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Case Report/Case Series |

Natalizumab Use During the Third Trimester of Pregnancy FREE

Aiden Haghikia, MD1; Annette Langer-Gould, MD, PhD2; Georg Rellensmann, MD3; Henriette Schneider, MD4; Tobias Tenenbaum, MD4; Birte Elias-Hamp, MD5; Sylvia Menck, MD6; Julian Zimmermann, MD7; Sandra Herbstritt, PharmD8; Martin Marziniak, MD9; Tania Kümpfel, MD10; Ingrid Meinl, MD10; Tatiana Plavina, PhD11; Ralf Gold, MD1; Kerstin Hellwig, MD1,2
[+] Author Affiliations
1Department of Neurology, St Josef-Hospital, Ruhr University Bochum, Bochum, Germany
2Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena
3Department of General Pediatrics, University Children’s Hospital Münster, Münster, Germany
4University Children’s Hospital Mannheim, Heidelberg University, Heidelberg, Germany
5Neurologic Practice Hamburg, Hamburg, Germany
6Neurologic Practice Barsinghausen, Barsinghausen, Germany
7Department of Neurology, University of Bonn, Bonn, Germany
8Faculty of Pharmacy, University of Dusseldorf, Dusseldorf, Germany
9Department of Neurology, kbo-Isar-Amper-Klinikum München-Ost, Munich, Germany
10Institute for Clinical Neuroimmunology, Ludwig-Maximilians-University, Munich, Germany
11Biogen Idec, Cambridge, Massachusetts
JAMA Neurol. 2014;71(7):891-895. doi:10.1001/jamaneurol.2014.209.
Text Size: A A A
Published online

Importance  Natalizumab reduces multiple sclerosis relapses very effectively; however, severe disease activity may return once natalizumab treatment is withdrawn, as recommended during pregnancy. Sometimes restarting natalizumab treatment may be the best option for the mother, but the consequences for the infant are unknown. Except for a few single case reports, to our knowledge, comprehensive data about third-trimester natalizumab exposure are scant.

Observations  In a case series of 12 women with 13 pregnancies and highly active multiple sclerosis who were treated with natalizumab during their third trimester of pregnancy, we assessed the clinical and laboratory effects on the newborns. We observed mild to moderate hematologic alterations in 10 of 13 infants including thrombocytopenia and anemia. In a subsample of 5 mother-child pairs, we analyzed natalizumab levels in the umbilical cord blood. Natalizumab was detectable in all 5 newborns.

Conclusion and Relevance  Natalizumab can be a therapeutic option in patients with highly active multiple sclerosis during pregnancy. We recommend that a pediatrician be available at the time of delivery to evaluate for potential complications of anemia and thrombocytopenia in newborns exposed to natalizumab during the third trimester.

Figures in this Article

Natalizumab is very effective at reducing relapses in patients with multiple sclerosis (MS).1 However, once natalizumab treatment is withdrawn—as recommended during pregnancy—severe rebound disease activity2,3 can occur.4 Although in general protective,5,6 pregnancy can fail to protect against natalizumab-withdrawal relapses.3,7 Sometimes restarting treatment with natalizumab during pregnancy to treat severe rebound relapses may be the best option for the mother; however, the consequences for the infant are unclear.

Teratogenic effects with late-pregnancy exposure to natalizumab would not be expected because organogenesis is completed. However, animal studies have shown hematological abnormalities in the offspring with exposure throughout pregnancy.8 A similar effect in humans is plausible because natalizumab is a monoclonal antibody and maternal antibodies are actively transported to the fetus at increasing rates during pregnancy starting in the second trimester.9 However, it is unknown to what extent natalizumab is transported to the human fetus—particularly during late pregnancy. Previous single case reports of late third-trimester exposure did not thoroughly assess hematological abnormalities or measure natalizumab levels in the offspring.10,11

Here we describe the hematological and birth outcomes of 13 infants born to 12 mothers exposed to natalizumab during the third trimester of pregnancy. The natalizumab levels in 5 of the mother-infant pairs are also presented.

