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USE OF ANTIDEPRESSANTS DURING PREGNANCY
1.Dr Javed Latoo MRCPsych
Staff Grade Psychiatrist
2. Dr Faiza Mufti MRCPsych
Consultant Perinatal & Adult Psychiatrist
Bethlem Royal Hospital
South London & Maudsley NHS Trust
Doctors are generally cautious about prescribing antidepressants during pregnancy or breast feeding due to their potential risk to the foetus and infant. Women with mood disorders commonly avoid taking psychotropic medication while they are attempting to conceive or while they are pregnant or breast feeding for the fear of harming their infants. Doctors are also cautious about prescribing medications for these women for the same reason even though both SSRIs and tricyclic have been found to be free of any serious teratogenic effects so far. Maternal depression during pregnancy and postnatal period is associated with a significant adverse effects not only in the mother but may also have both short and longterm effects on the offsprings.
In early pregnancy the risk of teratogenesis is the main concern. The main risks associated with psychotropic medication in later pregnancy are neonatal toxicity or withdrawal syndrome following delivery and possibility of long term impact on the infant’s neurodevelopment (1).
Decisions may have to be made about commencing antidepressants during pregnancy if a woman becomes ill or, more commonly, stopping medication if a woman finds that she is pregnant.
B. Prevalence of depression in pregnancy.
Major depression is twice as common in women than in men and frequently clusters during the childbearing years.Pregnancy and post partum period are considered to be relatively high risk times for a woman with pre-existing psychiatric illnesses, especially for depressive episodes in women(2).
The prevalence of depression has been reported to be between 10% and 16% during pregnancy(3,4,5) Pregnancy and post partum period appear to confer an even greater risk for a woman with bipolar disorder. There is a significant increase in new psychiatric episodes in the first three months of delivery, at least 80% are mood disorders primarily depression. A woman who have had a previous episode of depressive illness are at a higher risk for further episodes post partum.
Woman with recurrent major depression who have been maintained on an antidepressant medication before conception appear to be at an especially high risk for relapse during pregnancy(6) .
C. Risk of maternal depression on the infant.
Substantial literature documents the potential negative impact of maternal depression on children(Box 1). Compared with children of nondepressed mothers, children of mother’s who have experienced post natal depression perform worse on cognitive and behaviour measures(7-13) and exhibit higher rates of insecure attachment (7,8,14).
Depressive mothers have been observed to be intrusive or withdrawn and disengaged when interacting with their infants(15,16) and less sensitively attuned to their infants than healthy women(17).
The disturbances in mother-infant interactions observed among depressed mothers were found to be highly predict poor infant cognitive outcomes at 18 months(17). In a study of 2017 parents of children aged 0-3 years(18) identified parental depressive symptoms as the most consistent predictors of negative parenting behaviours ( like yelling, hitting, shaking) after controlling for social economic status,ethenic group, parental years of education, parental age, and parental employment status.
Research has found that if maternal depression is prevented infant problems associated with maternal depression, such as behavioural problems and insecure attachment(19) and decline in I.Q(8) can also be prevented.
D. Choice of antidepressant in pregnancy
Before starting/stopping an antidepressant in a pregnant woman following factors should be taken into consideration.
2. Toxicity to the neonate/withdrawal symptoms
3. Neurobehavioural effects
4. Risk of not treating depression during pregnancy
5. Risk of medication discontinuation
There is a vast amount of literature available to support the safety of tricyclic antidepressant and SSRIs in pregnant women.There have been various studies that have documented absence of teragegenic effects by SSRI and tricyclic antidepressants.. So far there has been no evidence that exposure to tricyclics or SSRI during pregnancy increases the risk of intrauterine fetal death(20,21,22)
In a recent review(23) of 15 published studies(n=2600 total) and the data of the Swedish Medical Birth Registry(n=4000) about the effect SSRI may have on the growing fetus, authors concluded that SSRIs given in therapeutic doses are not associated with increased risk of major malformations. In a recent study(2) the authors concluded older SSRIs and Venlafaxine seem to be devoid of teratogenic risks.
