Lithium and Pregnancy - The Latest From the NEJM

Lithium and pregnancy have always been a major concern for psychiatrists, obstetricians, and of course women who need to take the medication for mood stabilization.  In the Lithium Encyclopedia (published in 1983) - there is a chapter on the physiological effects of pregnancy and how that potentially affects lithium balance and a separate chapter on teratogenesis.  That chapter describes the Lithium Baby Registry that was established in 1970 to collect information on the effects of lithium in pregnancy.  In the first 10 years, 225 infants exposed to lithium were described and 25 had congenital malformations.  Of these births 18/25 had cardiovascular abnormalities including Ebstein's anomaly, 7 were stillborn, 2 had Down's syndrome and 1 had intracerebral toxoplasmosis.  The results suggested that lithium was a cardiovascular teratogen, but there was a question of reporting bias.  That is, results consistent with the study concern about lithium being a teratogen were more likely to be reported than normal births.  

Those references set the knowledge about lithium and  pregnancy for all residents trained in my era in the late 1980s.  The standard question by attendings and on examinations was: "What is the cardiac anomaly associated with intrauterine exposure to lithium?".  The answer was Ebstein's anomaly.  The follow up question was expected: "And what is Ebstein's anomaly?"  In those days the short answer was downward displacement of the tricuspid valve into the right ventricle.  Today Ebstein anomaly (no longer a possessive) is described in greater detail. A modern reference describes the extension of the tricupsid valve into the right atrium to the extent that most of the functional chamber chamber is collapse to a very small volume.  In some cases it is collapsed to the right ventricular outflow tract.  The downward valve displacement is due to a number of morphological abnormalities in the tricuspid valve.  The myocardium is also abnormal because the valve tissue has failed to completely separate from the myocardium during fetal development - a process called delamination.  That is associated with a thin and poorly contractile myocardium and poor right ventricle performance. There are several associated cardiac abnormalities including ventricular septal defect, patent foramen ovale, patent ductus arterious, and accessory conduction pathways that can lead to arrhythmias.  The associated clinical syndromes of cyanosis, congestive heart failure and arrhythmia can occur in infancy to adulthood depending on the degree of anatomical disruption.  The complications can be fatal at any age (2).

Ebstein abnormality is a preventable complication and one that must be avoided.  In real life that is easier to say than do.  In a controlled hospital or clinic environment it is a very straightforward process to take a history and determine the obstetric history and last menstrual period.  Urine and serum pregnancy tests can be done for confirmation.  The best advice to physicians in this situation is to treat very woman of childbearing age as if they were pregnant until proven otherwise.  In my experience life is less regimented.  There are lapses in contraception and planning that lead to pregnancies in women taking lithium who know that exposure to the infant is an avoidable risk.  Many of these women are on lithium maintenance.  Since lithium remains a mainstay of treatment for bipolar disorder and may be a superior agent in postpartum psychosis - the question of teratogenicity remains an important one.

There have been a number of estimates of congenital malformations due to psychiatric medications and I recently reviewed a few of them and cited extensive database references.  In one of the reviews very large databases were examined looking for major congenital malformations to lithium exposed women especially Ebstein anomaly.

The New England Journal of Medicine published another large retrospective database study of the question of lithium exposure in pregnancy and risk of cardiac malformations.  Their database involve a Medicaid cohort of 1,325,563 pregnancies over the ten year period between 2000 and 2010.  In this cohort there were cardiac malformations noted in 16 of 663 (2.4%) lithium exposed infants.  Lower rates of cardiac malformations were noted in nonexposed infants (1.15%) and lamotrigine exposed infants (1.39%).  In addition there appeared to be a dose related effect with increasing risk ratio noted with increasing doses of lithium.  For example at the dose of 600 mg or less/day the risk ratio was 1.11 but the risk ratio increased to 1.11 and 3.22 for doses of 601-900 mg/day and greater than 900 mg respectively.

The authors have a detailed report on how the cardiac malformations were determined.  They make an interesting point that a misclassification bias can occur with Ebstein anomaly.  Some clinicians may make the diagnosis of right ventricular outflow tract obstruction defects or Ebstein anomaly based on whether or not there has been a history of exposure to lithium.  That may make it more likely to misclassify Ebstein anomaly.  They provide data for the total prevalence of all cardiac malformations and cardiac malformations classified as right ventricular outflow obstruction.  They were focused on "major cardiac defects that were likely to be consequential for the infant."  The diagnostic codes had to be listed several times or associated with surgery.