Women were recruited through our nationwide MS pregnancy registry as previously described.6,7 The registry was approved by the institutional review board of Ruhr University Bochum. Written informed consent was obtained from all patients. We included 11 unique mother-infant pairs with third-trimester exposure to natalizumab and additional details on 2 previously described similarly exposed mother-infant pairs.12 Information was obtained directly from the treating physicians of the mothers and infants.

Serum natalizumab concentrations were determined using a validated sandwich enzyme-linked immunosorbent assay method (0.25-μg/mL lower detection level; Biogen Idec). Laboratory findings reported in the tables were obtained via routine blood analyses in certified diagnostic laboratories.

Demographic details of the mothers with MS and their clinical course are described in Table 1. Of the 12 women treated with natalizumab during the last trimester of pregnancy, 10 became pregnant while taking natalizumab. Five of these women stopped natalizumab treatment in the first trimester but required retreatment for severe relapses during pregnancy. The other 5 continued natalizumab treatment through the whole pregnancy owing to natalizumab-withdrawal relapses prior to pregnancy. Three additional women requiring third-trimester treatment had stopped natalizumab therapy before pregnancy and relapsed during the first trimester. All women with relapses during pregnancy were refractory to treatment with high-dose intravenous steroids. The natalizumab-withdrawal pregnancy relapses were severe (median Expanded Disability Status Scale score change, 1.5; range, 0.5-5.0). After natalizumab treatment was started, disease activity stabilized in all women.

Table Graphic Jump LocationTable 1.  Clinical Characteristics of the Mothers

The clinical characteristics and laboratory values of the infants are summarized in Table 2. The mean (SD) gestational age at birth and mean (SD) birth weight were 38.4 (1.2) weeks and 2723 (416) g, respectively. Laboratory abnormalities and/or medical conditions were observed in 11 of the 13 newborns. Hematological abnormalities were found in 10 newborns including anemia (n = 8) and thrombocytopenia (n = 6). The mother of newborn 2 experienced a catastrophic relapse requiring intense treatment. The child was born small for gestational age and has developmental delay at 1 year of age. Another child (newborn 8) had a cystic formation in the caudothalamic region (potentially compatible with an intracranial hemorrhage) detected by screening ultrasonography after delivery that was no longer detectable by 12 weeks of age.12 This child is now 2 years old and shows normal development.

Table Graphic Jump LocationTable 2.  Clinical Characteristics of the Infants

One malformation—an atrioventricular septal defect (atrial septal defect I and II) that needed surgical intervention—was reported (newborn 12, Table 2). However, this infant was also exposed to valproate in addition to natalizumab throughout pregnancy because the mother has epilepsy, hereditary proximal myotonic myopathy, and tumor necrosis factor receptor 1–associated periodic syndrome.

One mother contributed 2 pregnancies. Her first child (newborn 5) showed a moderate anemia. Interestingly, her second child (newborn 6), who was exposed to more natalizumab infusions, did not have hematological abnormalities.

The relationship between timing and frequency of natalizumab infusions, gestational age at birth, and maternal and cord blood natalizumab levels are depicted in the Figure. In general, those mother-infant pairs with the most recent exposure prior to birth and those with more frequent late-pregnancy exposures had higher natalizumab levels with one notable exception (mother 5–newborn 5). This mother had unusually low natalizumab levels despite negative antinatalizumab antibody titer results.

Place holder to copy figure label and caption
Figure.
Natalizumab Concentrations in Mothers and Newborns After Birth

Natalizumab concentrations in newborns and mothers after birth (B) dependent on the number of natalizumab infusions (N) during pregnancy and interval from last infusion to delivery.

