Postpartum Depression Project Newsletter Volume 4 August 2011
Does Exposure to SSRIs in Utero Increase the Risk of Autism?
A recent article published online in the Archives of General Psychiatry examined the association between maternal SSRI use in pregnancy and the risk of an autism spectrum disorder. This was a population based case-control study in which medical records were retrospectively evaluated for maternal use of antidepressant medications, mental health history of mothers, and demographic and medical covariates. The authors examined the records of 298 case children with autism spectrum disorders and 1507 control children. Prenatal antidepressant exposure (defined as maternal antidepressant use in the year prior to delivery) occurred in 20 of the case children and 50 of the control children and led the authors to conclude that there was a two-fold increase risk of ASD associated with antidepressant exposure; the risk was highest when the antidepressants were taken during the first trimester (adjusted odds ratio 3.8%) No increase in risk was found for mothers with a history of mental health treatment in the absence of prenatal exposure to selective serotonin reuptake inhibitors. The author, Lisa Croen Ph.D., points out however, in an interview with Medscape, that the results "should be interpreted with extreme caution" and that further studies are needed to determine if this association represents a causal connection; that “it is possible that the association we found between maternal SSRI use and autism is in fact explained by the underlying condition for which the woman took the medication." In fact, children with ASD have a higher incidence of family history of psychiatric disorders. Current use of SSRIs in pregnancy is an indication of maternal illness during pregnancy which may be less than adequately treated and can lead to physiologic changes which negatively affect neonatal outcomes and fetal development. While this study raises questions for further study it does not necessarily support a cause and effect relationship between prenatal SSRI exposure and increased risk for ASD. Since we know that the risk of depression with its associated physical and physiological effects can pose significant risks to the fetus, we need to weigh this risk against the possible small increase risk of ASD with SSRI exposure which would need to be replicated in future studies.
Opioid Analgesics and Pregnancy: What are the Risks
A recent article in the American Journal of Obstetrics and Gynecology (AJOG) in March 2011 raises concerns about maternal treatment with opioid analgesics during pregnancy. The authors, Cheryl Broussard, PhD, Sonja Rasmussen MD, MS et al, analyzed data from the National Birth Defects Prevention Study (NBDPS). The NBDPS is an ongoing population based case-control study. The researchers examined infants born October 1997 through December 2005. They found that 2.6% of the 17,499 mothers of case infants reported opioid analgesic treatment before 1 month and up to 3 months after conception. Among the case control mothers, 2.0% reported treatment in the same time frame.
The opioids most commonly reported were codeine, hydrocodone, oxycodone and meperidine. Opioids were most frequently prescribed for surgical procedures, infections, chronic disease and injuries. A statistically significant association was found with maternal opioid use and increased risk of ASD, VSD, hypoplastic left heart syndrome, Tetralogy of Fallot and pulmonary valve stenosis. There was also an association with an increased risk of spina bifida. This study is consistent with previous findings though is the largest data set analyzed. The authors conclude that it is imperative to weigh the benefits of these medications along with their potential risk.
Opioid Addiction and Pregnancy: Advances in Management:
It is difficult to obtain actual overall figures on the incidence of infants being born to mothers who have been addicted to opiates during their pregnancy, but we do know that the overall incidence appears to be increasing. An article in the New York Times in April 2010 cited the incidence of infants monitored or treated for neonatal in the two largest Maine hospitals as nearly quadrupling from 2005 to 2010. This seems to be reflective of the overall increase in the abuse in prescription drugs and presents a challenge for those treating women who are pregnant and addicted to opiates. For the past forty years the mainstay of treatment for opiate dependence during pregnancy has been methadone maintenance; however a number of studies over the past year have shown buprenorphine use during pregnancy to be superior to methadone for neonatal outcomes.
