On 2015 Jun 24, David Mage commented:

A Possible Cause of SIDS is Found in SIDS Data of Carpenter et al., BMJO 2013, Figure 1 and Table 1

David T Mage*, Health Scientist, E. Maria Donner# 

*WHO (retired), #DuPont

SIDS is characterized and diagnosed by exclusion, especially when expert pediatric pathologists, trained forensic investigators, and learned epidemiologists are unable to find a sufficient cause of infant death at autopsy, at the scene, or in the data, respectively. Therefore the cause of SIDS may be invisible or immeasurable. Furthermore, SIDS is characterized by the fact that in every such case that the parents had no premonition that their infant was at imminent risk of death and "there was a complete absence of prodromal symptoms or any departure from the normal sufficient to justify the parent in seeking medical advice (1)." Therefore, most authors now look at risk factors that are not causes of death (prone sleep position, maternal smoking, etc.) However, they overlook three possible causal factors that alone might be insufficient to cause SIDS, but may act simultaneously in order to do so, that appear in this paper, as follows:

1) An unknown X-linked recessive allele for SIDS susceptibility with frequency q = 2/3, in Hardy-Weinberg-Equilibrium (HWE), that predicts the 50% male excess of SIDS for equal numbers of males and females at risk. The XY male is at risk with q = 2/3 and the XX female is at risk with q x q = 4/9, a 50% male excess. Given a nominal 5% male excess birth rate the expected male fraction is 0.612 for 60 x 1.05 males per 40 females (2). Table 1 reports 898 male and 568 female SIDS, for male fraction = 0.613;

2) Physiological anemia (3) causing the lognormal-type age distribution of SIDS in their Figure 1 that is its most unique characteristic. Unfortunately, "cases and controls over 1 year of age were excluded", which is like 'throwing the baby out with the bathwater.' The upper 1-year limit for SIDS is an artifact of the perception that SIDS over 1 year may include more false positives, so they should not be included in research studies.(4) Physiological anemia occurs when fetal hemoglobin (HbF) decays rapidly after birth while adult hemoglobin (HbA) slowly begins to replace the HbF. The term infant has its lifetime maximal total Hb at birth and it rapidly falls to their lifetime minimal Hb at or about 2-months of life, and then it follows a slow increase until a new equilibrium Hb concentration is established [we neglect here the different binding strengths of oxygen molecules to HbF and HbA, and pre-term Hb relations]. We estimated 19 as the missing number over 1-year that the authors excluded, by fitting an exponential decay curve to the numbers of SIDS from 8 weeks to 52 weeks in Figure 1 and extrapolating it to 178 weeks as determined previously as the upper limit for SIDS.(5) We then fit these weekly data (w) by the Johnson SB transformation that y = Log[(w + 1.343)/(178 - w)] where y = mu + sigma z, and mu = -1.04, sigma = 0.313, w is age in weeks, and z is a standard normal deviate. We interpret this Figure 1 as the number of the most anemic genetically susceptible infants whose total mix of Hb = HbF + HbA falls below some critical threshold, and therefore cannot survive a respiratory infection (see below) that reduces blood oxygenation in the lungs sufficiently to create an acute anoxic encephalopathy resulting in neuronal death. Hemoglobin concentration cannot be measured accurately at autopsy because of the gravitational settling of red blood cells during hemostasis leading to lividity so it is missing in virtually all SIDS autopsy studies (6); and

3) A prodromal respiratory infection (PRI) contracted from a family member that begins to fulminate shortly before or after the infant is placed for its final sleep. Farber (7) reported such a case where a baby was cared for by a nurse because the mother had a severe sore throat at the time. After a 2 p.m. uneventful feeding by the nurse, the baby was found dead 1.5 hours later, "lying on his back. There was no evidence of bedclothes, pillow or any other object over his face." We propose that the only thing that could have changed from the immediately previous sleep condition, sufficiently to cause death and be unnoticed, had to be a PRI that began to fulminate and cause fatal anoxic encephalopathy "before an important or appreciable amount of lung parenchyma has been involved." The author's Table 1 can provide no data on a potentially fatal respiratory infection presence in the SIDS cases, because, if such visible evidence existed at autopsy, the diagnosis by definition would not be SIDS. However, these data in Table 1 cast a visible shadow of a fulminating PRI. The authors list the SIDS and Control Live-Birth-Order (LBO) as shown below. We assume that Cohabiting Family Members (CFM) = 2 adults + (LBO - 1) Siblings = LBO + 1. We then assume that the probability of not carrying a communicable respiratory infection (CRI) (symptomatic or asymptomatic) is P so the probability of at least one CFM carrying a CRI is 1 - P^CFM. Setting P = 0.92 by least squares gives the Model values shown. We previously fit U.S. LBO and SIDS data with P = 0.90 (8). Note that a plot of SIDS Fraction or SIDS Model vs CFM goes to the origin (0, 0) that implies that there are no SIDS cases here that are independent of CFM.

