Cardiorespiratory physiology in early infancy

Sudden infant death syndrome (SIDS) rates have remained relatively stable at about 0.55 deaths per 1000 live births (2234 infants) since the early 2000s 1, 2. In addition to unsafe sleep environments, other environmental risk factors include intrauterine exposure to alcohol, cigarette smoke and drugs of abuse. Many of the risk factors for SIDS overlap with risk factors for sudden intrauterine unexplained death or stillbirth. The aetiology of SIDS and stillbirth is likely multifactorial, with both environmental and genetic risk factors and dynamic gene–environment interactions affecting autonomic cardiorespiratory function 2, 3. Physiologic data are available for a limited number of infants later dying of SIDS and for infant groups thought to be at increased for SIDS 2. These studies have been consistent with impaired brainstem-related autonomic neuroregulation, including respiratory and heart rate variability. Infants studied in early infancy and dying of SIDS weeks later had higher heart rates and lower heart rate variability (HRV) in all sleep–wake states, and no decreases in the low-frequency to high-frequency power ratios observed in surviving infants, consistent with impaired autonomic nervous system (ANS) control resulting in higher vulnerability to stressors. The physiologic observations are consistent with anatomic and biochemical alterations in brainstem regions affecting serotonin-related autonomic nervous regulation, and with genetic polymorphisms affecting both serotonergic and ANS development genes pertinent to early embryologic development of the ANS 2. Infant cardiovascular control and HRV changes in early infancy have been studied in relation to gestational and postnatal age, sleep state and sleep position, sometime including a perturbation such as head-up tilt (HUT) 4-8. The report by Myers et al. 9 in this issue presents new autonomic cardiorespiratory data during baseline and HUT at birth and at one month of age in healthy full-term infants. The Prenatal Alcohol in SIDS and Stillbirth (PASS) Network was created to investigate prenatal alcohol exposure and risk for SIDS, stillbirth and foetal alcohol spectrum disorders, and includes about 12,000 subjects from North and South Dakota, and Cape Town, South Africa. Within PASS, the Safe Passage Study has been investigating the postnatal effects of prenatal alcohol exposure to better define physiologic mechanisms underlying vulnerability to SIDS, and perhaps with implications for stillbirth. Assessments included heart rate (HR), breathing frequency, HRV and blood pressure (BP) in the first four days of life and one month postnatal age in 510 infants, 44% of whom had data at both ages. Measurements were obtained in active and quiet sleep at baseline and following three 45 HUTs in healthy control infants without prenatal exposure to maternal alcohol, cigarette smoke or drugs of abuse. These new results are generally consistent with published data 4-9. New findings include the effect of age and sleep state on cardiorespiratory physiology 9. Although HR has been shown to increase significantly as infants enter the vulnerable age for SIDS, these new data indicate that during this same time period, BP, in particular diastolic BP, decreases, suggesting that infants may have more difficulty responding to conditions that decrease BP and/or increase HR. The absence of significant HR increases with HUT was paralleled by concurrent increases in both time and frequency domain indices of parasympathetic activity. Contrary to the expected vagal withdrawal with HUT in newborns, these infants are thus responding conversely to decreased BP with vagal activation. This study has several noteworthy strengths. This is a very large number of healthy full-term infants unexposed to prenatal maternal alcohol, cigarette smoke or drugs of abuse. Methods for the state-of-the-art physiologic assessments are presented in detail, and the investigators are very experienced in these assessments and their interpretation. In addition to confirming published data, they present new findings related to effects of age and sleep state that better characterise the apparent increased vulnerability to stressor as infants approach the age of greatest vulnerability for SIDS. Finally, the heterogeneity in regard to geographic, ethnic, racial, SES and prenatal exposures suggests that these results may have a high degree of generalisability. There are also limitations to this study. Of 666 infants meeting criteria, physiologic assessments were attempted in 456 infants at birth and 482 infants at one month. However, only 510 infants had data at either age and only 44% of these had data at both ages. Assuming a similar numbers of infants with foetal alcohol exposure being similarly assessed, the comparisons should yield new and important insights regarding foetal alcohol-related autonomic changes in cardiorespiratory function, especially