Pregnant women with chronic adrenal cortical insufficiency

　　First, Etiology

　　7. The most common cause of chronic adrenal cortex destruction leading to adrenal cortex insufficiency is tuberculosis. After liberation, tuberculosis in China has significantly decreased, so the number of patients with this disease has also decreased accordingly; other diseases such as syphilis and fungal infections can also cause adrenal cortex destruction; vascular diseases such as thrombosis, embolism blocking blood supply, or bilateral cortical hemorrhage after lesions can also cause adrenal cortex insufficiency.

　　6. Idiopathic adrenal atrophy is another important cause, which is related to autoimmune diseases.

　　5. Adrenal tumors can cause adrenal subtotal or total resection, leading to adrenal cortex insufficiency.

　　4. Congenital adrenal hypoplasia, etc.

　　Second, Pathogenesis

　　The main hormones produced by the adrenal cortex include cortisol, aldosterone, and dehydroepiandrosterone. When there is adrenal cortex insufficiency, there is insufficient secretion of glucose and salt corticoids, leading to increased excretion of sodium, sweat, saliva, and gastrointestinal sodium in the urine and decreased potassium excretion, resulting in low serum concentrations of sodium and chloride and high serum concentrations of potassium. Due to the poor ability of the body to concentrate urine, along with electrolyte imbalance, it can cause severe dehydration, decreased blood volume, hypotension, and circulatory collapse. The lack of cortisol can also cause metabolic disorders of proteins, fats, and carbohydrates, as well as severe insulin hypersensitivity, leading to hypoglycemia and decreased glycogen in the liver. The reduction in adrenal cortex hormone secretion weakens resistance to infections and trauma. The weakening of myocardial contraction and the decrease in blood volume can lead to decreased cardiac output and collapse. The deterioration of nervous and muscular function can also cause weakness. The reduction in cortisol can increase the production of ACTH by the pituitary and increase β-lipolysis, which can stimulate melanocytes, causing hyperpigmentation of the skin and mucous membranes.

　　Patients with adrenal cortex insufficiency and pregnancy that have not been treated often suffer from infertility due to low adrenal function. After treatment with corticosteroids, it is not uncommon to have pregnancy complications. Due to abnormal glucose metabolism, hypoglycemia is prone to occur during early pregnancy, especially when there is a lack of glucocorticoids, which can easily worsen hypoglycemia, leading to growth restriction in the fetus during pregnancy. When there is still some reserve of adrenal function, some pregnant women can maintain normal daily life without knowing they have this disease. However, under certain stresses such as labor, delivery, surgery, and puerperium, Addison's crisis may suddenly occur, characterized by extreme weakness, nausea, vomiting, pain in the upper abdomen and back, legs, hypothermia, and hypotension, peripheral vascular collapse, and renal failure, which are life-threatening conditions. It is only at this time that Addison's disease is diagnosed. Whether the disease is diagnosed before pregnancy is very important for the prognosis. Seaward et al. (1989) collected a total of 5 patients with pregnancy complicated by Addison's disease since 1972, among whom 1 was not diagnosed before pregnancy and developed Addison's crisis during pregnancy, accompanied by placental abruption and fetal death. On the other hand, Abett et al. (1989) reported 6 cases of pre-pregnancy diagnosed Addison's disease, all of which had successful pregnancies. The prognosis of the fetus is often parallel to the condition of the mother and child.

　　If adequate glucocorticoid replacement therapy is not used during pregnancy, the probability of premature birth and stillbirth in the fetus increases. Mild pregnant women can complete full-term delivery, and the weight of the infant may be 500g lower than that of the average infant born to normal pregnant women, which may be due to maternal hypoglycemia. If the cause is the active stage of adrenal tuberculosis or accompanied by active tuberculosis in other organs, symptoms such as low fever and night sweats, which are symptoms of tuberculosis intoxication, may occur. If accompanied by other autoimmune endocrine diseases, autoimmune polyendocrine failure syndrome may occur. With complete hypopituitarism, there may be hypothyroidism and hypogonadism, manifested as aversion to cold, constipation, amenorrhea, sparse axillary and pubic hair. Lesions in the hypothalamus or pituitary gland may cause headache, diabetes insipidus, decreased vision, and defects in the field of vision.

　　The typical clinical manifestations of this disease include the following points:

　　1. Hyperpigmentation is seen in primary patients. Due to increased secretion of adrenocorticotropic hormone (ACTH) by the pituitary gland, the melanocyte-stimulating hormone also increases, leading to hyperpigmentation of the skin and mucous membranes, which is particularly evident in areas of friction, palm prints, areolae, and scars. There is no such symptom in patients with secondary hypopituitarism.

　　2. Cardiovascular symptoms: nearly half of the patients may have blood pressure below 90/60 mmHg (12/8 kPa), and it may drop to zero during crises. Dizziness, orthostatic hypotension, and syncope are common.

