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Infant Circumcision Potential SIDS Factor
A recent publication in the Frontiers in Neurology, expands on the growing body of neurological examination of extreme pain and trauma in infancy, and soon after birth, and its triggering implication on SIDS. In "A 'Wear and Tear' Hypothesis to Explain Sudden Infant Death Syndrome" Eran Elhaik presents the following material on infant genital cutting in the United States and its relation to the atypically high SIDS rate in the U.S.
We also predict that neonatal male circumcision will account for the SIDS gender bias and that groups that practice high male circumcision rates, such as USA whites, will have higher SIDS rates compared to groups with lower circumcision rates. SIDS rates will also be higher in USA states where Medicaid covers circumcision and lower among people that do not practice neonatal circumcision and/or cannot afford to pay for circumcision. We last predict that winter-born premature infants who are circumcised will be at higher risk of SIDS compared to infants who experienced fewer nociceptive exposures.
Circumcision is one of the most common elective surgical procedures in the world and is performed primarily on males (56). Female circumcision is practiced in nearly 30 African countries, some Southeast Asian and Middle Eastern countries, and in immigrant communities in Europe and North America (57). Despite its relevancy, female neonatal circumcision will not be discussed here since in most western countries it is illegal and thereby under-reported and we lack SIDS data for the remaining countries. In North America, ~1.2 million male infants are circumcised every year (58) often within the first 2 days of life (59). Although not requiring general anesthesia, circumcision is an intensively painful procedure requiring adequate analgesia (60). Circumcision is associated with intraoperative and postoperative risks, including bleeding, shock, sepsis, circulatory shock, and hemorrhage (61–63) that can result in death (63, 64).
Infant deaths following religious neonatal circumcision have been known for at least two millennia (65). Talmud (the central text of Rabbinic Judaism) sages ruled in the first centuries A.D. that mothers with two children who have died following the surgery should receive an exemption from circumcising their infants. During the nineteenth century, developments in medical knowledge on one hand and the rise of Jewish “Enlightenment” on the other hand, brought many Jews to reject the authority of the Talmud and with that the practice of circumcision. A new wave of accusations toward Jewish circumcisers (mohels) and rabbis of infant deaths following circumcision soon appeared and prompted community leaders to appeal to the governing authorities to forbid this practice – efforts that were countered by rabbis’ threats to ban the admission of uncircumcised Jewish children from Jewish schools. The fierce arguments about the necessity of the procedure last to this day and led many Jews to opt their infants out of the procedure, including Theodor Herzl, one of the fathers of modern political Zionism (66). In the UK, Gairdner (67) estimated an annual rate of 16 per 100,000 circumcision-associated deaths for boys under 1-year old in a study that influenced the British government to exclude circumcision coverage from the National Health Service. Remarkably, the SIDS rates in the UK (0.38 per 1000) are much lower than in the USA (0.55 per 1000) (10) where most male infants are circumcised (58). Moreover, most of the deaths in the USA occur in non-Hispanic blacks (83% higher death rate compared with non-Hispanic whites). SIDS rates were 44% lower for Hispanics compared with non-Hispanic whites (68). Interestingly the circumcision rates among Hispanics are about half that of the two other groups (69).
Circumcision contributes to the rise in allostatic load and increased risk for SIDS through multiple conduits. Circumcision produces crush and incisional injuries during amputation, resulting in damage to normal prepuce tissue, the associated nerves, and blood vessels. Wound healing manifested by hyperaemia and swelling at day 7 postoperative is observed in 70% of infants with minimally retractile prepuces seen in infants circumcised before 1 year of age with subsequent bacterial carriage of skin commensals (70). Circumcised males have increased pain responses to childhood immunization 4–6 months post-surgery (71, 72) consistent with central sensitization (73). The abnormal development of sensory pathways in the developing nervous system elicited by the pain during critical postnatal periods is manifested in later life following nociceptive reexposure by abnormal sensory thresholds and pain responses that are not restricted to the original site of postnatal trauma (74–76). Neonatal nociceptive exposure induces long-term hypoalgesia or hyperalgesia depending on the nature and timing of the trauma (54, 77) and is consistent with surgery and pain adversely impacting neurodevelopment independent of anesthetic (76).