approaching the age of increased risk for SIDS. However, there will be too few infants dying of SIDS to permit any comparison of SIDS rates in foetal alcohol-exposed versus unexposed infants. Even if the SIDS rate in the foetal alcohol-exposed infants is several times greater than in unexposed infants, perhaps even as high as 2–3 per 1000 live births, there will still likely be <5 SIDS cases in exposed and ≤1 case in unexposed infants. Another limitation is the lack of any physiologic assessment during the peak risk range for SIDS, for example at three months of age, to more directly inform us about increased foetal alcohol-related risk for SIDS based on adverse maturational changes at this high-risk age 4, 5, 7, 8. Budget constraints notwithstanding, the other reasons for not including a postnatal assessment during the high-risk age for SIDS are less compelling. An additional goal was to identify or better define mechanisms that underlie foetal alcohol exposure-related vulnerability for SIDS and use these early markers of vulnerability to identify infants needing increased surveillance and intervention. However, the accuracy of any such identification strategies remains an unfulfilled goal and no cost-effective “interventions” have yet been identified. Another limitation is lack of any physiologic assessment during supine sleep even though only 24.5% apparently routinely slept prone based on ‘position last night’ at the one-month assessment. Of interest, however, supine-sleeping infants assessed in the high-risk prone sleep position had lower baseline diastolic BP during active sleep, and infants accustomed to prone sleep position compared to supine sleep position had the greatest decrease in systolic blood pressure following HUT during quiet sleep. There was no assessment of any physiologic assessment differences between the South Africa and U.S. populations, although the investigators plan such an assessment later. Age and location of the newborn assessments varied between the sites. Assessments in the North and South Dakota sites were performed in the nursery at 12–96 hours of age compared to outpatient assessments at 48–96 hours after birth in Cape Town infants; it is unknown whether these differences might in any way have affected the first cardiorespiratory physiology results. The gold standard for documenting sleep state is EEG-based 4-7. Although behavioural observation coding is often used as a surrogate for sleep state, these investigators also used an automated method for coding sleep state based on respiratory variability that has been shown to correlate well with standard polysomnographic EEG-based coding and with behavioural state coding. Sleep state for each HUT was based on state during the preceding last 30 sec of baseline recording. If sleep state changed during the HUT, then sleep state for that HUT would have been misclassified. The Safe Passage Study was designed to be longitudinal, with serial assessments at birth and one month. However, only 44% had a physiologic assessment at both ages. Although a limitation, this reflects the challenge of conducting a longitudinal study with outpatient cardiorespiratory physiologic recordings. It remains to be seen whether even this degree of success can be similarly achieved in the alcohol-exposed cohort. This lack of longitudinal maturational data was most striking for sleep state, with only 13 infants having quiet sleep data at both ages. Finally, although detailed methods for documenting foetal exposure were used, these details were not provided; as the authors state, there was likely some under-reporting of foetal exposure, perhaps especially for alcohol. In summary, despite these limitations, Myers et al. 9 have made a significant contribution to new knowledge. Confirmation of prior results has been achieved in a much larger and more diverse population of healthy full-term infants. Methods are well detailed and state of the art, and the study was conducted by experienced investigators. The Safe Passage Study, conducted by the Prenatal Alcohol in SIDS and Stillbirth Network, is a very ambitious study. Although not described in detail, enrollees have very diverse sociodemographic backgrounds including subgroups having higher SIDS mortality rates than in the United States overall. The cardiorespiratory data reported herein expand our knowledge regarding normal physiology and include a well-defined autonomic perturbation (HUT) that further clarifies normal autonomic physiology in early infancy. Contrasting autonomic brainstem function with similar assessments in infants with foetal alcohol exposure should yield important new insights regarding the effects of alcohol on brainstem autonomic development. Although it will not be possible to quantify the extent to which any observed differences in autonomic function actually increase risk for SIDS, these comparative analyses should nevertheless generate new and testable hypotheses for future research.