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PROFESSOR MARIE-LAURE RAFFIN-SANSON (Orcid ID : 0000-0001-5872-4544)
Article type : Original Article
Fetal exposure to mitotane/Op’DDD: post-natal study of four children.
Dimitra Magkou1, Christine Do Cao2, Claire Bouvattier’ Claire Douillard2 Capucine de Marcellus1,4, Laure Cazabat1,4,5, Maxime Gérard’, Marie-Laure Raffin-Sanson1,4,5 *, Jacques Young 7,8 *
1 Department of Endocrinology and Nutrition, Centre Hospitalier Universitaire Ambroise Paré, Assistance Publique-Hôpitaux de Paris , Boulogne Billancourt, France
2 Department of Endocrinology Centre Hospitalier Universitaire de Lille, Lille, France
3 Université Paris Sud, Assistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Department of Pediatrics, Le Kremlin Bicêtre, France.
4 INSERM U1173, Université de Versailles Saint-Quentin-en-Yvelines Montigny-le-bretonneux, France
5 French Adrenal Cancer Network (COMETE-Cancer) and FIRENDO Network
6 Department of Pediatrics, Centre Hospitalier Universitaire Ambroise Paré, AP-HP, Boulogne Billancourt, France
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/cen.13854
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7 Univ Paris Sud, Assistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Department of Reproductive Endocrinology, Le Kremlin Bicêtre, France.
8 INSERM U1185, Le Kremlin-Bicêtre, France
Correspondence:
Marie-Laure Raffin-Sanson MD, PHD Service d’Endocrinologie Nutrition, Hôpital Ambroise Paré, 9 Avenue Charles de Gaulle, 92100, Boulogne, France
Phone: +33 1 49095632, Fax: +33 1 49094627 Email: marie-laure.raffin-sanson@aphp.fr
Short title: Fetal exposure to mitotane: study of four children
Keywords: mitotane, pregnancy, fetus, adverse effects
*These two authors contributed equally to this article
Acknowledgements
We thank the patients and the clinical staff of the hospitals for their participation.
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Conflict of interest statement:
Nothing to declare
Funding:
Funding has been provided by Assistance Publique-Hôpitaux de Paris and French Adrenal Cancer Network COMETE and FIRENDO network funding
Summary
Objective: Mitotane/o,p’DDD is used in the treatment of adrenocortical carcinoma and for other causes of hypercortisolism. Mitotane inhibits cortisol secretion and displays adrenolytic and antitumor actions. This compound is a metabolite of the pesticide and endocrine disruptor DDT (Dichlorodiphenyltrichloroethane) and is classified among teratogenic compounds worldwide. However, little is known about its effects on human development.
Design: The outcome of four children exposed to mitotane during their intrauterine life was examined.
Patients: Patients having conceived while taking mitotane, or with detectable mitotane plasma levels, were retrospectively recruited via the French COMETE and FIRENDO networks.
Measurements: Mitotane in maternal plasma, adrenocortical hormones in children.
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Results: Three women treated with mitotane gave birth to four children. During early pregnancy, all patients had detectable mitotane plasma levels (0.9, 2.4 and 6.7 mg/L respectively). During pregnancy, no fetal malformations were detected. The four exposed newborns presented at birth with apparently normal adrenal function and genitalia. One twin female had a low birth weight. Evaluation at birth and after 3 months, 2 years and 7 years of follow-up showed no significant neurological abnormality. Evaluation of adrenocortical functions showed no cortisol deficiency.
Conclusions: Unexpectedly, exposure of these four children to mitotane during fetal life seemed to have no clear teratogenic effect- However, considering the sub-therapeutic mitotane concentrations used here, the small number of cases, and because long term follow- up is unknown, we strongly advise not to take mitotane during pregnancy and still recommend-avoiding pregnancy, at least as long as mitotane plasma levels remain detectable.
1. Introduction
Op’DDD [1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2-di-chloroethane] also called Mitotane (Lysodren; HRA Pharma, Paris, France) is a metabolite of the DDT pesticide (Dichloro Diphenyl Trichloroethane) and an isomer of its derivative, DDD (Dichloro Diphenyl Dichloroethane). Used since 1956 as a therapeutic agent, it still represents the first line drug therapy for advanced adrenocortical carcinoma (ACC) and is proposed as an adjuvant therapy after apparent complete resection of the primary tumor, especially in aggressive subtypes. 1,2 It is also used in ACTH- dependent hypercortisolism to control cortisol production prior to the surgical removal of the pituitary or when this surgery is not an option, while awaiting the effects of pituitary radiotherapy,3 in centers with an appropriate level of experience with mitotane and while closely monitoring drug levels.
