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Anti-Depressants During Pregnancy?

posted Aug 28, 2016, 9:55 AM by Dimitrios Simitas   [ updated Aug 28, 2016, 10:07 AM ]
August 28th 2016


    Well it's been a year since I posted here, ended up getting fairly busy with my newborn son. Also my wife ended up getting Post-Partum Depression. It's been a roller coaster. Anyways, she finally went to see a doctor about it. But the doctor said there were risks and complications with pregnancy and taking them. Ended up telling us that we need to make the decision ourselves, not only if she should take them, but which one we feel comfortable with. 

    He seemed to think Prozac (Fluoxetine) would be a good choice, but that any of the SSRI's would probably be best. So I ended up doing research, and compiled a bunch of different medical reports I could find about it. I looked over a bunch of sources, and this by no means is definitive, and obviously I am not a doctor, and my information should be taken at face value but this is what I ended up coming up with.

List of Anti-Depressants

    According to the UK National Association for Mental Health, They give a list of antidepressants by type in their "Making Sense of Anti-Depressants" as well as a couple of anti-depressants that are included in a National Institute of Health article titled "Antidepressant Use During Pregnancy: Current Controversies and Treatment Strategies". I've included the scores here that I will get into later. 

 Type Name Trade Name Score
 SSRI Citalopram Citalopram -7
  Escitalopram Lexapro -2
  Fluoxetine Prozac -6
  Fluvoxamine Luvox -2
  Paroxetine Paxil -7
  Sertraline Zoloft7
 SNRI Duloxetine Cymbalta -4
  Venlafaxine Effexor -3
 Tricyclics Amitriptyline Elavil -4
  Clomipramine Anafranil -5
  Desipramine Norpramin 1
  Dosulepin Dothep -7
  Doxepin Sinequan -6
  Imipramine Tofranil -4
  Lofepramine Lomont -7
  Nortriptyline Aventyl -5
  Trimipramine Surmontil -4
 Tricyclic Related Mianserin Norval -5
  Trazodone Oleptro -4
 MAOI's Isocarboxazid Marplan -9
  Phenelzine Nardil -8
  Moclobemide Amira -8
  Tranylcypromine Parnate -8
 Other Drugs Agomelatine Valdoxan 0
  Bupropion Zyban 3
  Mirtazapine Remeron -6
  Reboxetine Edronax -3
  Triptafen Triavil -3

First Information Received

    My first piece of the puzzle was the couple of sheets that the doctor gave us, specifically the NIH "Antidepressant Use During Pregnancy: Current Controversies and Treatment Strategies" Table 2 that he gave us with a very tiny summery of a select number of drugs.

 Name Pregnancy Lactation Score
 Sertraline No confirmed evidence of birth defects in 1st trimester exposure. Risk of SSRI withdrawal syndrome with 3rd trimester exposure.  Minimal detection of drug in infants serum. 2
 Paroxetine Small absolute increased risk of cardiac defects in 1st trimester exposure (no more then 2 per 1000 births). Risk of SRI withdrawal syndrome with 3rd trimester exposure. Minimal detection of drug in infants serum. -1
 Citalopram No confirmed evidence of birth defects in 1st trimester exposure. Risk of SSRI withdrawal syndrome with 3rd trimester exposure. High milk/plasma concentration at higher doses. -1
 Fluxetine No confirmed evidence of birth defects in 1st trimester exposure. Risk of SSRI withdrawal syndrome with 3rd trimester exposure. Long half-life can increase the potential for accumulation. -1
 Escitalopram No confirmed evidence of birth defects in 1st trimester exposure. Risk of SSRI withdrawal syndrome with 3rd trimester exposure. Very limited data to date shows lower milk/plasma concentrations as compared to citalopram.  1
 Desipramine No confirmed evidence of birth defects in 1st trimester exposure. Risk of SSRI withdrawal syndrome with 3rd trimester exposure. Minimal detection of drug in infants serum. 1
 Imipramine No confirmed evidence of birth defects in 1st trimester exposure. Risk of SSRI withdrawal syndrome with 3rd trimester exposure. Minimal detection of drug in infants serum. 1
 Nortriptyline No confirmed evidence of birth defects in 1st trimester exposure. Risk of SSRI withdrawal syndrome with 3rd trimester exposure.Minimal detection of drug in infants serum. 1
 Mirtazepine Limited data avalible; no confirmed evidence of brith defects in 1st trimester exposure. Limited data avalible. Well tolerated in small study. Always monitor for changes in sleep and eating behavoirs. 0
 Buproprion Limited data avalible; no confirmed evidence of brith defects in 1st trimester exposure. Limited data avalible. Small incease risk of infant seizure (case report). 0
 Venlafaxine Limited data avalible; no confirmed evidence of brith defects in 1st trimester exposure. Inadequate data avalible. 1
 Duloxetine Inadequate data avalible. Inadequate data avalible. 0
 Phenelzine Very limited data avalible; no confirmed evidence of brith defects in 1st trimester exposure. Inadequate data avalible. 1

