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Selective serotonin reuptake inhibitors during pregnancy do not increase the risk of Hirschsprung's disease
YJPSU-59105; No of Pages 4 Journal of Pediatric Surgery xxx (xxxx) xxx
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Selective serotonin reuptake inhibitors during pregnancy do not increase the risk of Hirschsprung's disease☆ Anna Löf Granström a,⁎, Charlotte Skoglund b, Tomas Wester a a b
Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
a r t i c l e
i n f o
Article history: Received 6 November 2018 Received in revised form 6 February 2019 Accepted 8 February 2019 Available online xxxx Key words: Hirschsprung disease Maternal risk factor SSRI Epidemiology
a b s t r a c t Purpose: Hirschsprung disease (HSCR) is a multifactorial disease. Maternal intake of selective serotonin reuptake inhibitors (SSRI) during early pregnancy has previously been associated with increased risk for HSCR. The aim of this study was to assess the risk for HSCR in newborns after maternal intake of SSRI in a population-based Swedish cohort. Methods: This was a Swedish nationwide, population-based, case–control cohort study containing all children born in Sweden between 1/12006 and 31/122012. The cases were identified in the Swedish National Patient Register and the controls (five age- and sex-matched controls per case) were randomly selected among children without HSCR in the cohort. Data on maternal SSRI use during pregnancy were collected from the Swedish Prescribed Drug Register. Results: Out of 775,024 born children during the study period, 150 cases of HSCR (112 males) and 750 controls (560 males) were included. Five (3.3%) mothers of newborns with HSCR had used SSRI during pregnancy compared to 16 (2.1%) mothers of the controls (p = 0.372). The mean age was similar in mothers who had used SSRI compared to those who had not (30.9 (SD +/− 5.1) versus 30.6 (SD +/− 5.0), p = 0.81). Conclusions: There was no increased risk of HSCR owing to maternal intake of SSRI in this cohort. Level of evidence: Level I. © 2019 Elsevier Inc. All rights reserved.
Hirschsprung disease (HSCR) is a congenital defect of the enteric nervous system characterized by a lack of ganglion cells in the distal hindgut. The birth prevalence of the disease in Sweden is approximately one in 5000, and most of the patients are diagnosed as neonates. [1] The exact mechanism of HSCR is unknown, but there is evidence that both genetic and environmental factors are involved. [2] Mutations in more than 10 different genes have been associated with HSCR, particularly the RET gene, in which 15% to 20% of patients with isolated HSCR have mutations. [3] HSCR can also be part of a syndrome, most commonly Down syndrome (trisomy 21). [4] The impact of environmental factors is not well known but maternal obesity has been suggested as a risk factor for HSCR [1]. In a small study ☆ Funding source: This study was supported by the Foundation Frimurare Barnhuset, Her Royal Highness Crown Princess Lovisa Foundation, and the Sällskapet Barnavård Foundation. Financial Disclosure: The authors have indicated they have no financial relationships relevant to this article to disclose. All Authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. ⁎ Corresponding author at: Division of Pediatric Surgery, Astrid Lindgren Children's Hospital, S3:02, Karolinska University Hospital, Solna, SE-17176 Stockholm. Tel.: +46 708 808544. E-mail address: [email protected] (A.L. Granström).