Graphic Jump Location

In this case series, we observed that exposure to natalizumab during the third trimester of pregnancy in women with aggressive MS led to hematological abnormalities in 10 of the 13 newborns. These hematological abnormalities included thrombocytopenia, anemia, and leukocytosis. In most of the infants, the hematological abnormalities resolved during the 4 months after birth and none of the infants needed any specific treatment, although 1 subclinical bleeding complication was reported.12

That natalizumab can interfere with fetal hematopoiesis has been shown in vitro13 and in cynomolgus monkey studies. The newborns of monkeys treated with natalizumab throughout pregnancy (at dosages higher than administered in patients with MS) were generally healthy with the exception of hematological abnormalities8 including thrombocytopenia, significantly reduced lymphocytes despite the anticipated leukocytosis, and mild anemia.8 We found detectable cord blood levels of natalizumab in all 5 infants tested. In general, the concentrations were higher in those exposed closer to the time of delivery and with more frequent late-pregnancy exposures. This is consistent with normal placental immunoglobulin transport mechanisms. Active transport of maternal immunoglobulins across the placenta increases throughout pregnancy starting during the second trimester, with only minimal transport of antibodies earlier in pregnancy.9 These findings are also similar to case reports of placental transfer of other therapeutic monoclonal antibodies. In women treated with tumor necrosis factor antagonists during pregnancy, later exposure and more frequent infusions led to higher cord blood concentrations often exceeding that of the mother.14 In addition, these monoclonal antibodies were still detectable in some infants up to 6 months of age, consistent with infants’ delayed antibody clearance mechanisms.14

All of the mothers treated with natalizumab during late pregnancy had experienced serious natalizumab-withdrawal relapses either prior to or during pregnancy. Many treatment strategies to prevent natalizumab-withdrawal relapses have been reported in nonpregnant patients (some of which were tried in these mothers); however, so far, only resuming natalizumab treatment appears effective. These unsuccessful strategies include prophylactic pulse steroids with or without glatiramer acetate or beta-interferons.15,16 In addition, in utero exposure to some of these agents has been associated with other fetal risks including low birth weight17,18 and potential tetratogenicity.19,20

Our observation was limited by the sample size and was not designed to identify risk factors for rebound or severe relapses after natalizumab withdrawal. Also, we were not able to analyze the infants’ natalizumab levels longitudinally nor do we have long-term developmental outcomes in most of the children.

However, in view of the various limitations and inherent difficulties of investigating the safety of drugs with potential fetotoxic adverse effects, our results are useful for therapeutic decisions in women with similarly severe disease activity as those described here.

Given the high frequency of hematological abnormalities observed, we recommend that late-pregnancy natalizumab treatment be a last resort, be administered by experienced MS centers, and that the pregnancy be considered high risk. These women should deliver in a hospital with an affiliated pediatric department, a pediatrician should be available at the time of delivery to evaluate the infant for potential complications of anemia and thrombocytopenia, and all newborns should undergo careful hematological evaluation. We propose a standardized blood draw with a full blood cell count, bilirubin lactate dehydrogenase, transaminases, and haptoglobin.

Corresponding Author: Kerstin Hellwig, MD, Department of Neurology, Ruhr University Bochum, St Josef-Hospital, Gudrunstr 56, 44791 Bochum, Germany (kerstin.hellwig@klinikum-bochum.de).

Accepted for Publication: January 29, 2014.

Published Online: May 12, 2014. doi:10.1001/jamaneurol.2014.209.

Author Contributions: Dr Hellwig had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Langer-Gould, Hellwig.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Haghikia, Langer-Gould, Hellwig.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Haghikia, Langer-Gould, Hellwig.

Obtained funding: Hellwig.

Administrative, technical, or material support: Haghikia, Langer-Gould, Tenenbaum, Marziniak, Plavina, Hellwig.

Study supervision: Gold, Hellwig.

Conflict of Interest Disclosures: Dr Langer-Gould is the site principal investigator for 2 industry-sponsored randomized clinical trials (Biogen Idec and Roche). Dr Marziniak has received payments for consultancy from Biogen, Novartis, and sanofi-aventis. He has also received speaker honoraria and research grants from Biogen Idec Germany, Teva Pharmaceutical Industries, sanofi-aventis, Novartis, Bayer HealthCare, and Merck Serono. Dr Kümpfel has received travel expenses and personal compensation from Bayer Schering Pharma, Teva Pharmaceutical Industries, Merck Serono, and Biogen Idec, as well as grant support from Bayer-Schering AG. Dr Meinl has received travel expense compensation from Bayer Schering Pharma. Dr Plavina is employed by Biogen Idec. Dr Gold has received payments for consultancy from Biogen Idec and Teva Pharmaceutical Industries. Dr Gold has also received speaker honoraria and research grants from Biogen Idec Germany, Teva Pharmaceutical Industries, sanofi-aventis, Novartis, Bayer HealthCare, and Merck Serono. Dr Hellwig has received speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries, sanofi-aventis, Novartis, Bayer HealthCare, and Merck Serono. No other disclosures were reported.