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Mitotane exerts cytotoxic effects on the adrenal cortex and inhibits enzymes in the steroidogenic pathway thus suppressing cortisol production.4 Because of its cytolytic effects, adrenal insufficiency may persist after the elimination of the drug. Interference with gonadal function in both males and females is now established.5,6 Beside its effects on steroidogenic tissues, this molecule can also adversely affect central nervous system functions and can interfere with cholesterol and hepatic metabolism.7
Fetal exposure to mitotane, used as a therapeutic agent, may be a concern in ACC since this condition is more prevalent in women and may be diagnosed in patients during reproductive age. Although the general ACC prognosis is poor, some patients may become pregnant after the diagnosis of the tumor8, even if this occurrence is rare. Cushing’s disease, another indication of mitotane therapy for the control of hypercortisolism, is also more frequent in women. Although the disease is usually associated with reduced fertility, pregnancy is still possible, especially when good control of cortisol secretion can be achieved.9 Thus, a number of women receiving mitotane therapy may become pregnant.
The effect of mitotane on human fetal development is unknown. Warnings concerning possible adrenal disturbance in the exposed embryo are included in the safety data sheet provided to patients. Furthermore, the drug is classified worldwide among teratogenic compounds because of its close structural similarity to organochlorine pesticides (FDA Pregnancy Category D : https://www.cdc.gov/niosh/docs/2014-138/pdfs/2014-138_v3.pdf, Product Information Lysodren (mitotane), European Medicines Agency (EMEA) http://www.emea.europa.eu/).
Women becoming pregnant while being treated with mitotane may be advised by some experts to terminate the pregnancy. However, little is firmly established about the teratogenic or mutagenic effects of this drug. Firstly, no animal studies have been conducted to evaluate teratogenic effects and very few exposed pregnancies have been reported during the last 30 years, and the majority of these were interrupted before term (8, 10-14). Additionally, data is almost completely lacking concerning infants born after in utero exposure to mitotane. Only two live births under such conditions have been reported in the literature, as isolated case reports.10,12
The aim of this study was therefore to describe the outcomes of four children exposed to mitotane in utero.
2. Subjects and Methods
In this French retrospective study, we included data from files of three female patients exposed to mitotane during pregnancy. Relevant female patient data was extracted from databases of the French COMETE network, from the CRMR HYPO (Centre de Reference Maladies Rares de l’HYPOphyse) and the FIRENDO network databases. Children’s data was extracted from their medical files after informed consent by the parents.
For patients with ACC, pathological diagnosis and tumor stage were determined according to Weiss score and ENSAT staging system.15 Hormonal evaluation and assays were performed as previously described.3,16,17 In brief: Cortisol, Testosterone, Delta4Androstenedione, SDHEA, 17 OH Progesterone, and aldosterone were measured by RIA, ACTH by IRMA, active Renin by ECIA or RIA performed in the accredited (COFRAC; www.cofrac.fr) clinical endocrinology laboratory in each centre.
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Plasma mitotane levels were measured by the Lysosafe service provided by HPA Pharma using high performance liquid chromatography combined with ultraviolet detection (HPLC-UV) except for most of the mitotane measurements in patient 2 where mitotane plasma levels were also assayed using a high-performance liquid chromatography, using a slightly different method, in the Department of Biochemistry at Cochin Hospital. Briefly, samples were subjected to de-proteinization with cold acetone, and O,p- DDD levels were quantified using a diode-array detector with 1,1-dichloro, 2,2-bis (p-chlorophenyl) ethylene as an internal standard. The quantification limit with this assay is 0.5 mg/L. The inter- and intra-assay precision, expressed as coefficient of variation, were ≤ 20% for the Low Limit Of Quantification and ≤ 15 % for other levels. 18
The COMETE and FIRENDO Registries were approved by the Ethics Committees of the respective hospitals and by the French Commission Nationale Informatique et Liberté (CNIL). All patients gave informed consent. The study was registered at the Agence Nationale de Sécurité du Médicament under the number 2017-A03432-51 and approved by the Comité d’éthique pour les recherches comportementales et en santé (CERCES).
3. Results
Three pregnancies resulting in four mitotane-exposed children were reported. The clinical and hormonal data are summarized in Tables 1 and 2.