Post-circumcision, tactile hypersensitivity increases due to post-surgical and -traumatic mechanisms that contribute toward allostasis and the risk of SIDS. This is evident by the increase in toll-like receptor 4 (78) associated with post-circumcision wound healing, which is also observed in post-surgical tactile hypersensitivity in males and dependent on testosterone (79). Following peripheral nerve injury, the purinergic receptors in the spinal cord microglial cells release BDNF (79) and mitogen-activated protein kinase p38 (80) that contribute to neuropathic pain and tactile hypersensitivity. Due to their testosterone dependency, they are seen only in males (79). The testosterone surge occurring during the first 2- to 4-month period may increase susceptibility to the initial stages of infection and is consistent with the peak in SIDS mortality (81).
Male neonates subjected to circumcision can experience severe cardiorespiratory pain responses, including cyanosis, apnea, increased heart rate (82), and increased pitch (fundamental frequency) of cry (as high as 800–2000 Hz) associated with decreased heart rate variability, i.e., decreased vagotonia (83–85), a likely risk factor for SIDS. Other circumcision sequelae of sufficient severity to require emergency room evaluation or hospital admission and contribute toward allostasis include infection, urinary retention, inflammatory redness and swelling ascribed to healing (86, 87), and amputation/necrosis of the glans (88). Behavioral abnormalities, such as eating disturbance and disturbed sleep, are also the consequence of pain exposure (89).
Postoperative circumcision pain of ample severity to require analgesia is expected for about 10 days for healing with incomplete wound healing past day 14 seen in up to 6% of infants depends on the device used to amputate the foreskin (88), which is also associated with various adverse events (56, 90). The overall complication rate for circumcision ranges from 0.2 to 10% with many USA physicians performing the procedure without formal training, being unaware of contraindications, and incapable of handling post-op complications (56, 91, 92). Lower complication rates for early and late adverse events have been attributed to underreporting with late adverse events mistakenly not attributed to circumcision (92, 93). Consequently, the low number ascribed to circumcision as the cause of death (63) may be underreported and erroneously attributed to other causes, such as sepsis (94) or SIDS.
One mechanism by which circumcision may elicit SIDS concerns the inhibition of nerves involved in nociception processing that produces prolonged apnea while impairing cortical arousal. Neonatal surgery that traumatizes peripheral nerves with associated tactile hypersensitivity followed by a subsequent surgery later in development can increase spinal cord microglia signaling and elicit persistent hyperalgesia (80). It can also produce post-surgical hyperalgesia that subsequently alters postnatal development of the rostral rostroventral medulla (RVM), which controls the excitability of spinal neurons by spinally projecting neurons from the nucleus paragigantocellularis lateralis (PGCL) and the nucleus raphe magnus. Alterations in the RVM result in a descending inhibition of spinal reflex excitability on nociception (95). Inhibition of RVM neurons was shown to limit the duration of the laryngeal chemoreflex and produce prolonged apnea that contributes toward SIDS, particularly when combined with stimuli that inhibit respiration (96). In SIDS, norepinephrine, which depresses respiration, is increased in the PGCL and serotonin 5-HT1A receptor that mediates nociceptive stimuli in the brainstem (97) and decreased in the raphe nuclei and the arcuate nuclei (98). The reduction in 5-HT1A receptors observed in the brainstem of SIDS infants prompts the hypothesis that SIDS is caused by a brainstem abnormality that impairs the ability to generate protective responses to life-threatening challenges (99, 100). This hypothesis, however, does not explain why SIDS peaks at 2–4 months, rather than in an earlier GA (101). Orexin is another important regulator of both pain and sleep dysfunction. Orexin knockout mice presented greater degree of hyperalgesia induced by peripheral inflammation and less stress-induced analgesia than wild-type mice (102). In the rostral ventrolateral medulla and PGCL, orexin receptors are expressed in sympathoexcitatory bulbospinal neurons (103). A significantly decreased orexin immunoreactivity in the hypothalamus and pontine nuclei was observed in SIDS infants (104).
