MANAGEMENT OF ENDOCRINE DISEASE: Fertility, pregnancy and lactation in women with adrenal insufficiency

in European Journal of Endocrinology
View More View Less
  • 1 Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, UniversitätsSpital Zürich, Zürich, Switzerland
  • 2 Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany

Correspondence should be addressed to F Beuschlein; Email: felix.beuschlein@usz.ch

With the introduction of hormonal substitution therapy in the 1950s, adrenal insufficiency (AI) has been turned into a manageable disease in pregnant women. In fact, in the light of glucocorticoid replacement therapy and improved obstetric care, it is realistic to expect good maternal and fetal outcomes in patients with AI. However, there are still a number of challenges such as establishing the diagnosis of AI in pregnant women and optimizing the treatment of AI and related comorbidities prior to as well as during pregnancy. Clinical and biochemical diagnoses of a new-onset AI may be challenging because of overlapping symptoms of normal pregnancy as well as pregnancy-induced changes in cortisol values. Physiological changes occurring during pregnancy should be taken into account while adjusting the substitution therapy. The high proportion of reported adrenal crisis in pregnant women with AI highlights persistent problems in this particular clinical situation. Due to the rarity of the disease, there is no prospective data-guiding management of pregnancy in patients with known AI. The aim of this review is to summarize the maternal and fetal outcomes based on recently published case reports in patients with AI and to suggest a practical approach to diagnose and manage AI in pregnancy.

Abstract

With the introduction of hormonal substitution therapy in the 1950s, adrenal insufficiency (AI) has been turned into a manageable disease in pregnant women. In fact, in the light of glucocorticoid replacement therapy and improved obstetric care, it is realistic to expect good maternal and fetal outcomes in patients with AI. However, there are still a number of challenges such as establishing the diagnosis of AI in pregnant women and optimizing the treatment of AI and related comorbidities prior to as well as during pregnancy. Clinical and biochemical diagnoses of a new-onset AI may be challenging because of overlapping symptoms of normal pregnancy as well as pregnancy-induced changes in cortisol values. Physiological changes occurring during pregnancy should be taken into account while adjusting the substitution therapy. The high proportion of reported adrenal crisis in pregnant women with AI highlights persistent problems in this particular clinical situation. Due to the rarity of the disease, there is no prospective data-guiding management of pregnancy in patients with known AI. The aim of this review is to summarize the maternal and fetal outcomes based on recently published case reports in patients with AI and to suggest a practical approach to diagnose and manage AI in pregnancy.

Invited Author's profile

Felix Beuschlein is Professor of Internal Medicine/Endocrinology and Director of the Clinic for Endocrinology, Diabetology and Clinical Nutrition at the University Clinic Zurich in Switzerland. Following a professorship for Endocrine Research at the University of Munich, he has been elected to a chair position at the University of Zurich. His scientific interests mainly relate to adrenal disorders and endocrine tumors.

Background and epidemiology

Adrenal insufficiency (AI) can either be caused by destruction of the adrenal glands through different mechanisms with glucocorticoid, mineralocorticoid and/or androgen deficiencies (primary AI), or may occur as a result of dysfunction of the pituitary with adrenocorticotropic hormone (ACTH) deficiency (secondary AI) or of the hypothalamus with corticotropin-releasing hormone (CRH) deficiency (tertiary AI). In developed countries, autoimmune adrenalitis is the most common cause of primary AI, which may occur in isolation or as part of an autoimmune polyglandular syndrome (APS). APS type 2 is the most common form presented as a combination of Addison’s disease, thyroid autoimmune disease, type 1 diabetes and/or premature ovarian failure. Type 1 and type 4 APS may also present with primary AI. In developing countries, tuberculosis with the involvement of the adrenal glands is still more common than autoimmune adrenalitis as a cause of primary AI. Other causes include fungal infections, adrenal hemorrhage, metastases or infarction involving both adrenal glands. Congenital adrenal hyperplasia as another cause of primary AI will not be discussed in this review.

Prolonged exogenous glucocorticoid administration for various conditions (such as asthma, rheumatoid arthritis and inflammatory bowel disease, among others) is the most common cause of combined secondary and tertiary AIs due to impaired ACTH and CRH secretion. Other pregnancy-related causes of secondary AI are Sheehan’s syndrome (due to postpartum pituitary necrosis) and lymphocytic hypophysitis occurring preferentially in postpartum setting or in the last trimester. A structural disease of the pituitary as a cause of secondary AI is mostly known and treated before conception. Similarly, all patients with bilateral adrenalectomy due to Cushing syndrome (CS), or with unilateral adrenalectomy due to a benign or malignant adrenal tumor, and after cranial radiotherapy, most likely have an established endocrine follow-up and optimal glucocorticoid replacement therapy where needed.

Although AI is very rare in pregnancy, yet it can lead to significant maternal and fetal morbidities if the diagnosis is missed during pregnancy or in the puerperium. In fact, prior to the introduction of glucocorticoid replacement therapy, Addison’s disease was associated with a high maternal mortality (35–45%), so that women were strongly discouraged from becoming pregnant (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11). Modern glucocorticoid replacement therapy and improved obstetric care have both contributed immensely in reducing maternal as well as fetal morbidity and mortality. Nowadays, an uneventful pregnancy with good maternal and fetal outcomes can be expected in the majority of patients with known AI (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12).

The exact prevalence of AI in pregnancy is unknown. Schneiderman and coworkers reported the incidence of primary AI to be 1 in 3000 pregnancies in a population-based cohort study on 7.7 million births with an observed increase in prevalence of Addison’s disease from 5.6 per 100 000 in 2003 to 9.6 per 100 000 in 2011 (13). In the literature (as summarized in Table 1), the underlying reasons for AI in pregnant patients are evenly distributed between primary (44%) and secondary (45%) causes, which also defines the presence of potential hormonal comorbidities. The most commonly reported coexisting endocrine disorders are hypothyroidism (50%) and a few cases of type 1 diabetes, among others.

Table 1

Overview in clinical annotations in pregnant patients with adrenal insufficiency. A Pub-Med search was performed on published English and German written articles from 1976 onward using keywords such as adrenal insufficiency, lactation and infertility. A detailed review of literature citations provided further references. To ensure evaluation of cases in the context of modern treatment, only cases dating 1976 onward were considered for inclusion (8, 20, 26, 27, 28, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52). This search identified 28 cases of primary AI, a case series with 17 cases of treated adrenocortical carcinoma patients, out of which 7 were included as they were on hydrocortisone treatment following surgical treatment (51), a literature review of 27 patients with secondary AI (20) and a literature review of 21 cases of acute Sheehan’s syndrome (29).