The calculated prevalence of Ebstein abnormality in unexposed pregnancies was 7 cases per 100,000 live births.  They did not provide the prevalence of Ebstein anomaly in the lithium exposed due to the low number.  After a detailed analysis and analysis of possible sources of error like terminate pregnancies where lithium exposure occurred the authors conclude that lithium had a modest effect in terms of increased risk of cardiac malformations.  Their final estimate was an increased risk of 1 additional case per 100 live births if the exposure occurred early in the pregnancy.  They describe this as a modest increase in risk of cardiac malformations due to lithium.  The difference in the ratio of cardiac malformations in this study (16/663) compared with the Lithium Baby Registry (18/225) is probably due to a more rigorous methodology.

The authors looked at five sources of error in their final discussion of the results.  For clinical psychiatrists the most relevant point was that other factors affecting treatment decisions in pregnancy were not investigated.  They are considerable given that it is highly likely that the women being treated with lithium have severe mood disorders and suicide in the postpartum period in the number one cause of death.  This study can best be viewed as a study that supports current clinical practice to avoid first trimester exposure to lithium by careful screening and then planning if additional adjustments need to be made for planned pregnancies based on the trimester.  In those cases of accidental exposure, consultation with high risk obstetrics and a decision based on a detailed discussion with the patient is usually the preferred option.                 




George Dawson, MD, DFAPA




References:

1.  Jefferson JW, Greist JH, Ackerman DL. Lithium Encyclopedia for Clinical Practice.  Washington, DC; American Psychiatric Press, Inc., 1983: 264-265.

2.  Connolly HM, Qureshi, MY.  Clinical manifestations and diagnosis of Ebstein anomaly. In UpToDate,  Greutmann M, Fulton DR, Yeon SB (Accessed on June 9, 2017).

3.  Patorno E, Huybrechts KF, Bateman BT, Cohen JM, Desai RJ, Mogun H, Cohen LS, Hernandez-Diaz S. Lithium Use in Pregnancy and the Risk of Cardiac Malformations. N Engl J Med. 2017 Jun 8;376(23):2245-2254. doi: 10.1056/NEJMoa1612222.

The Recurring Question Of Antidepressants During Pregnancy

Over the course of my career, the question of whether  or not women should take antidepressants while pregnant has been a recurring question.  The point-counterpoint seems to depend on whether you are a psychiatrist treating women with severe forms of depression or not.  A lot of these studies seem to be driven by the fact that there is a registry somewhere for pregnant women who have had exposure to various medications.  Studies like this make headlines and are simplistically interpreted.  That is a much different perspective than a psychiatrist who is talking with a woman who has had severe postpartum depression and does not want to experience that again.  There is also the case of acute care psychiatrists who have assessed many women who had a significant change in their mood and mental state during or after a pregnancy and never recovered from that.  They became chronically mentally ill at that point and sustained all of the expected comorbidity.  The first few times I encountered that situation it was difficult to accept.  Nobody teaches that in medical school or residency training.  It seemed like a well kept secret.  Since then I have seen many women who developed a chronic mental illness that started as a severe mood change in or immediately after pregnancy.

The most recent question arose as a result of the study in reference 1, an analysis of the Quebec Pregnancy Cohort.  These same authors have an additional 9 references in Medline.  Full text is available for the current study.  The conclusion of these authors is that SSRI, SNRI, and TCA type antidepressants are associated with a significant increase in congential malformations - specifically as cardiac, musculoskeletal, craniofacial, digestive and respiratory defects.  The authors have a detailed flow diagram that details patient selection from the original cohort of 289,688 pregnancies between 1998-2009.  The flow diagram is a good illustration of how the original cohort was narrowed down to 18,487 pregnancies with either first trimester exposure to antidepressants (3,640) or no exposure (14, 847).  Subgroups for the antidepressant exposure include SSRIs (2,327), SNRIs (738), TCAs (382), and other (193).  The numbers and percentages of major malformations for each group were no exposure 1650/14,847 (11.1%), SSRI 279/2327 (12%), SNRI 91/738 (12.3%), and TCA 51/382 (13.4%).    Over the ten year course of the study the prevalence of antidepressant use doubled from 21 to 43 women per 1,000 pregnancies.  Doing some quick arithmetic on those numbers we find that 11.6% (421/3,640) of the antidepressant exposed pregnancies resulted in major congenital malformations.  Using the baseline rate of the unexposed pregnancies to calculate the expected number of major malformations results in 404/3,640 or a difference or 17 major malformations in the exposed group of 3,640 pregnancies.