LBO = 1, SIDS = 407, Control = 1836, SIDS Fraction = 0.181, Model = 0.152;

LBO = 2, SIDS = 491, Control = 1566, SIDS Fraction = 0.239, Model = 0.219;

LBO = 3, SIDS = 280, Control = 748, SIDS Fraction = 0.272, Model = 0.280;

LBO = 4, SIDS = 149, Control = 304, SIDS Fraction = 0.329, Model = 0.337;

LBO = 5+, SIDS = 122, Control = 200, SIDS Fraction = 0.379, Model = 0.390.

In summary, SIDS may occur from these three causal factors (genetic susceptibility, physiological anemia, PRI) acting simultaneously that are a function of chance, age and CFM, respectively. There is no explanation we can find in the medical literature , other than an X-linkage in HWE, for a constant male fraction that is different from that of the male birth fraction. There is no explanation other than the maximum hemoglobin at birth for the virtual absence of SIDS immediately after live birth that is the most risky time for all other causes of infant death, the peak SIDS rate at or about the total Hb nadir, followed by an exponential decrease in SIDS rate as the infant's total HbA increases. We know of no other invisible cause of a sudden and unexpected infant death than a fulminating PRI that leaves no visible trace for the pathologist at autopsy or under the microscope in a genetically-susceptible physiologically-anemic infant.

REFERENCES

1.Davison WH. Accidental Infant Suffocation. Br Med J. 1945;2(4416):251-2.

2.Mage DT, Donner EM. A genetic basis for the sudden infant death syndrome sex ratio. Med Hypotheses 1997;48:137-42.

3.O'Brien RT, Pearson HA. Physiologic anemia of the newborn infant. J Pediat 1971;79:132-8.

4.Willinger M, James LS, Catz C. Defining the sudden infant death syndrome (SIDS): deliberations of an expert panel convened by the National Institute of Child Health and Human Development. Pediatr Pathol. 1991;11(5):677-84.

5.Mage DT. A probability model for the age distribution of SIDS. J Sudden Infant Death Syndrome and Infant Mortality 1996;1(1):13-31.

6.Poets CF, Samuels MP, Wardrop CA, et al. Reduced haemoglobin levels in infants presenting with apparent life-threatening events--a retrospective investigation. Acta Paediatr. 1992;81(4):319-21.

7.Farber S. Fulminating streptococcus infections in infancy as a cause of sudden death. NEJM 1934;211:154-9.

8.Mage DT, Donner M, A unifying theory for SIDS. Int J Pediat 2009; 2009:368270

On 2015 Jun 24, David Mage commented:

A Possible Cause of SIDS is Found in SIDS Data of Carpenter et al., BMJO 2013, Figure 1 and Table 1

David T Mage*, Health Scientist, E. Maria Donner# 

*WHO (retired), #DuPont

SIDS is characterized and diagnosed by exclusion, especially when expert pediatric pathologists, trained forensic investigators, and learned epidemiologists are unable to find a sufficient cause of infant death at autopsy, at the scene, or in the data, respectively. Therefore the cause of SIDS may be invisible or immeasurable. Furthermore, SIDS is characterized by the fact that in every such case that the parents had no premonition that their infant was at imminent risk of death and "there was a complete absence of prodromal symptoms or any departure from the normal sufficient to justify the parent in seeking medical advice (1)." Therefore, most authors now look at risk factors that are not causes of death (prone sleep position, maternal smoking, etc.) However, they overlook three possible causal factors that alone might be insufficient to cause SIDS, but may act simultaneously in order to do so, that appear in this paper, as follows:

1) An unknown X-linked recessive allele for SIDS susceptibility with frequency q = 2/3, in Hardy-Weinberg-Equilibrium (HWE), that predicts the 50% male excess of SIDS for equal numbers of males and females at risk. The XY male is at risk with q = 2/3 and the XX female is at risk with q x q = 4/9, a 50% male excess. Given a nominal 5% male excess birth rate the expected male fraction is 0.612 for 60 x 1.05 males per 40 females (2). Table 1 reports 898 male and 568 female SIDS, for male fraction = 0.613;

2) Physiological anemia (3) causing the lognormal-type age distribution of SIDS in their Figure 1 that is its most unique characteristic. Unfortunately, "cases and controls over 1 year of age were excluded", which is like 'throwing the baby out with the bathwater.' The upper 1-year limit for SIDS is an artifact of the perception that SIDS over 1 year may include more false positives, so they should not be included in research studies.(4) Physiological anemia occurs when fetal hemoglobin (HbF) decays rapidly after birth while adult hemoglobin (HbA) slowly begins to replace the HbF. The term infant has its lifetime maximal total Hb at birth and it rapidly falls to their lifetime minimal Hb at or about 2-months of life, and then it follows a slow increase until a new equilibrium Hb concentration is established [we neglect here the different binding strengths of oxygen molecules to HbF and HbA, and pre-term Hb relations]. We estimated 19 as the missing number over 1-year that the authors excluded, by fitting an exponential decay curve to the numbers of SIDS from 8 weeks to 52 weeks in Figure 1 and extrapolating it to 178 weeks as determined previously as the upper limit for SIDS.(5) We then fit these weekly data (w) by the Johnson SB transformation that y = Log[(w + 1.343)/(178 - w)] where y = mu + sigma z, and mu = -1.04, sigma = 0.313, w is age in weeks, and z is a standard normal deviate. We interpret this Figure 1 as the number of the most anemic genetically susceptible infants whose total mix of Hb = HbF + HbA falls below some critical threshold, and therefore cannot survive a respiratory infection (see below) that reduces blood oxygenation in the lungs sufficiently to create an acute anoxic encephalopathy resulting in neuronal death. Hemoglobin concentration cannot be measured accurately at autopsy because of the gravitational settling of red blood cells during hemostasis leading to lividity so it is missing in virtually all SIDS autopsy studies (6); and