In a study conducted at Maine Medical Center and presented by Dr. Czerkes and colleagues at the ACOG 58th Annual Meeting In May 2010, neonates born to mothers treated with methadone were compared to those born to mothers treated with buprenorphine through a retrospective chart review. There were no statistical differences in maternal characteristics but 75% of neonates born to methadone treated mothers required treatment for neonatal withdrawal compared with 50% of buprenorphine treated neonates. The neonates born to mothers treated with methadone stayed in the hospital on average one week longer. One possible explanation for this difference is that buprenorphine crosses the placenta less readily and results in lower exposure than methadone.
A prospective study presented in the New England Journal of Medicine in December 2010 also found buprenorphine to be superior to methadone in treating opiate dependence in pregnant women and in reducing neonatal withdrawal symptoms. This study, called the Maternal Opioid Treatment: Human Experimental Research (MOTHER) followed 131 opioid dependent pregnant women from enrollment until 28 days after delivery. This study once again found that neonates born to buprenorphine treated pregnant women had fewer withdrawal symptoms requiring less treatment and shorter hospital stays.
A third study presented at the 42nd Annual Medical Scientific Conference of the American Society of Addiction Medicine retrospectively compared the infants of two groups of women who were treated with either buprenorphine or methadone and once again found a lower incidence of withdrawal and shorter hospital stays in the buprenorphine group. Another striking finding on this study was that the incidence of cigarette smoking was 85% in the entire group of women and the fact that birth weights were low in both groups. They went on to test a subgroup of infants in for neurodevelopmental outcome at 10 months and there was no difference between the groups both of which appeared normal. While all three of these studies support the superiority of buprenorphine for the management of opiate dependence during pregnancy one caveat that has been raised is that there may be some differences between the two groups of mothers with the possibility that women on methadone may have more severe addictions and associated socioeconomic adversities.
PPD Project Newsletter Contributors: Leora Rabin M.D., P. Lynn Ouellette M.D. For more information about the MAPP PPD please visit the MAPP website www.mainepsych.org or contact Lynn Ouellette at plopsymd@myfairpoint.net
PPD Project Newsletter Volume 3 November 2010
Highlights from the Marce’ Society Meeting: Focus on Pregnancy, Depression and Medications Zolpidem (Ambien) use in Pregnancy
Highlights from the Marce’ Society Meeting: Focus on Pregnancy, Depression and Medications
This first section will focus on research updates presented at the 2010 Marce’ Society Biennial Meeting in Pittsburgh in October 2010. The Marce’ Society is an international society for the understanding, prevention and treatment of mental illness related to childbearing.
There was an overall consensus that we have ample data on use of antidepressants in pregnancy and that the overall absolute risk for SSRI’s of teratogenicity is small. Therefore the safest antidepressant in pregnancy is the one that is effective to maintain a stable mood for the individual patient. Several new studies were presented to support this perspective:
· A large retrospective analysis of the Medical Birth registry of Norway evaluated 180,000 pregnant women for antidepressant exposure and fetal outcome. First trimester SSRI use was found in 1497 (0.8%) and 2570 (1.4%) used SSRI’s through their pregnancies. There was no increase in fetal malformations in the antidepressant exposed group.
· Another study from the Motherisk Program of Canada, a prospective observational study of women who contacted that program regarding the use of Lexapro in pregnancy, reported no increase in malformations, but consistent with other recent studies, an elevated risk for spontaneous abortions. (Einerson et al.)
However, this is a vast oversimplification as there was also a consensus that concerns need to be focused on other issues such as the risk of spontaneous abortion, low birth weight, premature birth, and other potential risks of exposure to antidepressants and/or depression and further separating out the impact of depression from exposure to medication.
· In a sample of 1243 pregnant women comparing those who chose to continue vs. discontinue their antidepressants; a prospective study also at Motherisk in Canada examined the previously reported increased risk of both preterm birth and spontaneous abortions associated with antidepressant use during pregnancy. No difference in the rate of preterm births was found between the groups. However a 7-fold increase in spontaneous abortions was found in the women who chose to discontinue their antidepressants in the first trimester. This was an unexpected finding and researchers plan to do a larger scale study to replicate these findings before publication (Einerson, A et al).
