Description of the study
The study was authored by Christina D. Chambers, Ph.D., M.P.H., Sonia Hernandez-Diaz, M.D., Dr.P.H., Linda J. Van Marter, M.D., M.P.H., Martha M. Werler, Sc.D., Carol Louik, Sc.D., Kenneth Lyons Jones, M.D., and Allen A. Mitchell, M.D will be analyzed as a case-study for this paper. The study is part of a large case–control study of risk factors for PPHN, conducted within the Birth Defects Study of the Slone Epidemiology Center. The objective of the study is to discern the effects of the use of the selective serotonin-reuptake inhibitor (SSRI) fluoxetine of a pregnant mother on the occurrence of persistent pulmonary hypertension on the infant. The study focuses on the use of SSRI on the third trimester of pregnancy.
What is PPHN?
Persistent pulmonary hypertension of the new born or PPHN is a pulmonary disorder particularly that of the pulmonary vasculature. Abnormally high pressure on the pulmonary artery results in the creation of smooth muscle as well as hypertrophy in the smaller pulmonary walls and arterioles. Right to left shunting of occurs through the ductus arteriosus and/or the foramen ovale. The result is intractable systemic hypoxemia. (Persistent Pulmonary Hypertension of new born infant, 2006) PPHN occurs in almost 1 out of 700 live births in the United States. There is only a 10 to 20 percent chance of a child surviving PPHN. Infants with PPHN are commonly those born near or full term. They usually manifest grave respiratory problems after birth requiring mechanical incubation.
Selective serotonin-reuptake inhibitor (SSRI) is primarily a group of anti depressants. Compared to other popular selective serotonin reuptake inhibitors (SSRIs), fluoxetine has a strong energizing effect. This makes fluoxetine highly effective in treatment of clinical depression cases where symptoms like depressed mood and lack of energy prevail.
Although stimulating, it is also approved for a variety of anxiety disorders, including panic disorder and obsessive compulsive disorder. The study aims to find if any the association of taking Selective serotonin-reuptake inhibitor (SSRI) fluoxetine during the last trimester of pregnancy with the risk of the newborn being born with Persistent pulmonary hypertension of the new born.
The case control study was undertaken as a sequel to an earlier cohort study. The smaller cohort study was undergone by a teratogen information service. The results of the cohort study became the basis of the hypothesis that maternal use of selective Serotonin-reuptake inhibitors (SSRIs) in late pregnancy may be a risk factor for PPHN. The cohort study showed that 73 out of 174 women that were exposed to fluoxetine during the last trimester of pregnancy had a greater chance of having neonatal complications. This is as compared to the 101 infants that took fluoxetine only at the first two trimesters. 2 of the 73 infants developed PPNH as compared to none of the 101.
The study is a case control comparison to determine association between the two relevant variables. The study was centered on four major cosmopolitan areas (Boston; Philadelphia; San Diego, California; and Toronto). The study gathered subjects from 97 institutions in those areas between the years 1998 and 2003. Records, logbooks were utilized as well as basic research to identify potential subjects in the study. These include infants that have and did not have PPNH.
Approval for the study was obtained from the review boards of the participating institutions. Mothers involved in the study gave their oral, and when required, written consent. 69 percent of mothers with children positive for PPHN participated while 68 percent for the control. After exclusion of mothers who could not be located and invited to participate, the rates were 73 percent and 71 percent, respectively.
The study utilized a multivariate conditional logistic regression method to statistically show the association of serotonin-reuptake inhibitor (SSRI) fluoxetine taken during preganacy as well as other factors with instances of persistent pulmonary hypertension on the infant. The prevalence odds ratios were estimated using this to approximate the risks for rare outcomes. A 95 percent confidence interval was used to confirm or reject the hypothesis. Statistical Analysis was performed using SAS version 8.2 for windows.
PPHN is diagnosed with characterization like a gestational age of more than 34 weeks, usually evident after the birth of the infant. The infant will experience severe respiratory failure and a series of pulmonary hypertension. Severe respiratory failure needs immediate attention of incubation and mechanical ventilation. Infants who underwent echocardiography were designated to have PPHN with the following set of criteria mentioned. The attending cardiologist will assign the diagnosis of PPHN in the infant. The echocardiogram shows a hemodynamic shunting from right to left of the ductus arteriosus or the patent foramen ovale.
The echocardiogram also showed two direction hemodynamic shunting together with a leftward bowing of the ventricular septum to a degree consisting of a pulmonary arterial pressure more than half of the systematic pressure. Nurses and respiratory therapists are trained to screen patients for PPHN. One of the authors, a neonatologist, reviewed the records of infants that were said to have potential indication of PPHN. Potential risk to PPHN includes infants diagnosed with asphyxia, cyanotic congenital heart disease, respiratory distress syndrome, pneumonia, meconium aspiration, transient tachypnea of the newborn or pulmonary hypertension.