    This table made me question itself, mainly because it is talking about SSRI withdrawal symptoms with Desipramine, Imipramine, and Nortriptyline. Which are all tricyclics. Also all SSRI's carry the risk of birth defects, at varying degrees. This made me suspect enough of the source that I needed to do further research. 

Pregnancy Issues

    For this section, I mainly complied data from the UK Teratology Information Service. They have fact sheets on their websites primarily aimed at doctors. They have a disclaimer actually on every fact sheet on these drugs as "This is a UKTIS monograph for use by health care professionals."

    I looked at several things while going through them, Preterm Birth, Low Birth weight, PPHN, and Malformations. 

    Most of these intactions that caused spontaneous abortion, intrauterine death, and preterm delivery seemed to be interconnected, so I just summed it up in the most likely category based on my over all research as "Preterm Birth" as that is far more likely an outcome.

Most drugs here, tended to get negative results from the studies, as like many studies, they are focused primarily on the harm they can cause, not the benefits to the mother, but even so each sheet lists the following important points on anti-depressant use while pregnant. 

  • It is important to ensure that maternal mental health is treated appropriately. As such, (insert drug name) may be suitable for use in pregnancy, but the risks and benefits of use must be considered on a case by case basis.
  • Where a patient is stablized on (insert drug name) either prior to conception or during pregnancy, the risk of discontinuing treatment, changing medication, or reducing the dose should be carefully weighed against the risk of maternal relapse during pregnancy may pose to both mother and child. 
    Bullet 2, is primarily the reason why I also looked at breastfeeding issues that may arise, as stopping the drug to be able to breast feed may cause relapse of her symptoms based on my research, and during relapse the symptoms may amplify. 

 Anti-Depressant Score Preterm Birth Low Birth Weight PPHN Malformations
 Bupropion 1    1
 Sertraline 0 1 1 -1 -1
 Escitalopram 0 1 -1 -1 1
 Amitriptyline -2 -1   -1
 Duloxetine -2   -1 -1
 Fluoxetine -2 -1 -1 -1 1
 Paroxetine -2 -1 1 -1 -1
 Lofepramine -2 -1 -1  
 Venlafaxine -3 -1  -1 -1
 Mirtazpine -4 -1 -1 -1 -1
 Citalopram -4 -1-1  -1 -1

    PPHN can be caused by these drugs, but the rate listed of 0.2-1.2% isn't that much higher then 0.1-0.2%. A percent seems like a lot, but this is a range based on multiple studies, with indications that the range is effected by the specific type of SSRI used, and dosages, based on my reading online. But this source, like most isn't too specific as further study is needed.

Breastfeeding Issues

    Since anti-depressants will be taken both during her pregnancy, and after, a topic that popped up in my mind immediately, that I knew would effect the choice, is after birth how will breast feeding work, and will it be okay?

    The Specialist Pharmacy Service of the National Health Service UK, has a Q&A called "Management of depression in breastfeeding mothers - are SSRI's safe?".

    From the NHS their report can be summarized in the following points.
  • SSRIs and their metabolites pass into breast milk in small amounts, generally below 7% of the weight adjusted maternal dose. Infant ingestion via milk is lowest for sertraline and fluvoxamine and highest for fluoxetine.
  • Because of shorter half lives, lower passage into milk and larger pools of data, paroxetine or sertraline are the preferred SSRIs for use in lactation.
    Which gave Sertraline (2), Fluvoxamine (1), Paroxetine (1) and Fluoxetine (-1) in the scoring system.

Half Lives of Anti-Depressants

    The UK National Association for Mental Health, in their "Making Sense of Anti-Depressants" also list half-lives of anti-depressants. Which has been linked to both pre-birth issues, but also post both in the milk supply.

