Until the thalidomide disaster in the 1960's, many people believed that the placenta formed a barrier against potential harmful drugs. Now it is clear that any chemical substance administered to a pregnant woman is able to cross the placenta to some extent. In order to classify the risk to the fetus, the Food and Drug Administration (FDA) established five categories to indicate the potential of a drug which crosses the placenta to cause birth defects. These categories are:
A |
Controlled studies in pregnant women fail to demonstrate a risk to the fetus in the first trimester with no evidence of risk in later trimesters. |
B |
Either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, OR animal reproduction studies have shown an adverse effect that was not confirmed in controlled studies in women in the first trimester and there is no evidence of a risk in later trimesters. |
C |
Either studies in animals have revealed adverse effects on the fetus and there are no controlled studies in women, OR studies in women and animals are not available. |
D |
There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk. |
X |
Studies in animals or human beings have demonstrated fetal abnormalities OR there is evidence of fetal risk based on human experience, OR both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. |
Adapted from Drug Information Handbook1
The first trimester of pregnancy is the period of fetal organ development. It is within these three months that the fetus is at greatest risk of the teratogenic effects of drugs. Antidepressant agents represent a class of drugs in which concern has been raised over use in pregnancy. Approximately 35% of women take a psychoactive drug while pregnant.2 However, the psychiatric literature has recommended that psychotropic agent be administered with extreme caution to pregnant females.3 The concern is that the women will put their unborn baby more at risk from destructive behavior if the agent is discontinued than if the drug is allowed to continue throughout the pregnancy.
In the past, the Food and Drug Administration assigned antidepressant drugs such as the tricyclics and the monoamine oxidase inhibitors the Pregnancy category of C or D. In contrast, the majority of newer antidepressant agents (i.e. the selective serotonin reuptake inhibitors; SSRIs) have a category B rating. This article reviews the available pre- and post-marketing information about fetal outcomes in women who took SSRIs or venlafaxine during the first trimester of pregnancy.
Fluoxetine (Prozac®) is the antidepressant which has most extensively been studied in pregnancy during recent years. The first selective serotonin reuptake inhibitor marketed in the United States, it is used for the treatment of major depression and obsessive-compulsive disorder. The mechanism of action includes inhibition of central nervous system neuron serotonin uptake; minimal or no effect on reuptake of norepinephrine or dopamine and non-significant binding of a-adrenergic, histamine or cholinergic receptors. This agent is useful for patients at risk from sedation, hypotension, and anticholinergic effects of tricyclic antidepressants. Fluoxetine has been assigned a Pregnancy Risk Category B designation.
Lilly Research Laboratories estimates the population of patients treated with fluoxetine through August 31, 1994 to be approximately fifteen million, worldwide. Teratology studies performed in rats and rabbits at nine and eleven times the maximum daily human dose revealed no evidence of harm to the fetus. In presonal communication with Lilly, animal reproduction data was not included. Data from Lilly indicates during human clinical trials there were seventy-five first trimester fluoxetine exposures. Fluoxetine was discontinued as soon as pregnancy was determined. There were twenty-three normal births, twenty-five therapeutic abortions, eight spontaneous abortions, three twin pregnancies and one major malformation (hepatoblastoma).
As of August 31, 1994 Lilly had obtained 1446 prospective reports of pregnancy. Outcomes available: four hundred-seventy six normal births, twenty premature births, one hundred-five therapeutic and eighty one spontaneous abortions, three stillborn, fourteen twin pregnancies, fourteen perinatal major malformations and ten post perinatal malformations. There have been thirty-eight retrospectively reported pregnancies considered to be malformations.