of patients with Down syndrome and HSCR, extensive coffee drinking and maternal fever during the first trimester increased the risk for HSCR. [5] There have been speculations about the role of hypothyroidism, vitamin A deficiency, and maternal intake of ibumetin or mycophenolate during pregnancy, but none of these associations have been confirmed. [6–9] There have also been speculations about the maternal use of selective serotonin reuptake inhibitors (SSRI) and the risk for HSCR. [10] This hypothesis was supported by a recent Danish study. [11] Serotonin is a monoamine neurotransmitter, which is important for the development of the enteric nervous system. [12–14] The aim of this study was to assess if maternal intake of SSRI increased the risk for HSCR in the offspring in a Swedish population. 1. Patients and method 1.1. Design This was a nationwide, population-based case–control study. The study base includes all neonates born in Sweden during the observational period January 1, 2006, to December 31, 2012 and registered in the Swedish Medical Birth Register (MFR). The study outcome was
https://doi.org/10.1016/j.jpedsurg.2019.02.015 0022-3468/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: A.L. Granström, C. Skoglund and T. Wester, Selective serotonin reuptake inhibitors during pregnancy do not increase the risk of Hirschsprung's disease, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.02.015
2
A.L. Granström et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
HSCR and the study exposure was maternal SSRI prescription within one year before delivery. The outcome and exposure were assessed through linkage with the Swedish National Patient Register (NPR), the Swedish Medical Birth Register (MFR) and the Swedish Prescribed Drug Register for both cases and their mothers. All residents in Sweden are assigned a unique 10-digit personal identification number after birth or immigration, which enables linkage between different national registers. 1.2. Registers The MBR contains prospectively collected data on all pregnancies and deliveries in Sweden since 1973 and contains data on maternal age and parity, maternal weight and height, maternal smoking and diseases, duration of pregnancy, single or multiple birth, parity, and birth weight. The Swedish National Board of Health and Welfare administers the register. The NPR contains prospectively collected information on all hospital admissions in Sweden. The register is maintained by the Swedish National Board of Health and Welfare. It was initiated in 1964 and covers all hospitals in Sweden since 1987. The data include gender, age, geographical data, surgical procedures, primary and secondary diagnoses, and dates of admission and discharge. The International Classification of Diseases (ICD) has been modified over the years: ICD-8 in1969–1986; ICD-9 in 1987–1996, and ICD-10 since 1997. Since 2001 data on outpatient specialist care have also been included in the register. The latest validation of the register showed that the diagnoses are valid in 85%–95% of the cases. [15] The Swedish Prescribed Drug Register is also a national register maintained by the Swedish National Board of Health and Welfare. The register was initiated in 2005 and contains information on drug identity (Anatomical Therapeutic Chemical (ATC) codes) and dates of all registered prescriptions to the entire population in Sweden. 1.3. Study cohort All cases with an ICD code for HSCR in the Swedish NPR (ICD-8, 751.39; ICD-9, 751D; ICD-10: Q431) during the study period were
identified (n = 196). To confirm that the subjects had HSCR and were not misclassified by mistake each case had to satisfy one of the following inclusion criteria: 1) HSCR as the main diagnosis and a surgical intervention number specific for HSCR. 2) Admission to a pediatric surgical center at least twice, with a hospital stay of at least 4 days at least once, and HSCR as the main diagnosis for both hospital stays. 3) One long admission to a pediatric surgical center once and more than one outpatient visit to a pediatric surgical center with HSCR as the main diagnosis. Using these criteria, 46 patients were excluded, ending up with 150 HSCR cases. For each case, five controls, matched for birth year and gender and without a history of HSCR (n = 750), were randomly sampled by The Swedish National Board of Health and Welfare. A flowchart is shown in Fig. 1.
1.4. Variables Exposure data on maternal use of SSRI were categorized into two categories: first, prescription of SSRI during the year before birth of the offspring and second, SSRI prescription at any occasion before the offspring's birth. ATC codes of SSRI were following: N06AB03, N06AB04, N06AB05, N06AB05, N06AB06, N06AB08, N06AB10.
1.5. Statistical analysis The association between exposed and unexposed individuals was analyzed with R program. [16] Categorical data were presented as frequencies or proportions and analyzed with two-tailed Fisher's exact test. Continuous data were presented as median and range and twosided Mann–Whitney U test was used for analysis. P b 0.05 was considered statistically significant.
Fig. 1. Flowchart.
Please cite this article as: A.L. Granström, C. Skoglund and T. Wester, Selective serotonin reuptake inhibitors during pregnancy do not increase the risk of Hirschsprung's disease, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.02.015
A.L. Granström et al. / Journal of Pediatric Surgery xxx (xxxx) xxx Table 1 Summarizing results.
Total individuals (n) Male (n) SSRI during the year before birth (n) SSRI at any time before birth of the child (n) Maternal age at time of pregnancy (years, mean (SD))
HSCR
Controls
P-value
150 120 5 (3.3%) 13 (8.7%) 30.9 (5.1)
750 560 16 (2.1%) 54 (7.2%) 30.6 (5.0)
0.372⁎ 0.497⁎ 0.81⁎
⁎ Fisher exact test.