Funding/Support: Drs Haghikia (HA 6238) and Hellwig (HE 6841) were supported by the German Research Council (Deutsche Forschungsgemeinschaft [DFG]). Dr Langer-Gould receives funding from the National Institutes of Health and the National Multiple Sclerosis Society. With support from DFG grants, Drs Haghikia and Hellwig were able to analyze, interpret, prepare, and review the manuscript for publication. The German MS and Pregnancy Registry is partly supported by Biogen Idec, Teva Pharmaceutical Industries, Genzyme, sanofi-aventis, Novartis, Bayer HealthCare, and Merck Serono. Natalizumab concentrations were analyzed at Biogen Idec’s laboratory in Cambridge, Massachusetts.

Role of the Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank all the patients contributing data to the registry and all referring physicians and multiple sclerosis nurses. We also thank the German National Multiple Sclerosis Society (DMSG) for supporting the advertisement of the registry. The society did not receive compensation from any funder for its contribution.

Haghikia  A, Hohlfeld  R, Gold  R, Fugger  L.  Therapies for multiple sclerosis: translational achievements and outstanding needs. Trends Mol Med. 2013;19(5):309-319.
PubMed   |  Link to Article
Rigau  V, Mania  A, Béfort  P,  et al.  Lethal multiple sclerosis relapse after natalizumab withdrawal. Neurology. 2012;79(22):2214-2216.
PubMed   |  Link to Article
Hellwig  K, Gold  R.  Immune reconstitution inflammatory syndrome after withdrawal of natalizumab? Neurology. 2011;76(15):1362-1363, author reply 1363.
PubMed   |  Link to Article
Lenhard  T, Biller  A, Mueller  W, Metz  I, Schönberger  J, Wildemann  B.  Immune reconstitution inflammatory syndrome after withdrawal of natalizumab? Neurology. 2010;75(9):831-833.
PubMed   |  Link to Article
Confavreux  C, Hutchinson  M, Hours  MM, Cortinovis-Tourniaire  P, Moreau  T; Pregnancy in Multiple Sclerosis Group.  Rate of pregnancy-related relapse in multiple sclerosis. N Engl J Med. 1998;339(5):285-291.
PubMed   |  Link to Article
Hellwig  K, Haghikia  A, Rockhoff  M, Gold  R.  Multiple sclerosis and pregnancy: experience from a nationwide database in Germany. Ther Adv Neurol Disord. 2012;5(5):247-253.
PubMed   |  Link to Article
Hellwig  K, Haghikia  A, Gold  R.  Pregnancy and natalizumab: results of an observational study in 35 accidental pregnancies during natalizumab treatment. Mult Scler. 2011;17(8):958-963.
PubMed   |  Link to Article
Wehner  NG, Shopp  G, Osterburg  I, Fuchs  A, Buse  E, Clarke  J.  Postnatal development in cynomolgus monkeys following prenatal exposure to natalizumab, an alpha4 integrin inhibitor. Birth Defects Res B Dev Reprod Toxicol. 2009;86(2):144-156.
PubMed   |  Link to Article
Schneider  H, Miller  RK.  Receptor-mediated uptake and transport of macromolecules in the human placenta. Int J Dev Biol. 2010;54(2-3):367-375.
