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European Journal of Obstetrics & Gynecology and Reproductive Biology

Volume 92, Issue 1 SummaryPlus Not available here

September 2000 Article

Pages 161-165 Journal Format-PDF not available here

PII: S0301-2115(00)00441-3
Copyright © 2000 Elsevier Science Ireland Ltd. All rights reserved.

Pain and stress in the human fetus^*1

Richard P. Smith ^,, R. Gitau, V. Glover and Nicholas M. Fisk

Department of Maternal and Fetal Medicine, Centre for Fetal Care, Institute of Obstetrics and Gynaecology, Imperial College School of Medicine, Queen Charlotte's and Chelsea Hospital, Goldhawk Rd, London W6 0XG, UK

Available online 11 September 2000.

Abstract

Invasive diagnostic and therapeutic techniques are increasingly applied to the fetus. It is not known if the fetus feels pain during such procedures, but the fetus does mount significant stress hormonal and circulatory changes in response to these from 18_¯20 weeks. Perinatal stress may have long-term neurodevelopmental implications. During open fetal surgery, maternal general anaesthesia provides fetal anaesthesia. However, in closed procedures, fetal analgesia presents difficulties. The optimal drug, dose, and route of administration remain to be determined.

Author Keywords: Fetal response to pain; Analgesia; Intra-uterine intervention

1. Introduction

The recent ability to diagnose and treat the fetus in utero resulted from developments in invasive procedures, in understanding of fetal pathophysiology, and in technical advances in imaging. These procedures, ranging from ultrasound-guided needle aspiration through to open fetal surgery, are invasive, leading to the obvious question: does the fetus feel pain?

The concept that the fetus is a patient in its own right has led to increasing interest in the subject of fetal pain. A justification for providing fetal analgesia and anaesthesia has arisen not only because of a moral obligation to prevent suffering, but also because pain and stress may affect survival and have long-term neurodevelopmental sequelae.

However, the evidence base for this is limited, largely because research in human fetuses is hampered by ethical constraints, but also due to problems defining satisfactory outcome measures.

2. Fetal pain

There is no objective measurement of `pain'; it is a subjective experience. The fetus is unable to tell us if it feels pain, so other evidence must be used to decide at what gestation it is likely that the fetus starts to feel pain. Sensory innervation of the skin and neuronal connections between the periphery and spinal cord have begun by 8 weeks, with C fibres growing into the spine at about 10 weeks. The cerebral cortex starts to form at this stage, with differentiation into neurones, fibres, glia and blood vessels starting at about 17 weeks, and continuing long after birth. Pain fibres pass through the thalamus en route to the cortex. The timing of these thalamo-cortical connections is crucial in deciding when the fetus first becomes capable of feeling pain; this is an area of considerable controversy. Rapid Golgi-staining techniques have shown the ingrowth of afferent fibres into the cortical plate between 26 and 34 weeks of gestation [1], which has led some to conclude the fetus is incapable of feeling pain prior to 26 weeks [2]. However, between 20 and 26 weeks the subplate zone of the cortex contains an abundant mixture of cholinergic, thalamo-cortical and corticocortical waiting neurones, and there are transient fetal synaptic circuits between the subplate and cortical plate neurones [3]. Awareness of pain is considered to require connections between the cortex and periphery, although, this presumption would render animals lacking a cortex such as reptiles incapable of perceiving pain. It is not known at what point in the maturation from transient, possibly single, connections to permanent multiple connections the fetus may become capable of feeling pain, and it may be a gradual rather than sudden transition. In summary, prior to 22 weeks the fetus does not have the neuroanatomical pathways in place to feel pain, between 22 and 26 weeks thalamo-cortical connections are forming, and after 26 weeks the fetus has the necessary connections to feel pain.

3. Neonatal experience

Until the last decade, the neonate was treated as if it were incapable of feeling pain. However, studies showed that neonates, even when preterm, mounted a sizeable stress response to cardiac surgery [4], with rises in adrenaline, noradrenaline, and cortisol. Some of these changes were reduced by opioid analgesia [4]. In one randomised study, opioid anaesthesia was associated with a reduction in peri-operative mortality [5]. Since then, use of analgesia during neonatal surgery has become the standard of care.