Case 1: A 20 year old female patient was diagnosed with Cushing’s disease caused by a corticotroph macroadenoma. Because of a bilateral invasion of the cavernous sinus, only a biopsy was performed to confirm diagnosis. Transsphenoidal debulking surgery was not proposed and conventional radiotherapy (52 Gray) was performed. Pending the effects of radiotherapy, and in order to control
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hypercortisolism, the patient received mitotane in association with oral estro-progestin contraception. A few weeks later, hormone replacement therapy by hydrocortisone was initiated. Two years after the diagnosis and eighteen months after initiation of mitotane therapy, repeated measures of urinary cortisol showed values below the upper limit of normal indicating control of hypercortisolism. However, while the patient was still under mitotane therapy (2 g/day), she interrupted the prescribed oral contraception, and a spontaneous pregnancy occurred. After being informed about the teratogenic risk of mitotane and the potential deleterious effect of this drug on the development of the embryo, the patient refused the offer of a medical termination of pregnancy and decided to continue the pregnancy to term. At that time, sonography revealed a twin pregnancy of four weeks of gestation while the mitotane plasma level was at 6.7 mg/L. Mitotane was discontinued but hydrocortisone replacement therapy was continued. In this patient, mitotane remained detectable throughout gestation (range: 2.7- 5.2 mg/L) but the pregnancy continued uneventfully and no relapse of the Cushing’s syndrome occurred. At 38 weeks and three days, she presented spontaneously in labour with a twin 1 breech presentation leading to an emergency caesarean section, giving birth to two female infants. Birthweights were 2180 g in twin 1 (C1) and 2550 g in twin 2 (C2) i.e. a slightly decreased birth weight in C1: (normal birth weight at 40 weeks for twin gestations: 2258 to 3790g). 19 APGAR was 10 at 1, 2, 5 and 10 minutes in the two infants. Clinical examination of both infants showed normal genitalia, no additional apparent abnormality at birth and 8 days post natally (Table 2). Weight gain was 27g (for C1) and 30 g (for C2) respectively at 8 days. Plasma mitotane levels were still measurable (1.7 mg/L) in maternal plasma at birth. However, the drug was not detectable in cord blood (Table 1). In both twins, serum cortisol levels were above the upper limit of normal range for age at birth (Table 2) and remain either slightly increased or in the normal range. At birth serum DHEA sulfate (DHEA-S) levels were in the normal range for age in C1 but decreased in C2. Gamma Glutamyl Transpeptidases (GGT) were over ten times the upper normal limit in both infants. Liver enzymes were normal or slightly elevated in C2. At postnatal day 8, DHEA-S levels were decreased in both twins (Table 2). At 16 months, the infants had met all their developmental milestones. Additional hormonal evaluations were then performed: at that time serum cortisol, ACTH and DHEAS levels were in the normal range for age (before adrenarche), and liver function tests in C1
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was normal (Table 2). At the last follow up visit the twin girls aged 7 years, had a normal physical examination with normal height (123 cm, +1SD for C1 and 120 cm (M) for C2, normal weight (25 kg, BMI 16 kg/m2 for C1 and 21 kg, BMI 14.6 kg/m2 for C2), Clinical examination was normal and a normal school curriculum was being followed. During the 9 years of follow up, the mother remained free of relapse.
Case 2:
A 25-year-old female patient presented with secondary amenorrhea since the age of 16 years old, hirsutism, polycythemia and abdominal pain. Abdominal CT Scan revealed a left adrenal 15 cm mass, heterogeneous, with baseline Hounsfield Unit density of 43 and no wash out after injection. Plasma DHEA-S was ten times above the upper limit of normal. No additional hormonal secretion was detected. The patient underwent surgical resection of the adrenal mass. An adrenocortical carcinoma (ACC) with a Weiss score of 6 and Ki-67 of 2-3% without extra-adrenal invasion was diagnosed. The tumor was RO and ENSAT Stage 2.15 Adjuvant mitotane treatment was started at a dose of 3 g/day together with progestin contraception. Plasma mitotane levels never reached the therapeutic target (maximal mitotane plasma level: 2.8 mg/L). Three months later, the treatment was interrupted because of hepatic cytolysis. The patient was advised to maintain contraception as well as hydrocortisone and fludrocortisone replacement therapy; however, she discontinued the prescribed oral contraception. Five months after mitotane discontinuation, a three months pregnancy was diagnosed. At that time, the mitotane plasma level was 0.9 mg/L (Table 1). DHEA-S plasma level was in the normal range. Abdominal sonography was normal. The patient was informed of the potential teratogenic effect of mitotane but decided to continue the pregnancy. No relapse of the ACC was detected during the pregnancy. At 39 weeks of pregnancy, the patient gave birth to a healthy female infant, with a birth weight of 3470 g, Apgar score of 4 and 7 at 1 and 5 minutes respectively, and no clinical sign of adrenal insufficiency (Table 2). External genitalia appeared normal. Pelvic and abdominal sonography showed a uterus of normal position and dimensions of 22 x 13 x 10 x 11 mm.