PubMed   |  Link to Article
Henderson  CE.  Accidental natalizumab administration to the third trimester of pregnancy in an adolescent patient with multiple sclerosis. Acta Neurol Scand. 2012;126(1):e7.
PubMed   |  Link to Article
Hoevenaren  IA, de Vries  LC, Rijnders  RJ, Lotgering  FK.  Delivery of healthy babies after natalizumab use for multiple sclerosis: a report of two cases. Acta Neurol Scand. 2011;123(6):430-433.
PubMed   |  Link to Article
Schneider  H, Weber  CE, Hellwig  K, Schroten  H, Tenenbaum  T.  Natalizumab treatment during pregnancy: effects on the neonatal immune system. Acta Neurol Scand. 2012;127(1):e1-e4.
PubMed   |  Link to Article
Wehner  NG, Shopp  G, Oneda  S, Clarke  J.  Embryo/fetal development in cynomolgus monkeys exposed to natalizumab, an alpha4 integrin inhibitor. Birth Defects Res B Dev Reprod Toxicol. 2009;86(2):117-130.
PubMed   |  Link to Article
Mahadevan  U, Wolf  DC, Dubinsky  M,  et al.  Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2013;11(3):286-292; quiz e224.
PubMed   |  Link to Article
Havla  J, Gerdes  LA, Meinl  I,  et al.  De-escalation from natalizumab in multiple sclerosis: recurrence of disease activity despite switching to glatiramer acetate. J Neurol. 2011;258(9):1665-1669.
PubMed   |  Link to Article
Borriello  G, Prosperini  L, Mancinelli  C, Gianni  C, Fubelli  F, Pozzilli  C.  Pulse monthly steroids during an elective interruption of natalizumab: a post-marketing study. Eur J Neurol. 2012;19(5):783-787.
PubMed   |  Link to Article
Lu  E, Wang  BW, Guimond  C, Synnes  A, Sadovnick  D, Tremlett  H.  Disease-modifying drugs for multiple sclerosis in pregnancy: a systematic review. Neurology. 2012;79(11):1130-1135.
PubMed   |  Link to Article
Khan  AARA, Rodriguez  A, Kaakinen  M, Pouta  A, Hartikainen  AL, Jarvelin  MR.  Does in utero exposure to synthetic glucocorticoids influence birthweight, head circumference and birth length? a systematic review of current evidence in humans. Paediatr Perinat Epidemiol. 2011;25(1):20-36.
PubMed   |  Link to Article
Park-Wyllie  L, Mazzotta  P, Pastuszak  A,  et al.  Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology. 2000;62(6):385-392.
PubMed   |  Link to Article
Gelineau-van Waes  J, Rainey  MA, Maddox  JR,  et al.  Increased sphingoid base-1-phosphates and failure of neural tube closure after exposure to fumonisin or FTY720. Birth Defects Res A Clin Mol Teratol. 2012;94(10):790-803.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure.
Natalizumab Concentrations in Mothers and Newborns After Birth

Natalizumab concentrations in newborns and mothers after birth (B) dependent on the number of natalizumab infusions (N) during pregnancy and interval from last infusion to delivery.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Clinical Characteristics of the Mothers
Table Graphic Jump LocationTable 2.  Clinical Characteristics of the Infants