· There is a risk for transient jitteriness, restlessness, irritability, and other neonatal symptoms associated with the use of SSRIs during pregnancy referred to as neonatal adaptation syndrome. A study from the Women’s Behavioral Healthcare program at the Univ of Pittsburgh measured umbilical cord blood levels of SSRIs and demonstrated that the risk and severity of these symptoms showed NO correlation with the cord blood levels (currently in submission to J of Clin Psych, Sit, D et al). This is the first prospective study to really look at this issue of neonatal adaptation syndrome and whether or not it is correlated with quantitative level of exposure to maternal SSRI’s. This complements a previously published retrospective study by Warburten which showed no difference in symptoms in infants born to mothers who had taken SSRIS but tapered 2 weeks prior to delivery vs. those born to women who continued their SSRIs. (Warburten et al, 2010). Therefore the empiric recommendation that the dose of these drugs be decreased during the third trimester in an effort to decrease the risk of neonatal adaptation syndrome does not appear to be validated by scientific investigation. Further, it has been shown that maternal blood levels of these drugs often decrease during pregnancy when the dose remains stable such that any evidence for worsening in depressive symptoms would be a justification for increasing the dose (Sit, D et al, 2008)
· A study from the U of Washington did a literature review of 862 studies extracting 29 that met strict criteria for looking at the association between depression during pregnancy and risk for preterm birth (PTB), low birth weight (LBW)and intrauterine growth restriction (IUGR). The conclusion was that women with depression during pregnancy were at increased risk of PTB and LBW
· In another study from Emory University School of Medicine, both psychotropic medication use and significant depressive symptomatology (meeting criteria for MDE) were independently associated with diminished placental blood flow, a potential mechanism for poor birth outcomes such as premature birth and low birth weight.
There will be new FDA guidelines released in 2013 which will be much more helpful than the current guidelines for the use of medication during pregnancy and lactation which are most often misunderstood and behind the current state of knowledge. The new labeling will have 2 sections—one for pregnancy and one for lactation. The current labeling uses five categories—A, B, C, D, and X—which can mislead healthcare providers to believe that the risks increase from category A to B to C, etc. In fact, that is not the case. Categories C, D and X are based not just on risk, but on risk against benefit and the categories do not distinguish risk based on human vs. animal data or on differences in frequency, severity and type of developmental toxicities. Also new data is not frequently used to update the labeling such that the current state of knowledge is not reflected in category labeling. The proposed rule would remove the categories from the labeling of all drug products. Both pregnancy and lactation subsections would have three components: a risk summary, clinical considerations and a data section.
Lee Cohen MD (MGH Perinatal Psychiatry Research Program) presented and overview what we have learned about the use of antidepressants and mood stabilizers during pregnancy from the last 2 decades. The take home message was that relapse rates for both unipolar and bipolar mood disorders are very high during pregnancy. Maintaining mood stability during pregnancy is crucial to prevent adverse obstetrical and neonatal outcomes and diminish the risk of postpartum illness. Physicians and patients must collaborate to weigh the risks of fetal exposure to medications given the current state of knowledge and the patient’s individual history recognizing that no decision is perfect and no treatment is risk free.
- References: Warburton et al, A Register Study of the Impact of Stopping Third Trimester Selective Serotonin Reuptake Inhibitor on Neonatal Health, Acta Psychiatr Scand 2010; 121(6): 471-9.
- Sit, D. et al, Changes in antidepressant metabolism and dosing across pregnancy and early postpartum, J Clin Psychiatry. 2008 Apr; 69(4):652-8
Zolpidem (Ambien) use in Pregnancy
A review of a recent study published in Clinical Pharmacology and Therapeutics by Wang et al.