Neonates also have behavioural responses to pain, for example, by facial expression or by crying. The response to heel lancing by facial action varies depending on the sleep/wake state of the neonate, suggesting that the behavioural context of pain affects behavioural expression, even before the opportunity for learned response occurs [6].

4. Fetal stress

Because of the obvious difficulties in studying fetal behaviour, activation of the hypothalamo-pituitary-adrenal axis (a `stress response') has been proposed as a surrogate indicator of fetal pain. This has limitations: stress responses do not necessarily imply pain (for example, during exercise), and stress responses do not involve the cortex. However, the converse is the null hypothesis, i.e. in the absence of a stress response the fetus is unlikely to experience pain. Also, one could argue that the stress response is more relevant in terms of immediate and long-term sequelae, whether or not associated with pain in the fetus.

Studies in humans are limited by the need for an ethically-acceptable model, namely those fetuses undergoing clinically-indicated procedures for diagnostic or therapeutic reasons. We have studied fetuses undergoing intravascular blood transfusion, which allows collection of serial blood samples at the beginning and end of the procedure. Procedures at the placental cord insertion (PCI), which is not innervated, can be compared with transfusions at the intrahepatic vein (IHV), which involves transgressing the fetal trunk (Fig. 1). In our unit, the site of approach is based on technical access dependent on fetal and placental position, with each site used approximately 50% of the time. While the IHV approach may have a lesser risk of complication due to cord tamponade and arterial spasm, the PCI approach is technically easier.

Fig. 1. The model of clinically-indicated fetal blood sampling and transfusion used to study fetal haemodynamc
and hormonal stress responses in humans.

4.1. Hormonal response

Activation of the fetal hypothalamo-pituitary-adrenal axis can be assessed by measuring stress hormones such as noradrenaline, cortisol, and

-endorphin. Studying samples obtained at fetal blood transfusion allows comparison of levels of these hormones before transfusion (immediately after access to the fetal circulation is established), with levels at the end of transfusion (just before the needle is removed). After transfusion at the PCI there is little change in fetal noradrenaline, cortisol, or

-endorphin [7 and 8].

However, as illustrated in Fig. 2, piercing the fetal abdomen to access the IHV for transfusion is associated with substantial rises in these hormones from as early as 18 weeks gestation. The median increase in -endorphin levels was 590%, in cortisol levels was 183%, and in noradrenaline levels was 196% [7 and 8]. Shorter procedures such as blood sampling without transfusion were not associated with rises in cortisol and -endorphin, but there was a variable rise in the more rapid noradrenaline response.

Fig. 2. Summary of human fetal responses (cortisol, -endorphin [7], and noradrenaline [8], and MCA P1)
to IHV transfusion. There was no significant response in any parameters to transfusion at the PCI.

4.2. Circulatory response

The fetus in late gestation has a remarkable capacity to redistribute its blood flow in response to stressors to protect its more vital organs, such as brain and myocardium, at the expense of other organs such as gut, kidneys and the extremities [9]. Numerous experimental studies have confirmed such responses to acute hypoxaemia [10 and 11], haemorrhage [12], and reduced uterine blood flow [13]. Similarly, Doppler studies of human fetuses with intrauterine growth restriction (IUGR) have found decreased resistance indices in cerebral [14] and adrenal [15] blood flow velocity waveforms (FVW) consistent with vasodilatation, and increased indices in FVW from peripheral organ beds such as the renal [16], femoral [17] and pulmonary [18] arteries consistent with vasoconstriction.

Using Doppler ultrasound, our group has shown a fall of 1_¯2.5 standard deviations in middle cerebral artery pulsatility index, consistent with this fetal brainsparing response, after procedures involving transgression of the fetal trunk, from as early as 16 weeks. The mechanism for this is not clear, but is compatible with an increase in cerebral flow. There is also an increase in renal and femoral artery resistance indices after procedures involving transgression of the fetal trunk, similarly compatible with fetal brainsparing (manuscript in preparation). These changes are not seen after procedures at the PCI. This redistribution in blood flow may be mediated by the sympathetic system, or by other undetermined mechanisms.