　　3. Gastrointestinal symptoms include decreased appetite, preference for salty food, weight loss, nausea, vomiting, abdominal distension, poor digestion, diarrhea, abdominal pain, and constipation.

　　4. Muscle weakness is one of the main symptoms. There may be apathy, fatigue, drowsiness, mental disorders, lack of concentration, decreased memory, irritability, and frequent insomnia.

　　5. Other symptoms include hyperkalemia, hyponatremia, chronic dehydration, and body weight loss of 5 to 10 kg or more. Glucose production is weakened, and hypoglycemia may occur during fasting. Sexual function in both genders may decline, with male impotence and female alopecia of pubic and axillary hair, menstrual disorders or amenorrhea. Mild cases can be pregnant. If the cause is tuberculosis infection, symptoms such as low fever and night sweats are common, and the physical weakness and emaciation are more severe. If accompanied by other autoimmune diseases, corresponding disease manifestations may occur.

　　6. Crisis is the manifestation of the acute exacerbation of the disease. It often occurs under stress stimuli such as infection, trauma, surgery, childbirth, or sudden interruption of treatment. Symptoms include nausea, vomiting, abdominal pain, diarrhea, severe dehydration, decreased blood pressure, rapid heart rate, weak pulse, shock, hypoglycemia, low blood sodium, high fever, mental disorder. If not treated in time, it can rapidly progress to shock, coma, and death.

　　Typical patients are emaciated, with deep pigmentation of the skin and mucous membranes, decreased appetite, and fatigue. A correct diagnosis must be made by combining with laboratory tests. Mild and atypical patients may only show positive findings during stress states or after ACTH stimulation.

　　Educate patients to understand the nature of the disease, adhere to lifelong hormone replacement therapy, including long-term physiological dose replacement and short-term stress replacement therapy. The appropriate basic amount of physiological needs is supplemented in daily life; in case of complications or surgery and other stress states, to prevent crises, it is necessary to increase the dose by 3-5 times or more. Educate patients to carry disease cards with contact information and address for timely treatment.

　　I. Metabolic disorder, decreased blood sodium

　　Increased blood potassium, decreased serum chloride, decreasing blood glucose, and blood sodium/blood potassium ratio

　　II. Adrenal cortical function test

　　1. The excretion of 24h urine 17-hydroxycorticosteroids (17-OHCS) and 17-ketosteroids (17KS) is significantly lower than normal, generally below 5mg, even below 3mg or close to zero.

　　2. The 24h urine free cortisol is usually lower than the lower limit of normal, generally below 20μg/d.

　　3. The concentration of plasma 17-hydroxycorticosteroids is usually significantly lower than the lower limit of normal.

　　4. ACTH test can reflect the reserve function of the cortex.

　　III. Increase of lymphocytes in blood

　　It is usually above 40%, with an increase in eosinophils, usually above 4%, and the absolute count is usually above 300×10^6/L.

　　1. Radiographic examination of the abdominal flat film, calcification foci can be seen in the adrenal area caused by tuberculosis. Chest X-ray examination may sometimes reveal pulmonary tuberculosis and cardiac shrinkage.

　　2. Electrocardiogram shows low voltage and prolonged P-R, Q-T intervals, and electroencephalogram shows widespread α rhythm slow waves.

　　3. CT examination shows that the adrenal glands of patients with a history of tuberculosis may enlarge or calcify, while those caused by autoimmune factors may not enlarge.

　　1. Reasonable diet. The diet should be rich in carbohydrates, proteins, and vitamins, with more sodium salts and less potassium salts. If the sodium chloride in food is insufficient, it can be supplemented with tablets, with an approximate daily requirement of 10g to maintain electrolyte balance. Cereals are also foods high in protein, especially oats, which have the highest protein content, a reasonable composition of essential amino acids, and a lysine content higher than that of wheat flour and rice.

　　2. Avoid stress and prevent crises. Avoid excessive physical and mental fatigue, and try to prevent infections, injuries, vomiting, diarrhea, and other conditions.

　　First, treatment

　　The principles of treating adrenal cortical insufficiency are the same as those during non-pregnancy.

　　1. Treatment of the cause If tuberculosis is present, appropriate anti-tuberculosis treatment should be adopted.

　　2. Avoid stress to prevent critical conditions Avoid overfatigue physically and mentally, and try to prevent infection, injury, vomiting, diarrhea, and other conditions.

　　3. Correction of metabolic disorders The diet needs to be rich in carbohydrates, proteins, and vitamins, with more sodium salt and less potassium salt. If there is insufficient sodium chloride in food, it can be supplemented with tablets, about 10g per day to maintain electrolyte balance.

　　4. Endocrine replacement supplementation The dose of medication during pregnancy should be controlled at the minimum necessary amount, and appropriate increase should be made when stress occurs.