 Drug Half Life
 Agomelatine1-2 Hours 
 Tranylcypromine~2 Hours 
 Moclobemine2-4 Hours 
 Venlafaxine4-7 Hours 
 Trazodone5-13 Hours 
 Mianserin6-39 Hours 
 Duloxetine8-17 Hours 
 Amitriptyline9-25 Hours 
 Phenelzine11-12 Hours 
 Lofepramine12-24 Hours 
 Clomipramine12-36 Hours 
 Reboxetine~13 Hours 
 Fluvoxamine17-22 Hours
 Imipramine~19 Hours 
 Mirtazapine20-40 Hours 
 Sertraline22-36 Hours 
 Trimipramine~23 Hours 
 Paroxetine~24 Hours 
 Escitalopram30 Hours 
 Doxepin33-80 Hours 
 Citalopram~36 Hours 
 Isocarboxazid~36 Hours 
 Nortriptyline~36 Hours 
 Dosulepin~50 Hours 
 Fluoxetine96-144 Hours 

    This was pretty simple, I gave the top 1/3rd (1), and bottom 1/3rd (-1).

Drug Interactions with Neonatal Withdrawal Symptoms

    The Journal of the American Medical Association, Vol 293 No. 19 has a report called "Neonatal signs after Late in Utero Exposure to SRI's." Which mainly deals with the withdrawal symptoms a baby can feel after birth. Some highlights from the report by the group of doctors, that were notable, includes;

  • In 3 of 4 cases, exposure was associated with postnatal onset of signs within 4 hours of delivery, which suggested that these neonates experienced drug toxic effects as as opposed to withdrawal. In the forth case somnolence was apparent after discharge on day 2, with significant worsening by day 3 of life. Cord blood SRI levels equivalent to those found in adults and the prolonged half lives of fluoxetine, and norfluoxetine (the active metabolite) in neonates suggested that fluoxetine exposed neonates experienced SRI toxicity signs comparable with adult SRI adverse effects.
  • Paroxetine and fluoxetine are the SRI's most commonly reported with the neonatal syndrome. 
  • Late gestational exposure to SRI's with long half-lives, like fluoxetine, could be associated with a neonatal toxicity syndrome with immediate onset of signs at birth. 
    Table 1, "Case Reports of Neonatal Outcomes After Late In Utero SRI Exposure" Has several studies on the use of SRI's, Gestational weeks of birth, the time their effect started, duration and whether or not breastfeeding was completed. I am only listing cases where breastfeeding or not is specified, as my previous mentioned comment that post birth breast feeding is important to my wife and I.

 Anti-depressant Dose mg/d Gestational Age Sign Onset Duration in daysBreast Feeding 
 Paroxetine 40 35Day 3-4 10 No
  30 39Hour 12 3 No
  40 TermDay 5 21 Yes
  10 TermBirth10 Yes 
  40 TermDay 5> 28 Yes
  10 TermDay 3 2 No
 Citalopram 20-30TermBirth  > 7 Yes
 Sertraline 200 TermWeek 32 Yes
 Fluoxetine 60TermHour 414 No
  40 37Day 3 21 Yes


    So I ended up scoring Sertraline (1), Paroxetine (-1) and Fluoxetine (-1) based on this data. Although I guess because of both the withdrawal symptoms and the increase of the symptoms due to the drugs passing on through the milk supply, Paroxetine and Fluoxetine could potentially get a (-2) for each. But I treated this as one source and one score.

    It is interesting to note with these numbers, that Paroxetine, must be entering the milk at a significant quantity, to keep the baby suffering from withdrawal symptoms for a long period of time, never fully cutting off the baby from the drug. Smaller (10mg/day) doses, limit withdrawal symptoms both in breastfeeding and non-breastfeeding babies, by a significant amount. It seems that once the drug gets to 40mg/d, the symptoms jump from 3 days for 30mg/day to 10 days for 40mg/day. It also seems that the difference between breastfeeding and non-breasting feeding with low as compared to maximum doses plays a fairly large difference. From 10 days of duration of withdrawal symptoms to anywhere from 3-4 weeks or more for maximum dosages during breast feeding.

    The Citalopram study is a little incomplete and no real data to compare it with. But a low to mid-range dosage based on some of the sources I found seem to indicate that it too can stay in the blood for a significant amount of time, but without further data, it's hard to say if it's passing through the milk supply as readily. 

    The use of Sertraline, even at maximum dosage of 200mg/day, took 3 weeks to develop symptoms, and they only lasted for two days. Making it seem like the little amount passed through the breast milk is enough to keep the baby from experiencing any hard symptoms of withdrawal, and once the symptoms appear, they are relatively mild. As only Paroxetine, with no breast feeding, and minimum dosage of 10mg/day has the same duration of symptoms. 