Another mechanism that can explain the SIDS toll following circumcision is the loss of ~1–2 ounces (oz) of blood out of a total of ~11 oz that a 3,000 gram male newborn has (105), the equivalent of ~1–2 blood donations in an adult. Excessive bleeding is highly common in circumcision with reports range from 0.1 to 35% (91, 106) in neonates. However, even moderate bleeding puts the infant as risk, and, being an inherent part of the procedure, it is not reported as a complication. Blood loss of 2–2.5 oz, ~15% of the total blood volume at birth, is sufficient to cause hypovolemia and death. Since a large fraction of newborns (26%), particularly premature infants, weigh much less than 3,000 grams (107), a smaller amount of blood loss may trigger hypovolemic shock. Therefore, when bleeding an infant of low birth weight or GA, the effect may be pathological resulting in a reduced blood pressure that has been associated with obstructive sleep apnea (OSA), a condition where the walls of the throat relax and narrow during sleep, interrupting normal breathing (108). It is, therefore, not surprising that most of the deaths following circumcision in high-income countries were due to bleeding (63). While it is accepted that failure of neural mechanisms causing arousal from sleep may play a role in at least some SIDS cases [e.g., Ref. (109)], it is unclear what causes the initial failure of the respiratory control (110). Comparing the breathing characteristics of 40 infants who eventually died of SIDS with 607 healthy controls, Kato and colleagues reported that SIDS infants have a greater proportion of obstructive and mixed apneic episodes than the control group (111). Although the frequency of these episodes decreased with age, the decrease was smaller in the SIDS infants than in the controls, in support of either immature or impaired respiratory control. Looking at the data by gender, however, shows that only boys exhibit a difference in apnea frequency in support of an impaired respiratory control (111), perhaps due to circumcision.
To date, circumcision in the USA, despite being the most common pediatric surgery, has not been subjected to the same systematic scientific scrutiny looking at immediate and delayed adverse effects, including pain [e.g., Ref. (112)], nor has circumcision status been included as part of a thorough SIDS investigation/registry or analyses [e.g., Ref. (2)] in spite of the male predominance of both neonatal circumcision and SIDS. However, based on assessment of risk of harms versus benefit, despite the latter including decreased risk of urinary tract infection (113), the Royal Australasian College of Physicians, the British Medical Association, the Canadian Paediatric Society (87), and several west European medical societies have recommended against routine neonatal circumcision (114), arguing that the benefits of circumcision to children are minimal, non-existent, or outweighed by the risks, and that circumcision is thereby unwarranted. The AAP’s recommendation in favor of this routine (115) has been widely criticized [e.g., Ref. (116)].
The Significance of the Allostatic Load Model for SIDS
Sudden infant death syndrome occurs when an infant dies suddenly, unexpectedly, and without a cause identified through a forensic autopsy or death-scene investigation. We speculate that SIDS is caused by prolonged and repetitive iatrogenic stressful, painful, or traumatic experiences during critical development stages that constitute allostatic overload (156). Over the past years, allostatic load models were proposed to explain several leading medical conditions, including mental health disorders (157, 158), preterm birth (159), and chronic stress (160).