1.6. Ethics The study was approved by the Regional Ethics Review Board in Stockholm. 2. Results The study included 150 cases of HSCR (112 males) and 750 controls (560 males). Five (3.3%) mothers of newborns with HSCR had used SSRI during pregnancy compared to 16 (2.1%) mothers of the controls (p = 0.372). There were 13 (8.7%) mothers who had been prescribed SSRI any time before the pregnancy in the HSCR group compared to 54 (7.2%) in the control group (p = 0.497). There was no difference in maternal mean age of mothers who used SSRI compared with mothers who had not used SSRI (30.9 years (SD +/− 5.1) versus 30.6 years (SD +/− 5.0), p = 0.81). The results are summarized in Table 1.
3
Since SSRI increases the serotonin levels in the synapses one could speculate that the increased amount of serotonin also could have other effects especially during embryogenesis. Antidepressants are used by approximately 2.0%–10.0% of females during the first trimester. The use of SSRI during pregnancy is increasing. [26–29] There are also studies showing that untreated depression during pregnancy may have a negative impact on both the mother and the developing fetus, increasing the risk of premature delivery, low birth weight, small for gestational age and an increased risk emotional problems for the child. [24,25,30] There should be individual discussions with each pregnant woman about the indications for SSRI treatment. The role of environmental factors for the etiology of HSCR is unknown. Maternal intake of other drugs during pregnancy (ibuprofen and mycophenolate) has been associated with enteric nervous system malformations with an HSCR-like pathology in animal models. [19,20] Fu et al. have suggested that retinoic acid (Vitamin A) is essential for efficient enteric nervous system migration and proposed that some cases of HSCR might be preventable by ensuring adequate maternal vitamin A levels during early gestation. [21] Another possible environmental factor may be benzophenone-3, commonly used in personal care products for ultraviolet filter. It has been associated with HSCR in the child if used before pregnancy. [22] In a case report describing congenital hypothyroidism associated with HSCR, Kota et al. speculated about the importance of thyroxin levels for the development of the intestines. [23] In future studies it would be interesting to use national register data, as used in this study, to evaluate the risk for HSCR in the offspring owing to maternal intake of drugs during pregnancy.
3. Discussion This was a national population-based case–control study showing that maternal intake of SSRI during pregnancy did not increase the risk for HSCR in the offspring. The strengths of the study were that it was based on national registers, previously shown to have high validity, and included information on all children in Sweden during the study period. We had no loss to follow up, which prevents selection bias. Another strength was that the control cohort was randomly selected from Statistics Sweden, also reducing the risk for selection bias. To decrease the risk for confounders, the controls were matched for birth year and gender. To reduce the risk for misclassification, specific criteria were set in advance to identify both exposure and outcome. For the exposure, prescription of SSRI was used as a proxy for drug intake and not the patients recalling intake, therefore eliminating recall bias. One possible limitation owing to this proxy was the lack of information on drug compliance. We also had no opportunity to adjust our analyses for the severity of underlying depression, and it is unknown whether maternal depression itself may predispose to HSCR. For the outcome, the most proper criteria would have been to confirm the diagnosis with histopathology reports in each individual. Unfortunately, this is not possible using data from the National Patient Register. This is a limitation of the study, since we may have included patients without HSCR, but also excluded patients with HSCR. The birth prevalence in Sweden has been estimated to 1.91:10,000 [1]. During the study period there were 150 patients with Hirschsprung disease, 1.93:10,000. The study period was limited to 2006–2012 since the Swedish Prescribed Drug Register was initiated in 2005, which limited the sample size and increased the risk for type-2 errors. In the literature, the association between SSRI and HSCR has only been reported twice; first in a case report and then as a register-based study. [10,11] The authors suggested an association between maternal intake of SSRI during the first trimester and HSCR in the offspring. Other studies on maternal intake of SSRI during pregnancy have shown an association with congenital heart defect in the offspring. [17] Bérard et al. also showed an increased risk for major malformation in the offspring of mothers who had taken SSRI during pregnancy [18]
