SNRIs

Jul 26, 2018 | Articles

SNRIs

Are SNRIs safe during pregnancy?

This is a great question. Unfortunately, there is not a simple answer. SNRIs are not completely risk free, but neither is untreated maternal illness. Women should decide whether or not to take an SNRI during pregnancy after consultation with a perinatal psychiatric specialist. Together, they can evaluate the risks and benefits of taking an SNRI after considering the woman’s personal psychiatric history, preferences, and values.

Untreated maternal mental illness

Women with a history of depression who stop taking their antidepressant have a 70% chance their depression recurring during pregnancy (compared to a 25% chance for women who continue taking their antidepressant).[i] Depression during pregnancy has been linked to increased rates of miscarriage and exposure of a developing fetus to stress.[ii] It has also been linked to an increased risk of postpartum depression, which, in turn, can affect a mother’s bonding with her baby, her ability to tolerate breastfeeding, and her attention to her baby’s safety.[iii]

Anxiety during pregnancy has also been linked to bad outcomes. Research has found that prenatal anxiety is linked to a developing baby later having childhood emotional and behavioral problems.[iv]

Mental illness during pregnancy is risky, often—but not always—more risky than the use psychiatric medications.

SNRIs

Selective-norepinephrine reuptake inhibitors (SNRIs) are less commonly prescribed for women around pregnancy and childbirth than SSRIs. SNRIs are newer. Consequently, there is less available research regarding their safety. The most well-researched SNRIs are duloxetine (Cymbalta) and venlafaxine (Effexor). Other SNRIs include desvenlafaxine (Pristiq), levomilnacipran (Fetzima), and milnacipran (Savella). There is very little data available about these newer SNRIs.

Benefits of SNRIs in women with depression and/or anxiety
SNRIs are an effective treatment for depression and anxiety. The studies that compare SNRIs to SSRIs do not consistently suggest that one class of medication is better than the other. In perinatal women, SSRIs are generally preferred because of the more abundant safety data. However, in some women who have not responded to SSRIs, or who have history of responding well to SNRIs, it may be preferable to treat these disorders with an SNRI.[v]

Risks of SNRIs

Prior to pregnancy

  • Side effects
    Side effects of SNRIs are similar to those of SSRIs (see Are SSRIs safe in pregnancy?). SNRIs may also increase blood pressure, but this generally occurs only at high doses.[vi]
  • Fertility
    There is no strong evidence to suggest that SNRIs decrease the likelihood of conception. Animal studies (using doses that would correspond to massive doses in humans) suggest that these medications have no effect on fertility.[vii]

During pregnancy

  • Miscarriage
    There is no strong evidence to suggest that SNRIs are associated with miscarriage. While one study suggested that there might be an increased risk for mothers on duloxetine or venlafaxine, the study was not able to account for depression severity. Other studies are reassuring.[viii]
  • Congenital defects
    There is no strong evidence to suggest that SNRIs increase the risk of congenital defects. While one study suggested there might be an association between venlafaxine and respiratory defects, a more robust statistical analysis suggested that this association was an overinterpretation of the data. Other studies are reassuring.[ix]
  • Gestational hypertension and preeclampsia
    There is not enough evidence to make a strong conclusion regarding SNRIs and gestational hypertension and/or preeclampsia. There may be an association. If there is an association, a very rough approximation of the increased risk might be that SNRIs (or possibly just venlafaxine) double the risk of these complications. Preeclampsia is a serious condition. Fortunately, in the United States, the risk of death is relatively low with 1 maternal death in 100,000 births or 6 deaths per 10,000 cases of the condition. Again, this increase in risk may or may not be real. Potential risks of using an SNRI should be weighed against known risks of untreated maternal depression and anxiety.[x]
  • Preterm birth
    There is no strong evidence that SNRIs increase the risk of preterm birth. One study that appears to suggest an association did not account for depression and its possible contribution to preterm birth. Animal data is reassuring.[xi]
  • Birth weight
    There is no strong evidence that SNRIs decrease birth weight. The limited existing evidence is reassuring.[xii]

