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doi: 10.1111/ppe.12175
151
Undiagnosed Metabolic Dysfunction and Sudden Infant Death Syndrome – A Case-Control Study Ning An Rosenthal,a Robert J. Currier,a Rebecca J. Baer,a Lisa Feuchtbaum,a Laura L. Jelliffe-Pawlowskia,b a
Genetic Disease Screening Program, California Department of Public Health, Richmond
b
Department of Epidemiology and Biostatistics, Division of Preventive Medicine and Public Health, University of California San Francisco School of Medicine, San Francisco, CA
Abstract Background: Decades of research has yielded few clues about causes of sudden infant death syndrome (SIDS). While some studies have shown a link to inborn errors of metabolism (IEMs), few have examined the link in a large population-based sample. This population-based case–control study assessed the association between undiagnosed IEMs and SIDS. Methods: Children born in California during 2005–08 who died from SIDS were obtained from death records and linked to the newborn screening, birth certificate, and hospital discharge databases. Individuals with known chromosomal and neural tube defects, genetic disorders, and non-singleton births were excluded. Five controls were matched to each case on tandem mass spectrometry testing date and lab code. Rates of undiagnosed IEMs were compared between cases and controls using conditional logistic regression adjusting for known confounding factors. Results: After adjusting for known confounding factors, SIDS cases had similar risk of having IEMs as controls (adjusted hazard ratio [HR] 1.3, 95% confidence interval [CI] 0.3, 5.5). Infants who were male, Black, and born preterm had higher risk of SIDS with the highest risk observed for those born preterm [adjusted HR = 1.7, 95% CI 1.3, 2.2]. Younger maternal age at delivery, mother being born in the US, parity after current birth >3, and delayed prenatal care were also significantly associated with higher risk of SIDS. Conclusions: While many maternal and infant factors are associated with an increased risk of SIDS, there is no evidence that undiagnosed IEMs are associated with increased risk. Keywords: risk factors, tandem mass spectrometry, inborn errors of metabolism, sudden infant death syndrome.
Sudden infant death syndrome (SIDS) refers to the sudden death of an infant (5 First prenatal visit occurred after 3 months of pregnancy (Reference: before 3 months of pregnancy) Pre-existing diabetes Gestational diabetes Pre-existing hypertension Pre-eclampsia Gestational hypertension Premature rupture of membranes
dehydrogenase deficiency). As a result, eight types of IEMs were included in the analysis: Carnitine palmitoyl transferase deficiency-type 1, argininosuccinic acid lyase deficiency, ornithine transcarbamylase/ carbamoyl phosphate synthetase deficiency, carnitine uptake defect, 3-methylcrotonyl-CoA carboxylase deficiency, tyrosinemia type II, short chain acyl-CoA dehydrogenase deficiency, and remethylation defects. © 2015 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2015, 29, 151–155
SIDS cases n (%)
Non-SIDS n (%)
Crude HR [95% CI]
253 (61.4) 159 (38.6)
1006 (50.3) 993 (49.7)
1.5 [1.2, 1.8] 1.0 [Reference]
188 (45.3) 65 (15.9) 19 (4.6) 130 (31.1) 13 (3.1) 86 (21.8) 54 (13.0) 55 (14.1) 59 (14.2)
773 (38.6) 95 (4.8) 175 (8.7) 892 (44.6) 66 (3.3) 172 (9.9) 99 (5.0) 147 (8.5) 105 (5.3)
1.0 [Reference] 2.1 [1.6, 2.7] 0.5 [0.3, 0.8] 0.6 [0.5, 0.8] 0.8 [0.5, 1.5] 2.0 [1.6, 2.6] 2.2 [1.7, 2.9] 1.6 [1.2, 2.1] 2.3 [1.7, 3.0]
24 (14,44)
28 (14,49)
128 (37.2) 101 (29.4) 86 (25.0) 29 (8.4) 287 (81.3)
420 (27.9) 420 (27.9) 327 (21.7) 338 (22.5) 828 (53.4)
3.0 [2.0, 4.4] 2.4 [1.6, 3.7] 2.6 [1.7, 4.0] 1.0 [Reference] 3.0 [2.3, 4.0]
124 (30.5) 283 (69.5)
816 (46.1) 954 (53.9)
1.0 [Reference] 1.7 [1.4, 2.1]
323 (79.4) 84 (20.6) 8 (2.0)
1564 (88.4) 206 (11.6) 16 (0.9)
1.0 [Reference] 1.7 [1.3, 2.1] 1.8 [0.9, 3.6]
37 (9.3) 359 (90.7) 117 (30.0)
62 (3.5) 1701 (96.5) 305 (17.6)
2.1 [1.5, 3.0] 1.0 [Reference] 1.7 [1.4, 2.1]
7 (1.7) 24 (5.8) 11 (2.7) 24 (5.8) 11 (2.7) 27 (6.5)
26 (1.6) 120 (6.0) 36 (1.8) 60 (3.0) 32 (1.6) 74 (3.7)
1.0 [0.5, 2.2] 1.0 [0.6, 1.5] 1.4 [0.7, 2.5] 1.7 [1.1, 2.6] 1.5 [0.8, 2.7] 1.6 [1.1, 2.4]
The prevalence for suggested any IEMs were 0.5% among both cases and controls [crude HR = 1.0, 95% CI 0.2, 3.9] (Table 2). After adjusting for known risk factors, the HR for having any IEMs was still statistically insignificant [adjusted HR 1.3, 95% CI 0.3, 5.5]. Infants who were male, of Black race, and born preterm were found to be at increased risk for SIDS. Younger mothers and
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Table 2. Type of inborn errors of metabolism (IEMs) suggested by the multivariate pattern-recognition tool among cases with sudden infant death syndrome (SIDS) and non-SIDS controls SIDS cases Non-SIDS (n = 415) (n = 2001)
Full name of studied inborn errors of metabolism (Acronym) Carnitine palmitoyl transferase deficiency-type 1 (CPT-1 deficiency) Ornithine transcarbamylase/carbamoyl phosphate synthetase deficiency (OTC/CPS deficiency) Argininosuccinic acid lyase deficiency (ASAL) Carnitine uptake defect (CUD) 3-methylcrotonyl-CoA carboxylase deficiency (3MCC) Remethylation defects (RMD) Tyrosinemia Type II (Tyr-II) Short chain acyl-CoA dehydrogenase deficiency (SCAD deficiency) Had any IEMs
mothers who were born in the U.S., had later entry into prenatal care, and had four or more viable pregnancies had a higher risk of having a baby dying of SIDS compared with peers without these conditions (Table 3).
