Abstract
BACKGROUND:
Addison’s disease is an uncommon condition encountered during pregnancy; however, pregnant patients with Addison’s disease are at higher risk for multiple pregnancy related complications. Treatment during pregnancy involves steroid replacement therapy.
CASE REPORT:
A 34-year-old previously healthy G2P1001 presented with lethargy, skin hyperpigmentation, polyuria, and salt craving. Laboratory evaluation showed hyperkalemia, hyponatremia, elevated ACTH, and low cortisol. The patient terminated the pregnancy due to her symptoms. She was then placed on a regimen of hydrocortisone and fludrocortisone, leading to symptom resolution. On second presentation as a G5P1031, her Addison’s disease was managed with hydrocortisone and fludrocortisone. When Addison’s symptoms recurred, ACTH levels were checked to determine if her current medications could be optimized. She ultimately delivered a healthy male infant vaginally. For her third presentation as a G6P2032, her pregnancy was managed in a similar manner to the previous pregnancy.
CONCLUSION:
There is currently minimal cohesive literature on the management of Addison’s disease during pregnancy. Patients can be managed successfully by monitoring for recurrence of Addison’s symptoms and adjusting medication dosing as needed.
Background
Addison’s disease occurs when greater than 90 percent of the adrenal gland is destroyed. In developed countries, the most common etiology is autoimmune destruction [1]. Other causes include tuberculosis, granulomatous diseases, adrenal hemorrhage, and tumor metastases to the adrenals [2–4].
Prevalence of Addison’s disease in pregnancy has been predicted to be approximately 5.5/100,000 [5]. Most symptoms arise due to a deficiency of adrenal-produced hormones. Patients may present during pregnancy with fatigue, weakness, nausea, and/or hyperpigmentation [6–8]. Other symptoms include craving salty foods, weight loss, orthostatic hypotension, and hyperemesis [7, 9]. Based upon published data of 100 pregnancies, if patients with Addison’s disease are adequately treated throughout pregnancy, the pregnancy can generally proceed normally [10]. Even in cases of undertreated Addison’s disease, the developing fetus may not experience compromise due to the inherent steroidogenic properties of the fetoplacental unit [10]. Other reports have shown that, in general, patients with Addison’s disease are at an increased risk for adverse outcomes, including preterm premature rupture of membranes, preterm delivery and fetal growth restriction [5]. While there does not appear to be literature on effects of overtreatment of pregnant patients with Addison’s disease, literature on chronic overtreatment of patients with adrenal insufficiency include concerns such as diabetes mellitus, dyslipidemia, hypertension, and bone fractures [11].
The best screening tool for Addison’s disease is an adrenocorticotrophic hormone (ACTH) stimulation test. A normal response results in a cortisol level greater than 18 ug/dL after ACTH administration. Primary adrenal insufficiency would show elevated plasma ACTH, low cortisol levels, and low aldosterone levels [2]. During pregnancy, cortisol levels are normally increased; therefore, having low cortisol in pregnancy warrants an ACTH stimulation test [3].
Case
The patient, on initial presentation, was described as a 34-year-old G2P1001 with lethargy, hyperpigmentation, polyuria, and salt craving with elevated potassium and low sodium. Her ACTH was elevated to 12,034 pg/mL (reference range 7.2–63.3 pg/mL per outpatient laboratory service) with a cortisol 1.6 mcg/dL (reference range 6–23 mcg/dL per outpatient laboratory service). Computed tomography (CT) scan of her chest and abdomen showed atrophied adrenal glands, while magnetic resonance imaging (MRI) scan of the pituitary gland was normal. Adrenal antibodies were negative. She was diagnosed with Addison’s disease. She had a first trimester missed abortion. Following the abortion, her symptoms resolved on steroid replacement including hydrocortisone in the morning (10 mg), afternoon (5 mg) and evening (5 mg), as well as daily fludrocortisone (0.1 mg).
As a 36-year-old G5P1031, she was treated with hydrocortisone (25 mg) daily and fludrocortisone (0.1 mg) daily. At 11 weeks gestation, she was weak and tired at the end of the day; lab results showed an elevated ACTH (138 pg/mL; reference range 7.2–63.3 pg/mL); prednisone was increased. She continued to have fatigue through week 13, however by week 22 her fatigue had resolved. At 37 weeks 2 days, she had a nonstress test (NST) for advanced maternal age. She underwent an induction of labor due to fetal heart rate deceleration on NST. She vaginally delivered a healthy male infant. During the postpartum period, she was treated with low molecular weight heparin due to Factor V Leiden heterozygosity and MTHFR homozygosity.
When the patient presented as a 39-year-old G6P2032, she was on hydrocortisone (30 mg) and fludrocortisone (0.1 mg). At 36 weeks, hydrocortisone was increased. She delivered precipitously at 39 weeks gestation. She was given stress dose steroids and low molecular weight heparin in the postpartum period.
