 2001 Oct;158(10):1555-7.

Maternal sertraline treatment and serotonin transport in breast-feeding
mother-infant pairs.

Epperson N, Czarkowski KA, Ward-O’Brien D, Weiss E, Gueorguieva R, Jatlow P,
Anderson GM.

Department of Psychiatry, Yale University School of Medicine, New Haven, CT
06511, USA.

OBJECTIVE: Pharmacological treatment of postpartum depression is frequently
complicated by the mother’s desire to breast-feed. Although breast milk levels
of several selective serotonin reuptake inhibitors (SSRIs) have been reported to
be relatively low, a critical question is whether SSRI exposure during nursing
results in clinically significant blockade of serotonin (5-HT) reuptake in
infants. This study determined the degree of transporter blockade in infants
exposed to sertraline through maternal breast milk. METHOD: The extent of
maternal and infant transporter blockade was assessed by measurement of platelet
levels of 5-HT in 14 breast-feeding mother-infant pairs before and after 6-16
weeks of maternal treatment with sertraline for major depression with postpartum
onset. Plasma sertraline and desmethylsertraline levels were obtained in 13 of
these mothers and 11 of their infants. RESULTS: Marked declines in platelet 5-HT
levels of 70%-96% were observed in mothers after sertraline treatment, 25-200
mg/day. In contrast, infants showed little or no change in platelet 5-HT levels
after exposure through breast-feeding. Mean levels of maternal plasma sertraline
and its major metabolite, desmethylsertraline, were 30.7 ng/ml and 45.3 ng/ml,
respectively. Drug and drug metabolite concentrations in the infants were at or
below the lower limit of quantitation. CONCLUSIONS: The data indicate that while
mothers receiving clinical doses of sertraline experience substantial blockade
of the platelet 5-HT transporter, platelet 5-HT uptake in nursing infants of
treated mothers is unaltered. The observations suggest that mothers taking
sertraline can breast-feed without appreciably affecting peripheral or central
5-HT transport in their infants.

PMID: 11578995 [PubMed – indexed for MEDLINE]


15: Eur J Clin Pharmacol. 1999 Sep;55(7):503-8.

Delivery outcome after the use of antidepressants in early pregnancy.

Ericson A, Kallen B, Wiholm B.

Centre for Epidemiology, National Board of Health, Stockholm, Sweden.

OBJECTIVES: To investigate delivery outcome after the use of antidepressants in
early pregnancy.METHODS: Using an ongoing prospective recording of drug use in
early pregnancy, 969 women were identified who reported the use of
antidepressants: 531 used only SSRI (selective serotonin re-uptake inhibitor)
drugs (mostly citalopram, 375 exposures), 423 used only other antidepressants,
and 15 used both. Outcome was compared with all births in the population.
RESULTS: Women using these drugs were older and smoked more than three times as
often as other women. There seemed to be an excess of high parity women. The
frequency of multiple births was lower than expected, resulting from too few
twin births in women who had used SSRI. Gestational duration among singletons
was shorter but it did not affect infant survival and was similar after the use
of SSRI or non-SSRI antidepressants, perhaps the result of uncompensated for
confounding or related to the underlying disease. Infants were somewhat heavier
than expected, notably after non-SSRI treatment. No increase was seen in
congenital abnormalities, observable in the perinatal period.CONCLUSIONS: Based
on this database, the use of antidepressants in early pregnancy does not seem to
carry any significant risk for the infant that is detectable during the newborn

PMID: 10501819 [PubMed – indexed for MEDLINE]


16: J Clin Psychiatry. 2002;63 Suppl 4:42-55.

The reproductive safety profile of mood stabilizers, atypical antipsychotics,
and broad-spectrum psychotropics.

Ernst CL, Goldberg JF.

Department of Medicine, Cambridge Hospital-Harvard Medical School, Mass, USA.

There has been growing concern about the potential iatrogenic effects of several
newer psychotropic drugs on reproductive health safety in women. Areas of
particular concern in this regard include (1) controversies about a potential
association between the use of valproate and development of polycystic ovary
syndrome (PCOS), (2) the safety of use of newer psychotropic medications during
pregnancy, and (3) safety issues with these medications in women while
breastfeeding. This review summarizes current information about each of these
areas. In particular, existing data suggest that (1) PCOS very likely represents
a complex neuroendocrine disorder with multiple determinants; (2) menstrual
irregularities may be a frequently seen phenomenon in women with bipolar
illness, at least partially independent of psychotropic drug therapy; (3)
potential central nervous system teratogenicity remains substantial during
first-trimester exposure to valproate or carbamazepine; (4) with newer agents
used for bipolar disorder and schizophrenia, safety data during pregnancy, while
not definitive, are most abundant with olanzapine and with lamotrigine;
relatively less is known about systematic pregnancy outcomes with other atypical
antipsychotics or newer anticonvulsants; and (5) risks for neonatal safety
during lactation continue to appear substantial with lithium, are of potential
concern with lamotrigine and clozapine, are quite likely minimal with valproate
or carbamazepine, and are indeterminate with most other new anticonvulsants or
atypical antipsychotics. Recommendations are presented for clinical management
in each of these instances.

Publication Types:
Review, Tutorial

PMID: 11913676 [PubMed – indexed for MEDLINE]


17: Vet Hum Toxicol. 1997 Apr;39(2):92-3.

Neonatal lithium toxicity as a result of maternal toxicity.

Flaherty B, Krenzelok EP.

Pittsburgh Poison Center, Children’s Hospital of Pittsburgh, PA 15213, USA.

Lithium carbonate is used for the treatment of bipolar disorder. Because of its
widespread use, many women of childbearing age are taking lithium carbonate,
which belongs to the US FDA Category D. Administration during pregnancy can
result in fetal toxicity. A 17-y-old female with pre-eclampsia and a history of
manic depression gave birth to an infant at 37-w gestational age. Several hours
prior to delivery, the mother had a lithium level of 2.6 mEq/L. The infant’s
initial lithium level after birth was 2.1 mEq/L. A subsequent lithium level on
the 3rd d of the child’s life was 1.4 mEq/L; the half-life in the infant was >
24 h. During the first 4 d of life, the infant was lethargic and exhibited poor
suck-swallow coordination that required supplemental enteral feeding. By the 7th
d of life, the infant was alert and tolerating all oral feedings. Lithium
carbonate readily crosses the placental barrier and can produce teratogenic
effects and toxicity. Neonates exposed in utero should be carefully monitored
for symptoms of toxicity. In this case only minor toxic effects occurred.

PMID: 9080635 [PubMed – indexed for MEDLINE]


18: Ann Pharmacother. 2002 Nov;36(11):1745-8.

Goiter in a newborn exposed to lithium in utero.

Frassetto F, Tourneur Martel F, Barjhoux CE, Villier C, Bot BL, Vincent F.

Unite Fonctionnelle, Centre de pharmacovigilance, CHU de Grenoble, Grenoble,

OBJECTIVE: To report a case of neonatal goiter and biological hypothyroidism in
a newborn exposed to lithium in utero resulting from therapy given to the mother
before and during her pregnancy. CASE SUMMARY: A male neonate, born at 37 weeks’
gestation, presented with a goiter without other signs of hypothyroidism. His
serum thyroid-stimulating hormone concentration was high and unbound
tetrathyroxine concentration was low, indicating that chronic exposure to
lithium was present. Oral thyroxine treatment was initiated when the infant was
3 days old and continued for 11 weeks. Treatment was effective in reducing the
goiter and hormone concentrations, and allowing normal growth and psychomotor
development during the following 3.5 months. Other drugs taken by the mother
during pregnancy are not known to induce thyroid abnormalities. DISCUSSION:
Lithium is used for prophylaxis and treatment of bipolar disorder. Goiter and
hypothyroidism in adults have been described in patients treated with lithium;
thyroid disorders are reversible if lithium is discontinued. Few cases of goiter
and hypothyroidism have been reported in newborns exposed to lithium in utero.
In our patient, congenital hypothyroidism required longer thyroxine treatment
than lithium-induced thyroid disorders. The delay before improvement seems to be
similar to that observed in adults. The Naranjo probability scale indicated that
lithium was the probable cause of hypothyroidism resulting from in utero
exposure. CONCLUSIONS: Lithium is a well-known goitrogenic agent. Thus, if
lithium treatment needs to be continued during pregnancy in women with bipolar
disorder, adequate screening for morphology by ultrasonography and systematic
hormonal biological control in newborns are recommended.

PMID: 12398572 [PubMed – indexed for MEDLINE]


19: Ann Pharmacother. 1999 Jun;33(6):690-3.

Adverse effects in a newborn infant breast-fed by a mother treated with doxepin.

Frey OR, Scheidt P, von Brenndorff AI.

Department of Pharmacy, Hospital of Heidenheim, Germany.

OBJECTIVE: To report adverse effects in a newborn infant whose mother had been
treated with doxepin during pregnancy and while breast-feeding. CASE SUMMARY:
The nine-day-old white boy was admitted because of poor sucking and swallowing,
with muscle hypotonia and vomiting. He was drowsy and had lost 150 g. At the
time of admission, he was breast-fed by his mother who was being treated with
doxepin 35 mg/d. Samples of plasma and breast milk were taken and analyzed by
HPLC and fluorescence polarization immunoassay. The amount of doxepin and
N-desmethyldoxepin (DDP) ingested via breast-feeding was approximately 10-20
micrograms/kg/d (i.e., only 2.5% of the weight-adjusted dose of the mother).
Doxepin was detectable in small amounts in the infant’s plasma (approximately 10
micrograms/L); DDP was below the lower limit of detection of 10 micrograms/L.
All adverse effects subsided within 48 hours after breast-feeding was stopped.
DISCUSSION: Despite the small doses of doxepin and its active metabolite
ingested by breast-fed babies, there is a risk of accumulation and resultant
adverse effects. In newborns, the metabolic activity is considerably decreased
and may be further reduced by hyperbilirubinemia. CONCLUSIONS: Available data
suggest that women treated with doxepin should breast-feed their infants with
great caution, if at all, although much larger databases are needed to confirm

PMID: 10410181 [PubMed – indexed for MEDLINE]


20: Expert Opin Pharmacother. 2000 Jul;1(5):903-16.