4. Conclusion This was a national population-based case–control study evaluating maternal intake of SSRI and the risk for HSCR in the offspring. The data did not show an increased risk in contrast with a previous study. Further studies are required to evaluate if SSRI during pregnancy is a risk factor for HSCR or not. CRediT authorship contribution statement Anna Löf Granström: Conceptualization, Methodology, Formal analysis, Writing - original draft, Writing - review & editing. Charlotte Skoglund: Conceptualization, Methodology, Formal analysis, Writing - original draft, Writing - review & editing. Tomas Wester: Conceptualization, Methodology, Data curation, Formal analysis, Writing - review & editing. References [1] Löf Granström A, Svenningsson A, Hagel E, et al. Maternal risk factors and perinatal characteristics for Hirschsprung disease. Pediatrics 2016;138(1). [2] Puri P, Ohshiro K, Wester T. Hirschsprung's disease: a search for etiology. Semin Pediatr Surg 1998;7:140–7. [3] Tam PK, Garcia-Barceló M. Genetic basis of Hirschsprung's disease. Pediatr Surg Int 2009;25:543–58. [4] Ikeda K, Goto S. Additional anomalies in Hirschsprung's disease: an analysis based on the nationwide survey in Japan. Z Kinderchir 1986;41:279–81. [5] Torfs CP, Christianson RE. Maternal risk factors and major associated defects in infants with down syndrome. Epidemiology 1999;10:264–70. [6] Kota SK, Modi KD, Rao MM. Hirschsprungs disease with congenital hypothyroidism. Indian Pediatr 2012;49:245–6. [7] Fu M, Sato Y, Lyons-Warren A, et al. Vitamin a facilitates enteric nervous system precursor migration by reducing Pten accumulation. Development 2010;137:631–40. [8] Lake JI, Tusheva OA, Graham BL, et al. Hirschsprung-like disease is exacerabated by reduced de novo GMP synthesis. J Clin Investigation 2013;123:4875–87. [9] Schill EM, Lake JI, Tuscheva OA, et al. Ibuprofen slows migration and inhibits bowel colonization by enteric nervous system precursors in zebrafish, chick and mouse. Dev Biol. 2015 Nov 14. Epub ahead of print; 2015. [10] Nielsen SW, Qvist N. Citalopram taken during pregnancy and the child born with Hirschsprung's disease. Ugeskr Laeger 2013(9):175. [11] Nielsen SW, Ljungdalh PM, Nielsen J, et al. Maternal use of selective serotonin reuptake inhibitors during pregnancy is associated with Hirschsprung's disease in newborns — a nationwide cohort study. Orphanet J Rare Dis 2017;12:116.
Please cite this article as: A.L. Granström, C. Skoglund and T. Wester, Selective serotonin reuptake inhibitors during pregnancy do not increase the risk of Hirschsprung's disease, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.02.015
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[12] Hansson SR, Mezey E, Hoffman BJ. Serotonin transporter messenger RNA expression in neural crest-derived structures and sensory pathways of the developing rat embryo. Neuroscience 1999;89:243–65. [13] Li Z, Chalazonitis A, Huang Y-Y, et al. Essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons. J Neurosci 2011;31:8998–9009. [14] Gershon MD. 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract. Curr Opin Endocrinol Diabetes Obes 2013;20:14–21. [15] Ludvigsson JF, Andersson E, Ekbom A, et al. Eternal review and validation of the Swedish national inpatient register. BMC Public Health 2001;11:450. [16] Core R. Team. R: a language and environment for statistical computing. R Foundation for statistical computing. Vienna Austria; 2015. [17] Wemakor A, Casson K, Garne E, et al. Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of specific congenital anomalies: a European register-based study. Eur J Epidemiology 2015;30:1187–98. [18] Bérard A, Zhao JP, Sheehy O. Sertraline use during pregnancy and the risk of major malformations. Am J Obstet Gynecol 2015;212:795–812. [19] Lake JI, Tusheva OA, Graham BL, et al. Hirschsprung-like disease is exacerbated by reduced de novo GMP synthesis. J Clin Invest 2013;123:4875–87. [20] Schill EM, Lake JI, Tusheva OA, et al. Ibuprofen slows migration and inhibits bowel colonization by enteric nervous system precursors in zebrafish, chick and mouse. Dev Biol 2016;409:473–88.