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The infant’s ovaries were of normal volume (0.4 and 0.6 cc) and contained six and two follicles respectively. Maternal plasma mitotane level at delivery and cord blood levels were below the quantification limit (Table 1). The baby was re-evaluated at 3 months. No clinical sign of adrenal insufficiency was detected. Physical examination revealed a normal weight of 6890 g and a head circumference of 40 cm both within the reference range.2º Neurological development was considered as normal with an alert and attentive infant visually tracking, showing a social smile and a normal posture and muscle tone. Furthermore, clinical examination confirmed normal feminine genitalia without clitoromegaly and A1P1S1 Tanner stage. Plasma sodium and potassium, GGT, liver enzymes, Cortisol, ACTH, Aldosterone and Renin were in the normal range for age (Table 1). One year after giving birth, the mother remained free of relapse.
Case 3:
Severe primary hyperaldosteronism was diagnosed in a 20-year-old woman with hypertension and a left adrenal mass. She underwent surgical resection of the tumor revealing an ACC measuring 3.3 x 2.3 x 1.2 cm in size. Pathological examination showed myxoid features, classified Weiss 3, Ki67:10%, ENSAT1, RO. Mitotane was prescribed as adjuvant therapy at the highest digestive tolerated dose of 2.5 g/day but plasma mitotane concentration remained below therapeutic range (2.5 mg/L). Progestin contraception was also prescribed. Five months after the beginning of mitotane treatment, the patient was diagnosed as pregnant. Mitotane was discontinued (at that time the plasma mitotane level was 2.4 mg/L). Informed about the potential teratogenic effects of mitotane on fetal development, the patient elected to continue the pregnancy. At 40 weeks of gestation, she delivered a healthy male infant, with a birth weight of 4450 g, by vaginal delivery (Birth Weight > 95th percentile). The immediate outcome was favourable with no clinical sign suggesting adrenal insufficiency, and an absence of cryptorchidism and hypospadias. Growth and neurological development of the boy have continued to be considered normal, by his paediatrician, at 3 years of age.
4. Discussion
To our knowledge, this is the first reported series describing post-natal outcome of children born after in utero exposure to mitotane. Only six previous mitotane-exposed pregnancies have been reported, essentially as isolated case reports and, in most cases, leading to interruption of the pregnancy 8,10-14 (Summarized in Table 3).
In one of these reported cases, the pregnancy was interrupted because of evolution of the aggressive ACC tumor in the mother. Two other pregnancies were medically terminated because of concerns about exposure of the fetus to potential teratogenicity of the drug. A twin pregnancy was interrupted by a spontaneous abortion. Finally, prior to the present work, only two live births of children exposed to mitotane during fetal life have been reported during the last 30 years.10,12 Interestingly, although being exposed to mitotane throughout pregnancy, the two male infants showed no evidence of adrenal insufficiency and no apparent malformation.
In the four infants reported here the short-term outcome was more favorable than expected with a term birth in all infants, normal birth weight in two, macrosomia in the baby boy and moderate hypotrophy in one of the twin girls. No apparent malformation was noted.
Prenatal exposure to the closely related compound DDT was associated with an increase in preterm births and a slight decrease in birth weight21,22 in humans. In all four children we described here, newborns displayed no clinical signs suggesting adrenal insufficiency. The integrity of adrenal function was confirmed in three of them, although elevated GGT levels could indicate a toxic effect of the drug on hepatic metabolism, as is observed in adult patients. In one of the twin girls, plasma DHEA-S levels were decreased at birth and at post-natal day 8. This suggests possible impairment of the secretory capacity of the fetal zone that produces neonatal DHEA-S. In adults,-mitotane is
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cytotoxic for adrenal cortical cells, leading to apoptosis and cellular necrosis4,23, that could result in a non-reversible chemical adrenalectomy. In line with this hypothesis, is one of the previously published cases in which pregnancy was interrupted at 6 weeks while the mother had been taking 1,5 g to 4 g/day of mitotane during the two previous years, and the fetal autopsy revealed an abnormal development of the primordial adrenal cortex”, suggesting that mitotane was also cytotoxic for the human fetal adrenal. The apparent discrepancy between this published report and our present observations may result from a difference in the plasma concentration or cumulative dose of mitotane.