Women’s issues in mood disorders.

Goodnick PJ, Chaudry T, Artadi J, Arcey S.

Department of Psychiatry & Behavioural Sciences, University of Miami, School of
Medicine, D79, 1400 NW 10 Avenue, Ste 304A, Miami, FL 33136, USA.

Since the introduction of antidepressants in the 1950s, it was assumed for the
next several decades that there were no special reasons to look at the
application of these medications to women. In the past half-century,
particularly in the past decade, since the advent of the selective serotonin
re-uptake inhibitors (SSRI), a series of specific foci have developed. Firstly,
there appear to be differences in the degree of response to particular
antidepressants between the genders. Secondly, there is data concerning hormonal
effects of particular relevance to women, i.e. prolactin, which separates out
among the antidepressants. Also of concern to women are the potential
teratogenic effects of these medications, which impact on their use during
pregnancy. Finally, there are certain diagnostic syndromes that are particularly
relevant to women: premenstrual dysphoric disorder (PMDD); postpartum depression
(PPD) and perimenopausal depression (PMD). It appears that the SSRIs may be more
effective, relative to the older tricyclic antidepressants (TCA), in women than
in men. The SSRIs have shown to be effective in treating these disorders, with
the possibility of intermittent luteal phase treatment of PMDD.
Non-antidepressant (AD) approaches have generally been found to be less
effective. In the first trimester of pregnancy, there is data available
supporting the safe use of SSRIs, particularly those first released, i.e.
fluoxetine and sertraline. Finally, all SSRIs, with the exception of sertraline,
can increase the risk of hyperprolactinaemia. This can lead to a variety of
complications including amenorrhea and osteoporosis. This effect of sertraline,
due to its unique profile in blocking re-uptake of dopamine, extends itself into
additional relative benefits for sleep and memory. The issues associated for
women with bipolar disorder are dealt with in terms of both increased risk of
relapse during pregnancy and postpartum periods, as well as the relative risk of
use of lithium and mood stabilizers in pregnancy and lactation.

Publication Types:
Review, Tutorial

PMID: 11249499 [PubMed – indexed for MEDLINE]


21: Tidsskr Nor Laegeforen. 1997 Nov 10;117(27):3952-5.

Comment in:
Tidsskr Nor Laegeforen. 1998 Jan 10;118(1):100.

[Antidepressive agents and breast feeding] [Article in Norwegian]

Haberg M, Matheson I.

Farmasoytisk avdeling, Rogaland psykiatriske sjukehus, Stavanger.

Postpartum blues occurs in 50-80% of women. A few percent of the cases are
classified as serious postpartum depression, requiring antidepressant treatment.
There is a growing understanding that women should continue to breast-feed in
this situation. Data concerning the transfer of antidepressants into breast milk
has been researched. Calculations of the infant relative dose via breast milk
were done for the drugs concerned. Few antidepressants have been studied at
steady state conditions in nursing mothers. Nortriptyline and amitriptyline have
minimal relative doses and can be used when breast-feeding. Doxepine should be
avoided, as should lithium, which has a significant transfer. Among the
serotonine-reuptake inhibitors fluoxetine has been well studied in breast milk.
Since fluoxetine has a long half life and a high transfer, sertraline and
possibly paroxetine are better alternatives, but the latter has not yet been
studied in repeated doses. Moclobemide also lacks data from multiple dose
studies, but extrapolation to steady state indicates that the relative dose is
small. More observational studies should be carried out in infants breast-fed by
mothers using antidepressants. In the meantime, doctors prescribing
antidepressant drugs to nursing mothers should see that the infants are
monitored for side effects.

PMID: 9441422 [PubMed – indexed for MEDLINE]


22: Perinat Care. 1978 Sep;2(8):19-25.

Drugs in breast milk.

Hervada AR, Feit E, Sagraves R.

PIP: The amount of drug excreted into breast milk is dependent upon the lipid
solubility of the medication, the mechanism of transport, the degree of
ionization, and change in plasma pH. The higher the lipid solubility, the
greater the concentration in human milk. The majority of drugs are transported
into mammary blood capillaries by passive diffusion. The rest are transported
by reverse pinocytosis. Once the drug has entered the epithelial cells of
breast tissue, the drug molecules are excreted into the human milk by active
transport, passive diffusion, or apocrine secretion. The amount of free
(active) drug available for transport depends on the degree of protein binding
the plasma pH. Another factor affecting excretion of drugs is the time when
breast feeding occurs. In the 1st few days of life, when colostrum is present,
water-soluble drugs pass through the breast more easily than afterwards when
milk is produced. Then lipid-soluble drugs cross in higher concentrations. The
effect on nursing infants is dependent on the amount excreted into the milk, the
total amount absorbed by the infant, and the toxicity of the drug. The use of
the following drugs in breast feeding mothers is reviewed: anticoagulants,
antihypertensives and diuretics, antimicrobials, drugs affecting the central
nervous system (alcohol, chloral hydrate, meprobamate, lithium, and aspirin),
marijuana, other drugs (antihistamines, atropine, ergot alkaloids, laxatives,
nicotine, iodides, propylthiouracil, theophylline), hormones (insulin,
thyroxine, and oral contraceptives), and radiopharmaceuticals.

PMID: 12311408 [PubMed – indexed for MEDLINE]


23: Depress Anxiety. 2000;11(2):51-7.

Dose of selective serotonin uptake inhibitors across pregnancy: clinical

Hostetter A, Stowe ZN, Strader JR Jr, McLaughlin E, Llewellyn A.

Department of Psychiatry and Behavioral Sciences, Emory University School of
Medicine, Atlanta, GA 30322, USA.

The use of antidepressants during pregnancy has undergone considerable scrutiny
with respect to safety issues, though limited data with respect to dose
management and symptom resolution is available. Previous reports on tricyclic
antidepressants (TCAs) have demonstrated the need to adjust maternal dose later
in pregnancy to maintain therapeutic serum concentrations. However, there is no
data on the dosage of selective serotonin uptake inhibitors (SSRIs) required to
maintain symptom resolution in women treated for major depression during
pregnancy. The purpose of this study, then, was to assess the medication dosage
requirements of SSRIs during this time. In this naturalistic study, pregnant
women with a primary diagnosis of major depression were followed prospectively
through pregnancy at monthly intervals with symptom assessment. Subjects were
included in data analysis if they presented prior to 28 weeks gestation, were
treated with SSRI monotherapy, received all psychiatric treatment during the
pregnancy at the Emory Pregnancy and Postpartum Mood Disorders Program, and
achieved euthymia after initial treatment intervention (CGI = 1 and Beck
Depression Inventory (BDI) < 9) during pregnancy or failed to respond after
eight weeks of treatment. Medication selection was based on personal treatment
history or family treatment history (if any), and the published data on SSRIs in
pregnancy. All medication dose adjustments were based on depressive symptoms as
measured by the BDI and a psychiatric interview (ZNS). Thirty-four pregnant
women were included in final analysis. Two thirds of the subjects (n = 22)
required an increase in their daily dose of medication to maintain euthymia. The
dose increases occurred at 27.1 +/- 7.1 weeks gestation, with mean BDI scores of
16.4 +/- 9.6, compared to a mean treatment response BDI of 6.9 +/- 5.4.
Subject’s age, education, past personal and familial psychiatric history were
not significantly associated with dose adjustment. These novel data on SSRI
daily dose in pregnancy parallels the extant literature with tricyclic
antidepressants (TCA). Further work to determine the predictors of dose
adjustments will provide guidelines for minimizing fetal exposure to both
medication and maternal mental illness.

PMID: 10812529 [PubMed – indexed for MEDLINE]


24: Br J Clin Pharmacol. 1998 May;45(5):459-62.

Distribution and excretion of venlafaxine and O-desmethylvenlafaxine in human

Ilett KF, Hackett LP, Dusci LJ, Roberts MJ, Kristensen JH, Paech M, Groves A,
Yapp P.

Department of Pharmacology, University of Western Australia, Nedlands.

AIMS: To characterise the transfer of venlafaxine (V) and its O-desmethyl
metabolite (ODV) into human milk by measuring milk/plasma (M/P) ratio, and to
estimate the likely dose received by a breast-fed infant. METHODS: Milk and
plasma samples were collected from three lactating women who were taking
venlafaxine for depression, and were at steady-state. In two of the patients,
venous blood and milk samples were collected 0, 1, 2, 3, 4, 6, 8 and 12 h post
dose, while in the third patient a single pair of blood and milk samples was
obtained 0.83 h post dose. A plasma sample was obtained from each of their
infants. V and ODV were measured in plasma and milk by high performance liquid
chromatography. M/P was calculated and infant dose estimated as drug
concentration in milk x a milk intake of 0.15 l kg(-1) day(-1), relative to the
weight-adjusted maternal dose. RESULTS: Mean M/P for V was 4.1 (range 2.8-4.8)
and 3.1 for ODV (range 2.8-3.8). The mean total infant dose (as V equivalents)
was 7.6% (range 4.7-9.2%) of the maternal weight-adjusted dose, with
approximately equal amounts of V (3.5%) and ODV (4.1%) in the dose. ODV (median
100 microg I(-1)) was detected in the plasma of all three infants. The infants
were healthy and showed no acute adverse effects. CONCLUSIONS: These preliminary
data show that the total dose of V and ODV ingested by breast-fed infants can be
as high as 9.2% of maternal intake. Moreover there were measurable
concentrations of ODV in the infants’ plasma. We recommend that exposed infants
should be observed closely.