Comment Our findings suggest that while many maternal and infant factors are associated with an increased risk of SIDS, undiagnosed IEMs are not associated with sigTable 3. Multivariable analysis of the association between inborn errors of metabolism as well as other infant and maternal risk factors and sudden infant death syndrome (SIDS) by Conditional Logistic Regression Modelinga Characteristics Had any IEMs Male sex Race/ethnicity White Black Asian Hispanic/Latino Other Preterm birth Age at delivery (years) Mother born in the US First prenatal visit occurred after 3 months of pregnancy Parity after current birth
Adjusted HR (95% CI) 1.3 [0.3, 5.5] 1.3 [1.0, 1.6] 1.0 [Reference] 1.4 [1.0, 1.9] 1.1 [0.6, 1.9] 0.7 [0.5, 0.9] 0.8 [0.4, 1.6] 1.7 [1.3, 2.2] 0.93 [0.91, 0.95] 1.9 [1.4, 2.7] 1.4 [1.1, 1.8] 2.0 [1.5, 2.8]
Only variables with a P-value
doi: 10.1111/ppe.12175
151
Undiagnosed Metabolic Dysfunction and Sudden Infant Death Syndrome – A Case-Control Study Ning An Rosenthal,a Robert J. Currier,a Rebecca J. Baer,a Lisa Feuchtbaum,a Laura L. Jelliffe-Pawlowskia,b a
Genetic Disease Screening Program, California Department of Public Health, Richmond
b
Department of Epidemiology and Biostatistics, Division of Preventive Medicine and Public Health, University of California San Francisco School of Medicine, San Francisco, CA
Abstract Background: Decades of research has yielded few clues about causes of sudden infant death syndrome (SIDS). While some studies have shown a link to inborn errors of metabolism (IEMs), few have examined the link in a large population-based sample. This population-based case–control study assessed the association between undiagnosed IEMs and SIDS. Methods: Children born in California during 2005–08 who died from SIDS were obtained from death records and linked to the newborn screening, birth certificate, and hospital discharge databases. Individuals with known chromosomal and neural tube defects, genetic disorders, and non-singleton births were excluded. Five controls were matched to each case on tandem mass spectrometry testing date and lab code. Rates of undiagnosed IEMs were compared between cases and controls using conditional logistic regression adjusting for known confounding factors. Results: After adjusting for known confounding factors, SIDS cases had similar risk of having IEMs as controls (adjusted hazard ratio [HR] 1.3, 95% confidence interval [CI] 0.3, 5.5). Infants who were male, Black, and born preterm had higher risk of SIDS with the highest risk observed for those born preterm [adjusted HR = 1.7, 95% CI 1.3, 2.2]. Younger maternal age at delivery, mother being born in the US, parity after current birth >3, and delayed prenatal care were also significantly associated with higher risk of SIDS. Conclusions: While many maternal and infant factors are associated with an increased risk of SIDS, there is no evidence that undiagnosed IEMs are associated with increased risk. Keywords: risk factors, tandem mass spectrometry, inborn errors of metabolism, sudden infant death syndrome.