In the observation, the control group consists of infants born after 34 weeks of the gestation period without any malformations. The infants were matched with patients according to the hospital in which they were born and their date of birth. The result is an intended ratio of 1:2 patients with control. After the patients were classified with the PPHN confirmation, and finished with the interview, the control group was matched with patients and the mothers who are selected for the analysis.
Trained nurses are assigned to interview the mothers of the infants after 6 months of delivery. Interviews were also done through the telephone. The structure of the phone interview was detailed and organized and includes question regarding demographics, the mother’s medical history, the parents background, and the use of prescription drugs during two months before the conception period of the mother. The response of the interviewee is then encoded to the computer and the database. The interviewing process includes computer aids for example online drug dictionary and diagnoses so that responses are instantly included in the interview and the database. The interviewing process is through manual application of skills and the computer.
An important question for the mothers is whether they have undergone depression and had taken antidepressants. Any response having the medication taken is prompted to a series of follow-up questions about the drugs taken, the indication and prescription. The interviewer must be able to get the most detailed answers from the mothers as much as possible. Antidepressants mentioned are either SSRI’s or other forms of antidepressants. In conjunction with the hypothesis, late-pregnancy exposure is defined as the use of antidepressants any time between the second half of the gestation period
Results of the study show that in comparison to only six infants from the control which acquired PPHN, fourteen infants whose mothers had been exposed to an SSRI during the last trimester of pregnancy succumbed to the disorder. No evidence acquired in the study gives justification that SSRI use before the last trimester produces an increased risk of getting PPHN.
Critique of the study
The study was organized with its presentation. The hypothesis and objectives of the study are clear and apparent. Clear flow from the background to the results makes the study easy to comprehend. The use of the superscript style of referencing limits distraction as well as ensures the continuity of the discussions. The presentation of the methodology could have been improved, in particular by following a step by step approach.
The study was presented in a clear concise manner. The use of a table to summarize the results made comparing very easy. The study could have been presented in a less crowded manner as well as with fewer technicalities to facilitate quick comprehension with a non- medical audience. However, since the perceived audience of the study is those with an extensive background on the subject, the presentation in itself is sufficient.
Sources of Potential bias
The study approached the problem from a reverse perspective, taking cases and identifying the background. The use of a recollective means of obtaining data would provide a less accurate supply of information. Also, the respondents would have a bias to recollect however accurately the questions presented in the questionnaire. The authors minimized a potential bias by making the personnel (nurses) as well as the respondents involved in the project unaware of the hypothesis. Other data, like age, marital status among others ensured that no particular preference will be given by the respondents in answering the inquiries.
One of the authors, a neonatologist, who was blinded to the history of maternal exposure to medications, reviewed the medical records of all patients with potential PPHN, including infants with diagnostic codes for asphyxia, cyanotic congenital heart disease, respiratory distress syndrome, pneumonia, meconium aspiration, transient tachypnea of the newborn or pulmonary hypertension. This would mean that no prioritization and emphasis will be given to asking and answering questions related to selective serotonin-reuptake inhibitor use. Also, the exclusion of any patients with prior conditions that could likely lead to a case of PPHN like patent ductus arteriosus, foramen ovale, atrial septal defect or a single, small, muscular ventricular septal defect helped isolate the factors to be studied.
The study was a part of a larger inquiry undertaken by the Birth Defects Study of the Slone Epidemiology Center. The inquiry aims to provide sound scientific basis on the identification and effects of different factors that lead to PPHN. The present study tackles one part of the over all research, the effect of fluoxetine taken during the last trimester on occurrence of PPHN. The use of selective serotonin-reuptake inhibitors especially fluoxetine has been known to cause medical side effects. Also, the use of anti depressants during pregnancy has been documented to lead to a higher risk factor for the new born.
A 1999 article published in Prescribe Int. entitled Serotonin reuptake inhibitor antidepressants and pregnancy: many unanswered questions delved into the unknown regarding serotonin antidepressant use during pregnancy. They discuss the need for extensive research to the anti depressant class and its effects on human pregnancy particularly the fluoxetine group. Questions raise by Ebernhard-Gran et al. (2005) have shown the lack of conclusive case control studies regarding the use of selective serotonin re-uptake inhibitors. Their paper showed that the lack of controlled random trials on SSRI’s as well as other anti-depressants provide a knowledge gap by which extended research cannot be undergone.