Sleep disorders are common in women, particularly during pregnancy and the postpartum period. Studies report that 66% to 97% of women in the third trimester experience sleep problems. (1) While for some pregnant women, therapy and behavioral techniques may be beneficial, some require pharmacological management of insomnia. Zolpidem is often prescribed for women in pregnancy. However, there is limited data on its safety. To date, there have been case reports and two small studies showing the reproductive safety data of this medication in pregnancy. One small study of 18 women in England showed no increased rate of congenital anomalies in pregnancy with the use of Zolpidem. (2) Another study of 45 pregnant women with psychiatric illness using Zolpidem showed higher rates of low birth weight babies (26.7% vs. 13.3%) and preterm deliveries (15.6% vs. 4.4%) than the non-exposed group. (3) However, given the small size of these studies, the findings were not statistically significant and therefore insufficient to guide clinical practice.
Wang et al studied the use of Zolpidem in pregnancy using two nationwide population-based data sets in Taiwan. They studied 14,982 pregnant women with a mean age of 29.7 years. The results showed higher rates of low birth weight babies (7.61% in the exposed group vs. 5.19% in the unexposed group), preterm delivery (10.1% vs. 6.30%), small for gestational age babies (19.94% vs. 15.06%) and higher rates of caesarean delivery (46.86% vs. 33.46%). There was no statistical difference in the two groups in the rates of congenital anomalies (0.48% vs. 0.65%)
They also separated mothers into two groups: those that received the drug in the first trimester and those that who received the drug during the second or third trimester. Women with first trimester exposure did not have higher rates of adverse pregnancy outcomes than those exposed in the second and third trimester.
After adjusting for confounders, they found that mothers who received Zolpidem for more than 90 days had higher rates of adverse pregnancy outcomes.
The potential limitations of the study are that the level of severity of insomnia is largely unknown. Also, there is unknown adherence to the medication regimen and incomplete social history with unknown use of substances, including illicit drugs, OTC medication and nutritional status. Due to these findings, the authors suggest avoiding use of Zolpidem in pregnancy when possible. Other medication options for sleep with safety data in pregnancy are the tricyclic antidepressants and the benzodiazepines. Other options for addressing sleep problems during pregnancy include cognitive behavioral therapy, improving sleep hygiene and addressing underlying mood disorders.
In summary:
- Zolpidem use in pregnancy is associated with higher rates of low birth weight babies, preterm delivery, small for gestational age infants and higher rates of caesarean delivery.
- There is no increased rate of congenital anomalies (which is consistent with previous studies).
- There is no increased risk of adverse outcomes when used in the first trimester when compared to use in the second and third trimesters.
- If Zolpidem is used in pregnancy, it should be used for less than 90 days
References
- Selvaraj V, et al. Treating insomnia across women’s life stages. Current Psychiatry 2010; 9: 27-33
- Wilton, LV et al the outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. B. J Obstet. Gynecol. 105, 882-889 (1998)
- Juric, S. et al Zolpidem in pregnancy: placental passage and outcomes. Arch. Women’s Ment. Health 12, 441-446 (2009)
PPD Project Newsletter Contributors: Maya Bulman MD, Maine Medical Center, P. Lynn Ouellette MD, Brunswick, Director, PPD Project. For comments, questions, more information, please email P Lynn Ouellette at plopsymd@myfairpoint.net
PPD Project Newsletter Volume 2
Postpartum Obsessional Thoughts: Thoughts of harming the baby
Up to 80% of women will experience a form of mood disturbance during the postpartum period. These can vary in symptom presentation and severity. The majority of people experience a mild episode, which is transient and usually does not require intervention or treatment. Studies show that 10-15% of women develop Postpartum Depression (PPD). One feature of PPD that is very concerning for both patients and mental health providers is postpartum obsessional thoughts. These are characterized by disturbing, intrusive obsessional ruminations. It is very common, with one study reporting that up to 50% of women experience this. These ruminations are usually focused on the baby and can often be violent in nature. They are egodystonic and therefore very troubling to the mother. It is important to distinguish these thoughts from a psychotic disorder. With postpartum obsessional thoughts, there is no problem with reality testing and there are no associated psychotic symptoms. These thoughts are experienced in the women’s head and are often accompanied by protective and avoidant behaviors, such as hiding knives and refusing to bathe the baby for fear of doing harm. It is very important to note that these obsessional thoughts do NOT increase risk of harm to the baby and therefore the presence of these symptoms does not necessitate separating the mother from her baby.