ReferenceYearCountryPatients, nPregnancies, nPM/MPAgeTime of diagnosis of AI*Etiology of AI*Adrenal crisisTreatment*Other diseases*Mode of delivery*Outcome
MotherChild
(32)1976–1987Norway56n.a.19–45Before (3)PAI (5)Y (2/5)HC/FC (3) Cortisone (2)n.a.V (5), CS (1)Good (5)Good (6)
(33)1984Canada11MP31AfterPAIYHC/FCHPTCSGoodIUGR
(34)1984Italy11MP27BeforePAINCortisoneNoneVGoodGood
(35)1989Germany11n.a.29BeforePAIYHC/FCHPTVGoodGood
(28)1989South Africa12P235third TM (P1)PAIYHC/FCNoneVGood (2)P1: Stillbirth; P2: Good
(36)1992USA11P240Third TMPAIYPred/FCHPTCSGoodIUGR
(37)1993Germany11P230AfterPAIYGlucocorticoidsNoneCSGoodGood
(8)1997UK11MP44First TMPAIYHC/FCHPTVGoodGood
(38)1999Israel11P125AfterSAINHCn.a.CSGoodGood
(26)2001UK11P133First TMPAIYHCNonen.a.GoodDeath (Abortion)
(39)2003Turkey11P122first TMPAIYPredNoneCSGoodGood
(40)2003Czech Republic11P129BeforePAIYHC/FCT1D/HPTCSGoodGood
(41)2003Ireland11P128BeforePAINHC/FCNoneCSGoodGood
(42)2005Greece11P132BeforePAIYHC/FCHPTVGoodGood
(43)2005Italy11P134BeforePAIYHC/FCHPTCSGoodGood
(27)2008Argentina33n.a.22–36Before (2); first TM (1)PAI (3)Y (2/3)HC/FC (3)None (3)n.a.Good (3)Good (2)
(44)2009Italy11P136BeforePAINCortisone/FCNoneCSGoodGood
(20)20092731n.a.27–42Before (n = 27)SAI (27)n.a.n.a.n.a.n.a.GoodGood
(45)2010Finland11P121First TMPAIYHC/FCNoneVGoodGood
(46)2010Poland11P232Second TMPAIYHC/FCHPTCSGoodIUGR
(47)2011India11P334Second TMPAIYHC/FCNoneCSGoodGood
(48)2011Poland11P231Second TMPAIYHC/FCHPT, DIVGoodGood
(49)2012India11MP29Third TMPAIYPred/FCHPTVGoodGood
(50)2014Spain11P134BeforePAINHCT1DCSGoodGood
(51)2015ENSAT77n.a.n.a.Before (7)PO- ACC (7);n.a.HCn.a.n.a.Good (7)Good (7)
(29)2017Japan11P227After P1Sheehan/SAIn.a.HCPan-HPTVGoodGood
Total6470P1: 10/21 (47.6%);32 (19–45)Before: 47/62 (75.8%);PAI: 28/64 (44%);Y: 20/29 (69%);HC: 11/37 (29.7%);None: 12/24 (50%);V: 14/27 (51.9%);Good: 64/64 (100%)Good: 64/70 (91.4%);
P2: 6/21 (28.6%);first: 5/62 (0.08%);SAI: 29/64 (45%);N: 9/29 (31%)HC/FC: 18/37 (48.6%);HPT: 10/24 (41.7%);CS: 13/27 (48.1%)IUGR: 3/70 (0.04%);
P3: 1/21 (5%);second:, 3/62 (0.05%);PO- ACC: 7/64 (11%)other: 8/37 (21.6%)others: 4/24 (16.7%)stillbirth: 1/70 (0.01%);
MP: 4/21 (19%)third: 3/62 (0.05%);abortion: 1/70 (0.01%);
after: 4/62 (0.06%)neonatal death: 1/70 (0.01%)

*numbers within parentheses in these columns indicate n; ACC, adrenocortical carcinoma; CS, caesarian section; FC, fludrocortisone; good, alive; HC, hydrocortisone; IUGR, intrauterine growth retardation; PP, primipara; MP, multipara; n.a., not available/not applicable; Y, yes; N, no; PO-ACC, postoperative ACC; PAI, primary AI; P1, primipara; SAI, secondary AI; HPT, hypothyroidism; T1D, type 1 diabetes; TM, Trimester; Y, yes.

Effects of the feto–placental unit on steroid metabolism

The feto-placental unit is actively controlling the steroid milieu of the fetus. Additionally, it is responsible for various changes in the maternal hypothalamic pituitary adrenal (HPA) axis leading to a state of physiological hypercortisolism in pregnancy (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12).

In healthy pregnant women, total and free plasma cortisol, ACTH, CRH, cortisol-binding globulin (CBG) and urinary-free cortisol increase (13, 14, 15, 16). The placenta can itself produce biologically active CRH and ACTH stimulating the maternal pituitary and adrenal glands, respectively. CBG increases 3–4-fold following estrogen stimulation, thereby not only increasing the half-life of cortisol but also increasing total plasma cortisol values. Free cortisol increases by the 11th week of gestation. In contrast to CS, circadian rhythmicity is maintained throughout pregnancy implying an altered set point of the HPA axis and a relative tissue refractoriness to the effects of cortisol in pregnancy (13, 14, 15, 17).

Similarly, the activity of the renin–angiotensin–aldosterone system is increased by the 8th week of gestation. On the other hand, progesterone exerts anti-mineralocorticoid effects and results in a decrease in systemic vascular resistance. As a combined effect of these mechanisms, there is a net volume expansion during pregnancy (14).

Up to the 33rd week of gestation, 90–95% of fetal cortisol is derived from maternal adrenal secretion; thereafter, fetal adrenal cortisol production progressively increases with decreased maternal contribution. In cases of unrecognized maternal AI, transplacental passage of cortisol from the fetus to the mother might have a partial protective effect during the last trimester. On the other hand, the fetus is relatively protected from excessive hydrocortisone by the placental 11-β hydroxysteroid dehydrogenase 2 even in women receiving supra-physiological doses of glucocorticoid treatment (5).

Fertility and preconceptional considerations

In the majority of cases (75.8%; Table 1), AI is present and known well before pregnancy. Therefore, there are specific considerations to be taken into account before planning a pregnancy such as optimizing the glucocorticoid treatment and screening for comorbidities to optimize chances of conception. Erichsen and colleagues performed a survey in 269 females of the Norwegian Addison’s registry with 174 women (65%) participating in the survey. The author found a decreased standardized incidence ratio of 0.69 for birth (confidence interval, 0.52–0.86) as a proof of reduced fertility in females with Addison’s disease after excluding women with premature ovarian insufficiency (18). In untreated patients with primary AI, fertility can be reduced due to decreased generalized sense of well-being and reduced libido due to the lack of androgens among other mechanisms. Despite androgen depletion, impaired sexuality had not been reported in the mentioned study (18) and a common reason for sexual inactivity – the lack of a partner – has also to be considered.

Coexisting autoimmune disorders such as thyroid disease and premature ovarian insufficiency are other reasons for reduced fertility in patients with primary AI. Similarly, a common cause of reduced fertility in patients with pituitary disease is altered gonadotropin secretion. Overall, concomitant hormonal deficiencies should be addressed to enable conception in a patient with known AI as fertility may in fact be mainly reduced due to these hormonal deficits. For example, patients with complete loss of pituitary function need assistance of artificial reproductive techniques to conceive. These pregnancies are considered as high-risk (19, 20).

In addition to issues of fertility, a main focus of preconception endocrine counseling should be patient education regarding the need of treatment adjustment during gestation, especially during stress states. Also, the obstetrician should be informed regarding the need of adjustment of glucocorticoid dose in stress situations such as infections, hyperemesis and delivery. In fact, as discussed below, delivery can be considered as one of the most stressful situations, where use of an established protocol of parenteral stress dose glucocorticoid application could help in assuring optimal management.