At delivery

  • Postpartum hemorrhage
    As with SSRIs, SNRIs have been associated with an increased risk of postpartum hemorrhage. Any pregnancy carries a 3% chance of postpartum hemorrhage. Use of an SNRI increases this risk to perhaps 5%. Postpartum hemorrhage in developed countries has a low mortality rate (~0.05%). Thus, in the developed world, the risk of death from postpartum hemorrhage is about 1 in 70,000. For women on SNRIs, the risk may be increased to about 1 in 40,000.[xiii]
  • Neonatal adaptation syndrome
    As with SSRIs, SNRIs have been associated with neonatal adaptation syndrome (see Are SSRIs safe in pregnancy?). It is possible that the risk is slightly less with SNRIs than SSRIs.[xiv]
  • Persistent pulmonary hypertension of the newborn
    Given the similarities between SSRIs and SNRIs, it would not be unreasonable to expect SNRIs to have a similar risk of persistent pulmonary hypertension of the newborn (PPHN) (see Are SSRIs safe in pregnancy?). That said, one study did not find an association between SNRIs and PPHN, although the study may not have examined enough infants to detect an increased risk of this relatively rare condition.[xv]

After delivery

  • Future development of the baby
    While there is some research on SNRIs and babies’ future development, studies tend to be small and the research available is not sufficient to come to any useful conclusions. Again, it would be reasonable to suspect that any effect of SNRIs would be similar to those of SSRIs (see Are SSRIs safe in pregnancy?)[xvi]
  • Breastfeeding
    Breastfeeding on SNRIs is permissible. Duloxetine may be the preferred SNRI in breastfeeding, but this does not mean patients who have had a positive response to another SNRI, such as venlafaxine, should switch.[xvii]

Summary

SNRIs during pregnancy are not entirely risk free, but neither is untreated maternal mental illness. Women should decide whether or not to take an SNRI during pregnancy after consultation with a perinatal psychiatric specialist. Together, they can evaluate the risks and benefits of taking an SNRI after considering the woman’s personal psychiatric history, preferences, and values.

[i]

  1. Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC, Suri R, Burt VK, Hendrick V, Reminick AM, Loughead A, Vitonis AF, Stowe ZN. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006 Feb 1;295(5):499-507. Erratum in: JAMA. 2006 Jul 12;296(2):170.

[ii]

  1. Bonari L, Pinto N, Ahn E, Einarson A, Steiner M, Koren G. Perinatal risks of untreated depression during pregnancy. Can J Psychiatry. 2004 Nov;49(11):726-35.
  2. Siu AL; US Preventive Services Task Force (USPSTF), Bibbins-Domingo K, Grossman DC, Baumann LC, Davidson KW, Ebell M, García FA, Gillman M, Herzstein J, Kemper AR, Krist AH, Kurth AE, Owens DK, Phillips WR, Phipps MG, Pignone MP. Screening for Depression in Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2016 Jan 26;315(4):380-7.
  3. Vigod SN, Wilson CA, Howard LM. Depression in pregnancy. BMJ. 2016 Mar 24;352:i1547.
  4. Schaffir J. Consequences of Antepartum Depression. Clin Obstet Gynecol. 2018 Apr 13.

[iii]

  1. Field T. Postpartum depression effects on early interactions, parenting, and safety practices: a review. Infant Behav Dev. 2010 Feb;33(1):1-6.
  2. Banti S, Mauri M, Oppo A, Borri C, Rambelli C, Ramacciotti D, Montagnani MS, Camilleri V, Cortopassi S, Rucci P, Cassano GB. From the third month of pregnancy to 1 year postpartum. Prevalence, incidence, recurrence, and new onset of depression. Results from the perinatal depression-research & screening unit study. Compr Psychiatry. 2011 Jul-Aug;52(4):343-51
  3. Viguera AC, Tondo L, Koukopoulos AE, Reginaldi D, Lepri B, Baldessarini RJ. Episodes of mood disorders in 2,252 pregnancies and postpartum periods. Am J Psychiatry. 2011 Nov;168(11):1179-85.

[iv]

  1. Glover V. Maternal depression, anxiety and stress during pregnancy and child outcome; what needs to be done. Best Pract Res Clin Obstet Gynaecol. 2014 Jan;28(1):25-35.

[v]

  1. Gartlehner G, Hansen RA, Morgan LC, Thaler K, Lux L, Van Noord M, Mager U, Thieda P, Gaynes BN, Wilkins T, Strobelberger M, Lloyd S, Reichenpfader U, Lohr KN. Comparative benefits and harms of second-generation antidepressants for treating major depressive disorder: an updated meta-analysis. Ann Intern Med. 2011 Dec 6;155(11):772-85.