Publication Types:
Clinical Trial

PMID: 9643618 [PubMed – indexed for MEDLINE]


25: South Med J. 2001 Mar;94(3):304-22.

Effects of antimanic mood-stabilizing drugs on fetuses, neonates, and nursing

Iqbal MM, Gundlapalli SP, Ryan WG, Ryals T, Passman TE.

Department of Psychiatry and Behavioral Neurobiology, University of Alabama at
Birmingham School of Medicine, 35294-0017, USA.

Pregnancy presents a special problem to the clinician treating bipolar disorders
in women. Since the first episode of mania typically occurs before the age of
30, many women in their prime childbearing years may be exposed to potentially
teratogenic mood-stabilizing agents. This exposure may also continue for the
nursing infant during lactation. Pregnancy itself can exacerbate bipolar
symptoms and also alter the pharmacokinetics of mood-stabilizing drugs. Risks to
mother and fetus can be reduced with a number of simple strategies, including
monotherapy with the lowest effective dose of a drug for the shortest period
necessary, periconceptional use of multivitamins with folate, prescription of
drugs with established safety records, and avoidance of exposure to antimanic
agents during the first trimester of pregnancy. In this article, we review
existing evidence on the risks to fetuses and nursing infants of mothers taking
specific mood-stabilizing agents, and we present appropriate management
guidelines designed to minimize these risks.

Publication Types:
Review, Tutorial

PMID: 11284518 [PubMed – indexed for MEDLINE]


26: J Toxicol Clin Toxicol. 2001;39(4):381-92.

The effects of lithium, valproic acid, and carbamazepine during pregnancy and

Iqbal MM, Sohhan T, Mahmud SZ.

Department of Psychiatry & Behavioral Neurobiology, The University of Alabama at
Birmingham, 35294-0017, USA.

The chronic, complex, and episodic course of bipolar mood disorder presents a
particularly formidable challenge to the clinician making a treatment plan for
the onset or recurrence of the illness during pregnancy and lactation. Women
treated with anti-manic drugs who become pregnant are commonly considered to be
at high risk for fetal complications during the pregnancy or during lactation.
The risks of antimanic drug use during pregnancy include teratogenic effects,
direct neonatal toxicity, and the potential for longer-term neurobehavioral
sequela. The use of medications during pregnancy and lactation requires critical
attention to the timing of exposure, dosage, duration of use, and fetal
susceptibility. The postnatal period is a time of increased onset and relapse of
mental illness. No antimanic drug can be proven completely safe. Prescribing
antimanic medications with a long safety record, avoiding exposure in the first
trimester; avoiding multidrug regimens, and prescribing the lowest dose for the
shortest duration will minimize the fetal risk. This review considers treatment
with lithium, valproic acid, and carbamazepine. It assesses the risk to the
fetus, the perinatal risks for the infant, the risks associated with treatment
during the puerperium and breast-feeding, and the risks to the later development
of the child.

Publication Types:
Review, Tutorial

PMID: 11527233 [PubMed – indexed for MEDLINE]


27: Can Fam Physician. 1999 May;45:1173-5.

Continuing drug therapy while breastfeeding. Part 2. Common misconceptions of

Koren G, Moretti M, Ito S.

University of Toronto.

QUESTION: Is there any way to predict whether a drug taken by a mother is safe
for a suckling baby, or is it just trial and error? One of my patients is
receiving lithium for manic depression. She wishes to breastfeed, but clinically
there is no way she can discontinue the drug. My sources say the drug is
incompatible with breastfeeding. ANSWER: The amount of drug available to a baby
through breastmilk is estimated as the percentage of maternal dose per kg
ingested by the baby. Because infants’ clearance rate of many drugs is slower
than adults’, however, the true level of the drug circulating in the infant’s
blood might be much higher. Because lithium can be measured in plasma, it is
prudent to measure it in milk and to estimate the “baby dose.” If a baby shows
any adverse effects, lithium levels should be measured in its blood.

PMID: 10349056 [PubMed – indexed for MEDLINE]


28: Cas Lek Cesk. 1996 Nov 20;135(22):726-8.

[Is lithium a teratogen?] [Article in Czech]

Kucera V.

Psychiatricka klinika FN, Hradec Kralove.

Beginning with the seventies literature has brought a series of publications
drawing attention to possible effects of lithium on the origin of congenital
malformations. The discussion on the teratogenic effects of lithium in world
literature has not come to final conclusion yet. The paper reviews some
knowledge from home and foreign literature, dealing with the problems of lithium
teratogenicity. A series of information has been provided on the basis of
metaanalysis of data having been published until 1994 in the review systems
MEDLINE, TOXLINE and Lithium Information Center database. The aim of the
contribution has been to review the published data on this question. The
available literature has shown that teratogenicity of lithium has not been
proved univocally. Last studies rather suggest that lithium is not a strong
teratogen. In view of the fact that teratogenicity of lithium cannot be safely
excluded, the paper recommends that this kind of risk should be taken into
account, if lithium administration is considered to be applied in pregnant
women, especially during the first three months of pregnancy.

Publication Types:
Review, Tutorial

PMID: 8998825 [PubMed – indexed for MEDLINE]


29: Can Fam Physician. 1998 Oct;44:2081-3.

Are the new SSRIs safe for pregnant women?

Kulin NA, Pastuszak A, Koren G.

Hospital for Sick Children, Toronto, USA.

QUESTION: More and more of my female patients are switching to the new selective
serotonin reuptake inhibitors. Are they safe during pregnancy? ANSWER: Our data
suggest these drugs do not increase the malformation rate, but there are no data
on neurodevelopment. Because such data do exist on fluoxetine and tricyclic
antidepressants, those drugs should be considered first.

PMID: 9805157 [PubMed – indexed for MEDLINE]


30: JAMA. 1998 Feb 25;279(8):609-10.

Comment in:
JAMA. 1998 Jun 17;279(23):1873.
JAMA. 1998 Jun 17;279(23):1873.

Pregnancy outcome following maternal use of the new selective serotonin reuptake
inhibitors: a prospective controlled multicenter study.

Kulin NA, Pastuszak A, Sage SR, Schick-Boschetto B, Spivey G, Feldkamp M, Ormond
K, Matsui D, Stein-Schechman AK, Cook L, Brochu J, Rieder M, Koren G.

The Motherisk Program, The Hospital for Sick Children, and the University of
Toronto, Ontario, Canada.

CONTEXT: Although a large number of women of reproductive age use new selective
serotonin reuptake inhibitors (SSRIs) and half of all pregnancies are unplanned,
no data exist on the safety of these agents for the human fetus. OBJECTIVE: To
assess fetal safety and risk of fluvoxamine, paroxetine, and sertraline. DESIGN:
A prospective, multicenter, controlled cohort study. SETTING: Nine Teratology
Information Service centers in the United States and Canada. PATIENTS: All women
who were counseled during pregnancy following exposure to a new SSRI and
followed up by the participating centers. Controls were randomly selected from
women counseled after exposure to nonteratogenic agents. MAIN OUTCOME MEASURES:
Rates of major congenital malformations. RESULTS: A total of 267 women exposed
to an SSRI and 267 controls were studied. Exposure to SSRIs was not associated
with either increased risk for major malformations (9/222 live births [4.1%] vs
9/235 live births [3.8%] in the controls, relative risk, 1.06, 95% confidence
interval, 0.43-2.62) or higher rates of miscarriage, stillbirth, or prematurity.
Mean (SD) birth weights among SSRI users (3439 [505] g) were similar to the
controls (3445 [610] g) as were the gestational ages (39.4 [1.7] weeks vs 39.4
[1.9] weeks). CONCLUSION: The new SSRIs, fluvoxamine, paroxetine, and
sertraline, do not appear to increase the teratogenic risk when used in their
recommended doses.

Publication Types:
Multicenter Study

PMID: 9486756 [PubMed – indexed for MEDLINE]


31: Arch Gen Psychiatry. 2003 Jul;60(7):720-6.

Effects of exposure to selective serotonin reuptake inhibitors during pregnancy
on serotonergic symptoms in newborns and cord blood monoamine and prolactin

Laine K, Heikkinen T, Ekblad U, Kero P.

Department of Pharmacology and Clinical Pharmacology, University of Turku and
Turku University Central Hospital, Turku, Finland.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) have gained wide
acceptance in the treatment of mental disorders in pregnant women, but there
seems to be an increased risk for neonatal adaptation problems after exposure to
SSRIs in late pregnancy. We aimed to investigate the perinatal sequelae of
infants exposed to SSRIs during their fetal life and the relationship of these
symptoms to the cord blood monoamine and prolactin concentrations. METHODS: We
conducted a prospective, controlled, follow-up study with 20 mothers taking 20
to 40 mg/d of either citalopram or fluoxetine for depression (n = 10) or panic
disorder (n = 10) and their infants and 20 matched controls not receiving
psychotropic medication for confounding obstetric characteristics. Maternal cord
blood and infant citalopram, fluoxetine, and norfluoxetine, cord blood monoamine
and metabolite, and prolactin concentrations were measured. The newborns
underwent standard clinical examination and specific assessment of serotonergic
symptoms during the first 4 days of life and at the ages of 2 weeks and 2
months. RESULTS: There was a statistically significant (P =.008, V = 15, n = 20
for both groups), 4-fold difference in the serotonergic symptom score during the
first 4 days of life between the SSRI group and the control group. The
SSRI-exposed infants had significantly lower cord blood 5-hydroxyindoleacetic
acid (5-HIAA) concentrations (P =.02, t31 = 2.57) compared with the control
group. A significant inverse correlation (rs = -0.66, P =.007, n = 15) was seen
between the serotonergic symptom score and the umbilical vein 5-HIAA
concentrations in the SSRI-exposed but not the control infants. CONCLUSIONS:
Infants exposed to SSRIs during late pregnancy are at increased risk for
serotonergic central nervous system adverse effects, and the severity of these
symptoms is significantly related to cord blood 5-HIAA levels.