While the infant’s first environment is typically romanticized as peaceful, painless, hygienic, safe, and harmless, in practicality it may be anything but that. Already in the uterus, the fetus may be exposed to maternal substance use (e.g., smoking and drug use) associated with SIDS (19, 161). During a prolonged hospitalization in the Neonatal Intensive Care Unit that follows a preterm birth, infants may be exposed to extended and repeated pain, which thier unstable and immature physiological systems are unable to offset and will potentially render them more vulnerable to the effects of repeated invasive procedures (38). Neonatal circumcision typically involves maternal separation, pain, bleeding, and shock and, like any operation, puts the infant at risks of hemorrhage and sepsis even when anesthetic is used (67). The long-term consequences of circumcision include, among else, greater pain response to routine immunizations within the few months past birth (72). During winter time, the infant is at risk of infection and illnesses that grows with the number of household members, particularly older children (126), which explains why an elevated immune response is one of the hallmarks of SIDS (123, 128). Other common stressors may include birth trauma, birth injury, traumatic injury, life-threatening event, inadequate nutrition, heel lances, prolonged institutionalization, skin breaks, and air pollution – all contribute to the build-up of toxic allostatic load.
Our model represents a major departure from previous models, such as the “three interrelated causal spheres of influence model” that requires two out of three factors to act simultaneously (subclinical tissue damage, deficiency in postnatal development of reflexes and responses, and environmental factors) (162), or the more popular “triple-risk model,” which advocates that the combined effect of three factors (vulnerable infant, critical development period, and environmental stressors) causes SIDS (163). Our model posits that any infant may succumb to SIDS when the combined and cumulative effect of the environmental stressors has exceeded their tolerance level shaped by their unique genetic and environmental factors (Figure (Figure11).
Testing the Hypothesis (excerpt)
Neonatal Circumcision is a Risk Factor for SIDS
Double-blinded case–control human studies aiming to test our hypothesis are unfeasible due to ethical consideration and the difficulties in matching cases and controls (19). Fortunately, the prepuce has been well conserved throughout mammalian evolution (164), which attests to its functional importance, and allows carrying out animal studies. Our hypothesis can be tested by circumcising the prepuce of mammalian animal models and measuring whether an excess of SIDS is observed among cases when compared with untreated controls. Curiously, none of the studies purporting the “benefits” of neonatal circumcision has ever been demonstrated using animal models, which are the only viable means to carry out double-blinded case–control studies assessing the short- and long-term health impacts of circumcision. In humans, we can expect higher SIDS rates in Anglophone countries that adopted male neonatal circumcision in the nineteenth century, compared to Iberio-American that traditionally have opposed circumcision (66). We can also expect a higher incidence of SIDS in USA states where Medicaid, the most common health insurance, covers circumcision, compares to states where this procedure is not covered by Medicaid after accounting for culture and socioeconomic status. The data for such study can be obtained from the CDC’s SIDS registry (165). Finally, we can compare the circumcision status of SIDS victims versus healthy controls, obtained through autopsies and questionnaires, respectively. New genetic tools, such as Case-control matcher (http://www.elhaik-lab.group.shef.ac.uk/ElhaikLab/index.php), based on biogeographic ancestry tools [e.g., Ref. (166)], can be instrumental in optimizing case–control matches by identifying individuals that have similar population structure and genetic background and minimizing the bias studies due to population stratification.
Male Neonatal Circumcision Accounts for a Large Fraction of the Gender Bias in SIDS
We speculate that the male bias in SIDS observed in western countries may be due to both natural protections that render females more resilient to nociceptive stimuli and legal-cultural ones that protect females from circumcision in these countries. The weights of these two factors are unknown, yet we expect the gender deviations from even proportions in SIDS to be correlated with circumcision rates. Consequently, large male bias is expected in societies that practice neonatal circumcision whereas smaller bias is expected in societies that circumcise both males and females or avoid it altogether.
Circumcised Premature Infants Are at High Risk
We predict that circumcised premature infants would be at higher risk for SIDS compared with intact preterm infants. This can be tested by an analysis of hospital records after properly matching cases with controls (19).
Additional complications that should be considered when testing these predictions in humans include misclassification of SIDS to other categories, inconsistent reports of SIDS over time in certain countries due to changes in definitions, inconsistent reports of circumcision (167), and the absence of legislation requiring an autopsy or thorough death-scene investigation.
Elhaik, E. (2016). A “Wear and Tear” Hypothesis to Explain Sudden Infant Death Syndrome. Frontiers in Neurology, 7, 180.