　　(1) Corticosteroid hormone therapy: ①Cortisone (cortisone): 12.5-37.5mg of hydrocortisone acetate per day by mouth, some patients may require 50mg per day, with a larger dose in the morning, a smaller dose in the afternoon, and the smallest dose in the evening; ②Cortisol (hydrocortisone): Generally 5-30mg; ③Dexamethasone and dexamethasone (prednisolone): These are synthetic glucocorticoids, which can enhance sugar metabolism by 5 times after dehydrogenation between C1 and C2 positions in the structure of cortisone and cortisol. However, they are relatively weakened in salt metabolism, and the therapeutic dose can be reduced to 1/5 of that of cortisone and other related drugs. Generally taken orally, the disadvantage of this group of drugs is that they have a smaller regulatory effect on water and salt metabolism.

　　(2) Aldosterone (salt) hormone therapy: Generally, routine application is not required, unless blood sodium and blood pressure cannot be maintained at normal levels or there is significant weight loss after treatment with cortisone acetate and a high-salt diet. ①Fludrocortisone 0.05-0.2mg per day by mouth; ②11-Deoxycorticosterone 1-2mg per day, intramuscular injection, generally not exceeding 5mg per day.

　　(3) Liquorice Extract: 20-40ml per day (diluted 1:4 and taken orally) can substitute for desoxycorticosterone to regulate the metabolism of water and electrolytes, but it is best used with cortisone (or cortisol), the main component of which is glycyrrhizinic acid, which has the effects of retaining sodium, chlorine, water, and excreting potassium.

　　5. Management during pregnancy and childbirth: Special attention should be paid to the early stages of pregnancy, the stage of childbirth, and the early postpartum period, as improper management can lead to critical conditions.

　　(1) Early pregnancy: Early pregnancy reactions such as nausea, vomiting, often induce sodium deficiency, imbalance of water and salt, resulting in reduced blood volume, decreased blood sugar, and decreased blood pressure. Therefore, attention should be paid to the supplementation of electrolytes and water, and the dosage of hormones should be increased appropriately to prevent the occurrence of critical conditions. Pregnant women with adrenal cortical insufficiency do not necessarily need induced abortion. Due to the progress of substitute therapy and antibiotic treatment, it is generally believed that the prognosis is good and the mortality rate has significantly decreased. Cohen reported that the mortality rate of pregnant women with adrenal cortical insufficiency before 1903 was 35%, from 1940 to 1947 was 18%; MeFarlane et al. reported from 1948 to 1955 was 7%; Osler reported from 1956 to 1960, after sufficient endocrine treatment, there was no case of maternal and child death.

　　(2) Mid-pregnancy: Due to the increased production of cortisols and aldosterone in the body, the symptoms may improve, and some advocate reducing the dose of steroids or maintaining the original dose.

　　(3) Late pregnancy: Due to the increased levels of estrogen and progesterone secreted by the placenta, salt retention may be slightly improved, and the patient's subjective symptoms may improve. However, pregnancy does not have a protective effect on adrenal insufficiency, and hormone replacement therapy should be used throughout the entire pregnancy period. Pregnant women without treatment may cause the disease to progress progressively.

　　(4) Delivery period: Crises may occur due to physical exhaustion, pain, bleeding, etc., so early prevention and early hospitalization for delivery are necessary. ① Induction issue: Osler reported that pregnant women with this disease have a pregnancy period 13 days longer than the control group, so induction should be avoided as much as possible, and natural childbirth is the most ideal; ② Hormone dosage: Increase hydrocortisone by 100-200mg daily during labor, and continue to apply for 1-3 days after delivery, and gradually reduce to the normal maintenance dose within 7 days after delivery; ③ Delivery method: The simplest delivery method should be adopted to end delivery, such as perineal incision, shortening the second stage of labor, etc., any major surgery can cause serious consequences. All cesarean sections should have obstetric indications, and the indications for cesarean section can be appropriately relaxed. Pay attention to the supplement of glucose saline during the delivery process to prevent bleeding and infection. Patients have poor tolerance to opioids and anesthetics, so local anesthesia and nerve block anesthesia are appropriate. If opioids are needed, the dose should be halved.

　　(5) Postpartum and early puerperium: Physiological diuresis, sweating, and hypoglycemia can all promote the occurrence of crises, so attention should be paid to the dosage of water, electrolytes, glucose, and corticosteroids. Women who receive adequate treatment can consider breastfeeding; newborns, especially full-term infants, have a good prognosis. Newborns generally do not require special treatment, but some believe that due to the use of adrenal cortical hormones by pregnant women during pregnancy, which can enter the fetus through the placenta and affect the fetal adrenal cortical function, a small amount of cortisone can be used within 1-3 days after birth to prevent adrenal cortical insufficiency.

　　II. Prognosis

　　Long-term alternative therapy can help patients maintain a normal life.