Since the reports are voluntarily made, abnormal outcome is more likely to be reported to company and since the data is not compared to matched controls, it is hard to draw conclusions. Lilly Corporation recommends Prozac should be used during pregnancy only if clearly needed.4
An independent study by Pastuszak et al compared pregnancy outcome following first-trimester fluoxetine exposure with pregnancy outcome in two matched control groups. The researchers prospectively collected data on 256 women [74 women in each arm-fluoxetine, tricyclics, and nonteratogen controls] who contacted one of four Teratogen Information Service centers for counseling. The study suggested that the use of fluoxetine during the first trimester is not associated with major malformations. The study also reported that women concomitantly exposed to fluoxetine and tricyclic antidepressants tend to report higher rates of miscarriage. The study concluded that further studies are needed to confirm this observation and to separate the effects of the psychiatric condition from the associated drugs. The investigators called for long-term studies to rule out the potential developmental teratology of fluoxetine.5
Paroxetine (Paxil®) is also a selective serotonin reuptake inhibitor. It differs from fluoxetine in structure, metabolites, and half-life; paroxetine having no active metabolites, and a half-life of approximately one day. Paroxetine is classified as a Pregnancy Category B drug.
In animal reproduction studies performed in rats and rabbits at doses up to 50 and 6 times the maximum recommended human dose, respectively, paroxetine revealed no evidence of teratogenic effects. Impaired reproduction function (i.e. reduced pregnancy rate, increased pre- and post- implantation losses, decreased viability of pups) was found in reproduction studies in rats at doses which were 315 times the highest recommended human dose on a mg/kg basis. In addition, irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2-52 weeks. However, the company noted, animal reproduction studies are not always predictive of human response.
SmithKline Beecham, the manufacturer, estimates more than 2.5 million individuals have been treated with paroxetine worldwide. The company has a compilation of data on file from worldwide, pre-marketing and post-marketing clinical trials, spontaneous reports, and reports from Regulatory Authorities. These reports state that 232 women received treatment with paroxetine during pregnancy. Ninety-three per cent of the women received paroxetine during the first trimester of pregnancy. SmithKline Beecham categorizes these reports as follows:6
Of interest are the 129 pregnancies in which outcomes were not known. For 120 of these patients, exposure to paroxetine occurred during the first trimester. One patient had received paroxetine during the second trimester and another patient had received paroxetine during the third trimester. In 7 women, the exact time of paroxetine exposure was not known. This tremendous lost-to- followup makes it difficult to draw inferences about the data.
Of the fourteen reports of congenital abnormality or abnormal outcomes, three infants died either during or several days after birth. One of severe hyaline membrane disease, pneumonia, hypotension and metabolic acidosis, another of respiratory distress secondary to prematurity, and the third infant had its umbilical cord split into three parts and improperly attached to the placenta. In the remaining cases, the infants were born with the following anomalies: clubfoot; undescended testicle; hernia; skull asymmetry; pendular nystagmus and congenital cataracts; "clicky" left hip; vascular pigmentation; ductal murmur (later revealed to be atrial dilation and patent ductus arteriosus; patent foramen; icterus; polycythemia; bilirubinemia; peripheral stenosis murmur; congenital nystagmus; and erythema toxicum. One infant who was born at full term was described as "jittery".7 Another full-term infant had multiple vascular anomalies including small port wine stain and extensive vascular mottling over the limbs and trunk, horseshoe kidney at 11 weeks, and cutis marmorata telangeictatia with hypertrophy of the right leg. In all of these cases no association was found between the abnormal outcome and paroxetine exposure.
An independent Drug Safety Research Unit in Southampton, England reported the following:8
Timing of exposure |
Total pregnancies |
Live births |
Spontaneous abortions |
Termination of pregnancy |
Not Known |
D/C before last menstrual period |
66 |
12 |
9 |
5 |
40 |
First trimester |
63 |
39 |
8 |
11 |
5 |
Uncertain |
8 |
2 |
1 |
1 |
4 |
Total |
137 |
53 |
18 |
17 |
49 |
As with company data on file, methodological problems do not allow conclusion to be draw about the association between paroxetine exposure and abnormal outcomes. Like Lilly Corporation, SmithKline Beecham recommends that Paxil not be used during pregnancy and should only be used if clearly needed.