The normal external genitalia observed in the boy that we report here, in agreement with previous male cases showing no micropenis, hypospadias or cryptorchidism, suggest that fetal Leydig cell steroidogenesis and testosterone secretion were preserved and that mitotane and/or its metabolites did not behave as an antiandrogen in the male fetus at the dose used here. Similarly, no morphological abnormality of external or internal reproductive organs was seen in the three girls reported here,-in spite of-the deleterious effect of this compound on gonadal endocrine functions that have been observed in adult patients of both sexes.5,24 This observation is unexpected given the reproductive toxicity of DDT that has been observed in male rats25 and suggested in humans.6 Pubertal development, long term fertility and development of offspring might be affected.
Cerebral toxicity and, consequently, neurological side effects have been observed in adult patients receiving high doses of mitotane.27 The related compound DDT can also provoke harmful effects on prenatal neurocognitive development.28,29 Remarkably, development of the children in this study has remained favorable, with follow-up of 3 years in the boy and 7 years in the two elder girls, showing all have had quite normal neurological outcomes, including following a normal school curriculum. This original and unexpected data is worth mentioning as no publication has previously reported the neurological outcome of an exposed child beyond 12 months. However, long-term cognitive performance of these children remains unknown.
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Mitotane is a lipophilic compound, predicted to cross the placental barrier as do the related compound p,p’DDD as well as other DDT derivatives.30 Near term, fetal tissues are likely to be exposed to a similar drug concentration as maternal tissues. This prediction was not supported by our data: in the twin pregnancy, plasma mitotane levels were undetectable in cord blood whereas maternal plasma levels were still readily detectable. Similar feto-maternal difference was observed by Tripto-Shkolnik et al. in a pregnancy interrupted at 21 weeks : mitotane was present in maternal blood and undetectable in cord blood. 4 Taken together, these results suggest that the placental barrier at least partly protects the fetal compartment from this toxic compound. In only one report, by Knappe et al., mitotane levels in cord blood and maternal blood were similar at term10, suggesting that in a minority of cases full transplacental transfer of mitotane may occur.
Although the data presented here are surprisingly reassuringone must keep in mind that the number of cases reported here is very limited and that the follow-up period remains very short, considering the long term expected effect of endocrine disruptors.
Although this is the largest series ever presented, a far greater number of pregnancies need to be studied before any conclusion could be drawn. Furthermore, plasma mitotane levels measured in these patients (0.9 to 6.7 mg/L) are far below therapeutic targets in ACC (14 to 20 mg/L). Higher maternal circulating levels could provoke more serious consequences on fetal development, adrenal organogenesis and/or on steroidogenic functions. Above all, long-term follow up is necessary. Concerning gonadal function, animal studies suggest that the effects of environmental chemicals, including DDT, may not be detected until puberty or even later in life.31 Among expected side effects, consequences on male reproductive organs resulting from impaired testosterone exposure will manifest themselves only in adulthood. Similarly, a long follow-up is warranted to evaluate possible consequences of early ovarian exposure to the drug on female reproductive health.
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In conclusion, we report here the first series of children exposed to mitotane in utero and the first description of female infants in this condition. Although the outcome of these four children was unexpectedly favourable in the short and middle term, it should be stressed that complete uncertainty remains about the long-term development of these children. Moreover, the limited number of exposed pregnancies prevents us from drawing any firm conclusion. Thus, we strongly recommend maintaining effective contraception in patients under mitotane therapy, at least until complete clearance of the drug from plasma is confirmed.
Author contributions,
All authors were involved in care either of the children or of their mothers. DM, JY and MLRS were responsible for data collection and wrote the manuscript. All authors approved the manuscript.