Establishing the diagnosis of a new-onset AI during pregnancy

In general, the slowly progressive course of AI makes early diagnosis challenging. It is believed that more than 90% of the cells of adrenal cortex are destroyed before clinical manifestations of primary AI become apparent (21). Pregnancy can mirror some of the symptoms of AI and a biochemical diagnosis of a mild AI may be particularly challenging due to physiological state of hypercortisolism. Therefore, it is prudent to include AI in the differential diagnosis in patients presenting with excessive fatigue, malaise, weight loss, vomiting, dizziness, hyperpigmentation, abdominal pain and/or electrolyte disturbances. Clinical suspicion should be particularly high in patients with personal or family history of an autoimmune disease (16). In contrast to chloasma of pregnancy, hyperpigmentation of Addison’s disease involves non-exposed parts of skin/creases of hands, extensor surfaces and mucous membranes. Salt craving, hyponatremia with more than 5 mmol/L decrease in plasma sodium and metabolic acidosis are other specific clues for AI. As expected and according to the reviewed literature (Table 1), onset of AI within pregnancy accounts for only a minority of patients (17.7%) with even distribution over the duration of the pregnancy (first trimester; 8.1%, second trimester; 4.8% and third trimester; 4.8%, respectively).

Acute presentation can occur with adrenal crisis in stressful situations encountered in early pregnancy (hyperemesis gravidarum), infections during pregnancy/puerperium, operations or delivery (both vaginal and cesarean). In the case of severe AI, it is of utmost importance to initiate treatment with hydrocortisone before awaiting results of laboratory tests and testing can even be postponed until stabilization of the patient’s condition. In the event of obstetric hemorrhage where tachycardia and hypotension persist after adequate replacement of blood products, the possibility of acute Sheehan’s syndrome should be kept in mind and minimal investigation including baseline levels of ACTH, cortisol, prolactin and free thyroxine should be undertaken.

Currently, paired measurement of early morning cortisol and ACTH is recommended as screening investigation to diagnose primary AI. A low early morning cortisol <5 µg/dL in the setting of typical clinical symptoms is sufficient to confirm the diagnosis of AI and when accompanied with raised ACTH levels (>2-fold the upper limit of reference range) also establishes its cause to be primary AI. In equivocal cases with early morning cortisol between 5 and 32 µg/dL depending on the trimester, it is safe to employ the corticotropin stimulation test as diagnostic ‘gold standard’ (5). Suri and coworkers demonstrated higher peak cortisol responses of up to 36 µg/dL to 250 µg/dL of cosyntropin in 36 healthy pregnant women in the second and third trimesters. As a result, many authors suggest the use of trimester-specific cut-offs for stimulated cortisol values in the first, second and third trimesters of 25, 29 and 32 µg/dL, respectively, to diagnose or exclude AI (3, 6, 12, 17). Additionally, validated antibody assays should be used as adjuvant tests as 21-hydroxylase antibodies are positive in >90% of the patients and 17-hydroxylase antibodies in 30% of the patients with primary AI (22).

In cases with recent onset of secondary AI, corticotropin stimulation tests may give misleading results as adrenals may still respond normally to exogenous ACTH. However, insulin hypoglycemia testing is contraindicated in pregnancy due to safety reasons. Suri proposed the use of salivary cortisol as a more physiological measure of adrenal reserve in pregnancy (23) but it remains a challenge to diagnose or exclude AI based on these measures only. Fortunately, a new-onset secondary AI due to a structural disease of pituitary is very rare in pregnancy. These patients may also have additional symptoms such as headache or visual disturbances due to mass effects of a pituitary tumor. However, lymphocytic hypophysitis might present preferentially in the last trimester or postpartum. While treatment of secondary AI and secondary hypothyroidism is of particular importance during pregnancy, imaging can be delayed until delivery in patients without symptoms of mass effect. In the case of need to evaluate visual symptoms, MRI without contrast should be used in pregnant patients.

Substitution and dosage adjustment during pregnancy

The main aim of substitution therapy is to avoid both under- and over-replacement of glucocorticoid and mineralocorticoid treatments and to prevent adrenal crisis. Undesirable effects of over-replacement are increased risk of gestational diabetes, hypertension/preeclampsia, weight gain and bruising. In contrast, low substitution dosages might increase the risk of hyperemesis and put the patients at risk to develop an acute adrenal crisis.

Hydrocortisone has been advocated as the glucocorticoid substitution of choice. Accordingly, in the majority of reported cases in the literature, hydrocortisone is used (in 78.4% either alone or in combination with fludrocortisone; Table 1). High-dose glucocorticoid treatment is considered teratogenic in rodents causing cleft palate, fetal death and placental degeneration (24). In contrast, hydrocortisone exposure in humans is considered safe probably because of different glucocorticoid receptor–ligand systems and because of placental 11-β-hydroxysteroid dehydrogenase type 2 inactivating cortisol.

Based on the physiological increase in total and free cortisol values in normal pregnancy, the current approach is to increase hydrocortisone doses up to 20–40% in the last trimester (3). Due to the lack of sufficient evidence, patients should have clinical follow-up once every trimester with dosage adaptation based on the individual course of pregnancy as illustrated in the flow diagram (Fig. 1). Labor is a state of increased glucocorticoid requirement and should be preferably managed with hydrocortisone stress dose (100 mg hydrocortisone intravenously) followed by a continuous infusion of 100–200 mg/24 h at the beginning of the second stage of labor (3, 4, 5, 6). Similarly, hydrocortisone stress dose can be given as premedication followed by a continuous infusion of 100–200 mg/24 h in case of cesarean section. We suggest stepwise reduction of hydrocortisone supplementation therapy after the stress phase of delivery has passed. The duration of this transition period is mostly 24–48 h after delivery but may vary in individual cases.

Figure 1
Figure 1

Overview on diagnostic and therapeutic considerations in patients with newly diagnosed or known adrenal insufficiency (AI).

Citation: European Journal of Endocrinology 178, 2; 10.1530/EJE-17-0975

Fludrocortisone is mostly used as a mineralocorticoid replacement in Addison’s disease. In fact, mineralocorticoid requirement may slightly increase in the last trimester due to anti-mineralocorticoid effects of progesterone. Clinical parameters such as signs of orthostatic hypotension and increase in serum potassium should govern dose adjustment. Likewise, fludrocortisone must be reduced in cases of hypertension and or hypokalemia and even be withdrawn in cases of preeclampsia. In contrast, plasma renin cannot be used as a reliable marker to adjust mineralocorticoid dosing in pregnancy.

Management of adrenal crisis

As there had been no clear definition of adrenal crisis, in 2015 Allolio proposed a definition of adrenal crisis as a profound impairment of general health and the presence of at least two of the following signs or symptoms: hypotension (systolic blood pressure <100 mmHg), nausea or vomiting, severe fatigue, hyponatremia, hypoglycemia and hyperkalemia, making subsequent parenteral glucocorticoid administration necessary (25). According to the current literature search, a high incidence of adrenal crisis in pregnant women with AI of 69% can be assumed (Table 1) despite the fact that this clear definition had not been met in all cases. Although this percentage could also be an overestimation due to general over-reporting and due to the initial clinical presentation of newly diagnosed patients, adrenal crisis remains a clinically relevant problem. The probable triggers of adrenal crisis during pregnancy are hyperemesis, infections and non-adherence to substitution therapy.