Limited information concerning these two agents is available. Sertraline (Zoloft®, Roerig) is classified as Category B while Fluvoxamine (Luvox®, Solvay) is assigned Category C status. Sertraline at 2.5-10 times maximum human dose is associated with delayed ossification in the fetuses of rats and rabbits. Decreased litter survival was noted at doses of approximately 5 times the maximum human mg/kg dose. Likewise, reported animal studies of fluvoxamine in rats demonstrated increased pup mortality at birth and decreased postnatal pup weight and survival.9
Venlafaxine (Effexor®) is a unique antidepressant classified as a serotonin and norepinephrine reuptake inhibitor. Venlafaxine is reported in the package insert to be a pregnancy category C drug. Venlafaxine did not cause malformations in the offspring of rats or rabbits given doses up to 11 or 12 times the maximum recommended human daily dose on a mg/kg basis, respectively. In rat animal studies at 10 times (mg/kg basis) the maximum human daily dose, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation. It again is cautioned that animal reproductive studies are not predictive of human response.
Although a negative pregnancy test was required prior to enrollment in clinical trials, fourteen pregnancies were reported among 1239 venlafaxine-treated women. According to data on file from Wyeth-Ayerst laboratories, there were five full-term births in the venlafaxine group with normal outcomes. Fetal exposure to venlafaxine in the five pregnancies occurred in the first trimester. One ectopic pregnancy was reported in a woman with a history of two spontaneous abortions. Three spontaneous abortions were reported in total, one patient was lost to follow-up and the remaining women terminated their pregnancies via elective abortions. Wyeth-Ayerst also states they have received rare spontaneous reports of congenital anomalies (including craniofacial abnormalities) which coincide with the use of venlafaxine during the first trimester of pregnancy. The exact numbers were not stated in personal correspondence with the company.10
In conclusion, for a quarter-century psychiatric textbooks have instructed physicians to avoid administering psychotropic drugs to pregnant women based on case reports of fetal malformations. Better pre- and post-marketing surveillance of the newer antidepressants has allowed the Food and Drug Administration to make more informed decisions about the potential risk of antidepressants to the fetus. Animal reproduction studies of the selective serotonin reuptake inhibitors {fluoxetine, paroxetine, sertraline, fluvoxamine) as well as the unique antidepressant venlafaxine show that these agents cause increased mortality in litters of rats and rabbits but no teratogenic effect. Human clinical trials data revealed congenital abnormalities and abnormal outcomes in fetuses which were exposed to these agents however, without the availability of matched controls, no solid conclusion can be drawn about the association between antidepressant exposure and fetal outcome. More studies like the Pastuszak et al trial are needed. Since teratogenicity data can be conflicting, the potential benefits must outweigh the potential risk to the fetus before a recommendation can be made to start or continue therapy with one of the newer antidepressants.
1. Lacy C, Armstrong LL, Lipsy RJ. Drug Information Handbook, ed 2. Hudson, OH. Lexi- Comp, Inc. 1993, p 11.
2. Goldberg HL, Nissim R. Psychotropic drugs in pregnancy and lactation. Int J Psy Med 1994;2:129-49.
3. Tueth MJ. Psychotropic medications during pregnancy: risk to the fetus [letter]. JAMA 1993;270:2177.
4. Written communication, Goldstein DJ. Lilly Research Laboratories, August 8, 1995.
5. Pastuszak A, Schick-Boschetto B, Zuber C et al. Pregnancy outcome following first- trimester exposure to fluoxetine (Prozac). JAMA 1993;269:2246-9.
6. Written communication, Wheadon DE. SmithKline Beecham, August 8, 1995.
7. Spencer MJ. Fluoxetine hydrochloride (Prozac) toxicity in a neonate [letter]. Pediatrics 1992:721-2.
8. Inman W, Kubota K, Pearce G et al. Prescription event monitoring of paroxetine. PEM Reports 1993:1-44. PXL 1206.
9. Olin BR, ed. Selective Serotonin Reuptake Inhibitors-Pregnancy. Facts and Comparisons Loose-leaf Information Service St. Louis, MI, 1995 p. 264f.
10. Written communication, Albano DL. Wyeth-Ayerst Laboratories, August 10, 1995.
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