Neonatal Serotonin Syndrome

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Neonatal Serotonin Syndrome

 

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[sSRI-Research] Neonatal Serotonin Syndrome

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Neonatal Serotonin Syndrome

 

http://www.rednova.com/news/display/?id=161153 & source=r_health

 

With the increasing use of serotonin-enhancing

antidepressants, more

articles and anecdotal reports suggest problems for

infants born to

depressed mothers taking these drugs. A previous

column (Malone,

Papagni, Ramini, & Keltner, 2004), after a review of

existing

literature, concluded that effects of selective

serotonin reuptake

inhibitors (SSRIs) related to breastfeeding can be

observed in

neonates, for example, excessive sleepiness, poor

feeding, weight loss

(Hale, 2002), and that third-trimester consumption

leads to lower

birthweight, prematurity, lower Apgar scores,

respiratory distress,

jitteriness, and hypoglycemia (Carit, 2004; Chambers,

Johnson, Dick,

Felix, & Lyons-Jones, 1996). So, while these infants

experience

adverse effects associated with SSRI use, overall it

is believed that

such usage does not confer significant immediate risk

nor long-term

consequence. In fact, studies indicate teratogeneity

is not associated

with SSRI or tricyclic antidepressant (TCA) use

(Simon, Cunningham, &

Davis, 2002). However, the studies (i.e. studies

looking at the

breastfeeding dyad or at prenatal antidepressant use)

do not address

nonbreastfed infants of women taking

serotonin-enhancing agents nor do

they address infants (breastfed or not) of women

discontinuing

antidepressants after childbirth. Such neonates may be

subject to a

serotonin discontinuation syndrome; that is, the

neonatal serotonin

syndrome (NSS).

 

Probability of Depression among Women of Childbearing

Age

 

Is antidepressant use likely during the childbearing

years? The

answer, of course, is yes. The rate of depression

among women in

general is around 10% (American Psychiatric

Association, 2000) but may

reach a lifetime prevalency rate of 25% (Sadock &

Sadock, 2003). Twice

as likely among women as opposed to men, depression

has its greatest

prevalence during the childbearing years (Simon,

Cunningham, & Davis,

2002). While first-time episodes can occur between the

ages of 20 and

50, increasingly, clinicians voice a concern about an

upswing in

incidence of depression among women under the age of

20. That this age

group has a high birthrate, both with and without the

benefit of legal

marriage, is old news. Further, since SSRIs are the

agents of choice

for most women related to side effect profile and lack

of evidence of

SSRI-induced congenital or developmental problems,

many pregnant women

are prescribed SSRIs.

 

Thus, women during childbearing years suffer high

rates of depression

with about one-half of pregnancies unplanned (Einarson

et al., 2001).

Because SSRIs hold the largest market share for

antidepressants, many

if not most of these women take these drugs. Further,

because

clinicians are not hesitant to continue SSRI treatment

during

pregnancy due to aforementioned evidence of safety,

many of these

women will continue antidepressant therapy through

delivery. Hence,

the large number of pregnant women treated prenatally

(and not

breastfeeding) coupled with those mothers who choose

to discontinue

antidepressant therapy at birth, potentially create a

large cohort of

infants vulnerable to serotonin withdrawal syndrome or

NSS.

 

Evidence of Neonatal Serotonin Syndrome

 

Several groups have conducted studies of

antidepressant use during

pregnancy, especially during the third trimester.

Studies have

examined a single SSRI, compared SSRIs, studied SSRIs

in combination

with another class of antidepressant, and analyzed

differences between

SSRIs and TCAs. These studies suggest the presence of

NSS in babies

born to mothers using serotonin-enhancing

antidepressants. Table 1

outlines the evidence for NSS.

 

In a case study by Morag, Batash, Keidar, Bulkowstein,

and Heyman

(2004), a neonate born to a mother being treated

prenatally with

paroxetine received a 1 min Apgar score of 7 for lack

of spontaneous

cry and color. The neonate's Apgar score increased to

9 after 5 min.

