Female infants may be more vulnerable to long-term consequences of pain
Rita Agarwal MD, Elliot J. Krane MD, Lynne G. Maxwell MD, and Myron Yaster MD
There were several truly outstanding papers published over the past few months on neonatal pain. The PAAD’s pain team will discuss and review several of them over the next month, beginning with today’s article by Selvanathan et al.1
Original article
Selvanathan T, Ufkes S, Guo T, Chau V, Branson HM, Ibrahim GM, Ly LG, Kelly EN, Grunau RE, Miller SP. Pain Exposure and Brain Connectivity in Preterm Infants. JAMA Netw Open. 2024 Mar 4;7(3):e242551. doi: 10.1001/jamanetworkopen.2024.2551. PMID: 38488791; PMCID: PMC10943417.
Historically, newborns, particularly premature infants, were not treated for pain or painful procedures because of the belief that they neither responded to nor remembered pain compared to older children and adults. In its extremes, until the 1970’s, this led to surgery being performed without anesthesia or more commonly with only nitrous oxide and curare. Many of you may wonder, “How could this be?” The most commonly used induction agent was thiopental and inhalation agent was halothane, to which newborn hearts were particularly susceptible to depression, and high dose opioid anesthesia had not yet been invented. The rationale at the time was “We can all agree that no one can consciously remember anything from the first few months, or really years of life. Therefore, why use drugs to treat pain (or provide anesthesia) that may be harmful, if these patients have no conscious memory of the pain and the lethality of available anesthetics is nontrivial?”
After the advent of high dose opioid anesthesia in the 1980s,2,3 a new and safer way of providing anesthesia to the newborn became possible. In a landmark paper, Anand and Hickey4 compared halothane + morphine to high dose sufentanil which was administered both intra and postoperatively and found that adequate anesthesia with high dose opioids was associated with a lower mortality rate and lower hormonal evidence of the stress response. The high dose fentanyl technique quickly became the standard of care for newborn anesthesia.
In our current times, there are those who want us to turn back the clock and avoid general anesthetics during newborn surgery for fear of producing brain injury (neuroaptosis). Today’s PAAD should put this argument to rest: the failure to provide analgesia and limit pain have real and not hypothetical neurodevelopmental consequences.
Over the past 3 decades, accumulated evidence supports the notion that “greater early-life pain has been associated with altered brain maturation and poorer neurodevelopmental outcomes in children born preterm.5-7 Higher stress exposure, including to invasive procedures, has been associated with slower development of structural connectivity in preterm infants, and lower connectivity in the hippocampus and amygdala, that has been associated with changes in behavioral outcomes. 7
In today’s PAAD, Selvanathan et al, “sought to assess whether there were gender-specific associations between early-life pain and maturation of neonatal structural connectivity and associations of connectivity with 18-month neurodevelopment. They hypothesized that greater early-life pain would be associated with slower maturation of neonatal connectivity in female but not male infants and that reduced connectivity would be associated with poorer neurodevelopmental outcomes, as animal as well as human studies have shown greater vulnerability in females to long-term consequences of early life pain.”1
“150 Infants underwent early-life and/or term-equivalent-age (TEA) magnetic resonance imaging with diffusion tensor imaging to quantify structural connectivity using graph theory measures and regional connection strength. Eighteen-month neurodevelopmental outcomes were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition. Stratifying by gender, generalized estimating equations were used to assess whether pain exposure modified the maturation of structural connectivity using an interaction term (early-life pain exposure × postmenstrual age [PMA] at scan). Generalized estimating equations were used to assess associations between structural connectivity and neurodevelopmental outcomes, adjusting for extreme prematurity and maternal education.”1
What did they find? “Greater exposure to early-life pain was associated with altered maturation of neonatal structural connectivity, particularly in female infants. Alterations in structural connectivity were associated with poorer neurodevelopmental outcomes, with potential regional specificities.”1 That untreated pain would affect brain development shouldn’t be surprising. “The second and third trimesters of gestation are important for the formation and organization of cerebral connectivity, including the development of thalamocortical pathways, growth of long-distance corticocortical fibers, and then short-distance corticocortical connections.1,6,8 By affecting neuronal connectivity, untreated pain may aberrantly reorganize brain architecture and contribute to persistent hyperalgesia and altered neuroendocrine stress responses. Further, “greater early-life painful exposures have been associated with reduced regional brain volumes, more immature white matter microstructure, and altered functional connectivity.”1
Now, that is a massive extrapolation from the results of a retrospective descriptive uncontrolled study! So let us take a more jaundiced view of this paper.