    Fluoxetine, in non-breastfeed babies, seems to give toxicity symptoms, due to the massive concentrations in the cord blood. Lasting two weeks, and while breast feeding delayed the symptoms by a few days, it ended up lasting 3 weeks. Which to me makes it seem rather not preferred like Paroxetine. 

How it Effects the Mother?

    I also used, the UK National Association for Mental Health, in their Anti-Depressants from A to Z guide book looking at it for pregnancy risk factors, blood/liver issues, energy/sleep issues, dietary restrictions, withdrawal symptoms and whether or not it was either listed as dangerous, or seemed dangerous due to complications from non-prescription drug interactions.

    Most things were always going to be negative values, as there is little positive mentioned in this report, but the Withdrawal category is multiple scoring. For every underlined serious withdrawal symptom, I gave it a (-1) so lots of drugs ended up getting (-3) in the end. Agomelatine, has a note that it's withdrawal is actually okay, so it's the only drug in this entire list that got a positive score for a single item.

 Name Score Pregnancy Blood/Liver  EnergyDietary Withdrawal Dangerous 
 Sertraline -1   -1   
 Agomelatine -1 -1  -1    1  
 Mirtazapine -2   -1  -1 
 Reboxetine -3 -1  -1  -1 
 Triptafen -3 -1 -1 -1   
 Amitriptyline -3  -1   -2 
 Trimipramine -3  -1   -2 
 Escitalopram  -4   -1  -3 
 Fluvoxamine -4   -1  -3 
 Venlafaxine  -4   -1  -3 
 Duloxetine  -4   -1  -3 
 Imipramine  -4 -1  -1  -2 
 Trazodone -4   -1  -2 
 Clomipramine -4 -1  -1  -2 
 Doxepin -4 -1 -1   -2 
 Paroxetine -4   -1  -3 
 Citalopram -4   -1  -3 
 Fluoxetine -4   -1  -3 
 Lofepramine -4  -1 -1  -2 
 Mianserin -5 -1 -1   -2 -1
 Nortriptyline -5 -1 -1 -1  -1 -1
 Dosulepin -5 -1 -1   -2 -1
 Moclobemine -5 -1  -1 -1 -2 
 Isocarboxazid -5   -1 -1 -2 -1
 Tranylcypromine -6   -1 -1 -3 -1
 Phenelzine -7  -1 -1 -1 -3 -1



Educated Opinions Online?

   Finally there are also 3 websites, by the Mayo Clinic, Seleni Institute, and WebMD about anti-depressants while pregnant. This is more just general information, because as we see above, the risk factors for Fluoxetine, are relatively clear, but because of it's high prescription rate, even among pregnant women, it was recommended by all 3 groups.

 Anti-depressant Score Mayo ClinicSeleni InstituteWebMD 
 Sertraline 11 1 
 Fluoxetine 11
 Bupropion1  1 
 Venlafaxine 
 Duloxetine 1 
 Citalopram 1   1 
 Desipramine 1 
 1
 Escitalopram 1 1
 Amitriptyline 1   1
 Nortriptyline 1

 1
 Paroxetine -1-1 -1
 Moclobemide -1-1   
 Phenelzine -1-1   
 Tranylcypromine -1-1   
 Isocarboxazid-1  -1  


Conclusion

    Finally I can't help anyone make their own personal choice, I am not a doctor, but based on this, I feel confident my wife and I have made the right choice in selecting her medication.


Dimitrios Simitas



# Sources
1 National Association for Mental Health
2 https://www.sps.nhs.uk/articles/management-of-depression-in-breastfeeding-mothers-d-are-selective-serotonin-reuptake-inhibitors-ssris-safe/
3 http://www.mayoclinic.org/healthy-lifestyle/pregnancy-week-by-week/in-depth/antidepressants/art-20046420?pg=2
4 https://www.seleni.org/advice-support/article/depression-antidepressants-and-pregnancy
5 http://www.webmd.com/baby/pregnancy-and-antidepressants#1
6 http://www.mind.org.uk/media/2052030/making-sense-of-antidepressants_2014.pdf
7 http://www.mind.org.uk/information-support/drugs-and-treatments/antidepressants-a-z/#.V8IFGZgrKM8
8 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2749677/pdf/nihms-139491.pdf
9 http://uktis.org/html/exposures_abc.html for these 4 items
10 www.midlandsmedicines.nhs.uk/filestore/QA252_AntidepressantsSSRI-BM.pdf
11 http://lib.ajaums.ac.ir/booklist/jama_18%20May_8.pdf

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