Within 4 days, the neonate was admitted to the

hospital for lack of

cry and lethargy. After examination, it was also found

that this

neonate had an absence of reaction to pain stimuli.

The EEG, which was

conducted, " showed a pathologic pattern of depressed

background

activity with trace alternance and independent spike

and wave

activity. Somato-sensory-evoked potentials (SSEPs) on

the posterior

tibial were impossible to elicit " (Morag et al., 2004,

p. 99). By day

14, the newborn was crying spontaneously and had a

positive reaction

to pain stimuli.

 

Table 1. Evidence Indicating NSS from Third Trimester

Antidepressant

Use

 

In a study of 55 neonates with third-trimester

exposure to paroxetine,

researchers found a significant difference in the

occurrence of

complications between those neonates exposed during

the last semester

and the control group (p = .03). Twelve of the exposed

neonates

exhibited neonatal complications such as respiratory

distress (H = 9),

hypoglycemia (n = 2), and jaundice (n = 1) after birth

while three of

the control group neonates exhibited complications.

Exposed neonates

were also more likely to have been born prematurely

than the control

group (p = .02). When the occurrence of respiratory

distress was

examined further, maternal use of paroxetine in the

third trimester

was the only factor found to be a significant

contributor to

respiratory distress (Costei, Kozer, Ho, Ito, & Koren,

2002).

 

Oberlander, Misri, Fitzgerald, Kostaras, Rurak, and

Riggs (2004)

conducted a study comparing neonates with prenatal

exposure to one

SSRI (fluoxetine, paroxetine, or sertraline), or both

paroxetine and

the benzodiazepine clonazepam, to neonates with no

prenatal exposure

to psychotropic or antidepressant medications.

Approximately 30% of

infants in the exposure groups exhibited respiratory

distress and 11%

were born with hypotonia; only 9% of the control

infants had

adaptation problems at birth (likelihood ratio = 5.64;

95% CI: 1.1-

25.3). When the two exposure groups were compared,

there were no

significant differences in their symptom outcomes

(Oberlander et al.,

2004).

 

A study of fluoxetine, sertraline, paroxetine, and

citalopram by

Hendrick, Smith, Suri, Hwant, Haynes, and Altshuler

(2003)

investigated the birth outcomes of infants exposed to

these

medications prenatally. There were 28 total

complications in this

group (n = 138). Of the neonates, 2.9% were considered

low birthweight

and all had been exposed to at least 40 mg of

fluoxetine per day. Nine

preterm births were recorded after fluoxetine (n = 5),

paroxetine (n =

2), and sertraline (n = 2) exposures. The rates of low

birthweight and

preterm births were found to be below the national

averages for these

measures. Finally, there was no correlation found

between medication

dosage and gestational age (Hendrick et al., 2003).

 

An additional study of fluoxetine, sertraline, and

paroxetine examined

birth outcomes of neonates who had been exposed to one

of these

medications prenatally and compared to neonates of

mothers with

diagnosed depression but who chose not to take

medications during

pregnancy. The authors found a significant difference

in the 1 min (p

= .05) and 5 min (p = .00) Apgar scores of the exposed

group compared

to the non-exposed group. All of the neonates admitted

to the neonatal

intensive care unit (NICU) for respiratory distress (n

= 6), meconium

aspiration (n = 4), and cardiac murmur (n - 1) were in

the exposure

group. However, this was not a significant association

(p = .06).

Mental and motor development was compared in both

groups using the

Bayley Scales of Infant Development, second Edition

(BSID-II). There

was no difference between the two groups for the

mental development

index (MDI) but the associations for the psychomotor

development index

(PDI) and the behavioral rating scale (BRS) both

reached significance

(p - .03 and .04, respectively). For individual BRS

scales, motor

quality, especially fine motor movement, was the only

factor showing a

significant difference between the two groups (p =

..01) (Casper et

al., 2003).

