Bartter Syndrome and pregnancy

Bartter's syndrome and pregnancy


Ref: European Journal of Obstetrics & Gynecology and Reproductive Biology 121 (2005) 117–123

We found a 33 year-old woman, gravida 3 Para 1-0-1-1, showing hyperemesis, diarrhea and fever at 9 weeks gestation. Three years before she had a vaginal delivery of a healthy infant, born at term after normal pregnancy. She also presented a second trimester abortion.
With the diagnosis of gastroenteritis she was admitted to hospital. Routine analysis, including electrolytes, showed severe hypokalemia (1.5 mmol/L). The diagnosis of Bartter's syndrome was based on increased sodium and potassium fractional excretion, and the family history of a brother diagnosed and treated for classic Bartter's syndrome of adult onset subsequently revealed through the accurate collection of medical history data.
She was started on potassium replacement therapy to maintain serum levels at 2.5 mmol/L and was discharged and treated on an outpatient basis. She was closely followed up with potassium level determinations in our prenatal clinic until 19 weeks gestation when she presented a viral infection and required hospital admission. Serum potassium decreased to 1.7 mmol/L and was corrected to normal range with intravenous potassium (80 mmol/day). After discharge she was maintained on oral supplementation.
Serial ultrasonographic examination during pregnancy showed adequate intrauterine growth and normal amounts of amniotic fluid. Serum potassium was stabilized with oral potassium without needing spironolactone therapy to control symptoms. However, an increasing demand for potassium supplements was documented.
At 37 gestational weeks she presented a decrease in serum potassium and sodium levels (2.1 and 133 mmol/L), respectively. Pregnancy termination was proposed by prostaglandin induction. She had a vaginal delivery of a male infant weighing 3200 g with normal Apgar scores. Postpartum potassium controls at 24, 48, and 72 h were all over 2.4 mmol/L. The infant did not present the renal disorder and both were discharged normally. Because of maternal breastfeeding, ibuprophene and amiloride were used as treatment.
Bartter's syndrome is a rare recessive autosomal disorder characterized by hypokalemia secondary to renal potassium wasting, metabolic alkalosis, normal to low blood pressure and increased production of renal prostaglandins. Recent studies have described mutations in genes encoding transport proteins important in sodium and chloride reabsorption in the thick ascending limb of the loop of Henle. Different phenotypes of Bartter's syndrome have been recognized. Antenatal Bartter's syndrome is characterized by polyhidramnios and premature delivery while the classic Bartter's syndrome usually presents during childhood, adolescence, or in women in pregestational age as weakness or muscle cramps.
Bartter's syndrome, although extremely rare in pregnancy, requires prompt recognition and careful management as it may have significant maternal and neonatal implications [1], and should be suspected in case of hypokalemia without other origin.
There are few cases reported in literature of pregnant women with Bartter's syndrome of childhood onset [2], [3] and [4], and we have found a case of a pregnant diagnosed only during the treatment for preterm delivery in third trimester [5], but not either during the first part of pregnancy or during the course of the third pregnancy.
An increasing demand of potassium supplements is usually required in the treatment. Sometimes the use of spironolactone is needed as well as prostaglandin synthetase inhibitors to reduce potassium wasting and to control symptoms. Since the syndrome was diagnosed during the first term of pregnancy, using other treatments was not considered due to a possible repercussion on maternal and fetal hemodinamic. Our patient managed to reach 37th week gestation only with oral potassium supplements maintaining acceptable levels of serum potassium considered safe and well tolerated.
Absence of pregnancy complications such as polyhydramnios indicated that the fetus was unlikely to be affected. Although it seems patients with this syndrome may have an increased risk of developing intrauterine growth retardation [2], the fetus presented an adequate growth.




2. Bartter's syndrome and pregnancy

Ref: European Journal of Obstetrics & Gynecology and Reproductive Biology 82 (1999) 17–18


1. Introduction

Bartter's syndrome (BS) is a rare autosomal recessive inherited renal tubular disorder characterized by severe hypokalemia, metabolic alkalosis, hyperaldosteronism and normal blood pressure. Because of its rarity, reports on pregnancy associated to this disease are scant, and maternal and fetal risks are still unknown.

