3: In the unborn child, application of such painful stimuli is associated with significant increases in stress hormones known as the stress response.
1. Tran, 2010, p.44, col.1, para.7, “Invasive fetal procedures clearly elicit a stress response…”
Tran, KM. Anesthesia for fetal surgery. Seminars in Fetal & Neonatal Medicine. 15 (2010) 40-45.
2. Myers, 2004, p.242, para.2, “Human fetal endocrine responses to stress have been demonstrated from as early as 18 weeks’ gestation. Giannakoulopoulos et al99 first demonstrated increases in fetal plasma concentrations of cortisol and β-endorphin in response to prolonged needling of the intrahepatic vein (IHV) for intrauterine transfusion. The magnitude of these stress responses directly correlated with the duration of the procedure. Fetuses having the same procedure of transfusion, but via the non-innervated placental cord insertion, failed to show these hormonal responses. Gitau et al100 observed a rise in β-endorphin during intrahepatic transfusion from 18 weeks’ gestation, which was seen throughout pregnancy independent both of gestation and the maternal response. The fetal cortisol response, again independent of the mother’s, was observed from 20 weeks’ gestation.100 Fetal intravenous administration of the opioid receptor agonist, fentanyl, ablated the β-endorphin response and partially ablated the cortisol response to the stress of IHV needling, suggesting an analgesic effect.101 A similar, but faster, response is seen in fetal production of noradrenalin to IHV needling. This too is observed in fetuses as early as 18 weeks, is independent to the maternal response and increases to some extent with gestational age.102 Thus, from these studies one can conclude that the human fetal hypothalamic– pituitary–adrenal axis is functionally mature enough to produce a β-endorphin response by 18 weeks and to produce cortisol and noradrenalin responses from 20 weeks’ gestation.”
Myers LB, Bulich LA, Hess, P, Miller, NM. Fetal endoscopic surgery: indications and anaesthetic management. Best Practice & Research Clinical Anaesthesiology. 18:2 (2004) 231-258.
99 Giannakoulopoulos X, Sepulveda W, Kourtis P, Glover V, Fisk NM. Fetal plasma cortisol and β-endorphin response to intrauterine needling. Lancet. 344 (1994) 77-81.
100 Gitau R, Fisk NM, Teixeira JM, Cameron A, Glover V. Fetal hypothalamic–pituitary–adrenal stress responses to invasive procedures are independent of maternal responses. Journal of Clinical Endocrinology and Metabolism. 86 (2001) 104-109.
101Fisk NM, Gitau R, Teixeira MD, Giannakoulopoulos, X, Cameron, AD, Glover VA. Effect of Direct Fetal Opioid Analgesia on Fetal Hormonal and Hemodynamic Stress Response to Intrauterine Needling. Anesthesiology. 95 (2001) 828-835.
102Giannakoulopoulos X, Teixeira J, Fisk N, Glover V. Human fetal and maternal noradrenaline responses to invasive procedures. Pediatric Research. 45(1999) 494-499.
3. Derbyshire, June 2008, p.4, col.1, para.5, “Another stage of advancing neural development takes place at 18 weeks, when it has been demonstrated that the fetus will launch a hormonal stress response to direct noxious stimulation.”
Note: Derbyshire believes that pain requires subjective human experience, not possible until after birth; nonetheless, he acknowledges this finding.
Derbyshire SW. Fetal Pain: Do We Know Enough to Do the Right Thing? Reproductive Health Matters. 16: 31Supp. (2008) 117-126.
4. Gupta, 2008, p.74, col.2, para.3, “Fetal stress in response to painful stimuli is shown by increased cortisol and β-endorphin concentrations, and vigorous movements and breathing efforts.7,9 There is no correlation between maternal and fetal norepinephrine levels, suggesting a lack of placental transfer of norepinephrine. This independent stress response in the fetus occurs from 18 weeks gestation.10”
Gupta R, Kilby M, Cooper G. Fetal surgery and anaesthetic implications. Continuing Education in Anaesthesia, Critical Care & Pain. 8:2 (2008) 71-75.
7Boris P, Cox PBW, Gogarten W, Strumper D, Marcus MAE. Fetal surgery, anaesthesiological considerations. Current Opinion in Anaesthesiology.17 (2004) 235-240.
9Giannakoulopoulos X, Teixeira J, Fisk N. Human fetal and maternal noradrenaline responses to invasive procedures. Pediatric Research. 45 (1999) 494-499.
10Marcus M, Gogarten W, Louwen F. Remifentanil for fetal intrauterine microendoscopic procedures. Anesthesia & Analgesia. 88 (1999) S257.
5. Fisk, 2001, p.828, col.2, para.3, “Our group has shown that the human fetus from 18-20 weeks elaborates pituitary-adrenal, sympatho-adrenal, and circulatory stress responses to physical insults.” p.834, col.2, para.2, “This study confirms that invasive procedures produce stress responses….”
Fisk NM, Gitau R, Teixeira MD, Giannakoulopoulos, X, Cameron, AD, Glover VA. Effect of Direct Fetal Opioid Analgesia on Fetal Hormonal and Hemodynamic Stress Response to Intrauterine Needling. Anesthesiology. 95 (2001) 828-835.
6. Kadić, 2012, page 3, “As early as 16-18 weeks, fetal cerebral blood flow increases during invasive procedures.26,27 An elevation of noradrenaline, cortisol, and beta-endorphin plasma levels, in response to needle pricking of the innervated hepatic vein for intrauterine transfusion, was registered in a 23-week-old fetus [= 21 weeks post-fertilization].” (Table 2).”
Salihagić Kadić, A., Predojević, M., Fetal neurophysiology according to gestational age, SEMINARS IN FETAL & NEONATAL MEDICINE (2012) 1–5, 3, doi:10.1016/j.siny.2012.05.007.
26 Teixeira JM, Glover V, Fisk NM. Acute cerebral redistribution in response to invasive procedures in the human fetus. Am J Obstet Gynecol 1999;181:1018e25.
27 Smith RP, Gitau R, Glover V, et al. Pain and stress in the human fetus. Eur J Obstet Gynecol Reprod Biol 2000;92:161e5.