 

Research conducted by Laine, Heikkinen, Ekblad, and

Kero (2003)

compared 20 infants of mothers who took either

fluoxetine or

citalopram during pregnancy to matched controls whose

mothers did not

receive any psychotropic medications during pregnancy.

These infants

were compared during the first 4 days of life, at 2

weeks, and at 2

months based on vital signs and an established

serotonergic symptom

score. At birth, the exposed neonates had lower Apgar

scores at 1, 5,

and 15 min but this association was only found to be

significant at 15

min (p = .02). The only difference in vital signs was

seen at the age

of 2 weeks when the SSRI group had a significantly

higher heart rate

than the exposed group (p = .049). On days 1 to 4,

infants in the SSRI

group showed a significant increase in serotonergic

symptom scores

when compared to the controls (p = .008) with

restlessness, tremor,

and rigidity scoring highest. When this group was

stratified by

medication, the citalopram group showed no significant

difference from

the controls but the fluoxetine exposed group had

significantly higher

scores (p = .02). As the authors state, " the

difference in the symptom

score between fluoxetine-exposed infants and controls

was no longer

evident at the age of 2 weeks " (Laine et al, 2003, p.

723).

 

Zeskind and Stephens (2004) investigated infants who

were exposed \to

citalopram, fluoxetine, paroxetine, sertraline, a

combination of

these, or paroxetine along with sertraline and

bupropion compared to

infants of mothers who did not use SSRIs during

pregnancy. When

examining newborn birth characteristics, 1 and 5 min

Apgar scores were

not found to be significant. However, the SSRI group

had significantly

lower gestational ages than the control group (p =

..019). The outcome

variables examined were tremulousness, behavioral

states (different

states and number of changes), active sleep (number of

epochs, number

of bouts, longest bout, and number of startles), motor

activity, and

heart rate variability. Analysis of the variables

showed a significant

difference between the means for the exposed and

nonexposed groups for

all variables. However, when the means were adjusted

for gestational

age, number of epochs, number of startles, and heart

rate variability

were no longer significant (Zeskind & Stephens, 2004).

 

Kalln (2004), in a study based in Sweden, investigated

the birth

outcomes of nearly 1000 neonates whose mothers had

taken at least one

of the following medications: clompramine,

amitriptyline, citalopram,

paroxetine, fluoxetine, sertraline, or venlafaxine.

These infants were

compared to all other infants in the Swedish Medical

Birth Registry.

The exposed infants had more preterm births and lower

birthweights

when compared to the nonexposed group. However, there

was no

statistical difference between the SSRI group and the

TCA group. The

exposed infants also exhibited respiratory distress,

hypoglycemia, low

Apgar scores, and convulsions at significant levels.

However, the

association with SSRIs and hypoglycemia as well as

convulsions did not

reach the level of significance. For all outcomes, the

TCA exposed

group achieved higher odds ratios than the SSRI

exposed group, but

none of these associations reached significance. A

final analysis by

Kalln (2004) examined paroxetine compared to the other

SSRIs. None of

the associations reached statistical significance.

 

Summary

 

Babies born to mothers taking serotonin-enhancing

antidepressants

(e.g. SSRIs7 serotonin-elevating TCAs [amitriptyline,

imipramine,

clomipramine, etc], venlafaxine) are significantly

more likely to

exhibit a number of adverse effects related to

serotonin withdrawal

syndrome. While these effects seem to have a short

half-life, they

nonetheless deserve recognition and anticipation by

clinicians. In

some cases, discontinuation of antidepressants during

the third

trimester of pregnancy may be warranted.

 

References

 

American Psychiatric Association. (2000). Diagnostic

and statistical

manual of mental diseases (4th edn). TR. Washington,

D.C.: Author.

 

Carlat, DJ. (2004). SSRIs and pregnancy: Troubling

questions remain.

The Carit Report, 2(9), 1, 6.