PMID: 12860776 [PubMed – in process]


32: Nervenarzt. 1998 Jan;69(1):10-4.

[Psychopharmacotherapy in pregnancy and lactation. 2: Lactation] [Article in German]

Lanczik M, Knoche M, Fritze J.

Department of Psychiatry, University of Birmingham, Queen Elizabeth Hospital,
West Midlands, England.

Whilst the incidence of psychiatric disorders decreases during pregnancy, the
risk during the postpartum period increases significantly, often leading to the
necessity of psychopharmacological intervention during the puerperium, and
subsequently during lactation and breast-feeding. The necessity for lithium
prophylaxis in manic-depressive women after childbirth has been identified, and
it is recommended that weaning rather than omission of psychopharmacological
treatment is preferable during the puerperium.

Publication Types:
Review, Tutorial

PMID: 9522328 [PubMed – indexed for MEDLINE]


33: Nervenarzt. 1998 Jan;69(1):1-9.

[Psychopharmacotherapy during pregnancy and lactation. 1: Pregnancy] [Article in German]

Lanczik M, Knoche M, Fritze J.

Department of Psychiatry, University of Birmingham, Queen Elizabeth Hospital,
West Midlands, England.

Approximately one-third of all pregnant women take psychotropic drugs at least
once during pregnancy. At the same time, there are no preparations on the market
that can be considered entirely appropriate for expectant mothers. The effects
of psychopharmacological therapies have exclusively been discussed in the
context of their risk during the first trimester. However, treatment after this
phase is not absolutely without risk, and it is striking that there are grave
differences between various substances. There are currently controversial
discussions going on in literature as far as the teratogenicity of lithium is
concerned, especially during the formation of the heart. It is suggested that
the risk for congenital malformations is increased after intrauterine lithium
exposure, whereas such a risk cannot be proved for most of the antidepressants
and neuroleptics. Still, it should be noted that psychopharmacology is not
harmless even after the organogenesis, as intrauterine exposure during the 2nd
and 3rd trimester can lead to postnatal complications. For example,
floppy-infant syndrome after taking benzodiazepines, and the
extrapyramidal-motor effects on the newborn after neuroleptic therapy during
pregnancy should be mentioned.

Publication Types:
Review, Tutorial

PMID: 9522327 [PubMed – indexed for MEDLINE]


34: J Clin Psychiatry. 1998;59 Suppl 6:57-64; discussion 65.

The use of lithium and management of women with bipolar disorder during
pregnancy and lactation.

Llewellyn A, Stowe ZN, Strader JR Jr.

Department of Psychiatry and Behavioral Sciences, Emory University School of
Medicine, Atlanta, GA 30322, USA.

The introduction of lithium salts almost a century ago and the subsequent
approval of lithium carbonate for the treatment of patients with bipolar
disorder represent one of the cornerstones of modern psychopharmacology. The
onset of bipolar disorder in women often occurs during the childbearing years,
which complicates the treatment decisions secondary to the possibility of
conception while taking medication. The establishment of the lithium registry
for fetal teratogenesis in the late 1960s ushered in a heightened level of
concern for the use of lithium during the reproductive years; although, in the
years to come, it has become apparent that alternative pharmacologic treatments
for bipolar disorder may exceed the teratogenic risk of lithium monotherapy. In
this paper, the available data on the use of antimanic medications during
pregnancy and lactation are reviewed with an emphasis on providing a realistic
risk/benefit assessment for medication selection and management of these
patients. Treatment strategies are discussed for (1) women who are contemplating
pregnancy (2) women who inadvertently conceive while taking medications (3)
women who choose to become pregnant while taking medication, and (4) women who
intend to breastfeed while taking medications.

Publication Types:
Review, Tutorial

PMID: 9674938 [PubMed – indexed for MEDLINE]


35: J Clin Psychiatry. 1998;59 Suppl 2:41-52.

Psychotropic medications in lactation.

Llewellyn A, Stowe ZN.

Department of Psychiatry and Behavioral Sciences, Emory University School of
Medicine, Atlanta, GA 30322, USA.

The use of psychotropic medications during lactation has not been investigated
in a controlled and systematic fashion. The literature is laden with case
reports and small case series containing numerous confounds that render the
establishment of definitive treatment guidelines tenuous. The increasing number
of women who plan to breast-feed and the high rate of psychiatric illness during
the postpartum period underscore the need to develop such guidelines. A MEDLINE
search was conducted for key words either in the titles or abstracts of
publications citing the use of psychotropic medications in lactating women and
describing the pharmacokinetics of medication excretion into breast milk. The
publications identified span over three decades. The largest single study by one
group of investigators examined 12 mother-infant pairs. The majority of studies
report their results as a ratio of the breast milk concentration to the maternal
serum concentration (milk/plasma [M/P]) ratio. Estimations that use the M/P
ratio of the infant daily dose range from 0.1% to 6.2% of the maternal dose. Few
studies attempt to account for the complex variations in the maternal, breast
milk, and infant physiologic environments. The major confounds of the studies
reviewed include (1) failure to document portion of breast milk assayed
(foremilk versus hindmilk), (2) limited metabolite assay, (3) limited assay
sensitivity (1-25 ng/mL), not of research quality, (4) concomitant maternal
and/or infant medications, and (5) medication exposure during pregnancy. Despite
these confounds, there are remarkably few reports of adverse effects on nursing
infants exposed to psychotropic medications in breast milk. The limited data
confirm that psychotropic medications are excreted into breast milk and that the
infant is exposed to these medications. The ideal breast milk study that
accounts for the confounds identified has not been completed. The complex matrix
of breast milk and the changing infant metabolic capacity will require a more
detailed analysis with assays of improved sensitivity. Despite the limited
reports of adverse effects on nursing infants, the limitations of the available
literature and minimal sample sizes make it premature to recommend specific
medications from a given class. There is inadequate data on nursing infant
exposure to multiple medications to support changing medication to a different
agent in an otherwise stable patient. An individualized risk/benefit assessment
with the empirical goal of minimizing infant exposure while maintaining maternal
emotional health is the ideal approach.

PMID: 9559759 [PubMed – indexed for MEDLINE]


36: J Psychiatry Neurosci. 1997 May;22(3):192-6.

Pregnancy outcome and neurodevelopment of children exposed in utero to
psychoactive drugs: the Motherisk experience.

Loebstein R, Koren G.

Motherisk Program, Hospital for Sick Children, Toronto, Ontario, Canada.

This paper presents an overview of the Motherisk Program data on pregnancy
outcome and neurodevelopment of children exposed in utero to selected
psychoactive drugs. First, the use of cocaine during pregnancy has been
associated with increased risk of spontaneous abortions, abruptio placenta,
premature labor, and stillbirth. Twenty-three adopted children exposed in utero
to cocaine demonstrated an 8-fold increase in risk for microcephaly compared
with controls. Global intelligence quotients (IQ) did not differ between the 2
groups, but the cocaine-exposed children achieved significantly lower scores on
the Reynell language test. Second, the long-term neurobehavioral effects of
fetal alcohol syndrome (FAS) were studied in 384 children to show that
alcohol-induced brain insults, which consist of attention and memory deficits
together, and poor adaptability and organization are not attenuated with age.
Third, the rates of major malformations in children exposed in utero to
fluoxetine, tricyclic antidepressants, and nonteratogenic drugs did not differ
or exceed the expected rates in the general population. A 2nd phase of this
study established the safety of antidepressants during pregnancy by
demonstrating that the mean IQ and language scores are comparable in the 3
groups. A level 2 ultrasonography is recommended in cases of in utero exposure
to lithium and carbamazepine because of an increased risk of cardiac
malformations and spina bifida, respectively.

Publication Types:
Review, Tutorial

PMID: 9183118 [PubMed – indexed for MEDLINE]


37: J Clin Psychiatry. 1997 Mar;58(3):100-3.

Sertraline and norsertraline levels in three breastfed infants.

Mammen OK, Perel JM, Rudolph G, Foglia JP, Wheeler SB.

Department of Psychiatry, University of Pittsburgh, Pa., USA.

BACKGROUND: In assessing the safety of medication use in breastfeeding, it is
important to know whether the drug used by the mother will be present in the
breastfed infant. Compared with data for tricyclic antidepressants (TCAs), which
have generally not been found in the plasma of breastfed infants, there are few
data on the use of serotonin selective reuptake inhibitors (SSRIs) in
breastfeeding. This poses a dilemma for breastfeeding women and their treating
clinicians, because of the enhanced tolerability of SSRIs compared with TCAs,
and because some patients do not respond well to TCAs. METHOD: Sertraline and
norsertraline plasma concentrations were measured in three breastfeeding
mother-infant pairs. Maternal and infant plasma samples were drawn a few minutes
apart. Two of the infants had an additional sample assayed without
contemporaneous maternal samples examined. Drug assay was by high-performance
liquid chromatography. Limit of reproducible quantifiability was 2 ng/mL, and
limit of detectability was 1 ng/mL. RESULTS: Maternal sertraline dose ranged
from 50 to 100 mg/day. All infant plasma samples showed low levels (< 2 ng/mL)
of either sertraline and norsertraline or norsertraline alone. Breastfeeding was
continued, and the infants have shown no adverse effects on short-term
follow-up. CONCLUSION: These data suggest that sertraline and/or its almost
inactive metabolite may be present at very low concentrations in the plasma of
breastfed infants. No adverse effects were noted in the infants. Limitations of
the findings and possible implications for the use of sertraline during
breastfeeding are discussed.