Tsudin et al even promotes the use of selective serotonin re-uptake inhibitors in depressed pregnant women. Their paper says that SSRI’s are more viable due to their composition and lack of documented teratogenic effects. Sanz et al. in 2005 investigated the use of SSRI’s during pregnancy and the manifestation of withdrawal symptoms in newborns. However a 2005 study on the adverse effects of SSRI’s taken during late pregnancy said that it has no adverse effects and is benign. Also, Kalra et al (2005) found that use of anti depressants by women including selective serotonin re-uptake inhibitors is relatively safe.
An almost parallel line of research was undergone by Goldstein in his 1995 paper entitled Effects of third trimester fluoxetine exposure on the newborn. However, the paper concluded that there is no sign that use of fluoxetine results in adverse post natal effects. The safety of fluoxetine was also discussed by Cali H.M. in the paper Fluoxetine: a suitable long-term treatment. The results of this paper also conclude the notion that fluoxetine use is safe for pregnant women using a case control study. Hendrick et al. in the paper entitled Birth outcomes after prenatal exposure to antidepressant medication discusses the effects of anti depressants on newborns.
The paper shows that use of anti depressants during pregnancy leads to an increase in neo natal complications. They found out that there is sufficient evidence to show that dosages of fluoxetine taken during pregnancy causes low birth weight. The dilemma of whether pregnant mothers suffering from depression should be advised to take anti depressants was tackled by Kalra et al. They weighed the consequences of letting a pregnant mother undergo depression as opposed to letting the mother be exposed to anti- depressants which may have an adverse effect on the infant.
The results of the study confirm an association between late pregnancy SSRI fluoxetine use and PPHN. This is in contradiction to some studies like those done by Calil and Goldstein. However, the paper supports the premise set forth by Hendrick et al. The probable variance in the methods used in each of the studies could have led to this decrepancy.
Furthermore, differences in both parameters and subject selection could have caused the difference. The statistical affirmation of the hypothesis set forth in the study gives credence to the conclusion that SSRI’s are associated to PPHN, although the study itself is lacking in terms of causality and basic scientific justification. The study provides a basis for further research to be undergone on the subject. The lack of information of the effects of selective serotonin re-uptake inhibitors on pregnant women and newborns may provide a crucial gap since their apparent benignity induces their increased use among depressed would be mothers.
Generalization of the findings
The study is applicable outside the confines of the sample group. The group, consisting of different races, age and social and health status can be considered an apt representation of the American population. However, the small population size in comparison to the country’s population would make the findings inconclusive when elevated to a large scale. The area was narrowed down to four eastern cities, demographics which are different from other divisions across the American mainland.
Originality of the research
Much research has been undergone regarding persistent pulmonary hypertension of the new born. The research proposed various hypotheses regarding the result. These are that when using antidepressant drugs, the lung is very much at risk. The organ serves as a reservoir of the SSRI’s. Serotonin has vasoconstrictive properties that is found to increase pulmonary vascular resistance. The mitogenic and comitogenic properties of serotonin also have an effect on the pulmonary smooth muscles. The higher circulating level and accumulation of serotonin in the fetus may result to the proliferation of the smooth muscle cells which indicates the acquisition of PPHN. The SSRI’s also has inhibitory effects that can cause PPHN.
The synthesis of nitric oxide is a factor in the regulation of vascular tone and reaction to the utero and postnatal life. in a study conducted, the release of nitric oxide inhibits a dose-dependent fashion in synovial-cell structure medium treated with flouxetine. In the study, a sample of patients with cardiac disease was treated with paroxetine. The activity of the nitric oxide synthase inhibits the serum levels of the nitrite and nitrate was significantly decreased compared with the pretreatment levels. The findings of this study are significant and consistent with the transient neonatal complications that occur in about 20 to 30 percent of newborns with late prenatal exposure to SSRI’s. The complications observed were mild respiratory distress, transient tachypnes of the newborn and the failure of the infant to cry. Included in the complication is cyanosis.
Found with a possible cause is the less severity of the respiratory problems consistent with the PPHN. The study found a not so significant result to the reduction of PPHN risk when SSRI exposure is limited to the first half of the gestation period. The study conducted was specified to the assessment of the PPHN association with SSRI used in the second half of the gestation period. Another explanation used in the study is founded with the idea of indication. However, exposure to non SSRI is not associated with PPHN.
There is also no association between PPHN and SSRI’s when the exposure time is limited to the first half of the gestation period. Within these observations is the assumption that maternal depression is not independently associated with PPHN. Other potential causes of the disorder include maternal body mass index, smoking, the use of NSAID in during late pregnancy and diabetes, although these indicators does not affect the assoiciation between the use of SSRI, late pregnancy and PPHN.