Patient and partner education to adjust the hydrocortisone dosage in stressful situations and instruction to self-inject hydrocortisone are important measures to prevent an impending adrenal crisis. The main aims for the treatment of adrenal crisis are to treat hypotension with rapid fluid replacement and to reverse glucocorticoid deficiency with parenteral hydrocortisone (12). These aims also apply to pregnant women with additional attention to fetal monitoring to assure the well-being of the unborn child.

Outcome of pregnancies in AI

In the recent literature, there is no report of maternal death with a direct relation to the presence of AI (Table 1). In contrast, unfavorable outcomes of pregnancies have been described with intrauterine growth retardation (IUGR) being the most common (4.2%; Table 1). In an analysis of 31 pregnancies in 27 women with hypopituitarism of different etiologies, the rate of children who were small for gestational age was found to be higher (38% vs 12.7% in IVF control pregnancies) (20). As a potential cause, poor placental function was proposed in these women. In addition to growth retardation, there were more cesarean deliveries (89% vs 11.4%), more transverse lies (15% vs 2.1%) and more postpartum hemorrhages (5.26% vs 1%) (20). High rate of cesarean section was partly due to more malpresentations and partly due to obstetrician’s recommendation.

Gradden and colleagues reported on an abortion in the 11th week of pregnancy in a previously unknown case of primary AI, where the diagnosis was delayed as symptoms were initially thought to be related to hyperemesis of pregnancy (26). Furthermore, Otta and coworkers described one case of neonatal death from a mother with known primary AI occurring 20 h after birth due to acute cardiorespiratory failure (27). In this case, the patient was reported to be non-adherent to the recommended glucocorticoid treatment throughout the gestation period. In addition, Seaward and colleagues reported on two pregnancies in a patient, where stillbirth occurred in the first pregnancy at 31st week of gestation due to placental disruption (28). In this case, the patient also suffered from adrenal crisis before delivery, while the course of a second pregnancy was uneventful.

Lactation in the context of AI

Lactation can itself be affected by comorbidities of AI including pituitary insufficiency. Matsuzaki and colleagues compiled 21 cases of acute Sheehan’s syndrome from the literature (1990–2014) and included his own rare case of a successful second pregnancy after induction of ovulation in a patient with Sheehan’s syndrome under replacement treatment with hydrocortisone and thyroxine (Table 1 describes only his case). The authors reported variable onset of symptoms of different pituitary hormonal deficiencies with a median time of presentation of secondary AI being 7.9 days following delivery (29).

Given the ability as well as willingness of breastfeeding in patients with AI, the question arises, whether glucocorticoid substitution could potentially affect the child. In 1975, McKenzie and colleagues reported negligible excretion of prednisolone in breast milk over a period of 48 h after receiving 5 mg of 3H-prednisolone (range: 0.07–0.23% of the dose/L of milk/day). The authors concluded that the exposure of the suckling infant through the breast milk would be extremely small in a woman receiving 30 mg of prednisolone daily (30). Similarly, Öst and coworkers examined prednisolone excretion in milk in 6 lactating women receiving daily prednisolone doses ranging from 10 to 80 mg and concluded that even at a daily dose of 80 mg prednisolone, the infant would ingest <0.1% of that dose (31). These early studies indicate that the physiological dose of glucocorticoid required to substitute AI is unlikely to cause harm in breast-fed children.

Key points

In summary, there are a number of pathophysiological consequences of AI that can directly or indirectly affect pregnancy and complicate medical care of these patients. Overall, one can expect good maternal and fetal outcomes in properly treated patients with AI, which should reassure affected patients. However, the high proportion of reported adrenal crisis provides clear evidence that these patients require good education of their disease and close monitoring in specialized centers.

A new diagnosis of AI during pregnancy poses challenges due to the rarity of the disease, overlapping symptoms with normal pregnancy and difficulties in establishing biochemical diagnosis in mild cases. Consultation of an endocrinologist in a patient presenting with suggestive symptoms of AI should help in early diagnosis and management.

Clearly, many questions remain unanswered because of the lack of prospective data. Given the rarity of AI, we suggest collection of prospective information in pregnant patients as part of international registries.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review reported.

Funding

F B has received funding from the German research council (CRC/TRR 205).

References

  • 1

    Brent F. Addison’s disease and pregnancy. American Journal of Surgery 1950 79 645652. (https://doi.org/10.1016/0002-9610(50)90329-1)

    • Search Google Scholar
    • Export Citation
  • 2

    Cohen M. Addisons disease complicated by toxemia of pregnancy; review of the literature. Archives of Internal Medicine 1948 81 879887. (https://doi.org/10.1001/archinte.1948.00220240088006)

    • Search Google Scholar
    • Export Citation
  • 3

    Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, Husebye ES, Merke DP, Murad MH & Stratakis CA et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology and Metabolism 2016 101 364389. (https://doi.org/10.1210/jc.2015-1710)

    • Search Google Scholar
    • Export Citation
  • 4

    Kamoun M, Mnif MF, Charfi N, Kacem FH, Naceur BB, Mnif F, Dammak M, Rekik N & Abid M. Adrenal diseases during pregnancy: pathophysiology, diagnosis and management strategies. American Journal of the Medical Sciences 2014 347 6473. (https://doi.org/10.1097/MAJ.0b013e31828aaeee)

    • Search Google Scholar
    • Export Citation
  • 5

    Langlois F, Lim DST & Fleseriu M. Update on adrenal insufficiency: diagnosis and management in pregnancy. Current Opinion in Endocrinology, Diabetes and Obesity 2017 24 184192. (https://doi.org/10.1097/MED.0000000000000331)

    • Search Google Scholar
    • Export Citation
  • 6

    Lebbe M & Arlt W. What is the best diagnostic and therapeutic management strategy for an Addison patient during pregnancy? Clinical Endocrinology 2013 78 497502. (https://doi.org/10.1111/cen.12097)

    • Search Google Scholar
    • Export Citation
  • 7

    Bjornsdottir S, Cnattingius S, Brandt L, Nordenstrom A, Ekbom A, Kampe O & Bensing S. Addison’s disease in women is a risk factor for an adverse pregnancy outcome. Journal of Clinical Endocrinology and Metabolism 2010 95 52495257. (https://doi.org/10.1210/jc.2010-0108)

    • Search Google Scholar
    • Export Citation
  • 8

    Abu MA, Sinha P & Totoe L. Addison’s disease in pregnancy presenting as hyperemesis gravidarum. Journal of Obstetrics and Gynaecology 1997 17 278279. (https://doi.org/10.1080/01443619750113285)

    • Search Google Scholar
    • Export Citation
  • 9

    Yuen KC, Chong LE & Koch CA. Adrenal insufficiency in pregnancy: challenging issues in diagnosis and management. Endocrine 2013 44 283292. (https://doi.org/10.1007/s12020-013-9893-2)

    • Search Google Scholar
    • Export Citation
  • 10

    Ambrosi B, Barbetta L & Morricone L. Diagnosis and management of Addison’s disease during pregnancy. Journal of Endocrinological Investigation 2003 26 698702. (https://doi.org/10.1007/BF03347034)

    • Search Google Scholar
    • Export Citation
  • 11

    Lekarev O & New MI. Adrenal disease in pregnancy. Best Practice and Research: Clinical Endocrinology and Metabolism 2011 25 959973. (https://doi.org/10.1016/j.beem.2011.08.004)

    • Search Google Scholar
    • Export Citation
  • 12

    Nicolaides NC, Chrousos GP & Charmandari E. Adrenal insufficiency. In Endotext. Eds De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R & New M et al. South Dartmouth, MA, 2000.