Sudden infant death syndrome (SIDS) refers to the sudden death of an infant (5 First prenatal visit occurred after 3 months of pregnancy (Reference: before 3 months of pregnancy) Pre-existing diabetes Gestational diabetes Pre-existing hypertension Pre-eclampsia Gestational hypertension Premature rupture of membranes
dehydrogenase deficiency). As a result, eight types of IEMs were included in the analysis: Carnitine palmitoyl transferase deficiency-type 1, argininosuccinic acid lyase deficiency, ornithine transcarbamylase/ carbamoyl phosphate synthetase deficiency, carnitine uptake defect, 3-methylcrotonyl-CoA carboxylase deficiency, tyrosinemia type II, short chain acyl-CoA dehydrogenase deficiency, and remethylation defects. © 2015 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2015, 29, 151–155
SIDS cases n (%)
Non-SIDS n (%)
Crude HR [95% CI]
253 (61.4) 159 (38.6)
1006 (50.3) 993 (49.7)
1.5 [1.2, 1.8] 1.0 [Reference]
188 (45.3) 65 (15.9) 19 (4.6) 130 (31.1) 13 (3.1) 86 (21.8) 54 (13.0) 55 (14.1) 59 (14.2)
773 (38.6) 95 (4.8) 175 (8.7) 892 (44.6) 66 (3.3) 172 (9.9) 99 (5.0) 147 (8.5) 105 (5.3)
1.0 [Reference] 2.1 [1.6, 2.7] 0.5 [0.3, 0.8] 0.6 [0.5, 0.8] 0.8 [0.5, 1.5] 2.0 [1.6, 2.6] 2.2 [1.7, 2.9] 1.6 [1.2, 2.1] 2.3 [1.7, 3.0]
24 (14,44)
28 (14,49)
128 (37.2) 101 (29.4) 86 (25.0) 29 (8.4) 287 (81.3)
420 (27.9) 420 (27.9) 327 (21.7) 338 (22.5) 828 (53.4)
3.0 [2.0, 4.4] 2.4 [1.6, 3.7] 2.6 [1.7, 4.0] 1.0 [Reference] 3.0 [2.3, 4.0]
124 (30.5) 283 (69.5)
816 (46.1) 954 (53.9)
1.0 [Reference] 1.7 [1.4, 2.1]
323 (79.4) 84 (20.6) 8 (2.0)
1564 (88.4) 206 (11.6) 16 (0.9)
1.0 [Reference] 1.7 [1.3, 2.1] 1.8 [0.9, 3.6]
37 (9.3) 359 (90.7) 117 (30.0)
62 (3.5) 1701 (96.5) 305 (17.6)
2.1 [1.5, 3.0] 1.0 [Reference] 1.7 [1.4, 2.1]
7 (1.7) 24 (5.8) 11 (2.7) 24 (5.8) 11 (2.7) 27 (6.5)
26 (1.6) 120 (6.0) 36 (1.8) 60 (3.0) 32 (1.6) 74 (3.7)
1.0 [0.5, 2.2] 1.0 [0.6, 1.5] 1.4 [0.7, 2.5] 1.7 [1.1, 2.6] 1.5 [0.8, 2.7] 1.6 [1.1, 2.4]
The prevalence for suggested any IEMs were 0.5% among both cases and controls [crude HR = 1.0, 95% CI 0.2, 3.9] (Table 2). After adjusting for known risk factors, the HR for having any IEMs was still statistically insignificant [adjusted HR 1.3, 95% CI 0.3, 5.5]. Infants who were male, of Black race, and born preterm were found to be at increased risk for SIDS. Younger mothers and
154
N. A. Rosenthal et al.
Table 2. Type of inborn errors of metabolism (IEMs) suggested by the multivariate pattern-recognition tool among cases with sudden infant death syndrome (SIDS) and non-SIDS controls SIDS cases Non-SIDS (n = 415) (n = 2001)
Full name of studied inborn errors of metabolism (Acronym) Carnitine palmitoyl transferase deficiency-type 1 (CPT-1 deficiency) Ornithine transcarbamylase/carbamoyl phosphate synthetase deficiency (OTC/CPS deficiency) Argininosuccinic acid lyase deficiency (ASAL) Carnitine uptake defect (CUD) 3-methylcrotonyl-CoA carboxylase deficiency (3MCC) Remethylation defects (RMD) Tyrosinemia Type II (Tyr-II) Short chain acyl-CoA dehydrogenase deficiency (SCAD deficiency) Had any IEMs
mothers who were born in the U.S., had later entry into prenatal care, and had four or more viable pregnancies had a higher risk of having a baby dying of SIDS compared with peers without these conditions (Table 3).
Comment Our findings suggest that while many maternal and infant factors are associated with an increased risk of SIDS, undiagnosed IEMs are not associated with sigTable 3. Multivariable analysis of the association between inborn errors of metabolism as well as other infant and maternal risk factors and sudden infant death syndrome (SIDS) by Conditional Logistic Regression Modelinga Characteristics Had any IEMs Male sex Race/ethnicity White Black Asian Hispanic/Latino Other Preterm birth Age at delivery (years) Mother born in the US First prenatal visit occurred after 3 months of pregnancy Parity after current birth
Adjusted HR (95% CI) 1.3 [0.3, 5.5] 1.3 [1.0, 1.6] 1.0 [Reference] 1.4 [1.0, 1.9] 1.1 [0.6, 1.9] 0.7 [0.5, 0.9] 0.8 [0.4, 1.6] 1.7 [1.3, 2.2] 0.93 [0.91, 0.95] 1.9 [1.4, 2.7] 1.4 [1.1, 1.8] 2.0 [1.5, 2.8]
Only variables with a P-value