What did the authors consider to be major malformations?  They used definitions of major congenital malformations according to conventions in two databases and they provided ICD-9 and ICD-10 diagnostic codes.  There were very few named diagnoses as far as I could tell.  There is some concern here because the literature on congenital malformations varies a bit in terms of the rate of birth defects and whether they are considered to be major or not.  Some of this was expressed in a NEJM editorial by Greene in 2007(2).  In commenting on two papers (3,4) on the subject of major congenital malformations associated with SSRIs in that edition he notes that  "A survey of the aggregate data now available — positive, negative, and equivocal — makes it clear that neither SSRIs as a group nor individual SSRIs are major teratogens on the order of thalidomide or isotretinoin."  He goes on to elaborate that there is a low risk with SSRIs but it is not zero and it is not clear cut.  That opinion is in contrast to some written since suggesting that the risk is high enough that no women should be exposed to SSRIs. 

One of the strengths of this study is that they used depressed and anxious mothers as the reference group to attempt to remove any confounders due to those conditions.  A variety of diagnostic codes were determined including 33 ICD9/10 codes for episodic mood disorders, 17 ICD9/10 codes for neurotic disorders, 19 ICD9/10 codes for depressed, anxious, and other cognitive disorders, 3 ICD9/10 codes for adjustment disorders, and 2 ICD9/10 codes for depression not otherwise specified.  Data on indications for antidepressant use were not available but the authors sought to limit indication bias by comparing only women selected for diagnoses of depression.  Women were selected with diagnoses of anxiety or depression who were treated with antidepressants one year before their pregnancy and several exclusion criteria such as exposure to more than one antidepressant or multiple births were applied.  Total psychiatric visits were viewed as a proxy measure for severity rather than confirmation of the diagnosis.        

The primary statistic used in this paper was the Odds Ratio (OR) or Adjusted Odds Ratio (aOR).  I have been skeptical of some applications of OR in the past.  There are also theoretical concerns as discussed in reference 2 below.  The authors present an excellent argument that the OR is widely used in epidemiological studies because it characterizes population variations in risk.  The weakness is that it has low accuracy as a classifying marker and it tends to overestimate relative risk when sample size is low.  A number of papers also point out that when large numbers of comparisons are done like calculating the OR and aOR for a large number of antidepressants it is likely that some of the findings will be explained by chance.  In this case they do the calculations by antidepressant, overall major congenital malformations and by individual body systems.  They conclude that only exposure to citalopram  [(aOR) 1.36, 95% CI 1.08 to 1.73]  in the first trimester increases the risk of major malformations but that there was a trend with other antidepressants (ADs) and that some ADs seemed to result in more system specific malformations.  Another methodological problem that can occur and affect comparisons is when the control group has an unexpectedly large number of malformations and this has happened in some of the research studies.

A much larger study of the problem was provided by the NICE consortium in the UK and their 923 page document on the subject (17).  The supplement of Forest plots alone for this document is an additional 313 pages long.  The authors of this document carefully selected studies of prenatal exposure to psychiatric medications and compiled fairly large studies.  They also showed the actual numbers of lesions in the exposed and unexposed groups by rates and the absolute differences in addition to the OR.  The NICE methodology was exhaustive and included very large number of patients across 6 major drug classes - antidepressants, antipsychotics, anticonvulsants, lithium, benzodiazepines, and stimulants.  The antidepressants studies listed sample sizes ranging from 50,257 to 2,548,463.  According to the authors there was no statistically increased risk in major congenital malformations with SSRIs even though the absolute risk difference was 12 more per 1,000.  There were some possible system specific risks with paroxetine and fluoxetine with a range of absolute risk difference of 3-9 more per 1,000.  In their guideline they translated this to a series of prescribing principles that could be applied to prescribing antidepressants in pregnancy (p 813).  These principles amount to a detailed informed consent discussion about potential risk during pregnancy and breastfeeding.  The document also contains the observation that up to 90% of women stop taking medication when they find out they are pregnant.  That often happens without consultation.

Attending meetings where psychiatrists are the presenters and focused on maternal health provides a much different perspective than pregnancy databases focused on congenital malformations.  In the past couple of years I was to attend three conferences, two of which occurred at the University of Wisconsin Annual Updates.  In all three of those conferences the maternal burden of anxiety and depression is the context and is generally presented first.  Katherine Wisner (11) presented in Madison last year.  Here arguments were based on the fact that psychiatric disorders are the most common chronic conditions of women of childbearing age and that the rate of treatment is very low: 25.5% of non-pregnant women and 14.3% of women who were pregnant in the past year.  She pointed out that medication free and disease free pregnancies are a myth.  Pregnant women get sick and sick women get pregnant.  About 14.5% of pregnant women have a new episode of depression and about 14.5% of women have an episode of postpartum depression.  Dr. Wisner is one of several authors who referenced Cohen's work (6) on the recurrence risk of depression in women who discontinued antidepressants  around the time of conception versus those who did not (68% versus 26%).  Click to enlarge this graphic.