    • Search Google Scholar
    • Export Citation
  • 13

    Schneiderman M, Czuzoj-Shulman N, Spence AR & Abenhaim HA. Maternal and neonatal outcomes of pregnancies in women with Addison’s disease: a population-based cohort study on 7.7 million births. BJOG 2017 124 17721779. (https://doi.org/10.1111/1471-0528.14448)

    • Search Google Scholar
    • Export Citation
  • 14

    Eschler DC, Kogekar N & Pessah-Pollack R. Management of adrenal tumors in pregnancy. Endocrinology Metabolism Clinics of North America 2015 44 381397. (https://doi.org/10.1016/j.ecl.2015.02.006)

    • Search Google Scholar
    • Export Citation
  • 15

    Petraglia F, Sawchenko PE, Rivier J & Vale W. Evidence for local stimulation of ACTH secretion by corticotropin-releasing factor in human placenta. Nature 1987 328 717719. (https://doi.org/10.1038/328717a0)

    • Search Google Scholar
    • Export Citation
  • 16

    Mastorakos G & Ilias I. Maternal and fetal hypothalamic-pituitary-adrenal axes during pregnancy and postpartum. Annals of the New York Academy of Sciences 2003 997 136149. (https://doi.org/10.1196/annals.1290.016)

    • Search Google Scholar
    • Export Citation
  • 17

    Nolten WE, Lindheimer MD, Rueckert PA, Oparil S & Ehrlich EN. Diurnal patterns and regulation of cortisol secretion in pregnancy. Journal of Clinical Endocrinology and Metabolism 1980 51 466472. (https://doi.org/10.1210/jcem-51-3-466)

    • Search Google Scholar
    • Export Citation
  • 18

    Erichsen MM, Husebye ES, Michelsen TM, Dahl AA & Lovas K. Sexuality and fertility in women with Addison’s disease. Journal of Clinical Endocrinology and Metabolism 2010 95 43544360. (https://doi.org/10.1210/jc.2010-0445)

    • Search Google Scholar
    • Export Citation
  • 19

    Grossman AB. Clinical review#: the diagnosis and management of central hypoadrenalism. Journal of Clinical Endocrinology and Metabolism 2010 95 48554863. (https://doi.org/10.1210/jc.2010-0982)

    • Search Google Scholar
    • Export Citation
  • 20

    Kubler K, Klingmuller D, Gembruch U & Merz WM. High-risk pregnancy management in women with hypopituitarism. Journal of Perinatology 2009 29 8995. (https://doi.org/10.1038/jp.2008.116)

    • Search Google Scholar
    • Export Citation
  • 21

    Napier C & Pearce SH. Autoimmune Addison’s disease. Presse Medicale 2012 41 e626e635. (https://doi.org/10.1016/j.lpm.2012.09.010)

  • 22

    Bratland E & Husebye ES. Cellular immunity and immunopathology in autoimmune Addison’s disease. Molecular and Cellular Endocrinology 2011 336 180190. (https://doi.org/10.1016/j.mce.2010.12.015)

    • Search Google Scholar
    • Export Citation
  • 23

    Suri D, Moran J, Hibbard JU, Kasza K & Weiss RE. Assessment of adrenal reserve in pregnancy: defining the normal response to the adrenocorticotropin stimulation test. Journal of Clinical Endocrinology and Metabolism 2006 91 38663872. (https://doi.org/10.1210/jc.2006-1049)

    • Search Google Scholar
    • Export Citation
  • 24

    Goldman AS, Sharpior BH & Katsumata M. Human foetal palatal corticoid receptors and teratogens for cleft palate. Nature 1978 272 464466. (https://doi.org/10.1038/272464a0)

    • Search Google Scholar
    • Export Citation
  • 25

    Allolio B. Extensive expertise in endocrinology. Adrenal crisis. European Journal of Endocrinology 2015 172 R115R124. (https://doi.org/10.1530/EJE-14-0824)

    • Search Google Scholar
    • Export Citation
  • 26

    Gradden C, Lawrence D, Doyle PM & Welch CR. Uses of error: Addison’s disease in pregnancy. Lancet 2001 357 11971197. (https://doi.org/10.1016/S0140-6736(05)71786-4)

    • Search Google Scholar
    • Export Citation
  • 27

    Fux Otta C, Szafryk de Mereshian P, Iraci GS, Ojeda de Pruneda MR. Pregnancies associated with primary adrenal insufficiency. Fertility and Sterility 2008 90 e1117e1120.

    • Search Google Scholar
    • Export Citation
  • 28

    Seaward PG, Guidozzi F, Sonnendecker EW. Addisonian crisis in pregnancy. Case report. British Journal of Obstetrics and Gynaecology 1989 96 13481350. (https://doi.org/10.1111/j.1471-0528.1989.tb03236.x)

    • Search Google Scholar
    • Export Citation
  • 29

    Matsuzaki S, Endo M, Ueda Y, Mimura K, Kakigano A, Egawa-Takata T, Kumasawa K, Yoshino K & Kimura T. A case of acute Sheehan’s syndrome and literature review: a rare but life-threatening complication of postpartum hemorrhage. BMC Pregnancy and Childbirth 2017 17 188. (https://doi.org/10.1186/s12884-017-1380-y)

    • Search Google Scholar
    • Export Citation
  • 30

    McKenzie SA, Selley JA & Agnew JE. Secretion of prednisolone into breast milk. Archives of Disease in Childhood 1975 50 894896. (https://doi.org/10.1136/adc.50.11.894)

    • Search Google Scholar
    • Export Citation
  • 31

    Ost L, Wettrell G, Bjorkhem I & Rane A. Prednisolone excretion in human milk. Journal of Pediatrics 1985 106 10081011. (https://doi.org/10.1016/S0022-3476(85)80259-6)

    • Search Google Scholar
    • Export Citation
  • 32

    Albert E, Dalaker K, Jorde R & Berge LN. Addison’s disease and pregnancy. Acta Obstetricia et Gynecologica Scandinavica 1989 68 185187. (https://doi.org/10.3109/00016348909009909)

    • Search Google Scholar
    • Export Citation
  • 33

    Drucker D, Shumak S & Angel A. Schmidt’s syndrome presenting with intrauterine growth retardation and postpartum addisonian crisis. American Journal of Obstetrics and Gynecology 1984 149 229230. (https://doi.org/10.1016/0002-9378(84)90206-0)

    • Search Google Scholar
    • Export Citation
  • 34

    Pirisi G, Posadino PM, Virdis GP & Lai G. Addisons’s disease in pregnancy. Clinical and Experimental Obstetrics and Gynecology 1984 11 158160.

    • Search Google Scholar
    • Export Citation
  • 35

    Wieacker P, Alexopoulos A, DeGregorio G & Breckwoldt M. Pregnancy in Addison’s disease. Deutsche Medizinische Wochenschrift 1989 114 11171120. (https://doi.org/10.1055/s-2008-1066728)

    • Search Google Scholar
    • Export Citation
  • 36

    O’Shaughnessy RW, Hackett KJ. Maternal Addison’s disease and fetal growth retardation. A case report. Journal of Reproductive Medicine 1984 29 752756.