3) A prodromal respiratory infection (PRI) contracted from a family member that begins to fulminate shortly before or after the infant is placed for its final sleep. Farber (7) reported such a case where a baby was cared for by a nurse because the mother had a severe sore throat at the time. After a 2 p.m. uneventful feeding by the nurse, the baby was found dead 1.5 hours later, "lying on his back. There was no evidence of bedclothes, pillow or any other object over his face." We propose that the only thing that could have changed from the immediately previous sleep condition, sufficiently to cause death and be unnoticed, had to be a PRI that began to fulminate and cause fatal anoxic encephalopathy "before an important or appreciable amount of lung parenchyma has been involved." The author's Table 1 can provide no data on a potentially fatal respiratory infection presence in the SIDS cases, because, if such visible evidence existed at autopsy, the diagnosis by definition would not be SIDS. However, these data in Table 1 cast a visible shadow of a fulminating PRI. The authors list the SIDS and Control Live-Birth-Order (LBO) as shown below. We assume that Cohabiting Family Members (CFM) = 2 adults + (LBO - 1) Siblings = LBO + 1. We then assume that the probability of not carrying a communicable respiratory infection (CRI) (symptomatic or asymptomatic) is P so the probability of at least one CFM carrying a CRI is 1 - P^CFM. Setting P = 0.92 by least squares gives the Model values shown. We previously fit U.S. LBO and SIDS data with P = 0.90 (8). Note that a plot of SIDS Fraction or SIDS Model vs CFM goes to the origin (0, 0) that implies that there are no SIDS cases here that are independent of CFM.

LBO = 1, SIDS = 407, Control = 1836, SIDS Fraction = 0.181, Model = 0.152;

LBO = 2, SIDS = 491, Control = 1566, SIDS Fraction = 0.239, Model = 0.219;

LBO = 3, SIDS = 280, Control = 748, SIDS Fraction = 0.272, Model = 0.280;

LBO = 4, SIDS = 149, Control = 304, SIDS Fraction = 0.329, Model = 0.337;

LBO = 5+, SIDS = 122, Control = 200, SIDS Fraction = 0.379, Model = 0.390.

In summary, SIDS may occur from these three causal factors (genetic susceptibility, physiological anemia, PRI) acting simultaneously that are a function of chance, age and CFM, respectively. There is no explanation we can find in the medical literature , other than an X-linkage in HWE, for a constant male fraction that is different from that of the male birth fraction. There is no explanation other than the maximum hemoglobin at birth for the virtual absence of SIDS immediately after live birth that is the most risky time for all other causes of infant death, the peak SIDS rate at or about the total Hb nadir, followed by an exponential decrease in SIDS rate as the infant's total HbA increases. We know of no other invisible cause of a sudden and unexpected infant death than a fulminating PRI that leaves no visible trace for the pathologist at autopsy or under the microscope in a genetically-susceptible physiologically-anemic infant.

REFERENCES

1.Davison WH. Accidental Infant Suffocation. Br Med J. 1945;2(4416):251-2.

2.Mage DT, Donner EM. A genetic basis for the sudden infant death syndrome sex ratio. Med Hypotheses 1997;48:137-42.

3.O'Brien RT, Pearson HA. Physiologic anemia of the newborn infant. J Pediat 1971;79:132-8.

4.Willinger M, James LS, Catz C. Defining the sudden infant death syndrome (SIDS): deliberations of an expert panel convened by the National Institute of Child Health and Human Development. Pediatr Pathol. 1991;11(5):677-84.

5.Mage DT. A probability model for the age distribution of SIDS. J Sudden Infant Death Syndrome and Infant Mortality 1996;1(1):13-31.

6.Poets CF, Samuels MP, Wardrop CA, et al. Reduced haemoglobin levels in infants presenting with apparent life-threatening events--a retrospective investigation. Acta Paediatr. 1992;81(4):319-21.

7.Farber S. Fulminating streptococcus infections in infancy as a cause of sudden death. NEJM 1934;211:154-9.

8.Mage DT, Donner M, A unifying theory for SIDS. Int J Pediat 2009; 2009:368270