PMID: 9108810 [PubMed – indexed for MEDLINE]


38: Drug Saf. 2002;25(13):903-11.

Benefits and risks to mother and infant of drug treatment for postnatal

Misri S, Kostaras X.

Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada.

The postnatal period presents a special problem to healthcare providers treating
psychiatric disorders in women. Many new mothers who need antidepressant
treatment may wish to breastfeed their infants, but are hesitant to do so for
fear of passing on possible harmful effects of the medication through their
milk. The focus of this article will be on highlighting and interpreting the
existing literature on the benefits and risks to mother and infant of drug
treatment for postnatal depression, as well as outlining treatment guidelines
for the use of antidepressants in breastfeeding mothers. The article will
specifically focus on the use of fluoxetine, sertraline, paroxetine, fluvoxamine
and citalopram, which are more commonly used and belong to the selective
serotonin reuptake inhibitor group of antidepressants. The tricyclic and other
newer antidepressant medications will also be discussed. As there are no
published controlled studies on the use of antidepressants by breastfeeding
women, publications of individual case reports, case series, and pharmacokinetic
investigations serve as the basis for the development of treatment guidelines.
Results from this growing body of literature are promising in that, with the
exception of a few cases, no serious adverse events have been reported in
infants exposed to antidepressant medications through breast milk. In addition
nonpharmacological treatments consisting of different types of psychotherapies
will be discussed. It is critical that healthcare providers evaluate each
mother-infant dyad on an individual basis when faced with the decision to
prescribe antidepressant medications during the postnatal period.

Publication Types:
Review, Tutorial

PMID: 12381212 [PubMed – indexed for MEDLINE]


39: Can J Psychiatry. 2000 Apr;45(3):285-7.

Comment in:
Can J Psychiatry. 2000 Dec;45(10):939-40.
Can J Psychiatry. 2000 Dec;45(10):940.
Can J Psychiatry. 2001 Jun;46(5):452.
Can J Psychiatry. 2001 May;46(4):371.

The use of selective serotonin reuptake inhibitors during pregnancy and
lactation: current knowledge.

Misri S, Kostaras D, Kostaras X.

Department of Psychiatry, University of British Columbia, Vancouver.

This article reviews the effects of the selective serotonin reuptake inhibitor
(SSRI) class of antidepressants in pregnant and lactating women for the
treatment of depression and anxiety disorders. An examination of the literature
was conducted using Medline (1966 to present). Despite methodological concerns
and the scarcity of data on this important subject, the majority of recent
investigations demonstrate safety of the fetus exposed to SSRIs during
pregnancy. All of the SSRIs reported in the studies are excreted into breast
milk, and low levels have been found in infant serum. The implications of this
for practice include identifying the effects of treatment versus nontreatment on
the mother-infant dyad. Further research must examine long-term neurobehavioural
teratogenicity in exposed infants.

PMID: 10779887 [PubMed – indexed for MEDLINE]


40: Can Fam Physician. 2000 Mar;46:626-8, 631-3.

Are SSRIs safe for pregnant and breastfeeding women?

Misri S, Burgmann A, Kostaras D.

Department of Psychiatry, University of British Columbia, Vancouver.

OBJECTIVE: To summarize the literature on use of the selective serotonin
reuptake inhibitor (SSRI) class of antidepressants for pregnant and
breastfeeding women. DATA SOURCES AND STUDY SELECTION: MEDLINE was searched over
the past 9 years. An examination of the literature over the last 8 years was
included in this review. Primary studies consist of prospective investigations
and case studies. Evidence for the safety of SSRIs is limited, but some good
studies describe the effects of untreated depression. SYNTHESIS: All studies
report that infants are exposed to SSRIs; the drugs can be measured in their
plasma and urine. Some evidence shows an increase in minor perinatal
complications among infants exposed to SSRIs late in gestation or while nursing.
No studies, however, have found an increase in major fetal malformations or
pregnancy-related complications. The only investigation of long-term
neurodevelopmental outcomes found no negative outcomes among infants exposed to
SSRIs during pregnancy. Data are scarce, and readers are cautioned to take into
consideration the limitations of the studies reviewed before making definite
treatment decisions. CONCLUSIONS: Major fetal malformations and exposure to
SSRIs during pregnancy and lactation do not appear to be associated. Some minor
perinatal complications have been reported. Data on the long-term developmental
outcomes of children exposed to SSRIs in utero and during breastfeeding are

PMID: 10752001 [PubMed – indexed for MEDLINE]


41: Drug Saf. 1998 Jan;18(1):57-82.

Risks and benefits of selective serotonin reuptake inhibitors in the treatment
of depression.

Mourilhe P, Stokes PE.

New York Hospital-Cornell Medical Center, White Plains, USA.

Depression is a common, life-disrupting, potentially lethal illness that can
affect both sexes and all ages. Its peak onset is in the early adult years. It
is more common than hypertension in primary care practice. Recent studies show
that fewer than 1 in 20 depressed patients are correctly diagnosed and
adequately treated. Depression periodically destroys the productivity of those
with the condition, and depressed patients have a worse quality of life than
patients with debilitating, chronic conditions such as arthritis, hypertension,
diabetes mellitus and back pain. Suicide occurs in as many as 15% of patients
with depression, especially those with recurrent episodes and hospitalisations,
and may even occur in those with in subsyndromal depression. Suicide is one of
the leading causes of death, and individuals who complete suicide have usually
experienced mood disorders, mainly depression. Current data support a decreased
frequency of suicidal ideation with all antidepressants, including selective
serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs). Modern
pharmacotherapy is the cornerstone for effective treatment of depression. As
they are well tolerated, even in the presence of comorbid medical illness, and
easier to manage, SSRIs enhance compliance. A fully adequate antidepressant
dosage is suitable for patients of all ages and can be used by non-psychiatrist
physicians for the treatment of the acute episode, as well as the frequent
recurrences that often require long term maintenance antidepressant medication.
SSRIs have fewer drug interactions than older antidepressants, and even the SSRI
inhibition of hepatic cytochrome P450 enzymes has proven only very infrequently
to be of clinical importance. SSRIs also effectively treat anxious depression,
dysthymia and atypical depression. Fluoxetine may provide more rapid onset of
therapeutic effect because it can be started at closer to its usual full
therapeutic dosage than other SSRIs or older antidepressants. SSRIs, in
particular fluoxetine, are more suitable for use as long-term maintenance
therapy in these chronic relapsing diseases. These factors and the high efficacy
rate, increased safety in overdose, reduced incidence of adverse effects (mostly
decreasing with time) and superiority in ease of maintaining patients in
adequate treatment plans provides fluoxetine with an overall superior
therapeutic profile.

Publication Types:
Review, Academic

PMID: 9466088 [PubMed – indexed for MEDLINE]


42: J Clin Psychiatry. 2002;63 Suppl 7:24-30.

Depression during pregnancy: diagnosis and treatment options.

Nonacs R, Cohen LS.

Department of Psychiatry, Massachusetts General Hospital, Boston 02114, USA.

Women often seek clinical consultation for antidepressant use both prior to
conception and during pregnancy. Some women experience a new onset of symptoms
during pregnancy, while those with a history of depressive symptoms are at
increased risk. Nevertheless, clinicians are faced with the challenge of
treating the mother without posing risks to the fetus. This review discusses
risk factors for depression during pregnancy and the consequences of untreated
depression. Nonpharmacologic and pharmacologic treatment options are reviewed,
and guidelines for treating depression during pregnancy are presented.

Publication Types:
Review, Tutorial

PMID: 11995775 [PubMed – indexed for MEDLINE]


43: Acta Paediatr. 2001 Mar;90(3):288-91.

Neonatal withdrawal syndrome after in utero exposure to selective serotonin
reuptake inhibitors.

Nordeng H, Lindemann R, Perminov KV, Reikvam A.

Department of Pharmacotherapeutics, University of Oslo, Oslo, Norway.

Selective serotonin reuptake inhibitors (SSRIs) are a new group of
antidepressants used in mild to moderate cases of depression. In studies
evaluating the safety of SSRIs during pregnancy, no increase in major anomalies
has been reported. This might have led to increasing off-label prescription of
SSRIs to pregnant women. Neonatal withdrawal syndrome commonly occurs in infants
exposed during the third trimester to drugs known to cause addiction. We report
five cases of neonatal withdrawal syndrome after third trimester in utero SSRI
exposure. In three cases the mother used paroxetine in doses from 10 to 40 mg,
one mother used citalopram 30 mg, and one mother fluoxetine 20 mg. Withdrawal
symptoms occurred within few days after birth and lasted up to one month after
birth. Four of the infants needed treatment with chlorpromazine. Symptoms were
irritability, constant crying, shivering, increased tonus, eating and sleeping
difficulties and convulsions. CONCLUSION: Neonatal withdrawal syndrome can occur
after third trimester in utero SSRI exposure. Further research should focus on
whether it is safe to use SSRIs during the last trimester. All neonates exposed
to SSRIs during the last trimester should be followed-up closely for withdrawal
symptoms after birth.

PMID: 11332169 [PubMed – indexed for MEDLINE]


44: Am J Psychiatry. 2002 Nov;159(11):1889-95.

Child development following exposure to tricyclic antidepressants or fluoxetine
throughout fetal life: a prospective, controlled study.

Nulman I, Rovet J, Stewart DE, Wolpin J, Pace-Asciak P, Shuhaiber S, Koren G.

Motherisk Program, Division of Pediatrics and Psychology and the Reseaarch
Institute, The Hospital for Sick Children, Toronta, Ont. Canada.