References
. Terzolo M, Angeli A, Fassnacht M, et al. Adjuvant mitotane treatment for adrenocortical carcinoma. The New England Journal of Medicine 2007; 356:2372-2380. doi:10.1056/NEJMoa063360
2. Fassnacht M, Libé R, Kroiss M, Allolio B. Adrenocortical carcinoma: a clinician’s update. Nature Reviews. Endocrinology 2011; 7:323-335. doi:10.1038/nrendo.2010.235
3. Arnaldi G, Trementino L. Update on Hypercortisolism Therapy. Frontiers of Hormone Research 2016;46:87-105. doi:10.1159/000443869
4. Hescot S, Slama A, Lombès A, et al. Mitotane alters mitochondrial respiratory chain activity by inducing cytochrome c oxidase defect in human adrenocortical cells. Endocrine-Related Cancer. 2013; 20(3):371-81. doi: 10.1530/ERC-12-0368
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5. Kerkhofs TM, Baudin E, Terzolo M, et al. Comparison of two mitotane starting dose regimens in patients with advanced adrenocortical carcinoma. The Journal of Clinical Endocrinology and Metabolism. 2013; 98:4759-4767. doi:10.1210/jc.2013-2281
6. Salenave S, Bernard V, Cao C Do, et al. Ovarian macrocysts and gonadotrope-ovarian axis disruption in premenopausal women receiving mitotane for adrenocortical carcinoma or Cushing’s disease. European Journal of Endocrinology. 2015; 172:141-149. doi:10.1530/EJE- 14-0670
7. Donadille B, Groussin L, Waintrop C, et al. Management of Cushing’s syndrome due to ectopic adrenocorticotropin secretion with 1,ortho-1, para’-dichloro-diphenyl-dichloro-ethane: findings in 23 patients from a single center. The Journal of Clinical Endocrinology and Metabolism. 2010; 95:537-544. doi:10.1210/jc.2009-1317
8. Corbière P de, Ritzel K, Cazabat L, et al. Pregnancy in Women Previously Treated for an Adrenocortical Carcinoma. The Journal of Clinical Endocrinology and Metabolism. 2015; 100:4604-4611. doi:10.1210/jc.2015-2341
9. Lindsay JR, Jonklaas J, Oldfield EH, Nieman LK. Cushing’s syndrome during pregnancy: personal experience and review of the literature. The Journal of Clinical Endocrinology and Metabolism. 2005; 90:3077-3083. doi:10.1210/jc.2004-2361
10. Knappe G, Gerl H, Ventz M, & Rohde W. [The long-term therapy of hypothalamic-hypophyseal Cushing’s syndrome with mitotane (o,p’-DDD)]. Deutsche Medizinische Wochenschrift.1997; 122: 882-886. doi:10.1055/s-2008-1047704
11. Leiba S, Weinstein R, Shindel B, et al. The protracted effect of o,p’-DDD in Cushing’s disease and its impact on adrenal morphogenesis of young human embryo. Annales D’endocrinologie. 1989; 50:49-53.
12. Kojori F, Cronin CMG, Salamon E, Burym C, Sellers EAC. Normal adrenal function in an infant following a pregnancy complicated by maternal adrenal cortical carcinoma and mitotane exposure. Journal of pediatric endocrinology & metabolism: JPEM. 2011; 24:203-204. doi:10.1515/jpem.2011.123
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13. Baszko-Błaszyk D, Ochmańska K, Waśko R, Sowiński J. Pregnancy in a patient with adrenocortical carcinoma during treatment with mitotane - a case report. Endokrynologia Polska. 2011; 62:186-188.
14. Tripto-Shkolnik L, Blumenfeld Z, Bronshtein M, Salmon A, Jaffe A. Pregnancy in a patient with adrenal carcinoma treated with mitotane: a case report and review of literature. The Journal of Clinical Endocrinology and Metabolism. 2013; 98:443-447. doi:10.1210/jc.2012-2839
15. Fassnacht M, Johanssen S, Quinkler M, et al. German Adrenocortical Carcinoma Registry Group, & European Network for the Study of Adrenal Tumors. Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification. Cancer. 2009; 115:243-250. doi:10.1002/cncr.24030
16. Abiven G, Coste J, Groussin L, et al. Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients. The Journal of Clinical Endocrinology and Metabolism. 2006; 91:2650-2655. doi:10.1210/jc.2005-2730
17. Bouvattier C, Esterle L, Renoult-Pierre P, et al. Clinical Outcome, Hormonal Status, Gonadotrope Axis, and Testicular Function in 219 Adult Men Born With Classic 21- Hydroxylase Deficiency. A French National Survey. The Journal of Clinical Endocrinology and Metabolism. 2015; 100(6):2303-13. doi: 10.1210/jc.2014-4124