As a 42-year-old G7P3033, she received hydrocortisone up to 25 mg every morning and 20 mg every evening. During labor, she received stress doses of steroids. She vaginally delivered a healthy male infant at term. During the postpartum period, she received low molecular weight heparin.
Discussion
This case describes a patient diagnosed with Addison’s disease during pregnancy. There are no current practice guidelines published by organizations like the Society for Maternal Fetal Medicine or the American College of Obstetricians and Gynecologists outlining a standard of care for these patients. Below, we review the current literature for the management of pregnant patients with Addison’s disease.
During pregnancy, estrogen induces the liver to produce increased levels of corticosteroid-binding globulin, and total serum cortisol increases [12]. Treatment for Addison’s disease in non-pregnant individuals includes hydrocortisone and mineralocorticoid supplementation [2]. The primary goals for treatment of adrenal insufficiency are to adequately control the patient’s symptoms and to prevent adrenal crisis [2]. Monitoring pregnant patients on steroid replacement is difficult because side effects of over- and under-prescribing the medication are common symptoms seen during a normal pregnancy. A patient taking too much hydrocortisone may experience weight gain, develop violaceous stretch marks, and is at risk for gestational diabetes. A patient with too little hydrocortisone may experience fatigue and nausea, and is at risk for adrenal crisis [12].
First and second trimesters
Hydrocortisone is digested by a placental enzyme and cannot cross the placental barrier, making it the glucocorticoid treatment of choice in pregnant patients with Addison’s disease [10, 12]. Normally, a daily dose of hydrocortisone is 20 to 25 mg split into two to three doses. To mimic physiologic cortisol release, 50 to 75 percent of the total daily dose is administered after waking.
Case reports have shown multiple dosing strategies, such as (1) 20 mg of hydrocortisone every morning and 10 mg hydrocortisone every evening, (2) 12.5 mg of cortisone daily, (3) 25 mg of cortisone daily, and (4) body surface dosing of 12–15 mg/m2 [7, 15]. Timing of the medications can be changed to prevent symptoms of nausea [13]. Fludrocortisone replacement ranges from 0.05 to 0.25 mg daily and is usually continued at the same dose throughout pregnancy [12].
Third trimester
Patients nearing the end of their pregnancy should be treated with respect to the high levels of progesterone which has anti-mineralocorticoid properties [12–14]. During the third trimester, daily hydrocortisone doses can be increased 20 to 40 percent. Additionally, the fetus and placenta are not able to produce adequate steroids to act as replacement therapy during the third trimester, as seen in an article where cortisone was withheld at 34 weeks and addisonian symptoms resumed [14]. Treatment dosage of fludrocortisone may increase to 500 ug/day [12]. However, a study by Oliveria and colleagues reported that fludrocortisone dosing adjustment may not be necessary given the increase in hydrocortisone dosing during the third trimester [16]. Free cortisol levels rise; therefore, hydrocortisone is increased by 2.5 or 10 mg daily [12].
Antenatal surveillance
Currently, there is limited literature for proposed antenatal surveillance during pregnancy for patients with Addison’s disease. In the case of this patient, we performed serial growth ultrasounds and initiated antenatal surveillance at 36 weeks gestation for concomitant conditions, including thrombophilia and advanced maternal age.
Delivery
Cortisol treatment should be increased to stress doses during labor, delivery and postpartum which can reach 300 mg hydrocortisone [3, 4]. Typically, hydrocortisone 100 mg is given every eight hours [3]. In a review posted by Lekarev and New, they suggest an additional management plans including (1) doubling the oral dose of hydrocortisone, or (2) 50 mg of parenteral hydrocortisone given during the second stage of labor [10].
Considerations for breastfeeding patients
Hydrocortisone can be used for patients who plan on breastfeeding given the low excretion of hydrocortisone into breastmilk. The overall excretion of hydrocortisone into breastmilk is 0.5% per dose per liter of breastmilk [10].
Conclusion
This case report outlines successful pregnancy and delivery of a patient with concomitant Addison’s disease. Due to the increased likelihood of adverse outcomes in patients with Addison’s disease, it is essential that either a diagnosis is made prior to conception so the disease can be properly managed, or that Addison’s disease is kept in the differential diagnosis, as many addisonian symptoms mimic pregnancy. Proper management of the disease is best achieved through communication with the patient’s endocrinologist and obstetrician, both through pregnancy and postpartum. Management of Addison’s disease requires regular monitoring of electrolytes, cortisol, and ACTH, as well as making the necessary adjustments in the pharmacologic regimen [17]. In addition, due to the increased likelihood of adverse outcomes associated with Addisonian pregnancies, tertiary care centers with multidisciplinary teams should be utilized for antepartum care [5].
Financial disclosures
The authors of this paper have no financial disclosures.
Footnotes
Acknowledgments
We would like to thank The George Washington University School of Medicine and Health Sciences for supporting our researching and the patient for providing permission for publication.