OBJECTIVE: Previous work suggested that first-trimester exposure to tricyclic
antidepressants or fluoxetine does not affect adversely child IQ and language
development. However, many women need antidepressants throughout pregnancy to
avoid morbidity and suicide attempts. Little is known about the fetal safety of
tricyclic antidepressants and fluoxetine when taken throughout pregnancy. The
goal of this study was to assess the effects of tricyclic antidepressants and
fluoxetine used throughout gestation on child IQ, language, and behavior.
METHOD: In a prospective study, mother-child pairs exposed throughout gestation
to tricyclic antidepressants (N=46) or fluoxetine (N=40) and an unexposed, not
depressed comparison group (N=36) were blindly assessed. The three groups were
compared in terms of the children’s IQ, language, behavior, and temperament
between ages 15 and 71 months. The authors adjusted for independent variables
such as duration and severity of maternal depression, duration of
pharmacological treatment, number of depression episodes after delivery,
maternal IQ, socioeconomic status, cigarette smoking, and alcohol use. RESULTS:
Neither tricyclic antidepressants nor fluoxetine adversely affected the child’s
global IQ, language development, or behavior. IQ was significantly and
negatively associated with duration of depression, whereas language was
negatively associated with number of depression episodes after delivery.
CONCLUSIONS: Exposure to tricyclic antidepressants or fluoxetine throughout
gestation does not appear to adversely affect cognition, language development,
or the temperament of preschool and early-school children. In contrast, mothers’
depression is associated with less cognitive and language achievement by their
children. When needed, adequate antidepressant therapy should be instituted and
maintained during pregnancy and postpartum.

PMID: 12411224 [PubMed – indexed for MEDLINE]


45: N Engl J Med. 1997 Jan 23;336(4):258-62.

Neurodevelopment of children exposed in utero to antidepressant drugs.

Nulman I, Rovet J, Stewart DE, Wolpin J, Gardner HA, Theis JG, Kulin N, Koren G.

Motherisk Program, Hospital for Sick Children and University of Toronto, ON,

BACKGROUND: Many women of reproductive age have depression, necessitating
therapy with either a tricyclic antidepressant drug or a drug, such as
fluoxetine, that inhibits the reuptake of serotonin. Whether these drugs affect
fetal neurodevelopment is not known. METHODS: We studied the children of 80
mothers who had received a tricyclic antidepressant drug during pregnancy, 55
children whose mothers had received fluoxetine during pregnancy, and 84 children
whose mothers had not been exposed during pregnancy to any agent known to affect
the fetus adversely. The children’s global IQ and language development were
assessed between 16 and 86 months of postnatal age by age-appropriate Bayley
Scales of Infant Development or the McCarthy Scales of Children’s Abilities (for
IQ) and the Reynell Developmental Language Scales. RESULTS: The mean (+/-SD)
global IQ scores were 118+/-17 in the children of mothers who received a
tricyclic antidepressant drug, 117+/-17 in those whose mothers received
fluoxetine, and 115+/-14 in those in the control group. The language scores were
similar in all three groups. The results were similar in children exposed to a
tricyclic antidepressant drug or fluoxetine during the first trimester and those
exposed throughout pregnancy. There were also no significant differences in
temperament, mood, arousability, activity level, distractibility, or behavior
problems in the three groups of children. CONCLUSIONS: In utero exposure to
either tricyclic antidepressant drugs or fluoxetine does not affect global IQ,
language development, or behavioral development in preschool children.

PMID: 8995088 [PubMed – indexed for MEDLINE]


46: Am J Obstet Gynecol. 2002 Jul;187(1):245-9.

Case report and review of the perinatal implications of maternal lithium use.

Pinelli JM, Symington AJ, Cunningham KA, Paes BA.

School of Nursing and the Department of Pediatrics, McMaster University, Faculty
of Health Sciences, Hamilton, Ontario Canada.

The purpose of this study was to review the use of lithium in pregnancy and its
effects on the neonate. This was a case study and review of the published
literature.Lithium is commonly used in the treatment of psychiatric disorders,
specifically bipolar depression. Bipolar disorders that require treatment with
lithium demand special consideration when the woman becomes pregnant. Reported
neonatal problems with maternal lithium therapy include Ebstein’s anomaly, poor
respiratory effort and cyanosis, rhythm disturbances, nephrogenic diabetes
insipidus, thyroid dysfunction, hypoglycemia, hypotonia and lethargy,
hyperbilirubinemia, and large-for-gestational-age infants.Lithium can have
adverse effects on the fetus and newborn infant, but data suggest normal
behavioral patterns in childhood.

Publication Types:
Review of Reported Cases

PMID: 12114921 [PubMed – indexed for MEDLINE]


47: Rev Med Chil. 2001 May;129(5):556-60.

[Treatment of bipolar disorder during pregnancy and puerperium period. A case
report] [Article in Spanish]

Retamal P, Cantillano V.

Unidad de Enfermedades del Animo, Servicio de Psiquiatria, Campus Oriente,
Facultad de Medicina, Universidad de Chile, Hospital Salvador, Avda Infante 551,
Providencia, Santiago, Chile.

We report a 37 years old woman with a severe bipolar disorder, that became
pregnant during treatment with lithium. The patient and her family were informed
about the 0.05-0.1% risk of cardiac malformations of the newborn, but decided to
maintain her pregnancy and not to discontinue the use of lithium, fearing a
relapse of her psychiatric ailment. She continued under medical surveillance and
had a normal delivery, but no breast feeding was allowed.

PMID: 11464539 [PubMed – indexed for MEDLINE]


48: Rev Neurol. 2003 Apr 16-30;36(8):724-6.

[Neonatal convulsions and subarachnoid hemorrhage after in utero exposure to
paroxetine] [Article in Spanish]

Salvia Roiges MD, Garcia L, Gonce Mellgren A, Esque Ruiz MT, Figueras Aloy J,
Carbonell Estrany X.

Institut Clinic d Obstetricia, Ginecologia i Neonatologia (ICGON), Barcelona,
Espa a.

INTRODUCTION. Selective serotonin reuptake inhibitors (SSRIs) are often used as
antidepressants in pregnant women. SSRIs do not appear to increase the
teratogenic risk when used in their recommended doses. However, not enough
information is available at this time about the risk of toxicity and
complications in newborns, after mother treatment with SSRI during the third
trimester of pregnancy. We are limited to the existing reports that describe
newborns with symptoms due to hyperserotoninemia or withdrawal. CASE REPORT. One
newborn whose mother had been treated with paroxetine 20 mg/day during
pregnancy, presented convulsions and subarachnoid haemorrhage in the first six
hours of life. The newborn did not present symptoms of hypoxic ischaemic
encephalopathy, withdrawal syndrome, infection, metabolic alterations, cerebral
malformations or coagulopaties. DISCUSSION. The most probable etiology is that
the paroxetine could decrease the seizure threshold, taking place the first
seizure during delivery. The difficult fetal extraction would have provoked the
subarachnoid haemorrhage in a patient with an impaired haemostatic function due
to a depletion of platelet serotonin and may also contribute the increased
vascular fragility due to paroxetine and reported in adults or in animals.
CONCLUSION. Neonatal convulsions and subarachnoid haemorrhage may occur after
paroxetine treatment in the third trimester of pregnancy. An accurate follow up
of these newborns in the firsts days of life is strongly recommended.

PMID: 12717649 [PubMed – in process]


49: Drug Saf. 1998 Feb;18(2):143-52.

Treating recurrent affective disorders during and after pregnancy. What can be
taken safely?

Schou M.

Psychiatric Hospital, Risskov, Denmark.

Since pregnancy and the time thereafter is a precarious period for women with
recurrent affective disorders and their offspring, it is important to determine
the risk of various treatments for such disorders. This review assesses the risk
to the fetus, the perinatal risks for mother and infant, the risks associated
with treatment during the puerperium and breastfeeding, and the risks to the
later development of the child. This review considers treatment with lithium,
tricyclic antidepressants (TCAs), selective serotonin (5-hydroxytryptamine;
5-HT) reuptake inhibitors (SSRIs), monoamine oxidase inhibitors, other
antidepressants, and the anticonvulsants carbamazepine and valproic acid (sodium
valproate). According to available evidence, use of lithium, TCAs and SSRIs is
justified during and after pregnancy if treatment is required; no prophylactic
treatment has a lower risk: benefit ratio. The review provides guidelines for
the use of these drugs.

Publication Types:
Review, Tutorial

PMID: 9512921 [PubMed – indexed for MEDLINE]


50: Am J Psychiatry. 2002 Dec;159(12):2055-61.

Outcomes of prenatal antidepressant exposure.

Simon GE, Cunningham ML, Davis RL.

Center for Health Studies, Group Health Cooperative, 1730 Minor Avenue #1600,
Seattle, WA 98101, USA.

OBJECTIVE: This study evaluated the effects of prenatal antidepressant exposure
on perinatal outcomes, congenital malformations, and early growth and
development. METHOD: Within a group-model health maintenance organization, all
infants with apparent prenatal exposure to tricyclic or selective serotonin
reuptake inhibitor (SSRI) antidepressants were frequency matched to an unexposed
comparison group by year of birth, maternal age, and mother’s lifetime use of
antidepressant drugs and mental health care. A structured blind review of
mothers’ and infants’ medical records examined perinatal outcomes, congenital
malformations, and developmental delay. RESULTS: Tricyclic antidepressant
exposure was not associated with any significant difference in perinatal
outcomes. Exposure to SSRIs was associated with a 0.9-week decrease in mean
gestational age, a 175-g decrease in mean birth weight, and a 0.29 decrease in
mean Apgar score at 5 minutes, but differences in birth weights and Apgar scores
were not significant after adjustment for gestational age. Differences in
gestational age and birth weights were unrelated to length of exposure, but
differences in Apgar scores were limited to those with third-trimester exposure.
Neither tricyclic antidepressant nor SSRI exposure was significantly associated
with congenital malformations or developmental delay. CONCLUSIONS: The authors
found no association between tricyclic antidepressant or SSRI exposure and
either congenital malformations or developmental delay. SSRI exposure during
pregnancy was associated with earlier delivery and consequent lower birth
weight. Third-trimester SSRI exposure was also associated with lower Apgar
scores. Women considering taking SSRIs during pregnancy may balance any higher
fetal risk against the risk of persistent or recurrent depression.

