Normal adrenal function in an infant following a pregnancy complicated by maternal adrenal cortical carcinoma and mitotane exposure
Fatemeh Kojori1, Catherine M.G. Cronin1, Elizabeth Salamon2, Craig Burym3 and Elizabeth Ann Cameron Sellers1,*
1 Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
2 Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
3 Department of Obstetrics and Gynecology, University of Manitoba, Winnipeg, Manitoba, Canada
Abstract
Maternal adrenal cortical carcinoma in pregnancy is rare. We report a case of an infant born to a mother with a history of adrenal cortical carcinoma. The pregnancy was complicated by fetal exposure to mitotane and dexamethasone. Despite the potential teratogenic exposures, there was no evidence of adrenal dysfunction in the infant. Growth and development at 12 months of age are normal and prognosis appears favor- able. The long-term impact of fetal exposure to mitotane and glucocorticoid requires further investigation.
Keywords: adrenal cortical carcinoma; adrenal function; dexamethasone; fetus; mitotane; newborn; pregnancy.
Introduction
The incidence of adrenocortical carcinoma is 1-2 per million annually (1). Pregnancy in women with adrenocortical carci- noma is extremely rare (1, 2). The principal chemotherapeutic agent for its treatment is mitotane (o,p-DDD, or 1,1-dichloro- 2-[o-chlorophenyl]-2-[p-chlorophenyl] ethane). Mitotane is an adrenocortical toxin causing atrophic changes in the zona fasiculata and reticularis (3). Mitotane crosses the placenta (4). The teratogenic effects on the developing adrenal are unknown. Dexamethasone, which crosses the placenta, may suppress the fetal hypothalamic-pituitary-adrenal axis. The effects of concurrent use of mitotane and dexamethasone on the fetus are unknown.
Patient presentation
Maternal history: at age 24, the mother was diagnosed with adrenocortical carcinoma with pulmonary metastases. The primary malignancy was treated with right adrenalectomy and multiple pulmonary nodules were resected. Mitotane, 1000 mg daily, was given to suppress her adrenal cortex. She also received glucocorticoid and mineralocorticoid replace- ment therapy (hydrocortisone 10 mg and fludrocortisone 0.5 mg once daily). At age 27, she became pregnant while on mitotane and adrenal replacement therapy. The parents elected to continue the pregnancy, understanding that the effects of mitotane on the developing fetus are largely unknown.
At 17 weeks gestation, maternal hydrocortisone was stopped. Dexamethasone, 4 mg daily, was started in an attempt to protect the fetal adrenal glands from the potentially toxic effects of mitotane. Fetal ultrasound at 29 weeks gestation demonstrated normal fetal growth but suggested hypoplastic adrenal glands. No other anomalies were noted.
At 29 weeks gestation the mother developed epigastric pain. Mild elevations of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) were noted. Biliary colic was suspected and treated conservatively. At 31 weeks gestation, a maternal ultrasound demonstrated gallstones but no acute cholecystitis. She was admitted to hospital for further evaluation.
A significant elevation in AST (156 U/L, normal 0-32 U/L), ALT (190 U/L, normal 0-25 U/L), GGT (217 U/L, nor- mal 5-29 U/L) and a decreased platelet count of 106×109/L (106×103/uL), consistent with HELLP syndrome (Hemolytic anemia, Elevated Liver enzymes and Low Platelet count) was noted. She was normotensive. There was no proteinuria. A hypertensive response was thought to be masked by suppres- sion of endogenous steroid production. The mother received two doses of betamethasone to enhance fetal lung maturity. The maternal condition continued to deteriorate prompting the decision to proceed with delivery. A male infant was delivered breech by cesarean section at a gestation of 31 weeks 6 days.
Birth weight was 1409 g (10th percentile), length 45 cm (90th percentile) and head circumference 28.5 cm (50th per- centile). Apgar scores were 3, 5 and 6 at 1, 5 and 10 min, respectively. Newborn examination revealed no anomalies and no hyperpigmentation. Blood pressure, heart rate, and temperature were normal.
