Adrenal Cortical Response to Circumcision in the Neonate

AN IMPORTANT role of the fetal adrenal cortex in the initiation or labor^1-4 and in maturation of the fetal lung^5,6 has been suggested by several authors. While there is presumptive clinical evidence that the fetus and newborn are able to respond to stress with increased output of adrenal cortical hormones,^7,8 the responsiveness of the hypotholamic-pituitary-adrenal axis has not been studied in infants during the first few hours of life. This study was designed to measure changes in plasma cortisol and cortisone resulting from circumcision during the first 6 hours of extrauterine life.

MATERIALS AND METHODS

Five normal newborn male infants delivered vaginally after the spontaneous onset of labor were selected for study, and appropriate informed consent was obtained. After stabilization in the newborn nursery for a brief period and before 6 hours of age, 0.6 ml of blood was obtained by heel stick utilizing a long point B-D microlance after routine alcohol skin preparation and air drying. Circumcision was then performed by the Gomco clamp technic. Blood was again obtained as described above at 20 minutes and 40 minutes after initiation of the circumcision procedure.

Method for determination of cortisol and cortisone

The blood samples were centrifuged, and serum was drawn off and stored at 4 C until assayed.

Cortisone and cortisol were measured as previously described⁹ except that corticoid binding serum was obtained from pooled chicken blood and the thin-layer chromatography step was eliminated.

RESULTS

Table 1 shows the results of cortisol determinations in this group of infants. Cortisone data are given in Table 2. Mean baseline levels for cortisol and cortisone, respectively, were 5.8 and 7.3 ug/100 ml. Twenty minutes after the initiation of the circumcision procedure the mean cortisol level had risen to 14.7 ug/100 ml and the mean cortisone level had risen to 8.5ug/100 ml. Forty minutes after beginning the procedure the levels of cortisol remained significantly higher than baseline. Both the absolute and percentage rise in cortisone levels were of lesser magnitude than the rise in cortisol and, although consistent, did not achieve statistical significance in this small group of patients.

Table 1. Response of Plasma Cortisol to Circumcision in the Neonate.

Patient  Date  Age   Baseline   20 minutes     40 minutes
               (hr)             after          after
                                circumcision   circumcision
                                  (ug/100ml)
                       ---------------------------------
 NP    2/07/74  4       4.4        14.0            20.0
 NR    3/28/74  5      12.0        19.5            18.0
 WR    3/26/74  3       5.8        14.0            19.0
 WB   12/12/74  4       5.6        13.4             8.3
 CG   11/26/74  5       1.2        12.7            12.2
   Mean                 5.8        14.7            15.5
 SD                     3.9         2.7             5.0
                               t =  4.2        t =  3.4
                               P < .0025       P < .005

Table 2. Response of Plasma Cortisone to Circumcision in the Neonate

Patient  Date  Age   Baseline   20 minutes     40 minutes
               (hr)             after          after
                                circumcision   circumcision
                                    (ug/100ml)
                       ---------------------------------
 NP    2/07/74  4       7.5         8.5            10.1
 NR    3/28/74  5       6.5         7.5             9.0
 WR    3/26/74  3       8.7        10.1             8.8
 WB   12/12/74  4       8.3         7.9             9.0
 CG   11/26/74  5       5.3         8.7             5.9
   Mean                 7.3         8.5             8.5
 SD                     1.38        0.99            1.5
                                t = 1.68        t = 1.37
                                P >  .05        P >  .1

DISCUSSION

Liggins and Howie in 1972, reported on a large controlled series of premature infants whose mothers had been treated with betamethasone. There was a significant reduction in the incidence of respiratory distress syndrome in the infants of patients treated as long as 24 hours before delivery and whose infants were less than 32 weeks gestational age.⁵ Bauer et al showed a decreased incidence of the respiratory distress syndrome and increased cord blood cortisol levels in premature infants whose membranes had been ruptured longer than 16 hours. They suggested that the rise in cortisol level and resulting maturation of the fetal lungs were due to fetal stress.⁸ However, Jones et al, in a much larger study, were unable to show any beneficial effect of premature rupture of the membranes; specifically, there was no reduction in the incidence of the respiratory distress syndrome after prolonged premature rupture of the membranes.¹⁰

Anders et al studied plasma cortisol levels in various behavior states in infants from 1 to 15 weeks of life, and showed that there was a marked rise in plasma cortisol levels after 20 minutes of crying.⁷ More recently Tennes and Carter confirmed that cortisol levels were higher in crying infants than sleeping infants but found that babies circumcised in the 24 hours preceeding study had no significant elevation of plasma corticoids.¹¹

Infants suffering from the respiratory distress syndrome have higher levels of plasma cortisol than do those infants at the same gestational age without the respiratory distress syndrome.¹² However, if cortisol levels are studied at birth prior to the development of respiratory distress syndrome, those infants destined to develop respiratory distress syndrome have a lower level of plasma cortisol than those infants who will retain normal respiratory function.⁶ These data have been interpreted to indicate that cortisol participates in the maturation of the fetal lungs and the initiation of surfactin production and that those infants with low cortisol levels are, therefore more susceptible to development of respiratory distress syndrome.

Several studies have shown higher levels of cortisol and cortisone in the fetal circulation in patients delivered by cesarean section.^2,13 It has been suggested by some investigators that the increased cortisol levels in fetal circulation following labor may be at least partially due to the fetal stress induced by labor.^9,13 However it is equally plausible that part of the cause for increased levels may result from a prelabor surge of cortisol similar to that demonstrated in the sheep by Bassett et al¹ and suggested in the human by Murphy.⁴

While there is substantial body of clinical evidence that the fetus and neonate can respond to stress with increased output of adrenal corticoids,^7,8,11 to our knowledge this is the first study documenting such a response in the first 6 hours of life. During and following circumcision there was an immediate and consistent rise in both cortisol and cortisone levels, the former achieving greater statistical significance. Both the absolute and percentage rise in the cortisol level were greater than the rise in cortisone level, findings consistent with the data reported by Hillman and Giroud in 1965.¹⁴ These investigators stimulated newborns during the first 3 days of life with 5 IU of ACTH and showed a rise in plasma cortisol from a mean of 5.9 to 25.9ug/100 ml, along with a smaller but significant rise in the plasma cortisone level. This study documents similar changes resulting from circumcision, presumably in response to endogenous ACTH.

This study does not purport to answer the question of whether the elevated levels of cortisol and cortisone following vaginal delivery are a fetal response to the stress of labor as suggested by Pokoly¹³ or are a reflection of a prelabor surge of cortisol as suggested by others.^2,4 However, the data do suggest that the hypothalamic-pituitary-adrenal axis is responsive to the stress of circumcision during the first six hours of life.

Address reprint requests to:
Luther M. Talbert, MD
Department of Obstetrics and Gynecology
The University of North Carolina
School of Medicine
Chapel Hill, NC 27514

Submitted for publication December 1, 1975.
Accepted for publication February 10, 1976.

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