References

Haghikia  A, Hohlfeld  R, Gold  R, Fugger  L.  Therapies for multiple sclerosis: translational achievements and outstanding needs. Trends Mol Med. 2013;19(5):309-319.
PubMed   |  Link to Article
Rigau  V, Mania  A, Béfort  P,  et al.  Lethal multiple sclerosis relapse after natalizumab withdrawal. Neurology. 2012;79(22):2214-2216.
PubMed   |  Link to Article
Hellwig  K, Gold  R.  Immune reconstitution inflammatory syndrome after withdrawal of natalizumab? Neurology. 2011;76(15):1362-1363, author reply 1363.
PubMed   |  Link to Article
Lenhard  T, Biller  A, Mueller  W, Metz  I, Schönberger  J, Wildemann  B.  Immune reconstitution inflammatory syndrome after withdrawal of natalizumab? Neurology. 2010;75(9):831-833.
PubMed   |  Link to Article
Confavreux  C, Hutchinson  M, Hours  MM, Cortinovis-Tourniaire  P, Moreau  T; Pregnancy in Multiple Sclerosis Group.  Rate of pregnancy-related relapse in multiple sclerosis. N Engl J Med. 1998;339(5):285-291.
PubMed   |  Link to Article
Hellwig  K, Haghikia  A, Rockhoff  M, Gold  R.  Multiple sclerosis and pregnancy: experience from a nationwide database in Germany. Ther Adv Neurol Disord. 2012;5(5):247-253.
PubMed   |  Link to Article
Hellwig  K, Haghikia  A, Gold  R.  Pregnancy and natalizumab: results of an observational study in 35 accidental pregnancies during natalizumab treatment. Mult Scler. 2011;17(8):958-963.
PubMed   |  Link to Article
Wehner  NG, Shopp  G, Osterburg  I, Fuchs  A, Buse  E, Clarke  J.  Postnatal development in cynomolgus monkeys following prenatal exposure to natalizumab, an alpha4 integrin inhibitor. Birth Defects Res B Dev Reprod Toxicol. 2009;86(2):144-156.
PubMed   |  Link to Article
Schneider  H, Miller  RK.  Receptor-mediated uptake and transport of macromolecules in the human placenta. Int J Dev Biol. 2010;54(2-3):367-375.
PubMed   |  Link to Article
Henderson  CE.  Accidental natalizumab administration to the third trimester of pregnancy in an adolescent patient with multiple sclerosis. Acta Neurol Scand. 2012;126(1):e7.
PubMed   |  Link to Article
Hoevenaren  IA, de Vries  LC, Rijnders  RJ, Lotgering  FK.  Delivery of healthy babies after natalizumab use for multiple sclerosis: a report of two cases. Acta Neurol Scand. 2011;123(6):430-433.
PubMed   |  Link to Article
Schneider  H, Weber  CE, Hellwig  K, Schroten  H, Tenenbaum  T.  Natalizumab treatment during pregnancy: effects on the neonatal immune system. Acta Neurol Scand. 2012;127(1):e1-e4.
PubMed   |  Link to Article
Wehner  NG, Shopp  G, Oneda  S, Clarke  J.  Embryo/fetal development in cynomolgus monkeys exposed to natalizumab, an alpha4 integrin inhibitor. Birth Defects Res B Dev Reprod Toxicol. 2009;86(2):117-130.
PubMed   |  Link to Article
Mahadevan  U, Wolf  DC, Dubinsky  M,  et al.  Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2013;11(3):286-292; quiz e224.
PubMed   |  Link to Article
Havla  J, Gerdes  LA, Meinl  I,  et al.  De-escalation from natalizumab in multiple sclerosis: recurrence of disease activity despite switching to glatiramer acetate. J Neurol. 2011;258(9):1665-1669.
PubMed   |  Link to Article
Borriello  G, Prosperini  L, Mancinelli  C, Gianni  C, Fubelli  F, Pozzilli  C.  Pulse monthly steroids during an elective interruption of natalizumab: a post-marketing study. Eur J Neurol. 2012;19(5):783-787.
PubMed   |  Link to Article
Lu  E, Wang  BW, Guimond  C, Synnes  A, Sadovnick  D, Tremlett  H.  Disease-modifying drugs for multiple sclerosis in pregnancy: a systematic review. Neurology. 2012;79(11):1130-1135.
PubMed   |  Link to Article
Khan  AARA, Rodriguez  A, Kaakinen  M, Pouta  A, Hartikainen  AL, Jarvelin  MR.  Does in utero exposure to synthetic glucocorticoids influence birthweight, head circumference and birth length? a systematic review of current evidence in humans. Paediatr Perinat Epidemiol. 2011;25(1):20-36.
PubMed   |  Link to Article
Park-Wyllie  L, Mazzotta  P, Pastuszak  A,  et al.  Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology. 2000;62(6):385-392.
PubMed   |  Link to Article
Gelineau-van Waes  J, Rainey  MA, Maddox  JR,  et al.  Increased sphingoid base-1-phosphates and failure of neural tube closure after exposure to fumonisin or FTY720. Birth Defects Res A Clin Mol Teratol. 2012;94(10):790-803.
PubMed   |  Link to Article

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