The following is a real case example of a woman who experienced such symptoms:
A 30 y/o married mother of 4 year old and 7 month old sons revealed that she was having intrusive violent images of harming her infant son. The NP in her PCP’s office began her on Zoloft 50 mg and also sent her to the ER for a crisis evaluation where it was recommended that she not care for her baby without supervision until she had additional mental health treatment. She was referred for psychiatric consultation. The patient reported that she had similar violent images after the birth of her first son and that she was generally more stressed and anxious then because her first baby “never slept.” They also had just moved to the area and she was isolated and without support. She had intrusive images in which she would see herself putting the baby in a pot of boiling water. She was horrified by the images and could not imagine ever harming her baby. She managed these thoughts and images which were the most intense when she was in the kitchen by either moving the baby out of the kitchen or keeping him on the periphery while she worked in the kitchen. Gradually over months, as the baby slept better and she became more involved with activities and established new relationships her anxiety and the depression that accompanied it subsided. She was so horrified that she never disclosed these experiences to anyone. She did well for the subsequent 3 years and through her next pregnancy though was fearful that this experience would recur following the birth of her second son. She began to have the same intrusive thoughts and images soon after he was born. Despite this baby being a good sleeper and not having the same level of exhaustion, the images and thoughts persisted and had been so horrifying that her anxiety escalated to the point of panic attacks on a couple of occasions. She was horrified images of putting this baby in a pot of boiling water as she would never want to harm her baby. She had begun to have disturbed sleep and to experience some depressive symptoms as well. She had no history of prior psychiatric treatment. Her mental status exam revealed an alert, oriented articulate woman with logical and coherent thought processes. She was distressed by her intrusive images and thoughts, and the idea that she could not be trusted with her baby. There were no delusions, hallucinations, or no suicidal ideation. Her affect was slightly tearful and appropriate. The interventions from the psychiatric consultation included psycho education for the patient and referring provider regarding postpartum depression and the nature of obsessional thoughts including the recommendation that the patient no longer needed supervision in caring for her infant. She was to continue with Zoloft and individual psychotherapy.
Acupuncture for Depression during Pregnancy
Depression during pregnancy is quite common, and there are many treatment options available. However, there are few studies that help guide the patient and provider towards treatment decisions. While some providers and pregnant women feel comfortable taking medication during pregnancy, many would prefer to avoid their use altogether. There is a need for more studies looking at non-pharmacologic treatment options for depression during pregnancy.
A study published in Obstetrics and Gynecology in March 2010 by Dr. Rachel Manber and colleagues at Stanford looked at the efficacy of Acupuncture for Depression during Pregnancy. This was a randomized controlled trial, which studied 150 pregnant women. The women were diagnosed with Major Depressive Disorder by the DSM-IV and a score of >14 on the 17 item Hamilton Rating Scale for Depression (HAMD-17).
The women were randomly assigned to one of three treatment arms; acupuncture specific for depression, control acupuncture and massage. They received a total of 12 sessions (25 min. each) during 8 weeks. The acupuncturist was blinded, as were the HAMD raters. Both the acupuncture specific for depression as well and the control acupuncture consisted of 7-12 acupuncture points in the same areas of the body. The patients in the massage group received Swedish massage while lying on their side, focusing on face, back, neck, head, shoulders and feet.
The outcome measure was the HAMD-17 score administered at baseline and again after 4 and 8 weeks of treatment by blinded raters. The results showed that those participants that received acupuncture specific for depression had a significantly greater reduction in the HAMD-17 scores than those in the combined controlled intervention group. Response rates were 63% in the acupuncture specific for depression group, 37.5% in the control acupuncture group and 50% in the massage group.
These findings suggest that acupuncture is a reasonable and effective treatment option for women with depression during pregnancy.