JAMA. 2006 Feb 1;295(5):499-507 with permission

The presentation by Zachary Stowe (10) used the Cohen survival curve to illustrate recurrent depression with antidepressant discontinuation in pregnancy.  He also showed survival curves of treated versus untreated bipolar disorder by Viguera (16) showing that 90% of untreated pregnant bipolar patient relapse during the pregnancy out ot 12 weeks post partum compared to 40% of treated bipolar patients.  He also had two excellent slides on the acute maternal and neonatal consequences of a relapse to a mood disorder documenting numerous neonatal complications maternal complications including suicide.

Michelle Wiersgalla (12) expanded the postpartum disorders to include anxiety and psychosis.  She pointed out that suicide accounts for 20% of the post partum deaths and that suicide was the second leading cause of death in post partum women.   Some sources have classified it as the leading cause of maternal death (13, 14).  Infanticide occurs at the rate of about  8/100,000 and is associated with post partum psychosis.

All of those presenters would seem to have made a strong case for treating mood and anxiety disorders in pregnancy.  And of course the sterile research statistics are nothing like stress of clinical practice when a patient suddenly is destabilized and becomes unpredictable to both their family and the treating physician.  There is also the stress of an unplanned pregnancy in a woman who is being treated for a psychiatric disorder and that speaks to one of Dr. Stowe's main point and that is to treat all women of childbearing age in your practice as being potentially pregnant and documenting method of contraception and advice adn planning on pregnancy given the medication that they are taking.

It seems to me that the recurring problem of antidepressant safety during pregnancy is driven by a large body of research with widely discrepant low frequency findings.  We are generally talking about rates that are in the single to low double digits out of a thousand.  I think the conclusions of that research are probably affected by who is doing it.  You can find people who are interested in "proving" that antidepressants are harmful on the one hand.  They are likely to write from that perspective and minimize or completely ignore the severity of the associated women's mental health problems and the fact that they can be clearly treated with antidepressants.  They also never mention the potentially severe outcomes associated with untreated postpartum depression that can be observed in acute care settings.  On the other hand, there is research written from the perspective of treating women's mental health problems that (unexpectedly) will show less harm.  Clinicians - especially psychiatrists on the front lines who are often left advising women with unexpected pregnancies on what to do about their antidepressant treatment are stuck in the middle.  

A reasonable informed consent discussion with women of childbearing age begins by treating all women in this category as though they are potentially pregnancy or will be at some time. That includes a history of pregnancy and any associated changes in mood or anxiety.  It also includes a discussion of going from a no risk state for the fetus of not being pregnant while taking medications  to pregnancy while taking medication.  That includes plans for pregnancy and documenting the method of birth control.  With some high risk drugs - screening for pregnancy can be done.  If there is any concern about absolute minimization of risk pregnancy screening can be done and repeated if necessary.  In the case of planned pregnancies a window of 6-12 months prior to conception allows for a scheduled taper and discontinuation of the antidepressant medication.  The psychiatric evaluation can be valuable to determine the risk of relapse in these situations.  There are many patients who started taking antidepressants in acute situations where the stressor no longer applies.  There are many patients taking antidepressants for anxiety disorders who have never received psychotherapies for anxiety.  After these practical measures have been exhausted the decision comes down to whether or not there is an unplanned pregnancy and exposure or a situation where the discontinuation of the antidepressants would potentially be problematic.  In the cases I have been involved in, the women were also seeing high risk obstetric specialists and their pregnancies were closely monitored.    

As far as the actual drugs go, I do not think that paroxetine should be prescribed.  I am not basing that on anything in the pregnancy or congenital malformation literature.  I am basing it on my experience in psychiatry and the fact that in the first few years of its release - I determined it was a problematic drug in terms of drug interactions and discontinuation symptoms.  Why prescribe a problematic drug when there are plenty of other equivalent drugs?  I do not understand why anyone prescribes paroxetine these days.  That said, you can look at all of the data from the analyses of pregnancy registries and the difference in complication rates between drugs is so narrow and so small that the difference in changing to another drug with a lower odds ratio for congenital malformations probably makes little sense.  That does not mean that nobody will want to change and patient preference in this case requires a thorough and neutral discussion.



George Dawson, MD, DFAPA


References:

 1: 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. PubMed PMID: 28082367

2: Greene MF. Teratogenicity of SSRIs--serious concern or much ado about little? N Engl J Med. 2007 Jun 28;356(26):2732-3. PubMed PMID: 17596609.