[vi]

  1. Thase ME. Effects of venlafaxine on blood pressure: a meta-analysis of original data from 3744 depressed patients. J Clin Psychiatry. 1998 Oct;59(10):502-8.

[vii]

  1. Product labeling. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022516lbl.pdf. Accessed on June 24, 2018.
  2. Product labeling. https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020699s059lbl.pdf. Accessed on June 24, 2018.

[viii]

  1. Einarson A, Fatoye B, Sarkar M, Lavigne SV, Brochu J, Chambers C, Mastroiacovo P, Addis A, Matsui D, Schuler L, Einarson TR, Koren G. Pregnancy outcome following gestational exposure to venlafaxine: a multicenter prospective controlled study. Am J Psychiatry. 2001 Oct;158(10):1728-30.
  2. Hoog SL, Cheng Y, Elpers J, Dowsett SA. Duloxetine and pregnancy outcomes: safety surveillance findings. Int J Med Sci. 2013;10(4):413-9.
  3. Kjaersgaard MI, Parner ET, Vestergaard M, Sørensen MJ, Olsen J, Christensen J, Bech BH, Pedersen LH. Prenatal antidepressant exposure and risk of spontaneous abortion – a population-based study. PLoS One. 2013 Aug 28;8(8):e72095.

[ix]

  1. Byatt N, Deligiannidis KM, Freeman MP. Antidepressant use in pregnancy: a critical review focused on risks and controversies. Acta Psychiatr Scand. 2013 Feb;127(2):94-114. doi: 10.1111/acps.12042. Epub 2012 Dec 14. Review.
  2. Huybrechts KF, Palmsten K, Avorn J, Cohen LS, Holmes LB, Franklin JM, Mogun H, Levin R, Kowal M, Setoguchi S, Hernández-Díaz S. Antidepressant use in pregnancy and the risk of cardiac defects. N Engl J Med. 2014 Jun 19;370(25):2397-407.
  3. Bérard A, Zhao JP, Sheehy O. Antidepressant use during pregnancy and the risk of major congenital malformations in a cohort of depressed pregnant women: an updated analysis of the Quebec Pregnancy Cohort. BMJ Open. 2017 Jan 12;7(1):e013372. doi: 10.1136/bmjopen-2016-013372.

[x]

  1. MacKay AP, Berg CJ, Atrash HK. Pregnancy-related mortality from preeclampsia and eclampsia. Obstet Gynecol. 2001 Apr;97(4):533-8.
  2. Livingston JC, Livingston LW, Ramsey R, Mabie BC, Sibai BM. Magnesium sulfate in women with mild preeclampsia: a randomized controlled trial. Obstet Gynecol. 2003 Feb;101(2):217-20.
  3. Palmsten K, Setoguchi S, Margulis AV, Patrick AR, Hernández-Díaz S. Elevated risk of preeclampsia in pregnant women with depression: depression or antidepressants? Am J Epidemiol. 2012 May 15;175(10):988-97.
  4. Palmsten K, Huybrechts KF, Michels KB, Williams PL, Mogun H, Setoguchi S, Hernández-Díaz S. Antidepressant use and risk for preeclampsia. Epidemiology. 2013 Sep;24(5):682-91.
  5. De Ocampo MPG, Araneta MRG, Macera CA, Alcaraz JE, Moore TR, Chambers CD. Risk of gestational hypertension and preeclampsia in women who discontinued or continued antidepressant medication use during pregnancy. Arch Womens Ment Health. 2016 Dec;19(6):1051-1061.
  6. Newport DJ, Hostetter AL, Juul SH, Porterfield SM, Knight BT, Stowe ZN. Prenatal Psychostimulant and Antidepressant Exposure and Risk of Hypertensive Disorders of Pregnancy. J Clin Psychiatry. 2016 Nov;77(11):1538-1545.
  7. Uguz F. Is There Any Association Between Use of Antidepressants and Preeclampsia or Gestational Hypertension?: A Systematic Review of Current Studies. J Clin Psychopharmacol. 2017 Feb;37(1):72-77.

[xi]

  1. Lennestål R, Källén B. Delivery outcome in relation to maternal use of some recently introduced antidepressants. J Clin Psychopharmacol. 2007 Dec;27(6):607-13.
  2. da-Silva VA, Altenburg SP, Malheiros LR, Thomaz TG, Lindsey CJ. Postnatal development of rats exposed to fluoxetine or venlafaxine during the third week of pregnancy. Braz J Med Biol Res. 1999 Jan;32(1):93-8.