PMID: 12450956 [PubMed – indexed for MEDLINE]


51: Medscape Womens Health. 1998 Jan;3(1):1.

Managing psychiatric medications in the breast-feeding woman.

Suri RA, Altshuler LL, Burt VK, Hendrick VC.

UCLA Neuropsychiatric Institute and Hospital, Los Angeles, Calif., USA.

Given the high risk of postpartum psychiatric problems, clinicians need to be
prepared to appropriately manage the breast-feeding woman who needs
psychotropics. These psychiatric researchers examine the issues and offer
guidelines. Following childbirth, many women are at high risk for the onset or
recurrence of psychiatric illness. Women who need psychopharmacologic treatment
may wish to breast-feed their infants, but the data regarding the degree of drug
passage to the infant and the subsequent effects of this exposure on infant
growth and development are very limited, leaving clinicians with little guidance
for responding in ways that protect the health and well-being of both mother and
infant. In general, the less protein-bound, the more lipid-soluble, and the more
weakly basic a drug is, the more likely it is to diffuse into breast milk. When
a psychotropic medication is administered, the infant’s clinical status and
serum concentrations, including metabolite concentrations, should be closely
monitored. Among the agents that have been the subject of at least limited
studies in breast-feeding women are tricyclic antidepressants, selective
serotonin reuptake inhibitors, benzodiazepines, and the mood stabilizers
lithium, carbamazepine, and divalproex. This article examines the factors that
influence infant exposure to psychotropic medication through breast-feeding and
includes clinical guidelines for managing the breast-feeding woman on
psychotropics as well as protecting and caring for her infant.

Publication Types:
Review, Tutorial

PMID: 9732101 [PubMed – indexed for MEDLINE]


52: Ugeskr Laeger. 2002 Apr 1;164(14):1914-9.

[Breast feeding and treatment with antidepressive agents. A literature review] [Article in Danish]

Videbech P.

Institut for psykiatrisk grundforskning, afdeling for biologisk psykiatri,
Psykiatrisk Hospital i Arhus, DK-8240 Risskov.

Depression after delivery occurs frequently and, apart from being very painful,
it may cause disturbance in the child’s development. A number of these
depressions are so severe that medical antidepressant treatment is indicated.
This raises the question whether this kind of treatment should call for
interruption of breast-feeding. The problem is, however, that breast-feeding is
of major importance to the child, as well as to the mother. A review of present
knowledge about the excretion of antidepressants in breast milk and the reports
on the possible effects on the child would be useful, in order to create a
qualified basis for decision-making, together with the patient, on whether or
not to interrupt the breast-feeding. Furthermore, examination of the references
would result in concrete guidelines for the most appropriate way of dealing with
the treatment, if it is decided to continue the breast-feeding.

Publication Types:
Review Literature

PMID: 11957425 [PubMed – indexed for MEDLINE]


53: Can J Psychiatry. 2002 Jun;47(5):426-36.

Managing bipolar disorder during pregnancy: weighing the risks and benefits.

Viguera AC, Cohen LS, Baldessarini RJ, Nonacs R.

Perinatal and Reproductive Psychiatry Program, Massachusetts General Hospital,
Harvard Medical School, Boston, Massachusetts, USA.

BACKGROUND: Challenges for the clinical management of bipolar disorder (BD)
during pregnancy are multiple and complex and include competing risks to mother
and offspring. METHOD: We reviewed recent research findings on the course of BD
during pregnancy and postpartum, as well as reproductive safety data on the
major mood stabilizers. RESULTS: Pregnancy, and especially the postpartum
period, are associated with a high risk for recurrence of BD. This risk appears
to be limited by mood-stabilizing treatments and markedly increased by the
abrupt discontinuation of such treatments. However, drugs used to treat or
protect against recurrences of BD vary markedly in teratogenic potential: there
are low risks with typical neuroleptics, moderate risks with lithium, higher
risks with older anticonvulsants such as valproic acid and carbamazepine, and
virtually unknown risks with other newer-generation anticonvulsants and atypical
antipsychotics (ATPs). CONCLUSIONS: Clinical management of BD through pregnancy
and postpartum calls for balanced assessments of maternal and fetal risks and

Publication Types:
Review Literature

PMID: 12085677 [PubMed – indexed for MEDLINE]


54: Psychopharmacol Bull. 1998;34(3):339-46.

The course and management of bipolar disorder during pregnancy.

Viguera AC, Cohen LS.

Perinatal and Reproductive Psychiatry Research Program, Massachusetts General
Hospital, Boston 02114, USA.

Although the postpartum period has typically been considered a period of risk
for relapse of bipolar disorder, systematic data regarding the course of bipolar
disorder during pregnancy is essentially unknown. The management of bipolar
women who plan to conceive or who are pregnant poses significant challenges for
clinicians who care for these patients. Recent data suggest that pregnancy is
not protective and the risk for relapse after lithium discontinuation is similar
in pregnant and nonpregnant women with 50 percent relapsing within 6 months.
This article reviews the major clinical dilemmas in managing pregnant bipolar
patients and recent data on the course of bipolar disorder during pregnancy.
Treatment guidelines are presented.

Publication Types:
Review, Tutorial

PMID: 9803767 [PubMed – indexed for MEDLINE]


55: Am Fam Physician. 2002 Aug 15;66(4):629-36.

Summary for patients in:
Am Fam Physician. 2002 Aug 15;66(4):639.

Benefits and risks of psychiatric medications during pregnancy.

Ward RK, Zamorski MA.

Medical College of Wisconsin, St Mary’s Family Practice Center, Milwaukee 53211,

Traditionally, psychiatric medications were withheld during pregnancy because of
fear of teratogenic and other effects. The emergence of evidence of the safety
of most commonly used psychiatric medications, the availability of this
information in the form of online databases, and the documentation of the
adverse effects of untreated maternal mental illness have all increased the
comfort of physicians and patients with respect to the use of psychiatric
medications during pregnancy. The tricyclic antidepressants and fluoxetine
(Prozac) appear to be free of teratogenic effects, and emerging data support
similar safety profiles for the other selective serotonin reuptake inhibitors.
The mood stabilizers appear to be teratogenic. With the exception of the known
risk for depression to worsen in the postpartum period, there is little
consistent evidence of the effects of pregnancy on the natural history of mental
illness. Decisions regarding the use of psychiatric medications should be
individualized, and the most important factor is usually the patient’s level of
functioning in the past when she was not taking medications.

Publication Types:
Review, Tutorial

PMID: 12201556 [PubMed – indexed for MEDLINE]


56: J Psychopharmacol. 2000 Mar;14(1):77-80.

Evidence-based psychopharmacology 3. Assessing evidence of harm: what are the
teratogenic effects of lithium carbonate?

Warner JP.

Imperial College of Science, Technology and Medicine, St Charles Hospital,
London, UK.

Critical appraisal techniques are not only useful in evaluating evidence of
therapeutic trials. In this final article of the series of evidence-based
psychopharmacology, the evidence about the teratogenic effects of lithium
carbonate is considered. This exercise highlights the importance of assessing
the evidence oneself and not relying on the interpretation others put on it.

Publication Types:

PMID: 10757258 [PubMed – indexed for MEDLINE]


57: JAMA. 1999 Oct 6;282(13):1264-9.

Pharmacologic treatment of depression during pregnancy.

Wisner KL, Gelenberg AJ, Leonard H, Zarin D, Frank E.

Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.

CONTEXT: Despite the frequency of depression in women of childbearing age,
information to guide patients and physicians through a consideration of
treatment during pregnancy is limited. OBJECTIVE: To identify risk factors
associated with treatment of major depression during pregnancy to help
physicians develop treatment plans that optimize clinical care. DATA SOURCES:
Reports of prospective controlled trials in English were identified from MEDLINE
and Health STAR using the search terms antidepressant during pregnancy and
depression during pregnancy, by manually searching bibliographies of review
articles, and through discussions with investigators for 1989-1999. STUDY
SELECTION: We selected studies in which maternal and infant health outcomes
associated with antidepressant exposure were compared with those of
non-teratogen-exposed controls. Four studies published since 1993 were
identified and included in the analysis. DATA EXTRACTION: We abstracted
information about identification of subjects, comparison groups, pregnancy, and
birth outcomes. We organized the data along 5 domains of reproductive toxicity:
intrauterine fetal death, morphologic teratogenicity, growth impairment,
behavioral teratogenicity, and neonatal toxicity. DATA SYNTHESIS: Data were
available for tricyclic antidepressants (collectively), fluoxetine, and newer
selective serotonin reuptake inhibitors (collectively). Exposure to these agents
did not increase risk for intrauterine death or major birth defects. Decreased
birth weights of infants exposed to fluoxetine in the third trimester were
identified in 1 study. The development of children whose mothers took tricyclics
or fluoxetine during gestation did not differ from that of controls. Direct drug
effects and withdrawal syndromes occurred in some neonates whose mothers were
treated with antidepressants near term. CONCLUSIONS: Although few in number, new
information from prospective studies provides a welcome change from decision
making based on nonprospective data. Monitoring and interventions for patients
with identified risks (eg, poor weight gain) are recommended.