Residual cofounding is also said to affect the elevated risk of its size. It must also be noted that the study is statistically significant but is based on a relatively small number of exposed mothers. The limitation of the study is the restrospective design that includes the possibility of inaccurate recall or called the recall bias. Recall bias is attributed with the disorder if reduced to neither the interviewers nor the mothers unaware of the study hypothesis. It is also noted that differential recall during the gestational period and the exposure time to SSRI is unlikely.
The research undergone provides basis to say that use of SSRI’s during the last trimester of pregnancy is associated with PPHN. Other research showed no definite scientific basis for confirming or rejecting that SSRI’s have a negative effect on the new born. The knowledge that SSRI’s in particular fluoxetine is associated with PPHN is a significant finding since based on past researches and studies, SSRIs are considered to be safe. The knowledge that SSRIs were safe has led to them being usually recommended in cases of pregnancy depression.
Recommended in the research is the assessment of the relationship of the different types and dosages of antidepressants and the replication of the further researches findings. Further studies should also include any association between SSRI and PPHN in the infants of women who discontinue the use of SSRI during late pregnancy. Patients must also be identified who are at risks and must explore interactions between environmental and genetic factor. It should also include mutations related to PPHN. Major depressive disorders among women during their reproductive age are between 10 to 15 percent.
Common medications include the use of SSRI to treat these disorders. The treatment should be continued throughout the pregnancy period. The results of the study must be factored into an assessment of both benefits and risks for each mother. There is an assumption that relative risk for PPHN in the study is concluded as true, the relation may be causal, but the absolute risk among users of SSRI during late pregnancy is relatively low.
Recorded between 6 to 12 percent per 1000 women, or 99 percent of women exposed to the use of antidepressants during the late period of their pregnancy places a low risk on their infants to get the disorder. Further studies must confirm the findings of this particular study and consider both the benefits and drawbacks of using SSRI as an antidepressant and the potential risk to PPHN. The alternatives must also be included in further studies.
The study provides a basic stepping stone for other researches on the matter. It is a fundamental start to extended research. Now that association has been established, further research should be done. Causality as mentioned in the study must be established. The study provides basis for association only. Significant study as to prove whether SSRI use in late pregnancy could cause PPHN could be undergone. Also, various hypotheses as to why there is such association must be investigated.
- Calil, H. M. “Fluoxetine: A Suitable Long-Term Treatment.” J Clin Psychiatry 62 Suppl 22 (2001): 24-9.
- Chambers, C. D., S. Hernandez-Diaz, L. J. Van Marter, M. M. Werler, C. Louik, K. L. Jones, and A. A. Mitchell. “Selective Serotonin-Reuptake Inhibitors and Risk of Persistent Pulmonary Hypertension of the Newborn.” N Engl J Med 354, no. 6 (2006): 579-87.
- Cissoko, H., D. Swortfiguer, B. Giraudeau, A. P. Jonville-Bera, and E. Autret-Leca. “[Neonatal Outcome after Exposure to Selective Serotonin Reuptake Inhibitors Late in Pregnancy].” Arch Pediatr 12, no. 7 (2005): 1081-4.
- Eberhard-Gran, M., A. Eskild, and S. Opjordsmoen. “Treating Mood Disorders During Pregnancy: Safety Considerations.” Drug Saf 28, no. 8 (2005): 695-706.
- Goldstein, D. J. J Clin Psychopharmacol 15, no. 6 (1995): 417-20.
- Hendrick, V., L. M. Smith, R. Suri, S. Hwang, D. Haynes, and L. Altshuler. “Birth Outcomes after Prenatal Exposure to Antidepressant Medication.” Am J Obstet Gynecol 188, no. 3 (2003): 812-5.
- Kalra, S., L. Born, M. Sarkar, and A. Einarson. “The Safety of Antidepressant Use in Pregnancy.” Expert Opin Drug Saf 4, no. 2 (2005): 273-84.
- Kalra, S., A. Einarson, and G. Koren. “Taking Antidepressants During Late Pregnancy. How Should We Advise Women?” Can Fam Physician 51 (2005): 1077-8.
- Sanz, E. J., C. De-las-Cuevas, A. Kiuru, A. Bate, and R. Edwards. “Selective Serotonin Reuptake Inhibitors in Pregnant Women and Neonatal Withdrawal Syndrome: A Database Analysis.” Lancet 365, no. 9458 (2005): 482-7.
- “Serotonin Reuptake Inhibitor Antidepressants and Pregnancy: Many Unanswered Questions.” Prescrire Int 8, no. 43 (1999): 157-9.
- Tschudin, S., and O. Lapaire. “[Antidepressants and Pregnancy].” Ther Umsch 62, no. 1 (2005): 17-22.