A recent meta-analysis concluded, as a group, the newer antidepressants are not associated with an increased risk of major malformations above the baseline of 1-3% in the population(24).Fluoxetine is by far the most studied of the SSRIs The most of authors have concluded that the use of Fluoxetine in the first trimester is not associated with increased risk of major malformations(24,25,26,27).
There are some preliminary reports of a possible increase in the risk of birth abnormalities with paroxetine(28) and development of pulmonary hypertension with flouxetine(29).At the moment it is difficult to conclude whether a casual relationship exists. SSRI`s have however been associated with both decreased gestational age (1 week) and birth weight (mean175g).(23,2,30).
Tricyclic antidepressants have not been found to have any serious effects on the featus(31,32) and have been used thoughout pregnancy for years. A meta-analysis(31) of the use of tricyclics in pregnancy,reviewing over 300,000 live births(including 414 first trimester exposure),failed to show a significant association between tricyclics and congenital malformation,although withdrawal symptoms were noted. In a retrospective study apparent prenatal tricyclic exposure was not associated with malformation, developmental delay or any adverse perinatal outcomes. (30).
The information about teratogenic effects of bupropion,mirtazapine and reboxetine is incomplete or absent.However a recent study did not find bupropion associated with an increased rate of major malformations(33).
MAOI`s have been associated with increased risk of congenital malformations and hypertensive crises(34).MAOI`s may also interect with drugs used in labour(e.g Pethidine).
2.Toxicity to the neonate
There have been various reports of neonatal withdrawal symptoms after the use of SSRIs,SNRI and tricyclics during late pregnancy. Use of tricyclics in the third trimester is known to produce neonatal withdrawal effects including agitation, irritability and seizures(35).
SSRIs have been associated with decreased gestational age(1 week), low birth weight(175g) and decreased early apgar scores in a recent review(23,2,30) .But untreated depression during pregnancy has been suggested to predispose to various adverse effects included in Box 1.
Effects of postnatal depression on infant
1.Poor cognitive development
Effects of postnatal depression on mother
1.Intrusive or Withdrawn when interacting with children
SSRIs or SNRIs use in late pregnancy has been implicated in causing withdrawal symptoms(36,37) or poor neonatal adoption(PNA) see Box 2.
Symptoms associated with poor neonatal adoption(38) include:
For this reason, the new born child is best kept under surveillance if exposure to SSRI or SNRI has occurred during late pregnancy. Some experts(38) suggest that discontinuing clinically needed antidepressants in a woman near term is unwarranted and may put the mother at an unjustified perinatal risk. They suggest neonatal symptoms occur in the minority of cases and are self limited and on the basis of currently available data regulatory agencies and manufacturers should not perpetuate anxiety among pregnant depressed women.
3.Postnatal developmental or neurobehavioural effects
Studies have shown that exposure to Fluoxetine throughout the pregnancy showed no detectable adverse effects on cognition, language development or temperament whereas untreated depression was associated with poor cognitive and language achievement in children(39).An earlier study by same author had concluded that exposure to fluoxetine had no effect on global IQ,language and behavioural development(40).
In a study of children(40) whose mothers had taken either a trycyclic or no drug showed tryclcylics to have no effect on global IQ, language development, behavioural development , cognition or temperament compared to no drug. Whereas untreated depression was associated with poor cognitive and language development in neonate children. (40).
4.The risk of not treating the depression during pregnancy(41,38)
There is now growing concerns about the adverse effects of untreated depression in pregnancy.A number of studies have shown relationship between untreated depression during pregnancy and adverse effects on mother as well as the developing baby(Box 3).
Adverse effects of untreated depression during pregnancy include
Maternal depression,through its action as stressor,may have an impact on fetal development through its effect on the hypothalamic-pituitary-adrenal axis,adrenocorticotropic hormones and beta endorphins(42).Maternal anxiety is associated with increased uterine artery resistance.(43)
Post natal depression has been associated with various problems in the developing child, including behavioural problems, insecure attachment and declining IQ.
5.Risks of antidepressant discontinuation during pregnancy.
Even though pregnancy was historically considered as a time of emotional well being providing protection against psychiatric disorders. This has been recently disputed as there have been high risks of relapse in women who discontinued their antidepressant medication during pregnancy.
In women who has been diagnosed with recurrent depression prior to conception and in whom antidepressant medication have been discontinued, the rate of relapse can be approximately 75% and can be seen frequently during the first trimester(6,44).