    • Search Google Scholar
    • Export Citation
  • 37

    Schelling M & Schneider KT. Complications after cesarean section in untreated Addison disease. Geburtshilfe Und Frauenheilkunde 1993 53 416419. (https://doi.org/10.1055/s-2007-1022907)

    • Search Google Scholar
    • Export Citation
  • 38

    Perlitz Y, Varkel J, Markovitz J, Ben Ami M, Matilsky M & Oettinger M. Acute adrenal insufficiency during pregnancy and puerperium: case report and literature review. Obstetrical and Gynecological Survey 1999 54 717722. (https://doi.org/10.1097/00006254-199911000-00023)

    • Search Google Scholar
    • Export Citation
  • 39

    Ozdemir I, Demirci F, Yucel O, Simsek E & Yildiz I. A case of primary Addison’s disease with hyperemesis gravidarum and successful pregnancy. European Journal of Obstetrics and Gynecology and Reproductive Biology 2004 113 100102. (https://doi.org/10.1016/j.ejogrb.2003.01.001)

    • Search Google Scholar
    • Export Citation
  • 40

    Stechova K, Bartaskova D, Mrstinova M, Cerny M, Snajderova M, Cinek O, Sumnik Z & Vavrinec J. Pregnancy in a woman suffering from Type 1 diabetes associated with Addison’s disease and Hashimoto’s thyroiditis (fully developed autoimmune polyglandular syndrome type 2). Experimental and Clinical Endocrinology and Diabetes 2004 112 333337. (https://doi.org/10.1055/s-2004-820912)

    • Search Google Scholar
    • Export Citation
  • 41

    Donnelly JC, O’Connell MP & Keane DP. Addison’s disease, with successful pregnancy outcome. Journal of Obstetrics and Gynaecology 2003 23 199.

    • Search Google Scholar
    • Export Citation
  • 42

    Adonakis G, Georgopoulos NA, Michail G, Spinos N, Papadopoulos V, Kourounis GS & Kyriazopoulou V. Successful pregnancy outcome in a patient with primary Addison’s disease. Gynecological Endocrinology 2005 21 9092. (https://doi.org/10.1080/09513590500099388)

    • Search Google Scholar
    • Export Citation
  • 43

    Scrimin F, Panerari F & Guaschino S. Addison’s disease and hypothyroidism untreated until twenty-four weeks of pregnancy. Acta Obstetricia et Gynecologica Scandinavica 2005 84 198199. (https://doi.org/10.1111/j.0001-6349.2005.0255b.x)

    • Search Google Scholar
    • Export Citation
  • 44

    Cosimo C & Franco C. Addison’s disease and pregnancy: case report. Journal of Prenatal Medicine 2009 3 5354.

  • 45

    Ebeling F, Rahkonen L, Saastamoinen KP, Matikainen N & Laitinen K. Addison’s disease presenting as hyperemesis, hyponatremia and pancytopenia in early pregnancy. Acta Obstetricia et Gynecologica Scandinavica 2011 90 121122. (https://doi.org/10.1111/j.1600-0412.2010.01003.x)

    • Search Google Scholar
    • Export Citation
  • 46

    Lewandowski K, Hincz P, Grzesiak M, Cajdler-Luba A, Salata I, Wilczynski J & Lewinski A. New onset Addison’s disease presenting as prolonged hyperemesis in early pregnancy. Ginekologia Polska 2010 81 537540.

    • Search Google Scholar
    • Export Citation
  • 47

    Mittal A, Dexter S, Marcus S & Tremble J. First presentation of Addison’s disease in the 2nd trimester of pregnancy. Journal of Obstetrics and Gynaecology 2011 31 342342. (https://doi.org/10.3109/01443615.2011.563330)

    • Search Google Scholar
    • Export Citation
  • 48

    Krysiak R & Okopien B. Coexistence of autoimmune polyglandular syndrome type 3 with diabetes insipidus. Wiadomosci Lekarskie 2015 68 204207.

    • Search Google Scholar
    • Export Citation
  • 49

    Ganie MA, Bhat RA, Irfan UlQ, Dangroo MA, Kotwal S, Bhat MA, Ahmed S, Hassan S & Shah ZA. Unassisted successful pregnancy in a case of Addison’s disease with recurrent pregnancy loss. Indian Journal of Endocrinology and Metabolism 2012 16 481482. (https://doi.org/10.4103/2230-8210.95747)

    • Search Google Scholar
    • Export Citation
  • 50

    Vinagre I, Gimenez M, Pericot A, Bellart J & Conget I. Sensor augmented pump therapy in the management of type 1 diabetes complicated with Addison’s disease prior to and during pregnancy. Endocrinología y Nutrición 2014 61 341343. (https://doi.org/10.1016/j.endonu.2014.02.002)

    • Search Google Scholar
    • Export Citation
  • 51

    de Corbiere P, Ritzel K, Cazabat L, Ropers J, Schott M, Libe R, Koschker AC, Leboulleux S, Deutschbein T & Do Cao C et al. Pregnancy in women previously treated for an adrenocortical carcinoma. Journal of Clinical Endocrinology and Metabolism 2015 100 46044611. (https://doi.org/10.1210/jc.2015-2341)

    • Search Google Scholar
    • Export Citation
  • 52

    Matsuzaki S, Endo M, Ueda Y, Mimura K, Kakigano A, Egawa-Takata T, Kumasawa K, Yoshino K & Kimura T. A case of acute Sheehan’s syndrome and literature review: a rare but life-threatening complication of postpartum hemorrhage. BMC Pregnancy and Childbirth 2017 17.

    • Search Google Scholar
    • Export Citation

 

     European Society of Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 3803 1053 113
PDF Downloads 4253 2492 296
  • View in gallery

    Overview on diagnostic and therapeutic considerations in patients with newly diagnosed or known adrenal insufficiency (AI).

  • 1

    Brent F. Addison’s disease and pregnancy. American Journal of Surgery 1950 79 645652. (https://doi.org/10.1016/0002-9610(50)90329-1)

    • Search Google Scholar
    • Export Citation
  • 2

    Cohen M. Addisons disease complicated by toxemia of pregnancy; review of the literature. Archives of Internal Medicine 1948 81 879887. (https://doi.org/10.1001/archinte.1948.00220240088006)

    • Search Google Scholar
    • Export Citation
  • 3

    Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, Husebye ES, Merke DP, Murad MH & Stratakis CA et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology and Metabolism 2016 101 364389. (https://doi.org/10.1210/jc.2015-1710)

    • Search Google Scholar
    • Export Citation
  • 4

    Kamoun M, Mnif MF, Charfi N, Kacem FH, Naceur BB, Mnif F, Dammak M, Rekik N & Abid M. Adrenal diseases during pregnancy: pathophysiology, diagnosis and management strategies. American Journal of the Medical Sciences 2014 347 6473. (https://doi.org/10.1097/MAJ.0b013e31828aaeee)

    • Search Google Scholar
    • Export Citation
  • 5

    Langlois F, Lim DST & Fleseriu M. Update on adrenal insufficiency: diagnosis and management in pregnancy. Current Opinion in Endocrinology, Diabetes and Obesity 2017 24 184192. (https://doi.org/10.1097/MED.0000000000000331)