[xii]

  1. Einarson A, Fatoye B, Sarkar M, Lavigne SV, Brochu J, Chambers C, Mastroiacovo P, Addis A, Matsui D, Schuler L, Einarson TR, Koren G. Pregnancy outcome following gestational exposure to venlafaxine: a multicenter prospective controlled study. Am J Psychiatry. 2001 Oct;158(10):1728-30.

[xiii]

  1. Shakur H, Elbourne D, Gülmezoglu M, Alfirevic Z, Ronsmans C, Allen E, Roberts I. The WOMAN Trial (World Maternal Antifibrinolytic Trial): tranexamic acid for the treatment of postpartum haemorrhage: an international randomised, double blind placebo controlled trial. Trials. 2010 Apr 16;11:40.
  2. Palmsten K, Hernández-Díaz S, Huybrechts KF, Williams PL, Michels KB, Achtyes ED, Mogun H, Setoguchi S. Use of antidepressants near delivery and risk of postpartum hemorrhage: cohort study of low income women in the United States. BMJ. 2013 Aug 21;347:f4877.
  3. Sheldon WR, Blum J, Vogel JP, Souza JP, Gülmezoglu AM, Winikoff B; WHO Multicountry Survey on Maternal and Newborn Health Research Network. Postpartum haemorrhage management, risks, and maternal outcomes: findings from the World Health Organization Multicountry Survey on Maternal and Newborn Health. BJOG. 2014 Mar;121 Suppl 1:5-13.
  4. Hanley GE, Smolina K, Mintzes B, Oberlander TF, Morgan SG. Postpartum Hemorrhage and Use of Serotonin Reuptake Inhibitor Antidepressants in Pregnancy. Obstet Gynecol. 2016 Mar;127(3):553-61.
  5. Jiang HY, Xu LL, Li YC, Deng M, Peng CT, Ruan B. Antidepressant use during pregnancy and risk of postpartum hemorrhage: A systematic review and meta-analysis. J Psychiatr Res. 2016 Dec;83:160-167.

[xiv]

  1. Kieviet N, Hoppenbrouwers C, Dolman KM, Berkhof J, Wennink H, Honig A. Risk factors for poor neonatal adaptation after exposure to antidepressants in utero. Acta Paediatr. 2015 Apr;104(4):384-91.

[xv]

  1. Bérard A, Sheehy O, Zhao JP, Vinet É, Bernatsky S, Abrahamowicz M. SSRI and SNRI use during pregnancy and the risk of persistent pulmonary hypertension of the newborn. Br J Clin Pharmacol. 2017 May;83(5):1126-1133.

[xvi]

  1. Nulman I, Koren G, Rovet J, Barrera M, Pulver A, Streiner D, Feldman B. Neurodevelopment of children following prenatal exposure to venlafaxine, selective serotonin reuptake inhibitors, or untreated maternal depression. Am J Psychiatry. 2012 Nov;169(11):1165-74.
  2. Nulman I, Koren G, Rovet J, Barrera M, Streiner DL, Feldman BM. Neurodevelopment of children prenatally exposed to selective reuptake inhibitor antidepressants: Toronto sibling study. J Clin Psychiatry. 2015 Jul;76(7):e842-7.
  3. Johnson KC, Smith AK, Stowe ZN, Newport DJ, Brennan PA. Preschool outcomes following prenatal serotonin reuptake inhibitor exposure: differences in language and behavior, but not cognitive function. J Clin Psychiatry. 2016 Feb;77(2):e176-82.
  4. Rai D, Lee BK, Dalman C, Newschaffer C, Lewis G, Magnusson C. Antidepressants during pregnancy and autism in offspring: population based cohort study. BMJ. 2017 Jul 19;358:j2811.

[xvii]

  1. Larsen ER, Damkier P, Pedersen LH, Fenger-Gron J, Mikkelsen RL, Nielsen RE, Linde VJ, Knudsen HE, Skaarup L, Videbech P; Danish Psychiatric Society; Danish Society of Obstetrics and Gynecology; Danish Paediatric Society; Danish Society of Clinical Pharmacology. Use of psychotropic drugs during pregnancy and breast-feeding. Acta Psychiatr Scand Suppl. 2015;(445):1-28.
  2. Orsolini L, Bellantuono C. Serotonin reuptake inhibitors and breastfeeding: a systematic review. Hum Psychopharmacol. 2015 Jan;30(1):4-20.