[21] Fu M, Sato Y, Lyons-Warren A, et al. Vitamin A facilitates enteric nervous system precursor migration by reducing Pten accumulation. Development 2010;137:631–40. [22] Huo W, Cai P, Chen M, et al. The relationship between prenatal exposure to BP-3 and Hirschsprung's disease. Chemosphere 2016;144:1091–7. [23] Kota SK, Modi KD, Rao MM. Hirschsprungs disease with congenital hypothyroidism. Indian Pediatr 2012;49:245–6. [24] Bonari L, Pinto N, Ahn E, et al. Perinatal risks of untreated depression during pregnancy. Can J Psychiatry 2004;49:726–35. [25] Stein A, Pearson RM, Goodman SH, et al. Effects of perinatal mental disorders on the fetus and child. Lancet 2014;384:1800–19. [26] Cooper WO, Willy ME, Pont SJ. Increasing use of antidepressants in pregnancy. Am J Obstet Gynecol 2007;196:544–5. [27] Andrade SE, Raebel MA, Brown J, et al. Use of antidepressant medications during pregnancy: a multisite study. Am J Obstet Gynecol 2008;198:194. [28] Jimenez-Solem E, Andersen JT, Petersen M, et al. Prevalence of antidepressant use during pregnancy in Denmark, a nation-wide cohort study. PLoS One 2013;8: e63034. [29] akker K, lling K. van den Berg PB, de Walle HEK, de Jong van den Berg LTW. Increase in use of selective serotonin reuptake inhibitors in pregnancy during the last decade, a population-based cohort study from the Netherlands. Br J Clin Pharmacol 2008;65:600–6. [30] Stein A, Pearson RM, Goodman SH, et al. Rahman a et al. Effects of perinatal mental disorders on the fetus and child. Lancet 2014;384:1800–19.
Please cite this article as: A.L. Granström, C. Skoglund and T. Wester, Selective serotonin reuptake inhibitors during pregnancy do not increase the risk of Hirschsprung's disease, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.02.015
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Selective serotonin reuptake inhibitors during pregnancy do not increase the risk of Hirschsprung's disease☆ Anna Löf Granström a,⁎, Charlotte Skoglund b, Tomas Wester a a b
Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
a r t i c l e
i n f o
Article history: Received 6 November 2018 Received in revised form 6 February 2019 Accepted 8 February 2019 Available online xxxx Key words: Hirschsprung disease Maternal risk factor SSRI Epidemiology
a b s t r a c t Purpose: Hirschsprung disease (HSCR) is a multifactorial disease. Maternal intake of selective serotonin reuptake inhibitors (SSRI) during early pregnancy has previously been associated with increased risk for HSCR. The aim of this study was to assess the risk for HSCR in newborns after maternal intake of SSRI in a population-based Swedish cohort. Methods: This was a Swedish nationwide, population-based, case–control cohort study containing all children born in Sweden between 1/12006 and 31/122012. The cases were identified in the Swedish National Patient Register and the controls (five age- and sex-matched controls per case) were randomly selected among children without HSCR in the cohort. Data on maternal SSRI use during pregnancy were collected from the Swedish Prescribed Drug Register. Results: Out of 775,024 born children during the study period, 150 cases of HSCR (112 males) and 750 controls (560 males) were included. Five (3.3%) mothers of newborns with HSCR had used SSRI during pregnancy compared to 16 (2.1%) mothers of the controls (p = 0.372). The mean age was similar in mothers who had used SSRI compared to those who had not (30.9 (SD +/− 5.1) versus 30.6 (SD +/− 5.0), p = 0.81). Conclusions: There was no increased risk of HSCR owing to maternal intake of SSRI in this cohort. Level of evidence: Level I. © 2019 Elsevier Inc. All rights reserved.
Hirschsprung disease (HSCR) is a congenital defect of the enteric nervous system characterized by a lack of ganglion cells in the distal hindgut. The birth prevalence of the disease in Sweden is approximately one in 5000, and most of the patients are diagnosed as neonates. [1] The exact mechanism of HSCR is unknown, but there is evidence that both genetic and environmental factors are involved. [2] Mutations in more than 10 different genes have been associated with HSCR, particularly the RET gene, in which 15% to 20% of patients with isolated HSCR have mutations. [3] HSCR can also be part of a syndrome, most commonly Down syndrome (trisomy 21). [4] The impact of environmental factors is not well known but maternal obesity has been suggested as a risk factor for HSCR [1]. In a small study ☆ Funding source: This study was supported by the Foundation Frimurare Barnhuset, Her Royal Highness Crown Princess Lovisa Foundation, and the Sällskapet Barnavård Foundation. Financial Disclosure: The authors have indicated they have no financial relationships relevant to this article to disclose. All Authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. ⁎ Corresponding author at: Division of Pediatric Surgery, Astrid Lindgren Children's Hospital, S3:02, Karolinska University Hospital, Solna, SE-17176 Stockholm. Tel.: +46 708 808544. E-mail address: [email protected] (A.L. Granström).