18. Hermsen IG, Fassnacht M, Terzolo M, et al. Plasma concentrations of o,p’DDD, o,p’DDA, and o,p’DDE as predictors of tumor response to mitotane in adrenocortical carcinoma: results of a retrospective ENS@T multicenter study. The Journal of Clinical Endocrinology and Metabolism. 2011; 96(6):1844-51. doi: 10.1210/jc.2010-2676
19. Ananth CV, Vintzileos AM, Shen-Schwarz S, Smulian JC, Lai YL. Standards of birth weight in twin gestations stratified by placental chorionicity. Obstetrics and Gynecology. 1998 Jun; 91(6):917-24
20. WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards based on length/height, weight and age. Acta Paediatrica Supplement. 2006; 450:76-85
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21. Longnecker MP, Klebanoff MA, Zhou H, Brock JW. Association between maternal serum concentration of the DDT metabolite DDE and preterm and small-for-gestational-age babies at birth. Lancet 2001; 358:110-114. doi:10.1016/S0140-6736(01)05329-6
22. Guo H, Jin Y, Cheng Y, et al. Prenatal exposure to organochlorine pesticides and infant birth weight in China. Chemosphere. 2014; 110:1-7.doi:10.1016/j.chemosphere.2014.02.017
23. Bertagna X. Plasma concentrations of o,p’DDD, o,p’DDA, and o,p’DDE as predictors of tumor response to mitotane in adrenocortical carcinoma: results of a retrospective ENS@T multicenter study. European Journal of Endocrinology. 2018; 178(5):R183-R200. doi: 10.1530/EJE-18- 0062
24. Chortis V, Taylor AE, Schneider P, et al. Mitotane therapy in adrenocortical cancer induces CYP3A4 and inhibits 5a-reductase, explaining the need for personalized glucocorticoid and androgen replacement. The Journal of Clinical Endocrinology and Metabolism. 2013; 98:161- 171. doi:10.1210/jc.2012-2851
25. Rhouma K Ben, Tébourbi O, Krichah R, Sakly M. Reproductive toxicity of DDT in adult male rats. Human & Experimental Toxicology. 2001; 20:393-397. doi:10.1191/096032701682692946
26. Thankamony A, Pasterski V, Ong KK, Acerini CL, Hughes IA. Anogenital distance as a marker of androgen exposure in humans. Andrology. 2016; 4:616-625. doi:10.1111/andr.12156
27. Daffara F, Francia S De, Reimondo G, et al. Prospective evaluation of mitotane toxicity in adrenocortical cancer patients treated adjuvantly. Endocrine-Related Cancer. 2008; 15:1043- 1053. doi:10.1677/ERC-08-0103
28. Bornman MS, Pretorius E, Marx J, Smit E, Merwe CF van der. Ultrastructural effects of DDT, DDD, and DDE on neural cells of the chicken embryo model. Environmental Toxicology. 2007; 22:328-336. doi:10.1002/tox.20261
29. Torres-Sánchez L, Rothenberg SJ, Schnaas L, et al. In utero p,p’-DDE exposure and infant neurodevelopment: a perinatal cohort in Mexico. Environmental Health Perspectives. 2007; 115:435-439. doi:10.1289/ehp.9566
30. Sapbamrer R, Prapamontol T, Prakobvitayakit O, Vaneesorn Y, Mangklabruks A, Hock B. Placental transfer of DDT in mother-infant pairs from Northern Thailand. Journal of
Environmental Science and Health. Part. B, Pesticides, Food Contaminants, and Agricultural Wastes. 2008; 43:484-489. doi:10.1080/03601230802174615
31. Gray LE, Ostby J. Effects of pesticides and toxic substances on behavioral and morphological reproductive development: endocrine versus nonendocrine mechanisms. Toxicology and Industrial Health. 1998; 14:159-184. doi:10.1177/074823379801400111
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| cle | Indication | MMP at conception (mg/L) | Term of mitotane arrest | Delivery and Term (weeks of gestation) | MMP at term | Mitotane in cord blood | Birth weight | Sex | APGAR Clinical exam at birth |
|---|---|---|---|---|---|---|---|---|---|
| (mg/L) | (mg/L) | (g) | |||||||
| P1-C1 | CD | 6.7 | 6 weeks | 40 (CS) | 1.7 | Undetectable | 2180 | Female | 10/10 |
| Normal | |||||||||
| P1-C2 | CD | 6.7 | 6 weeks | 40 (CS) | 1.7 | Undetectable | 2550 | Female | 10/10 |
| Normal | |||||||||
| P2-C3 | ACC | 0.9 | 5 months | 39 (CS) | Undetect | Undetectabl | 3470 | Female | 4/10 (1') |
| before | able | e | 7/10 (5') | ||||||
| conception | Normal | ||||||||