    • Search Google Scholar
    • Export Citation
  • 6

    Lebbe M & Arlt W. What is the best diagnostic and therapeutic management strategy for an Addison patient during pregnancy? Clinical Endocrinology 2013 78 497502. (https://doi.org/10.1111/cen.12097)

    • Search Google Scholar
    • Export Citation
  • 7

    Bjornsdottir S, Cnattingius S, Brandt L, Nordenstrom A, Ekbom A, Kampe O & Bensing S. Addison’s disease in women is a risk factor for an adverse pregnancy outcome. Journal of Clinical Endocrinology and Metabolism 2010 95 52495257. (https://doi.org/10.1210/jc.2010-0108)

    • Search Google Scholar
    • Export Citation
  • 8

    Abu MA, Sinha P & Totoe L. Addison’s disease in pregnancy presenting as hyperemesis gravidarum. Journal of Obstetrics and Gynaecology 1997 17 278279. (https://doi.org/10.1080/01443619750113285)

    • Search Google Scholar
    • Export Citation
  • 9

    Yuen KC, Chong LE & Koch CA. Adrenal insufficiency in pregnancy: challenging issues in diagnosis and management. Endocrine 2013 44 283292. (https://doi.org/10.1007/s12020-013-9893-2)

    • Search Google Scholar
    • Export Citation
  • 10

    Ambrosi B, Barbetta L & Morricone L. Diagnosis and management of Addison’s disease during pregnancy. Journal of Endocrinological Investigation 2003 26 698702. (https://doi.org/10.1007/BF03347034)

    • Search Google Scholar
    • Export Citation
  • 11

    Lekarev O & New MI. Adrenal disease in pregnancy. Best Practice and Research: Clinical Endocrinology and Metabolism 2011 25 959973. (https://doi.org/10.1016/j.beem.2011.08.004)

    • Search Google Scholar
    • Export Citation
  • 12

    Nicolaides NC, Chrousos GP & Charmandari E. Adrenal insufficiency. In Endotext. Eds De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R & New M et al. South Dartmouth, MA, 2000.

    • Search Google Scholar
    • Export Citation
  • 13

    Schneiderman M, Czuzoj-Shulman N, Spence AR & Abenhaim HA. Maternal and neonatal outcomes of pregnancies in women with Addison’s disease: a population-based cohort study on 7.7 million births. BJOG 2017 124 17721779. (https://doi.org/10.1111/1471-0528.14448)

    • Search Google Scholar
    • Export Citation
  • 14

    Eschler DC, Kogekar N & Pessah-Pollack R. Management of adrenal tumors in pregnancy. Endocrinology Metabolism Clinics of North America 2015 44 381397. (https://doi.org/10.1016/j.ecl.2015.02.006)

    • Search Google Scholar
    • Export Citation
  • 15

    Petraglia F, Sawchenko PE, Rivier J & Vale W. Evidence for local stimulation of ACTH secretion by corticotropin-releasing factor in human placenta. Nature 1987 328 717719. (https://doi.org/10.1038/328717a0)

    • Search Google Scholar
    • Export Citation
  • 16

    Mastorakos G & Ilias I. Maternal and fetal hypothalamic-pituitary-adrenal axes during pregnancy and postpartum. Annals of the New York Academy of Sciences 2003 997 136149. (https://doi.org/10.1196/annals.1290.016)

    • Search Google Scholar
    • Export Citation
  • 17

    Nolten WE, Lindheimer MD, Rueckert PA, Oparil S & Ehrlich EN. Diurnal patterns and regulation of cortisol secretion in pregnancy. Journal of Clinical Endocrinology and Metabolism 1980 51 466472. (https://doi.org/10.1210/jcem-51-3-466)

    • Search Google Scholar
    • Export Citation
  • 18

    Erichsen MM, Husebye ES, Michelsen TM, Dahl AA & Lovas K. Sexuality and fertility in women with Addison’s disease. Journal of Clinical Endocrinology and Metabolism 2010 95 43544360. (https://doi.org/10.1210/jc.2010-0445)

    • Search Google Scholar
    • Export Citation
  • 19

    Grossman AB. Clinical review#: the diagnosis and management of central hypoadrenalism. Journal of Clinical Endocrinology and Metabolism 2010 95 48554863. (https://doi.org/10.1210/jc.2010-0982)

    • Search Google Scholar
    • Export Citation
  • 20

    Kubler K, Klingmuller D, Gembruch U & Merz WM. High-risk pregnancy management in women with hypopituitarism. Journal of Perinatology 2009 29 8995. (https://doi.org/10.1038/jp.2008.116)

    • Search Google Scholar
    • Export Citation
  • 21

    Napier C & Pearce SH. Autoimmune Addison’s disease. Presse Medicale 2012 41 e626e635. (https://doi.org/10.1016/j.lpm.2012.09.010)

  • 22

    Bratland E & Husebye ES. Cellular immunity and immunopathology in autoimmune Addison’s disease. Molecular and Cellular Endocrinology 2011 336 180190. (https://doi.org/10.1016/j.mce.2010.12.015)

    • Search Google Scholar
    • Export Citation
  • 23

    Suri D, Moran J, Hibbard JU, Kasza K & Weiss RE. Assessment of adrenal reserve in pregnancy: defining the normal response to the adrenocorticotropin stimulation test. Journal of Clinical Endocrinology and Metabolism 2006 91 38663872. (https://doi.org/10.1210/jc.2006-1049)

    • Search Google Scholar
    • Export Citation
  • 24

    Goldman AS, Sharpior BH & Katsumata M. Human foetal palatal corticoid receptors and teratogens for cleft palate. Nature 1978 272 464466. (https://doi.org/10.1038/272464a0)

    • Search Google Scholar
    • Export Citation
  • 25

    Allolio B. Extensive expertise in endocrinology. Adrenal crisis. European Journal of Endocrinology 2015 172 R115R124. (https://doi.org/10.1530/EJE-14-0824)

    • Search Google Scholar
    • Export Citation
  • 26

    Gradden C, Lawrence D, Doyle PM & Welch CR. Uses of error: Addison’s disease in pregnancy. Lancet 2001 357 11971197. (https://doi.org/10.1016/S0140-6736(05)71786-4)

    • Search Google Scholar
    • Export Citation
  • 27

    Fux Otta C, Szafryk de Mereshian P, Iraci GS, Ojeda de Pruneda MR. Pregnancies associated with primary adrenal insufficiency. Fertility and Sterility 2008 90 e1117e1120.