of patients with Down syndrome and HSCR, extensive coffee drinking and maternal fever during the first trimester increased the risk for HSCR. [5] There have been speculations about the role of hypothyroidism, vitamin A deficiency, and maternal intake of ibumetin or mycophenolate during pregnancy, but none of these associations have been confirmed. [6–9] There have also been speculations about the maternal use of selective serotonin reuptake inhibitors (SSRI) and the risk for HSCR. [10] This hypothesis was supported by a recent Danish study. [11] Serotonin is a monoamine neurotransmitter, which is important for the development of the enteric nervous system. [12–14] The aim of this study was to assess if maternal intake of SSRI increased the risk for HSCR in the offspring in a Swedish population. 1. Patients and method 1.1. Design This was a nationwide, population-based case–control study. The study base includes all neonates born in Sweden during the observational period January 1, 2006, to December 31, 2012 and registered in the Swedish Medical Birth Register (MFR). The study outcome was
https://doi.org/10.1016/j.jpedsurg.2019.02.015 0022-3468/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: A.L. Granström, C. Skoglund and T. Wester, Selective serotonin reuptake inhibitors during pregnancy do not increase the risk of Hirschsprung's disease, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.02.015
2
A.L. Granström et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
HSCR and the study exposure was maternal SSRI prescription within one year before delivery. The outcome and exposure were assessed through linkage with the Swedish National Patient Register (NPR), the Swedish Medical Birth Register (MFR) and the Swedish Prescribed Drug Register for both cases and their mothers. All residents in Sweden are assigned a unique 10-digit personal identification number after birth or immigration, which enables linkage between different national registers. 1.2. Registers The MBR contains prospectively collected data on all pregnancies and deliveries in Sweden since 1973 and contains data on maternal age and parity, maternal weight and height, maternal smoking and diseases, duration of pregnancy, single or multiple birth, parity, and birth weight. The Swedish National Board of Health and Welfare administers the register. The NPR contains prospectively collected information on all hospital admissions in Sweden. The register is maintained by the Swedish National Board of Health and Welfare. It was initiated in 1964 and covers all hospitals in Sweden since 1987. The data include gender, age, geographical data, surgical procedures, primary and secondary diagnoses, and dates of admission and discharge. The International Classification of Diseases (ICD) has been modified over the years: ICD-8 in1969–1986; ICD-9 in 1987–1996, and ICD-10 since 1997. Since 2001 data on outpatient specialist care have also been included in the register. The latest validation of the register showed that the diagnoses are valid in 85%–95% of the cases. [15] The Swedish Prescribed Drug Register is also a national register maintained by the Swedish National Board of Health and Welfare. The register was initiated in 2005 and contains information on drug identity (Anatomical Therapeutic Chemical (ATC) codes) and dates of all registered prescriptions to the entire population in Sweden. 1.3. Study cohort All cases with an ICD code for HSCR in the Swedish NPR (ICD-8, 751.39; ICD-9, 751D; ICD-10: Q431) during the study period were
identified (n = 196). To confirm that the subjects had HSCR and were not misclassified by mistake each case had to satisfy one of the following inclusion criteria: 1) HSCR as the main diagnosis and a surgical intervention number specific for HSCR. 2) Admission to a pediatric surgical center at least twice, with a hospital stay of at least 4 days at least once, and HSCR as the main diagnosis for both hospital stays. 3) One long admission to a pediatric surgical center once and more than one outpatient visit to a pediatric surgical center with HSCR as the main diagnosis. Using these criteria, 46 patients were excluded, ending up with 150 HSCR cases. For each case, five controls, matched for birth year and gender and without a history of HSCR (n = 750), were randomly sampled by The Swedish National Board of Health and Welfare. A flowchart is shown in Fig. 1.