In my (EJK) view, this paper reproduces the very same errors of the early alarmist papers about anesthesia and neuro apoptosis:
First, the study population was “very premature” newborns, a population that would be the most vulnerable to cerebral developmental abnormalities that may or may not be associated with painful procedures. Many other events happen in these vulnerable infants after birth.
Second, their quantification of “untreated pain” was the number of invasive procedures performed during their NICU stay, not the intensity or invasiveness of the procedures. Their list of painful procedures ranged from the trivial (PICC dressing change, ostomy bag change, ultrasound, eye exam) to the very painful (chest compressions, ETT suctioning, circumcision, intubation, etc.), without any attempt at stratifying these events or associating the MRI findings with specific events.
Third, it would seem obvious that the sicker a newborn is, and the more premature they are, the longer they will be in the NICU and therefore the more numerous invasive procedures will be; and that the more severe the illness, the more episodes of hypoxia, hypercarbia, hypotension will occur, and these are equally or more likely to be associated with cerebral injury.
Fourth, Table 1 in the paper shows several differences between the males and females studied that may have confounded or even explained the MRI and developmental findings, and no statistical analysis seems to have been done to determine the significance of these differences. For example, there were more females in the extremely premature population, the birthweights of females was less than males, and more females were SGA.
Fifth, we are not told whether the investigators counting the painful encounters, the radiologists analyzing the MRI scans, or the people performing the neurodevelopmental assessments were blinded to prior data gathered or the clinical histories of the subjects. I would assume they were blinded given the quality of the investigators and their institutions, but it would be necessary to be assured of that.
Finally, many regular readers of the PAAD know my (MY) profound skepticism of the general anesthesia/neuroapoptosis studies. Today’s PAAD reminds us that untreated pain may also be associated with abnormal structural brain development, particularly in females, and is something we should strive to prevent for humanitarian reasons, whether there are neurodevelopmental consequences of not treating pain bear further study. Further, remember what our good friend and PAAD reviewer, Dr. Jim DiNardo, always likes to remind us: association does not necessarily mean causation.
Send your thoughts and comments to Myron who will post in a Friday reader response.
References
1. Selvanathan T, Ufkes S, Guo T, et al. Pain Exposure and Brain Connectivity in Preterm Infants. JAMA network open 2024;7(3):e242551. (In eng). DOI: 10.1001/jamanetworkopen.2024.2551.
2. Yaster M. The dose response of fentanyl in neonatal anesthesia. Anesthesiology 1987;66(3):433-435.
3. Anand KJ, Sippell WG, Aynsley-Green A. Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response [published erratum appears in Lancet 1987 Jan 24;1(8526):234]. Lancet (London, England) 1987;1(8524):62-66.
4. Anand KJ, Hickey PR. Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery [see comments]. NEnglJMed 1992;326(1):1-9.
5. Lammertink F, Benders M, Hermans EJ, et al. Vulnerability of the Neonatal Connectome following Postnatal Stress. J Neurosci 2022;42(48):8948-8959. (In eng). DOI: 10.1523/jneurosci.0176-22.2022.
6. Kostović I, Radoš M, Kostović-Srzentić M, Krsnik Ž. Fundamentals of the Development of Connectivity in the Human Fetal Brain in Late Gestation: From 24 Weeks Gestational Age to Term. J Neuropathol Exp Neurol 2021;80(5):393-414. (In eng). DOI: 10.1093/jnen/nlab024.
7. Batalle D, Hughes EJ, Zhang H, et al. Early development of structural networks and the impact of prematurity on brain connectivity. Neuroimage 2017;149:379-392. (In eng). DOI: 10.1016/j.neuroimage.2017.01.065.
8. Kostović I, Jovanov-Milosević N. The development of cerebral connections during the first 20-45 weeks' gestation. Semin Fetal Neonatal Med 2006;11(6):415-22. (In eng). DOI: 10.1016/j.siny.2006.07.001.