Nasal CPAP was started for respiratory distress. The infant was intubated at 2 h of age for administration of surfactant. He was extubated to nasal CPAP on day 2. There was no hypoglycemia.
| 6 h | 12 h | 24 h | 48 h | 72 h | |
|---|---|---|---|---|---|
| Cortisol range 55-304 nmol/L [20-110 µg/L] | 135 [50] | 283 [103] | 271 [98] | 360 [131] | 304 [110] |
| ACTH range | 2.8 [12.7] | 2.9 [13.2] | – | – | |
| 0-10 pmol/L [0-45.4 pg/L] | 9.9 [45.0] |
Cortisol levels were measured at 6, 12, 24, 48 and 72 h and ACTH levels at 6, 12, 24 h (Table 1). Electrolytes were monitored every 12 h. Initial serum sodium was 143 nmol/L (normal 135-145 mmol/L) (143 mEq/L; normal 135-145 mEq/L) and potassium was 4.4 mmol/L (normal 3.0-7.0 mmol/L) (4.4 mEq/L; normal 3.0-7.0 mEq/L) and remained normal. An abdominal ultrasound on day 4 demonstrated normal adrenal size and appearance. An ACTH stimulation test was performed at 1 month of age prior to discharge. Cortisol was 190 nmol/L (68.9 ug/L) at baseline and rose to 1031 nmol/L (373.7 µg/L) at 60 min (normal: peak cor- tisol level >550 nmol/L [199.3 ug/L]). Baseline ACTH was 6.3 pmol/L (28.6 pg/L) (normal 0-10 pmol/L [0-45.4 pg/L]).
At 3 months of age, he had normal development and growth (weight 6.02 kg [75-90th percentile], length 59.2 cm [75th percentile], and head circumference of 41 cm [50th percen- tile]). At 12 months of age, growth and development continued to be normal (weight 8.86 kg [10th percentile], length 76.2 cm [50th percentile], and head circumference 49 cm [97th percen- tile]). The mother’s carcinoma recurred shortly after delivery. She continues to be actively treated for her recurrence.
Discussion
Despite exposure to mitotane and dexamethasone in utero, this infant had no evidence of adrenal dysfunction. There is one report of a patient with Cushing disease who became pregnant while on mitotane and who underwent a therapeutic abortion because of possible embryotoxicity of this drug (4). Histopathological examination of the embryo (aged 42 days) revealed a dysmorphogenetic event in the cortical primor- dium (4). Mitotane may affect the viability of the migrat- ing sympathoblasts in the developing cortex (3). In our case, ultrasound in the newborn period demonstrated normal adre- nal structure. Transgenerational effects of mitotane have been observed in rats: a reduction in reproductive capacity. An increase in neonatal mortality was seen in the offspring of rats exposed in utero to large doses of mitotane (5).
By mid gestation, maternal cortisol is transmitted into the fetal circulation, exerting feedback on the fetal hypothalamic- pituitary-adrenal (HPA) axis suppressing fetal cortisol pro- duction (6). During the third trimester, as placental metabolic activity matures, less maternal cortisol reaches the fetus, resulting in increased fetal ACTH and cortisol production (6). Administration of dexamethasone to the mother suppresses the fetal HPA axis which may result in an Addisonian presen- tation in the newborn. In our case, the HPA functioned nor- mally. This may be related to the enzyme 11ß-hydroxysteroid
dehydrogenase type 2 (11ß-HSD2). 11ß-HSD2 is responsible for oxidizing cortisol to the biologically inactive cortisone, and it is the primary regulator of fetal exposure to maternal cortisol. It is possible that 11ß-HSD2 is more active in fetuses exposed to increased maternal glucocorticoid. The long- term effect of prenatal glucocorticoid exposure is unknown. Elevated blood pressure and glucose intolerance have been reported as possible long-term effects (6).
Conclusion
This is the first report of a successful pregnancy outcome after concurrent fetal exposure to mitotane and dexamethasone for maternal adrenal cortical carcinoma. Newborn surveillance and long-term follow-up of infants exposed to mitotane, with or without glucocorticoids, in utero, is indicated.
Acknowledgments
The authors acknowledge Dr. Heather Dean for critical review of the manuscript and are grateful to the family involved for their permis- sion to share this experience.
Conflict of interest statement
The authors have no conflicts of interest to declare related to this report.
References
1. Coonrod DV, Rizkallah TH. Virilizing adrenal carcinoma in a woman of reproductive age: a case presentation and literature review. Am J Obstet Gynecol 1995;172:1912-5.
2. White FA. Functioning adrenal cortical carcinoma in pregnancy. South Med J 1994;87:380-3.
3. Kaminsky N, Luse S, Hartroft P. Ultrastructure of adrenal cor- tex of the dog during treatment with DDD. J Natl Cancer Inst. 1962;29:127-59.
4. Leiba S, Weinstein R, Shindel B, Lapidot M, Stern E, et al. The protracted effet of o,p’-DDD in Cushing’s disease and its impact on adrenal morphogenesis of young human embryo. Ann Endocrinol 1989;50:49-53.
5. Clement JG, Okey AB. Reproduction in female rats born to DDT treated parents. Bull Environ Contam Toxicol 1974;12:373-7.
6. Clark PM. Programming of the hypothalamicuitary-adrenal axis and the fetal origins of adult disease hypothesis. Eur J Pediatr 1998;157(Suppl 1):S7-10.