    • Search Google Scholar
    • Export Citation
  • 28

    Seaward PG, Guidozzi F, Sonnendecker EW. Addisonian crisis in pregnancy. Case report. British Journal of Obstetrics and Gynaecology 1989 96 13481350. (https://doi.org/10.1111/j.1471-0528.1989.tb03236.x)

    • Search Google Scholar
    • Export Citation
  • 29

    Matsuzaki S, Endo M, Ueda Y, Mimura K, Kakigano A, Egawa-Takata T, Kumasawa K, Yoshino K & Kimura T. A case of acute Sheehan’s syndrome and literature review: a rare but life-threatening complication of postpartum hemorrhage. BMC Pregnancy and Childbirth 2017 17 188. (https://doi.org/10.1186/s12884-017-1380-y)

    • Search Google Scholar
    • Export Citation
  • 30

    McKenzie SA, Selley JA & Agnew JE. Secretion of prednisolone into breast milk. Archives of Disease in Childhood 1975 50 894896. (https://doi.org/10.1136/adc.50.11.894)

    • Search Google Scholar
    • Export Citation
  • 31

    Ost L, Wettrell G, Bjorkhem I & Rane A. Prednisolone excretion in human milk. Journal of Pediatrics 1985 106 10081011. (https://doi.org/10.1016/S0022-3476(85)80259-6)

    • Search Google Scholar
    • Export Citation
  • 32

    Albert E, Dalaker K, Jorde R & Berge LN. Addison’s disease and pregnancy. Acta Obstetricia et Gynecologica Scandinavica 1989 68 185187. (https://doi.org/10.3109/00016348909009909)

    • Search Google Scholar
    • Export Citation
  • 33

    Drucker D, Shumak S & Angel A. Schmidt’s syndrome presenting with intrauterine growth retardation and postpartum addisonian crisis. American Journal of Obstetrics and Gynecology 1984 149 229230. (https://doi.org/10.1016/0002-9378(84)90206-0)

    • Search Google Scholar
    • Export Citation
  • 34

    Pirisi G, Posadino PM, Virdis GP & Lai G. Addisons’s disease in pregnancy. Clinical and Experimental Obstetrics and Gynecology 1984 11 158160.

    • Search Google Scholar
    • Export Citation
  • 35

    Wieacker P, Alexopoulos A, DeGregorio G & Breckwoldt M. Pregnancy in Addison’s disease. Deutsche Medizinische Wochenschrift 1989 114 11171120. (https://doi.org/10.1055/s-2008-1066728)

    • Search Google Scholar
    • Export Citation
  • 36

    O’Shaughnessy RW, Hackett KJ. Maternal Addison’s disease and fetal growth retardation. A case report. Journal of Reproductive Medicine 1984 29 752756.

    • Search Google Scholar
    • Export Citation
  • 37

    Schelling M & Schneider KT. Complications after cesarean section in untreated Addison disease. Geburtshilfe Und Frauenheilkunde 1993 53 416419. (https://doi.org/10.1055/s-2007-1022907)

    • Search Google Scholar
    • Export Citation
  • 38

    Perlitz Y, Varkel J, Markovitz J, Ben Ami M, Matilsky M & Oettinger M. Acute adrenal insufficiency during pregnancy and puerperium: case report and literature review. Obstetrical and Gynecological Survey 1999 54 717722. (https://doi.org/10.1097/00006254-199911000-00023)

    • Search Google Scholar
    • Export Citation
  • 39

    Ozdemir I, Demirci F, Yucel O, Simsek E & Yildiz I. A case of primary Addison’s disease with hyperemesis gravidarum and successful pregnancy. European Journal of Obstetrics and Gynecology and Reproductive Biology 2004 113 100102. (https://doi.org/10.1016/j.ejogrb.2003.01.001)

    • Search Google Scholar
    • Export Citation
  • 40

    Stechova K, Bartaskova D, Mrstinova M, Cerny M, Snajderova M, Cinek O, Sumnik Z & Vavrinec J. Pregnancy in a woman suffering from Type 1 diabetes associated with Addison’s disease and Hashimoto’s thyroiditis (fully developed autoimmune polyglandular syndrome type 2). Experimental and Clinical Endocrinology and Diabetes 2004 112 333337. (https://doi.org/10.1055/s-2004-820912)

    • Search Google Scholar
    • Export Citation
  • 41

    Donnelly JC, O’Connell MP & Keane DP. Addison’s disease, with successful pregnancy outcome. Journal of Obstetrics and Gynaecology 2003 23 199.

    • Search Google Scholar
    • Export Citation
  • 42

    Adonakis G, Georgopoulos NA, Michail G, Spinos N, Papadopoulos V, Kourounis GS & Kyriazopoulou V. Successful pregnancy outcome in a patient with primary Addison’s disease. Gynecological Endocrinology 2005 21 9092. (https://doi.org/10.1080/09513590500099388)

    • Search Google Scholar
    • Export Citation
  • 43

    Scrimin F, Panerari F & Guaschino S. Addison’s disease and hypothyroidism untreated until twenty-four weeks of pregnancy. Acta Obstetricia et Gynecologica Scandinavica 2005 84 198199. (https://doi.org/10.1111/j.0001-6349.2005.0255b.x)

    • Search Google Scholar
    • Export Citation
  • 44

    Cosimo C & Franco C. Addison’s disease and pregnancy: case report. Journal of Prenatal Medicine 2009 3 5354.

  • 45

    Ebeling F, Rahkonen L, Saastamoinen KP, Matikainen N & Laitinen K. Addison’s disease presenting as hyperemesis, hyponatremia and pancytopenia in early pregnancy. Acta Obstetricia et Gynecologica Scandinavica 2011 90 121122. (https://doi.org/10.1111/j.1600-0412.2010.01003.x)

    • Search Google Scholar
    • Export Citation
  • 46

    Lewandowski K, Hincz P, Grzesiak M, Cajdler-Luba A, Salata I, Wilczynski J & Lewinski A. New onset Addison’s disease presenting as prolonged hyperemesis in early pregnancy. Ginekologia Polska 2010 81 537540.

    • Search Google Scholar
    • Export Citation
  • 47

    Mittal A, Dexter S, Marcus S & Tremble J. First presentation of Addison’s disease in the 2nd trimester of pregnancy. Journal of Obstetrics and Gynaecology 2011 31 342342. (https://doi.org/10.3109/01443615.2011.563330)

    • Search Google Scholar
    • Export Citation
  • 48

    Krysiak R & Okopien B. Coexistence of autoimmune polyglandular syndrome type 3 with diabetes insipidus. Wiadomosci Lekarskie 2015 68 204207.

    • Search Google Scholar
    • Export Citation
  • 49

    Ganie MA, Bhat RA, Irfan UlQ, Dangroo MA, Kotwal S, Bhat MA, Ahmed S, Hassan S & Shah ZA. Unassisted successful pregnancy in a case of Addison’s disease with recurrent pregnancy loss. Indian Journal of Endocrinology and Metabolism 2012 16 481482. (https://doi.org/10.4103/2230-8210.95747)

    • Search Google Scholar
    • Export Citation
  • 50

    Vinagre I, Gimenez M, Pericot A, Bellart J & Conget I. Sensor augmented pump therapy in the management of type 1 diabetes complicated with Addison’s disease prior to and during pregnancy. Endocrinología y Nutrición 2014 61 341343. (https://doi.org/10.1016/j.endonu.2014.02.002)

    • Search Google Scholar
    • Export Citation
  • 51

    de Corbiere P, Ritzel K, Cazabat L, Ropers J, Schott M, Libe R, Koschker AC, Leboulleux S, Deutschbein T & Do Cao C et al. Pregnancy in women previously treated for an adrenocortical carcinoma. Journal of Clinical Endocrinology and Metabolism 2015 100 46044611. (https://doi.org/10.1210/jc.2015-2341)

    • Search Google Scholar
    • Export Citation
  • 52

    Matsuzaki S, Endo M, Ueda Y, Mimura K, Kakigano A, Egawa-Takata T, Kumasawa K, Yoshino K & Kimura T. A case of acute Sheehan’s syndrome and literature review: a rare but life-threatening complication of postpartum hemorrhage. BMC Pregnancy and Childbirth 2017 17.

    • Search Google Scholar
    • Export Citation