In a recent study by Cohen et al 2006(45) among the 82 women who maintained their medication throughout the pregnancy only 21( 26%) relapsed compared with 44(68%) of the 65 women who discontinued their antidepressant medication during pregnancy. Careful treatment planning is necessary for those women on antidepressants who plan to conceive or become pregnant.
E. Antidepressants and breast feeding
Even though all SSRIs are excreted into breast milk, no serious adverse effects have been reported in children whose mothers were taking SSRI during breast feeding. Recent review (23), available on use of SSRIs during breast feeding, suggests that exposure for the nursing child is lowest with sertraline and fluvoxamine,higher with paroxetine and highest with citalopram and fluoxetine.Authors concluded that available data are insufficient to form a basis for clear clinical recommendations as to which SSRI is the safest to use during breastfeeding. They could not find a reason for changing an ongoing successful treatment with a particular SSRI to another which is excreted to a smaller extent.
The limited evidence available for TCA suggests no short term toxic effects for the infant except in the use of doxepin. No long term developmental effects.for the infant have been demonstrated.A tricyclic with a short half life for itself and any active metabolite would appear to be better option.Amitriptyline and imipramine are the preffered tricylic antidepressants during breast feeding(46).
Currently both groups of antidepressants(SSRIs and TCA) seem to be devoid of teratogenic effects. In the light of available data, the risk of serious complications due to treatment with SSRIs during pregnancy appears small(23). The exception may be the use of SSRI in late pregnancy during which doses of SSRIs would best be kept at the minimum effective dose because of possibility of premature birth and adverse drug effects in the new born(23). The new born child is best kept under surveillance if exposure to SSRI or SNRI has occurred during late pregnancy even though withdrawal symptoms are rare and mostly self limiting.It is important that babies of mothers taking SSRI or SNRI be observed for longer than typical 1-2 days postpartum,so that neonatal symptoms of withdrawal or toxicity can be recognised and,if necessary,treated.
Currently the most experience is with Amitriptyline , Imipramine, Fluoxetine, nortriptyline and desipramine(last two not available in UK). If the patient is established on other antidepressant medication always obtain the most update advise. Experience with other drugs is continuing and a change in treatment may not be necessary or wise.
Clinician should follow some general principles in treating depression during pregnancy.
Clinicians should also remember that the normal outcome of pregnancy can never be guaranteed. The spontaneous abortion rate in confirmed early pregnancy is 10% - 20% and risk of spontaneous major malformation is 2% - 3% (47).
1.When advising a patient about treatment options the severity of illness, history of symptoms off medication, current medications and plans for breast feeding are important considerations.The presence of a stable support system(e.g partner and family support) and availability of child care assistance during postpartum period are also important.
2.Each case should be assessed on individual basis and ensure that prospective parents are fully involved in all discussions.Clinicians should discuss the risks and benefits of all possible management options including risks of not treating depression during pregnancy and risk of relapse.
3. Use an established drug at the lowest effecient dose and avoid using multiple drugs.
4.Clinicians should also be aware of potential problems with individual drugs around the time of delivery and should inform obstetric team of psychotropic drug use and possible complications so that neonates can be monitored for withdrawal effects after birth.
5.Always take into account the risk of relapse when considering discontinuing medication as relapse may ultimately be more harmful to the mother and the child than continued effective drug therapy.
6.Patients who are already receiving antidepressants and are at high risk of relapse are best maintained on antidepressants during and after pregnancy. Those who develop a depressive illness during pregnancy should be treated with antidepressant drugs if psychological management has failed or is not available.
7.Any risk associated with maternal treatment with antidepressants must be weighed against the known risks associated with untreated depression particularly major postpartum depression.
8.The risks of stopping tricylic or SSRI antidepressants medication should be carefully assessed in relation to the mother`s mental state and previous history.There is no indication to stop tricylic or SSRI antidepressants medication as a matter of routine in early pregnancy.
9.All decisions should be documented.
Other treatments that have been found effective in the treatment of depression during pregnancy may include psychological treatment in the form of cognitive behaviour therapy and interpersonal therapy(48-51). ECT has also been found safe during pregnancy in various studies(52-55).
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