PPD Project Newsletter - Volume 1 - January 26, 2010
This is the first of a quarterly newsletter aimed at promoting recognition, education and updates on psychiatric treatment of women during pregnancy and the postpartum period. We will try to provide a summary of the most recent pertinent publications and address one frequently asked question.
This newsletter is created by members of the MAPP PPD Project, which is a statewide project funded by a grant from the APA for the purpose of collaborating with other medical specialties and other members of the mental health community to promote understanding of postpartum depression as a psychiatric illness with serious consequences to mothers and infants, decrease stigma and increase recognition and treatment of PPD.
Why the MAPP PPD Project?
-Depression is the leading cause of disease-related disability in women
-1 of 8 new mothers experience depression
-The most common complication of childbirth is depression
-10-20% of women will experience significant depression during pregnancy
-The peak lifetime prevalence for psychiatric disorders and hospital admissions for women occurs in the first 3 months after childbirth
-The most significant factor in the duration of postpartum depression is delay in receiving treatment
APA/ACOG Guidelines
A recent report with joint guidelines from the American Psychiatric Association and the American College of Obstetricians and Gynecologists on the management of depression during pregnancy was published in the September/ October 2009 issue of General Hospital Psychiatry.
The article describes the rate of depression in pregnancy (14%-23%) and the difficulty in interpreting the literature on the use of antidepressants during pregnancy. The article describes the correlation of maternal depression and adverse obstetrical outcomes. It provides a good summary of the impact of antidepressants on birth outcomes.
Treatment guidelines include flowcharts for the following:
Patient considering pregnancy and on medications for depression
-for women with mild or no symptoms, can consider taper and discontinuation of medication
-if possible recommended reasonable period of stability before attempt to conceive
-for women with history of severe and recurrent depression, consider continuation of medication unless the patient has responded to psychotherapy alone in the past
Pregnant patient in an episode of Major Depression (no SI and no psychotic sx) and not taking medications
-psychotherapy may be indicated as first line of treatment if woman wants to avoid antidepressants
-if medication preferred, evaluate and discuss risks and benefits (including stage of gestation, history of depression, maternal and infant impact)
Pregnant patient with Major Depression currently taking antidepressants
-women who are not experiencing depression, have no history of relapse with discontinuation and request discontinuation of medication, may attempt taper
- women with continued depressive symptoms may benefit from addition of therapy
- women with a history of recurrent severe depression should remain on medication
A full copy of the article is available on line at www.sciencedirect.com
Q. Should valproate medications be prescribed to women of reproductive age?
Considering the number of unplanned pregnancies, up to 49 in one study, valproate should be prescribed with great caution or not at all in women with reproductive potential.
First trimester exposure to valproate has been associated with a 3-5% risk of neural tube defects. In the general population, neural tube defects occur in 1 in 1,000-2,000 births. Valproate increases the risk of other malformations affecting the heart, limbs and genitals. Fetal hepatic failures have been reported in newborns of mothers who used valproate while pregnant.
A 2009 New England Journal of Medicine article based on a prospective study of 309 women found that at age 3 years, children exposed to valproate in utero had significantly lower IQs compared with other antiepileptic medications. On average, children exposed to valproate had an IQ score 9 points lower than those exposed to lamotrigine, The association between valproate use and IQ was dose dependent. Children's IQs were significantly related to maternal IQ among children exposed to other antiepileptic medications but not among those exposed to valproate.
All women should supplement their diets by taking prenatal multivitamins (containing 0.8mg to 1.0mg of folate). A woman taking valproate (or other anitepileptic) should receive 3.0mg of folate in addition to other prenatal vitamins. If a woman becomes pregnant while on valproate, she should be offered screening for neural tube defects.
For more information about the MAPP PPD Project or to get involved please contact us at: plopsymd@myfairpoint.net or rabinl@mmc.org
Postpartum Depression Project Newsletter Committee
Leora Rabin, MD, Maine Medical Center
Maya Rydewski, MD, Maine Medical Center
P. Lynn Ouellette MD, PPD Project Director, Private Practice, Brunswick Maine