3: Alwan S, Reefhuis J, Rasmussen SA, et al. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med 2007;356:2684-2692

4: Louik C, Lin AE, Werler MM, Hernandez-Diaz S, Mitchell AA. First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med 2007;356:2675-2683

5: Andrade C. Understanding relative risk, odds ratio, and related terms: as simple as it can get. J Clin Psychiatry. 2015 Jul;76(7):e857-61. doi: 10.4088/JCP.15f10150. PubMed PMID: 26231012.

6:  Pepe MS, Janes H, Longton G, Leisenring W, Newcomb P.  Limitations of the odds ratio in gauging the performance of a diagnostic, prognostic, or screening marker.  Am J Epidemiol (2004) 159 (9): 882-890 https://doi.org/10.1093/aje/kwh101

7: Davies HT, Crombie IK, Tavakoli M. When can odds ratios mislead? BMJ. 1998 Mar 28;316(7136):989-91. Review. PubMed PMID: 9550961.

8: Deeks J. When can odds ratios mislead? Odds ratios should be used only in case-control studies and logistic regression analyses. BMJ. 1998 Oct 24;317(7166):1155-6; author reply 1156-7. PubMed PMID: 9784470.

9: Bracken MB, Sinclair JC. When can odds ratios mislead? Avoidable systematic error in estimating treatment effects must not be tolerated. BMJ. 1998 Oct 24;317(7166):1156; author reply 1156-7. PubMed PMID: 9841055.

10: Zachary N. Stowe, MD  Treatment of Mood Disorders in Pregnancy and Lactation: Where Are We Now?  Presented at 2nd Annual Update And Advances In Psychiatry.  October 10-11, 2014; Madison, Wisconsin

11: Katherine Wisner, MD, MS.  Treating Depression During Pregnancy: Are We Asking the Right Questions?  Presented at 4th Annual Update And Advances In Psychiatry.  October 14-15, 2016; Madison, Wisconsin

12: Michelle Wiersgalla, MD.  Postpartum Mood and Anxiety Disorders.  Presented at the Minnesota Psychiatric Society.  October 1, 2016.

13: Oates M. Suicide: the leading cause of maternal death. Br J Psychiatry. 2003 Oct;183:279-81. PubMed PMID: 14519602.

14: Knight M, Nair M, Tuffnell D, Kenyon S, Shakespeare J, Brocklehurst P, Kurinczuk JJ (Eds.) on behalf of MBRRACE-UK. Saving Lives, Improving Mothers’ Care - Surveillance of maternal deaths in the UK 2012-14 and lessons learned to inform maternity care from the UK and Ireland Confidential Enquiries into Maternal Deaths and Morbidity 2009-14. Oxford: National Perinatal Epidemiology Unit, University of Oxford 2016.

"Maternal suicides have now been reclassified by the World Health Organisation as a direct cause of maternal death. The rate of maternal death by suicide remains unchanged since 2003 and maternal suicides are now the leading cause of direct maternal deaths occurring within a year after the end of pregnancy" p. 11.

15:  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. PubMed PMID: 16449615.

16:  Viguera AC, Whitfield T, Baldessarini RJ, Newport DJ, Stowe Z, Reminick A,Zurick A, Cohen LS. Risk of recurrence in women with bipolar disorder during pregnancy: prospective study of mood stabilizer discontinuation. Am J Psychiatry. 2007 Dec;164(12):1817-24; quiz 1923. PubMed PMID: 18056236.

17.  National Collaborating Centre for Mental Health.  Antenatal and Postnatal Mental Health Clinical Management and Service Guidance (Updated  Edition 2014). National Clinical Guideline Number 192.

Specific guidelines on treating depression in pregnancy for psychiatrists starts on about page 848 and continues.  A full gamut of treatment interventions in the context of clinical history and evaluation, patient preferences, and informed consent is presented.


antidepressants "congenital malformation"

antidepressants congenital malformation 

antidepressants pregnancy



Attribution:

The figure in the above post if from reference 15 - the figure is entitled:  "Figure. Kaplan-Meier Curves Illustrating the Time to Relapse by the 4 Medication Categories and Medication Reintroduction Categories" with permission from the American Medical Association, order number 4043410033700.  Thank you AMA.


Supplementary 1:

I tried to get permission to post survival curves from references 16.  The APA (of which I am a 32 year member) wanted to charge me $150 to repost a single 10 year old graphic that I have seen used in presentations.

Supplementary 2:

The graphics at the top are the actual fliers for the two conferences mentioned.  Other than two years of residency training, I have no affiliation with the University or Wisconsin Department of Psychiatry.