 

Casper, R.C., Fleisher, B.E., Lee-Ancajas, J.C.,

Gilles, ?., Gaylor,

E., DeBattista, ?., & Hoyme, H.E. (2003). Follow-up of

children of

depressed mothers exposed or not exposed to

antidepressant drugs

during pregnancy. Journal of Pediatrics, 142, 402-408.

 

Chambers, C, Johnson, K.A., Dick, L.M., Felix, R.J., &

Lyons- Jones,

K. (1996). Birth outcomes in pregnant women taking

fluoxetine. New

England Journal of Medicine, 335, 1010-1015.

 

Costei, A.M., Kozer, E., Ho, T., Ito, S., & Koren, G.

(2002).

Perinatal outcome following third trimester exposure

to paroxetine.

Archives of Pediatrics and Adolescent Medicine, 156,

1129-1131.

 

Einarson, A., Fatoye, B., Sarkar, M., Lavigne, S.V.,

Brochu, }.,

Chambers, C., Mastroiacovo, P., Addis, A., Matsui, D.,

Schuler, L.,

Einarson, T.R., & Koren, G. (2001). Pregnancy outcome

following

gestational exposure to venlafaxine: A multicenter

prospective

controlled study. American Journal of Psychiatry,

158(10), 17281730.

 

Hale, T.W. (2002). Medications and mothers' milk (10th

edn). Amarillo,

TX: Pharmasoft.

 

Hendrick, V., Smith, L.M., Suri, R., Hwant, S.,

Haynes, D., &

Altshuler, L. (2003). Birth outcomes after prenatal

exposure to

antidepressant medication. American Journal of

Obstetrics and

Gynecology, 188, 812-815.

 

Kalln, B. (2004). Neonate characteristics after

maternal use of

antidepressants in late pregnancy. Archives of

Pediatrics and

Adolescent Medicine, 158, 312-316.

 

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

(2003). Effects of

exposure to selective serotonin reuptake inhibitors

during pregnancy

on serotonergic symptoms in newborns and cord blood

monoamine and

prolactin concentrations. Archives of General

Psychiatry, 60, 720-726.

 

Malone, K.J., Papagni, K., Ramini, S., & Keltner, N.L.

(2004).

Antidepressants, antipsychotics, benzodiazepines, and

the

breastfeeding dyad. Perspectives in Psychiatric Care,

40(2), 73-85.

 

Morag, L, Batash, D., Keidar, R., Bulkowstein, M., &

Heyman, E.

(2004). Paroxetine use throughout pregnancy: Does it

pose any risk to

the neonate? Journal of Toxicology, 42(1), 97-100.

 

Oberlander, T.F., Misri, S., Fitzgerald, C.E.,

Kostaras, X., Rurak,

D., & Riggs, W. (2004). Pharmacologie factors

associated with

transient neonatal symptoms following prenatal

psychotropic medication

exposure. Journal of Clinical Psychiatry, 65(2), 230-

237.

 

Sadock, BJ. & Sadock, V.A. (2003). Synopsis

ofpsychiatn/.

Philadelphia: Lippincott.

 

Simon, G.E., Cunningham, ML., & Davis, R.L. (2002).

Outcomes of

prenatal antidepressant exposure. American Journal of

Psychiatry,

159(12), 2055-2061.

 

Zeskind, P.S., & Stephens, L.E. (2004). Maternal

selective serotonin

reuptake inhibitor use during pregnancy and newborn

neurobehavior.

Pediatrics, 113(2), 368-375.

 

Norman L. Keltner, EdD, RN, and Stephanie Hall, BA,

MPH

 

Norman L. Keltner, EdD, RN is Professor in the School

of Nursing

University of Alabama at Birmingham

 

Stephanie Hall, BA, MPH is a student in the School of

Nursing

University of Alabama at Birmingham

 

Author contact: NKeltner, with a copy to the

Editor:

mary

 

Copyright Nursecom, Inc. Apr-Jun 2005

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Published: 2005/07/03 03:01:09 CDT

 

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