1.4. Variables Exposure data on maternal use of SSRI were categorized into two categories: first, prescription of SSRI during the year before birth of the offspring and second, SSRI prescription at any occasion before the offspring's birth. ATC codes of SSRI were following: N06AB03, N06AB04, N06AB05, N06AB05, N06AB06, N06AB08, N06AB10.
1.5. Statistical analysis The association between exposed and unexposed individuals was analyzed with R program. [16] Categorical data were presented as frequencies or proportions and analyzed with two-tailed Fisher's exact test. Continuous data were presented as median and range and twosided Mann–Whitney U test was used for analysis. P b 0.05 was considered statistically significant.
Fig. 1. Flowchart.
Please cite this article as: A.L. Granström, C. Skoglund and T. Wester, Selective serotonin reuptake inhibitors during pregnancy do not increase the risk of Hirschsprung's disease, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.02.015
A.L. Granström et al. / Journal of Pediatric Surgery xxx (xxxx) xxx Table 1 Summarizing results.
Total individuals (n) Male (n) SSRI during the year before birth (n) SSRI at any time before birth of the child (n) Maternal age at time of pregnancy (years, mean (SD))
HSCR
Controls
P-value
150 120 5 (3.3%) 13 (8.7%) 30.9 (5.1)
750 560 16 (2.1%) 54 (7.2%) 30.6 (5.0)
0.372⁎ 0.497⁎ 0.81⁎
⁎ Fisher exact test.
1.6. Ethics The study was approved by the Regional Ethics Review Board in Stockholm. 2. Results The study included 150 cases of HSCR (112 males) and 750 controls (560 males). Five (3.3%) mothers of newborns with HSCR had used SSRI during pregnancy compared to 16 (2.1%) mothers of the controls (p = 0.372). There were 13 (8.7%) mothers who had been prescribed SSRI any time before the pregnancy in the HSCR group compared to 54 (7.2%) in the control group (p = 0.497). There was no difference in maternal mean age of mothers who used SSRI compared with mothers who had not used SSRI (30.9 years (SD +/− 5.1) versus 30.6 years (SD +/− 5.0), p = 0.81). The results are summarized in Table 1.
3
Since SSRI increases the serotonin levels in the synapses one could speculate that the increased amount of serotonin also could have other effects especially during embryogenesis. Antidepressants are used by approximately 2.0%–10.0% of females during the first trimester. The use of SSRI during pregnancy is increasing. [26–29] There are also studies showing that untreated depression during pregnancy may have a negative impact on both the mother and the developing fetus, increasing the risk of premature delivery, low birth weight, small for gestational age and an increased risk emotional problems for the child. [24,25,30] There should be individual discussions with each pregnant woman about the indications for SSRI treatment. The role of environmental factors for the etiology of HSCR is unknown. Maternal intake of other drugs during pregnancy (ibuprofen and mycophenolate) has been associated with enteric nervous system malformations with an HSCR-like pathology in animal models. [19,20] Fu et al. have suggested that retinoic acid (Vitamin A) is essential for efficient enteric nervous system migration and proposed that some cases of HSCR might be preventable by ensuring adequate maternal vitamin A levels during early gestation. [21] Another possible environmental factor may be benzophenone-3, commonly used in personal care products for ultraviolet filter. It has been associated with HSCR in the child if used before pregnancy. [22] In a case report describing congenital hypothyroidism associated with HSCR, Kota et al. speculated about the importance of thyroxin levels for the development of the intestines. [23] In future studies it would be interesting to use national register data, as used in this study, to evaluate the risk for HSCR in the offspring owing to maternal intake of drugs during pregnancy.