| P2-C4 | ACC | 2.4 | 9 weeks | 40 (VD) | Not | Not Done | 4450 | Male | 10/10 |
| Done | Normal |
MMP: Mitotane in maternal plasma, CD: Cushing Disease, ACC: Adrenocortical Carcinoma, CS: caesarean section, VD: Vaginal Delivery
Accepted
ccepted Article
Table 2: Clinical, biological and hormonal evaluation of the children born after in utero mitotane exposure
| Age at evaluation | Appearance of external genitalia | Neurological development | Cortisol (nmol/L) | ACTH (pmol/L) | DHEA-S (nmol/L) | Renin (pmol/L) | Aldosterone (pmol/L) | GGT (IU/L) | ALT (IU/L) | AST (IU/L) |
|---|---|---|---|---|---|---|---|---|---|---|
| C1 1st day | Normal | Normal | 5959 | 21.8 | 3808 | 11.8 | ND | 360 | 8 (<34) | 29 |
| (47-386) | (11.8-32.2) | (2391-9674) | (0.17-9.7) | (7-35) | (<31) | |||||
| 8 days | Normal | Normal | 675 | 26 | 1042 | ND | ND | ND | ND | ND |
| (55-301) | (9.6-12.8) | (2391-9674) | ||||||||
| 16 months | Normal | Normal | 317 | 15 | 133 | 1.12 | ND | 11 | ND | ND |
| (82-497) | (<13) | (<1549) | (0.35-1.54) | (7-35) | ||||||
| 1st day | Normal | Normal | 458 | 22.9 | 1338 | 2.83 | ND | 480 (7- | 4 (<34) | 37 |
| (47-386) | (11.8-32.2) | (2391-9674) | (0.17-9.7) | 35) | (<31) | |||||
| 8 days | Normal | Normal | 750 | 30 | 768 | ND | ND | ND | ND | ND |
| (55-301) | (9.6-12.8) | (2391-9674) |
C2
ccepted. Article
C3
| 16 months | Normal | Normal | 254 | 6 | 478 | 0.66 | ND | ND | ND | ND |
|---|---|---|---|---|---|---|---|---|---|---|
| (82-578) | (<13) | (<1549) | (0.35-1.54) | |||||||
| 3 months | Normal | Normal | 114 | 7 | ND | 52 | 1291 | 19 | 26 | 35 |
| (77-633) | (<13) | (11-160) | (194-2493) | (<38) | (<34) | (<31) | ||||
| C4 2 years | Normal | Normal | ND | ND | ND | ND | ND | ND | ND | ND |
ACTH : Corticotropin, DHEA-S : Dehydroepiandrosterone sulphate, GGT : Gamma-glutamyl transpeptidase, ALT : Alanine transaminase, AST : Aspartate transaminase, ND: Not done.
ccepted Article
| Publication | Indication of mitotane | Dose of mitotane | Timing of mitotane | Mitotane Plasma level (mg/L) | Age of the | Pregnancy outcome | Birth weight | Sex | Adrenal function at birth | External genitalia | Neurological development |
|---|---|---|---|---|---|---|---|---|---|---|---|
| (mg/day) | arrest | mother | (g) | appearance | |||||||
| Leiba 1989 | CD | 1500 | 4 weeks | ND | 30 | Therapeutic | NA | Unknown | Dysmorphogenic | NA | NA |
| Abortion at 6 | primordial cortex at | ||||||||||
| weeks | autopsy | ||||||||||
| Knappe | CD | 1500 | Continued | During pregnancy: | 28 | Spontaneous | Normal | Male | Healthy Infant | Normal | Normal |
| 199710* | until 34w at | 3.9-4.7 | term delivery | High ACTH | |||||||
| 1000 mg/d | At delivery: 1.4 | at 38 weeks | Normal cortisol | ||||||||
| Cord blood: 1.4 | |||||||||||
| Kojori | ACC | 1000 | Continued | ND | 27 | HELLP | 1409 | Male | Apgar 6 at 10' | Normal | Normal |
| 201112 | ENSAT 4 | throughout | syndrome | (10th | (respiratory | ||||||
| pregnancy | Premature | percent) | distress) | ||||||||
| delivery/ CS | Normal ACTH and | ||||||||||
| at 32weeks | Cortisol | ||||||||||
| Ultrasound: normal | |||||||||||
| adrenals | |||||||||||
| Baszko- | ACC | Unknown | Continued | At conception: 12.5 | 26 | Twin pregnancy | NA | Unknown | NA | NA | NA |
| Błaszyk | ENSAT 2 | Spontaneous | |||||||||
| 201113 | abortion at 10 | ||||||||||
| weeks | |||||||||||
| Tripto- | ACC | 1500 | 6 weeks | At conception: 9.8 | 33 | Therapeutic | NA | Female | NA | Normal | NA |
| Shkolnik | ENSAT 4 | At 21w: 5.99 | Abortion at 21 | (ultrasound) | |||||||
| 201314 | Cord Blood: 0 | weeks | |||||||||
| De Corbiere | ACC | Unknown | Continued | ND | 39 | Therapeutic | NA | Unknown | NA | NA | NA |
| 20158 | ENSAT 2 | Abortion at 8 | |||||||||
| weeks |
ccepted Article
CD: Cushing Disease, ACC: Adrenocortical Carcinoma, ENSAT: ENSAT staging, NA: Not applicable, percent: percentile, ND: Not Determinated, ACTH : Corticotropine, HELLP: Hemolytic anemia, Elevated Liver enzymes and Low Platelet count, CS, cesarean section
*Also reported by Gerl et al (Gerl 1992)