Publication Types:
Review Literature

PMID: 10517430 [PubMed – indexed for MEDLINE]


58: Psychopharmacol Bull. 1997;33(2):249-51.

Nortriptyline and its hydroxymetabolites in breastfeeding mothers and newborns.

Wisner KL, Perel JM, Findling RL, Hinnes RL.

Women’s Services, Case Western Reserve University School of Medicine, Cleveland,
OH 44106, USA.

We previously reported the serum nortriptyline levels of a series of
breastfeeding mother-infant pairs. Nortriptyline was below the level of
detectability in the infants’ sera; however, two young infants aged 10 weeks or
less had low concentrations of 10-hydroxy-nortriptyline. Because very young
breastfeeding infants are likely to be at increased risk for toxicity, we have
focused our study on breastfeeding newborns. We present additional data from six
mothers and their infants (4 weeks of age), as well as data from one prematurely
born baby. We were able to quantify nortriptyline in one infant and another had
higher levels of hydroxymetabolites than previously reported, although still
very low. No adverse clinical effects were observed in the infants.

PMID: 9230638 [PubMed – indexed for MEDLINE]


59: Am J Psychiatry. 1996 Sep;153(9):1132-7.

Comment in:
Am J Psychiatry. 1997 Aug;154(8):1174.
Am J Psychiatry. 1997 Aug;154(8):1174-5.
Am J Psychiatry. 2001 Jan;158(1):144-5.

Antidepressant treatment during breast-feeding.

Wisner KL, Perel JM, Findling RL.

Mood Disorders Program, Case Western Reserve, University School of Medicine,
Cleveland, OH 44106, USA.

OBJECTIVE: The primary purpose of this article is to review critically the
literature about use of antidepressants during lactation. Strategies for the
clinical management of depressed breast-feeding mothers are also suggested.
METHOD: The authors conducted a computerized search of MEDLINE for articles. The
review includes studies in which serum levels of drugs were obtained from
nursing infants. RESULTS: Fifteen published reports were located that provided
information for the following nine antidepressants: amitriptyline,
nortriptyline, desipramine, clomipramine, doxepin, dothiepin, fluoxetine,
sertraline, and bupropion. CONCLUSIONS: Amitriptyline, nortriptyline,
desipramine, clomipramine, dothiepin, and sertraline were not found in
quantifiable amounts in nurslings, and no adverse effects were reported.
Therefore, these are the drugs of choice for breast-feeding women. Adverse
effects were described in some young infants whose mothers had been treated with
doxepin or fluoxetine during breast-feeding. The collective serum level data
suggest that infants older than 10 weeks are at low risk for adverse effects of
tricyclics, and there is no evidence of accumulation. Research needs include an
expanded database of mother-baby serum levels, behavioral assessments of infants
during nursing, and longitudinal developmental evaluation of nurslings.
Prescription of an antidepressant for a breast-feeding woman is a case-specific
risk-benefit decision.

Publication Types:
Review, Tutorial

PMID: 8780414 [PubMed – indexed for MEDLINE]


60: J Psychopharmacol. 1999;13(1):64-80.

Psychotropic drugs in mothers’ milk: a comprehensive review of assay methods,
pharmacokinetics and of safety of breast-feeding.

Yoshida K, Smith B, Kumar R.

Perinatal Section, Institute of Psychiatry, Denmark Hill, London, UK.

Many mentally ill women want to breast-feed their babies but, if they are taking
psychotropic drugs, there is very little systematic data upon which to base
decisions about whether or not it is safe to do so. We therefore attempt to
provide a comprehensive and critical summary of existing case reports and of
studies of breast-feeding in relation to commonly used psychotropic drugs. The
literature review focuses on the following drugs: antidepressants: tricyclics
and serotonin selective reuptake inhibitors (SSRIs); antipsychotic drugs:
chlorpromazine, perphenazine, haloperidol and clozapine; mood stabilizers:
lithium and carbamazepine; and benzodiazepines. The research literature consists
mainly of single case reports and there have been very few attempts at
controlled, longitudinal investigations. Findings are often difficult to compare
because of differences in methods or because of lack of key information. Most
data are available about the tricyclic antidepressants but even here we have
found that the reports cover only a grand total of 66 mother-infant pairs.
Dilemmas about whether or not to contraindicate breast-feeding arise most
commonly in relation to postnatal depression. The findings to date suggest that
provided that infants are healthy at the outset it is likely that the benefits
of breast-feeding will outweigh potential hazards if their mothers are taking
established tricyclic drugs at recommended dose levels. Much less is known about
risks associated with SSRI antidepressants or about antipsychotic drugs such as
phenothiazines and butyrophenones or mood stabilizers such as carbamazepine, all
of which enter breast-milk. Safeguards are suggested for future single case
studies, which, as they accumulate, will provide a platform for mounting
controlled prospective studies properly to test for any acute toxic effects and
for possible long-term adverse effects of such drugs on infants’ development.
Appendix 1 is a review of assay methods. Appendix 2 examines pharmacokinetic
factors in newborn preterm and sick infants with special reference to
contraindications to breast-feeding. Appendix 3 is a review of methods for
assessing infant health and development.

Publication Types:
Review, Academic

PMID: 10221361 [PubMed – indexed for MEDLINE]


61: Psychol Med. 1998 Jan;28(1):81-91.

Neuroleptic drugs in breast-milk: a study of pharmacokinetics and of possible
adverse effects in breast-fed infants.

Yoshida K, Smith B, Craggs M, Kumar R.

Section of Perinatal Psychiatry, University of London.

BACKGROUND: Very little is known about the pharmacokinetics of neuroleptic drugs
in breast-feeding mothers and their infants or about possible adverse effects in
the infants. METHOD: Twelve mothers who breast-fed their infants were prescribed
haloperidol, chlorpromazine or trifluoperazine. Two methods, enzyme immunoassay
(EIA) and high performance liquid chromatography (HPLC) were used to assay these
drugs in samples from mothers, but infants’ samples were assayed only by the
more sensitive EIA. Repeated clinical and developmental assessments of the
breast-fed infants were carried out up to 30 months of age. The control subjects
were 18 bottle-fed infants whose mothers were also prescribed neuroleptic or
mood-stabilizing drugs. RESULTS: The total concentrations of neuroleptic drugs
and their principal metabolites in maternal plasma were correlated with
concentrations in fore-milk. Infants were ingesting up to 3% of the maternal
daily dose per kg body weight and small amounts of the drugs were detected in
infants’ plasma and urine. Concentrations of haloperidol in the adult range were
found in plasma from 2 of 5 infants assayed by EIA but there was no evidence of
any acute or delayed adverse effects. Three other breast-fed infants whose
mothers were prescribed both haloperidol and chlorpromazine showed a decline in
their developmental scores from the first to the second assessment at 12-18
months. CONCLUSION: More extensive longitudinal studies are needed but, in the
meantime, there appears to be grounds for caution if breast-feeding mothers are
prescribed doses of single or two neuroleptic drugs at the upper end of their
recommended ranges.

PMID: 9483685 [PubMed – indexed for MEDLINE]


62: J Affect Disord. 1997 May;43(3):225-37.

Investigation of pharmacokinetics and of possible adverse effects in infants
exposed to tricyclic antidepressants in breast-milk.

Yoshida K, Smith B, Craggs M, Kumar RC.

Section of Perinatal Psychiatry, Istitute of Psychiatry, London, UK.

We have studied ten breast-feeding mothers who were prescribed tricyclic
antidepressant drugs and have also compared their infants’ development with a
similar group (n = 15) who were bottle-fed. Concentrations of tricyclic drugs in
maternal plasma and urine, in fore-milk and hind-milk and in infant plasma (n =
6) and urine (n = 9) were measured by gas chromatography (GC) and by an enzyme
immunoassay (EIA). The fat concentration in milk was also measured. Infants
health and development were monitored by physical examination and by the Bayley
Scales of Infant Development up to 30 months. The amounts of tricyclic drugs and
their principal metabolites in maternal plasma were significantly correlated
with the oral dose and with the amounts in breast-milk. Drug concentrations in
fore-milk, but not in hind-milk, increased in line with its fat content, which
was maximal in hind-milk. Correlations between gas chromatographic and enzyme
immunoassays of maternal samples were high provided that the values for
amitriptyline and nortriptyline were excluded; immunoreactivities to these
compounds were abnormally high, suggesting that metabolites were also being
measured by EIA. The daily doses of drugs ingested by breast-fed infants were
about 1% of the maternal dose/kg and the immunoassay detected very small amounts
of tricyclics in infants’ plasma and urine. No acute toxic effects were found in
the ten medicated breast-fed infants and there was no evidence of developmental
delays in comparison with bottle-fed infants. Although the number of subjects in
this study is small, when taken in conjunction with other published findings, we
have not found any reason to prevent mothers who are taking established
tricyclic antidepressants from breast-feeding their babies if they want to do

PMID: 9186793 [PubMed – indexed for MEDLINE]


63: Prescrire Int. 2002 Feb;11(57):17.

Drugs and breast-feeding.

[No authors listed]

(1) Report of severe adverse effects in infants from drugs passing into breast
milk are rare. (2) Two reports of neurological disorders in infants due to
doxepin, a tricyclic antidepressant, necessitating hospitalisation, serve as a
reminder that this risk exists. (3) Epidemiological data are almost non
existent. A prospective follow-up study of more than 800 breast-fed infants
whose mothers were taking medicinal drugs showed minor adverse effects in 11% of
the children (mainly diarrhoea, drowsiness and irritability). None of the
mothers sought medical advice. (4) When a breast-feeding mother requires drug
therapy, all available information should be weighed up before advising her to
switch to bottle feeding.

PMID: 11985371 [PubMed – indexed for MEDLINE]