5. Long-term sequelae

There is increasing evidence that early painful or stressful events can sensitise an individual to later pain or stress. Evidence from animal studies indicates that a stressful perinatal event can have long-term effects on hippocampal development and stress behaviour. In rats, which are born at a stage equivalent in development to the late human fetus, early postnatal handling causes an increase in glucocorticoid receptor density in the hippocampus and a lifelong modification in behavioural stress responses [19]. Rats stressed perinatally secrete more corticosterone and show a slower return to basal levels in stressful situations [20].

The primate model has also been used to study the effects of stress hormones and stress. Administration of dexamethasone to pregnant rhesus monkeys in the latter third of pregnancy at a dose similar to that used in humans is associated with degenerative changes in the fetal hippocampus [21]. Exposure to a 2-week period of exogenous ACTH is associated with impaired motor coordination and muscle tonicity, reduced attention span, and greater irritability [22]. Exposure to stress in the latter third of pregnancy is associated with higher levels of ACTH and cortisol in the neonate when stressed [23]. Exposure to stress in utero, especially during the first third of pregnancy, is also associated with lower scores of attention and neuromotor maturity after birth [24].

In humans, neonatal circumcision without analgesia has been shown to increase subsequent pain behaviour (measured objectively from videotape by an independent observer) following vaccination 4_¯6 months later when compared to uncircumcised controls [25]. This suggests that a single stressful event early in life, when the nervous system is still developing, can influence neurodevelopment and may have a lifelong effect on stress responses. Furthermore, preoperative treatment with local anaesthetic cream attenuated the response to vaccination, suggesting that analgesia can alter the effect of stress on neurodevelopment [25].

In response to vaccination in infancy, we have found that babies born by instrumental delivery have a greater rise in salivary cortisol and cry for longer than those born normally, while those born by elective Caesarean section have a smaller rise and cry less than the normal group [26].

Whether pain or stress in utero has long-term implications is not known, and studies are limited by the ethical need to confine invasive procedures to those for which there is a diagnostic or therapeutic indication. Many such fetuses will be abnormal, making it difficult to correct for confounding factors when comparing them to control fetuses not undergoing invasive procedures. Further, the number of invasive procedures continues to decline with the advent of rapid molecular methods of chromosomal analysis, and a fall in the incidence of Rh disease due to antenatal prophylaxis.

6. Fetal analgesia

Awareness of the need for fetal analgesia increased following Anand's work on opiates in neonates [4]. The rationale was that if a premature infant was capable of feeling pain then there is no reason why a fetus of the same gestation should not also feel pain [27]. The case strengthened following the demonstration that human fetuses mount sizeable biochemical and circulatory stress responses to invasive procedures [7, 8 and 28].

Potential indications include any procedure from which the fetus could probably experience pain. These can be grouped into `open' fetal surgical procedures via laparotomy, and `closed' percutaneous procedures via endoscopes and needles. Fetal surgery is now being offered in highly selected circumstances where fetal prognosis is otherwise poor [29]. Such circumstances are rare, and include fetal lung lesions (congenital cystic adenomatoid malformation and bronchopulmonary sequestration), congenital diaphragmatic hernia, sacrococcygeal teratoma, and myelomeningocele. As well as IHV fetal blood sampling and transfusion discussed earlier, other `closed' surgical and needling techniques may be used on the fetus. These include vesicoamniotic shunting, fetal cystoscopy, thoraco-amniotic shunting, and fetal tissue biopsy.

