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

 

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

 

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