3. Discussion This was a national population-based case–control study showing that maternal intake of SSRI during pregnancy did not increase the risk for HSCR in the offspring. The strengths of the study were that it was based on national registers, previously shown to have high validity, and included information on all children in Sweden during the study period. We had no loss to follow up, which prevents selection bias. Another strength was that the control cohort was randomly selected from Statistics Sweden, also reducing the risk for selection bias. To decrease the risk for confounders, the controls were matched for birth year and gender. To reduce the risk for misclassification, specific criteria were set in advance to identify both exposure and outcome. For the exposure, prescription of SSRI was used as a proxy for drug intake and not the patients recalling intake, therefore eliminating recall bias. One possible limitation owing to this proxy was the lack of information on drug compliance. We also had no opportunity to adjust our analyses for the severity of underlying depression, and it is unknown whether maternal depression itself may predispose to HSCR. For the outcome, the most proper criteria would have been to confirm the diagnosis with histopathology reports in each individual. Unfortunately, this is not possible using data from the National Patient Register. This is a limitation of the study, since we may have included patients without HSCR, but also excluded patients with HSCR. The birth prevalence in Sweden has been estimated to 1.91:10,000 [1]. During the study period there were 150 patients with Hirschsprung disease, 1.93:10,000. The study period was limited to 2006–2012 since the Swedish Prescribed Drug Register was initiated in 2005, which limited the sample size and increased the risk for type-2 errors. In the literature, the association between SSRI and HSCR has only been reported twice; first in a case report and then as a register-based study. [10,11] The authors suggested an association between maternal intake of SSRI during the first trimester and HSCR in the offspring. Other studies on maternal intake of SSRI during pregnancy have shown an association with congenital heart defect in the offspring. [17] Bérard et al. also showed an increased risk for major malformation in the offspring of mothers who had taken SSRI during pregnancy [18]
4. Conclusion This was a national population-based case–control study evaluating maternal intake of SSRI and the risk for HSCR in the offspring. The data did not show an increased risk in contrast with a previous study. Further studies are required to evaluate if SSRI during pregnancy is a risk factor for HSCR or not. CRediT authorship contribution statement Anna Löf Granström: Conceptualization, Methodology, Formal analysis, Writing - original draft, Writing - review & editing. Charlotte Skoglund: Conceptualization, Methodology, Formal analysis, Writing - original draft, Writing - review & editing. Tomas Wester: Conceptualization, Methodology, Data curation, Formal analysis, Writing - review & editing. References [1] Löf Granström A, Svenningsson A, Hagel E, et al. Maternal risk factors and perinatal characteristics for Hirschsprung disease. Pediatrics 2016;138(1). [2] Puri P, Ohshiro K, Wester T. Hirschsprung's disease: a search for etiology. Semin Pediatr Surg 1998;7:140–7. [3] Tam PK, Garcia-Barceló M. Genetic basis of Hirschsprung's disease. Pediatr Surg Int 2009;25:543–58. [4] Ikeda K, Goto S. Additional anomalies in Hirschsprung's disease: an analysis based on the nationwide survey in Japan. Z Kinderchir 1986;41:279–81. [5] Torfs CP, Christianson RE. Maternal risk factors and major associated defects in infants with down syndrome. Epidemiology 1999;10:264–70. [6] Kota SK, Modi KD, Rao MM. Hirschsprungs disease with congenital hypothyroidism. Indian Pediatr 2012;49:245–6. [7] Fu M, Sato Y, Lyons-Warren A, et al. Vitamin a facilitates enteric nervous system precursor migration by reducing Pten accumulation. Development 2010;137:631–40. [8] Lake JI, Tusheva OA, Graham BL, et al. Hirschsprung-like disease is exacerabated by reduced de novo GMP synthesis. J Clin Investigation 2013;123:4875–87. [9] Schill EM, Lake JI, Tuscheva OA, et al. Ibuprofen slows migration and inhibits bowel colonization by enteric nervous system precursors in zebrafish, chick and mouse. Dev Biol. 2015 Nov 14. Epub ahead of print; 2015. [10] Nielsen SW, Qvist N. Citalopram taken during pregnancy and the child born with Hirschsprung's disease. Ugeskr Laeger 2013(9):175. [11] Nielsen SW, Ljungdalh PM, Nielsen J, et al. Maternal use of selective serotonin reuptake inhibitors during pregnancy is associated with Hirschsprung's disease in newborns — a nationwide cohort study. Orphanet J Rare Dis 2017;12:116.
Please cite this article as: A.L. Granström, C. Skoglund and T. Wester, Selective serotonin reuptake inhibitors during pregnancy do not increase the risk of Hirschsprung's disease, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.02.015
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Please cite this article as: A.L. Granström, C. Skoglund and T. Wester, Selective serotonin reuptake inhibitors during pregnancy do not increase the risk of Hirschsprung's disease, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.02.015