Fetal analgesia for open fetal surgery is facilitated by maternal anaesthesia. The potent inhalational agents all cross the placenta, with fetal uptake depending on uterine blood flow, the solubility of the drug in fetal blood, and its distribution in the fetal compartment [30]. Isoflurane is rapidly taken up by the fetus [31] and both maternal and fetal anaesthesia can theoretically be achieved. Work in sheep suggests that the fetus requires a lower concentration of isoflurane to achieve the same level of anaesthesia as the adult [32], so concentrations, which provide maternal anaesthesia, are likely to provide adequate fetal anaesthesia. Inhalational agents also provide uterine relaxation, which allows handling of the uterus without contractions and the risk of placental separation. High levels of isoflurane may reduce uterine blood flow, although, in contrast work in pregnant ewes has shown that at lower concentrations uterine blood flow increases slightly [33]. Direct fetal administration of fentanyl and pancuronium is reserved for cases where the fetus moves during the procedure [30].

During `closed' endoscopic or needling procedures, administration of safe and effective analgesia presents difficulties. The risks of maternal (and consequently fetal) general anaesthesia are unlikely to be justified by the degree of pain inflicted on the fetus. Similar procedures in adults involving cutaneous puncture are usually performed using no analgesia or local analgesia, depending on the size of needle. Local anaesthesia is not practical in the fetus: it would be difficult to administer to the fetal skin accurately, and the fetus may move before the needle is advanced into the target organ. Opioids cross the placenta, but fetomaternal ratios are low, only about 0.3:1 for fentanyl [34]. Thus, to provide fetal analgesic levels, the higher maternal levels required would expose the mother to a risk of sedation and respiratory depression. Intra-amniotic opioids have been tried in experimental animal models but not surprisingly result in subtherapeutic fetal levels due to impermeability of the fetal skin [35]. Administering drugs to the fetal IHV or intramuscularly would itself involve fetal puncture and thus potentially pain.

Accessing the PCI to administer analgesia before proceeding to the fetus would increase the procedure-related risks, and cannot be justified at least until analgesia has been shown to be beneficial in closed procedures.

Our group is currently investigating the effects of direct opioid analgesia during closed procedures at the IHV. One problem with this approach is that the fetus is punctured before analgesia is administered. Even if shown efficacious, the optimal drug, dose, and route of administration remain to be determined.

7. Conclusion

Evidence in neonates of stress responses to surgical insults and their prevention with analgesia has led to increased awareness of pain and the need for analgesia in newborns. This raises the obvious question if and when the fetus can feel pain. The critical thalamo-cortical connections for nociception form from 20_¯26 weeks, while substantial hormonal and circulatory stress responses to invasive procedures are observed by 20 weeks. Although, there is yet no evidence that analgesia works in the human fetus, fetal analgesia warrants investigation, both because of a moral imperative to prevent possible suffering, and because of the increasing evidence in animals and humans suggesting that exposure to perinatal stress has long-term neurodevelopmental sequelae.

During open fetal surgery under maternal general anaesthesia, inhalational agents are considered to provide adequate fetal anaesthesia. In contrast, the more common closed needling and shunting procedures are usually performed using only maternal local anaesthesia. Fetal analgesia provides a challenge in such circumstances, due to the desire to avoid both maternal sedation, and the procedure-related risk of accessing the fetal circulation. Research is needed into safe, efficacious methods of administering analgesia to the human fetus in utero.

Acknowledgements

Our work in this area is supported by the Henry Smith Charity, WellBeing, and the Women & Children's Welfare Fund. We acknowledge equipment support from the Children Nationwide Medical Research Fund.

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*1 Review for the European Journal of Obstetrics and Gynaecology and Reproductive Biology. Presented at `Invasive Fetal Diagnosis and Therapy in the Third Millennium', a Joint Eurofetus/National Institute of Child Health and Human Development Meeting.

Corresponding author. Tel.: +44-208-383-3190; fax: +44-208-748-6311; email: r.p.smith@ic.ac.uk

European Journal of Obstetrics & Gynecology and Reproductive Biology
SummaryPlus Not available here
Article
Journal Format-PDF Not available here

Volume 92, Issue 1

September 2000

Pages 161-165

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Volume 92, Issue 1		SummaryPlus Not available here
September 2000		Article
Pages 161-165		Journal Format-PDF not available here

European Journal of Obstetrics & Gynecology and Reproductive Biology		SummaryPlus Not available here Article Journal Format-PDF Not available here
Volume 92, Issue 1
September 2000
Pages 161-165