2. Case report

A 31-year-old white pregnant woman with Bartter's syndrome was referred to the Maternal-Fetal Unit of the Department of Obstetrics and Gynecology, Santa Maria University Hospital, Lisbon, in October 1996 with a 9-week gestation. She had a long standing history of frequent vomiting, polyuria, polydipsia, growth retardation and learning difficulties, until she was presented to the Pediatric Nephrology Unit at the age of 19 years. She had a thin distinctive appearance with a triangular face, emotional lability, mild mental retardation (IQ 61%), hyperreflexia, intentional tremor and slightly spastic gait. Cortical atrophy was noted at magnetic resonance image. On initial presentation, hypokalemia (2.4 mEq/l), hypochloremia (87 mEq/l), metabolic alkalosis (HCO3 32 mEq/l) and increased urinary calcium/creatinine ratio (1.4 mmol/mmol) were noted, with normal serum calcium and magnesium. Renal ultrasound showed extensive medullar nephrocalcinosis. The glomerular filtration rate was low (70 ml/min/1.73 m2).
After extensive testing the diagnosis of Bartter's syndrome was defined based on the above mentioned electrolytic alterations and increased plasma renin (35.4 ng/min/h; normal=1.8–6.7) and aldosterone (736 pg/ml; normal=70–295) with normal blood pressure, increased urinary potassium excretion (CK/100 ml GFR 37.8%) and a low fractional distal reabsorption of chloride (CH2O/CH2O+Cl=58.7%) during hypotonic saline diuresis (performed according to the protocol of Rodriguez Soriano [1]). Treatment with potassium chloride and indomethacin (2 mg/kg/day) was started with clinical and laboratorial improvement. She had her growth spurt and menarche by the age of 21 years. When she was 23 years old, her weight was 44 kg and her height 145 cm. Later, in 1995, genetic study (performed by the Boyer Center for Molecular Medicine of Yale University School of Medicine) showed a mutation in the Na-K-2Cl cotransporter (NKCC2).
Indomethacin was intentionally discontinued 6 months before pregnancy and she was put only on oral potassium supplementation. Diuresis increased from 4.5 to 6 l/day and urinary calcium creatinine rate from 0.4 to 0.6 (mg/mg). Throughout the first and second trimesters of pregnancy the daily dose of oral potassium chloride supplementation was progressively increased (320 to 480 mEq/day). Although she had no clinical complaints, hypokalemia was frequently found with levels of 2.5–3.0 mEq/l. In the third trimester potassium serum levels stabilized at levels of 3.3–3.7 mEq/l with a regimen of 480 mEq potassium chloride daily. During pregnancy, blood pressure and plasma creatinine (90–95 mmol/l) remained within normal levels. At 29 weeks, gestational diabetes mellitus was diagnosed and controlled only with dietary measures. Follow-up sonographic examination demonstrated adequate fetal growth. At 38 weeks a cesarean delivery was done for breech presentation. The male infant weight was 3850 g and the Apgar scores were 8 and 9 at the 1st and 5th min, respectively. At birth his serum potassium was normal (3.8 mEq/l) and was discharged with the mother on the fifth day after delivery.
Maternal medication at discharge was 480 mEq potassium chloride per day. Over the next 6 weeks the daily dose was reduced and indomethacin was added.

3. Comments

In BS, clinical disease results from defective renal reabsorption of sodium chloride in the ascending thick limb of Henle's loop [1, 2, 3]. There are few reports of pregnancy in women with BS but fetal risks do not seem to be increased [4, 5]. The mainstay of medical management of these patients, especially during pregnancy, is close monitoring of potassium serum levels since maintenance of normal levels is difficult, probably due to the increase of potassium needs. Indomethacin, the drug most frequently used in these patients, should be avoided in gestation, since oligohydramnios and/or fetal renal failure may occur. Potassium sparing diuretics (amiloride and spironolactone) have been used during pregnancy in patients with BS without hazards to the fetus [5, 6, 7] however undervirilization in the male fetus induced by spironolactone and its natriuretic effect may increase the risk of volume depletion.
In our patient, an almost normal serum potassium level was achieved in the third trimester only with oral potassium supplementation and no fetal growth retardation was noted despite the maternal episodes of hypokalemia. Since the potential ominous effects of the treatment on the fetus are a clinical concern the outcome of our case allows the conclusion that conservative therapy with potassium chloride supplementation alone may be effective and safe in the management of this subtype of maternal Bartter's syndrome. In fact, three genetic defects have been described in BS: mutation in the Na-K-2Cl cotransporter (type I BS), in ROMK 1 (type II BS) and recently in ClCNKB (type III BS) [8]. Although all of these patients have the same clinical features of hypokalemic alkalosis, salt wasting, normal serum magnesium and normal or increased calciuria, nephrocalcinosis was only found in patients who have the ROMK or the Na-K-2Cl cotransporter mutations, as in our patient.