Aust NZ J Obstet Gynaecol
1992; 32: 3: 243
Indomethacin for the Treatment of Polyhydramnios: A Case of Constriction of the Ductus Arteriosus Diane Mohen:s4 MBBS, John P. Newnham:~~ MD, FRACOG, DDU and Luigi D’Orsogna:,5 MBBS, FRACP King Edward Memorial Hospital4 and Department of Paediatric Cardiology, Princess Margaret Hospital5, Subiaco, Western Australia
Summary: Prenatal administration of indomethacin for the treatment of polyhydramnios at 27 weeks’ gestation resulted in the rapid restoration of normal amniotic fluid volume. However, after 16 days therapy, fetal echocardiography revealed constriction of the fetal ductus arteriosus which did not reverse during the 17 days after the therapy was discontinued. The constriction resulted in right heart failure but no long-term effects on the infant after birth. Indomethacin is a powerful treatment for polyhydramnios but its use requires close monitoring of the fetal heart.
Polyhydramnios of any cause increases the risk of preterm labour and early birth. Surgical drainage of the fluid will reduce the uterine distension but often will precipitate placental separation and labour. Recently, indomethacin has been proposed as a medical treatment for polyhydramnios because of its known action on fetal urine output (1,2). However, enthusiasm for use of this drug in pregnancy is tempered by the possible side-effect of prenatal constriction of the ductus arteriosus (3,4). This side-effect has been observed in cases in which indomethacin was prescribed as a treatment to arrest preterm labour, but the constriction usually reverses after discontinuation of the drug (4). We report a case in which indomethacin was used successfully for the treatment of polyhydramnios but resulted in constriction of the ductus arteriosus which was displayed by prenatal echocardiography and did not reverse after the drug was ceased.
Case report A 28-year-old woman whose 2 previous pregnancies had resulted in the delivery of healthy infants.at term, presented at 24 weeks’ gestation with dyspnoea, abdominal discomfort and irregular, painful contractions. On examination the uterus was tense and the symphysialfundal height was 34 cm. Ultrasound imaging examination confirmed the presence of an increased amniotic fluid volume. Fetal growth as assessed by biparietal diameter and femur length measurements was approp1. Registrar. 2. Clinical Associate Professor. 3. Paediatric cardiologist.
Address for correspondence: John P. Newnham, Clinical Associate Professor, King Edward Memorial Hospital for Women, 374 Bagot Road, Subiaco, Western Australia, 6008.
riate for the gestational age of 24 weeks. The placenta appeared normal. A 7 cm dilatation of the fetal left renal pelvis was seen. The right kidney and bladder appeared normal. A provisional diagnosis of left ureteropelvic junctional obstruction was made. Another cause for polyhydramnios could not be identified. The woman was admitted to hospital for bed rest and corticosteroids were administered to enhance lung maturation. In order to confirm the origin of this cystic swelling and to investigate function of the kidney, the fluid was aspirated under ultrasound guidance; 130 ml of pale yellow urine were removed, biochemical analysis of which revealed a sodium concentration of 127 mmol/l and an osmolality of 250 mosm/l; these values were greater than would be expected for normal fetal urine and suggested impaired function of that kidney (5). Cordocentesis was performed and laboratory investigation of the fetal blood sample confirmed a female with normal karyotype and normal blood film. A glucose tolerance test revealed that the mother had mild gestational diabetes and her blood glucose levels thereafter were well controlled by alterations to her diet. Over the following days the left renal pelvis increased in size. Since the patient reported temporary symptomatic relief and reduced uterine activity following the previous renal aspiration, the procedure was repeated. However, by 27 weeks’ gestation the woman was in constant discomfort from the polyhydramnios and the maximum amniotic fluid pocket depth had increased to 11 cm; 170 ml of urine were aspirated after which a thorough examination of the fetal heart by colour and pulsed Doppler studies confirmed normal anatomy and a patent ductus arteriosus. Indomethacin was commenced at an oral dose of 25 mg every 6 hours. Over the next 48 hours the woman reported a copious urine output and the amniotic fluid volume decreased to normal levels, as assessed by both clinical and ultrasound examination. The indomethacin was continued
244
AUST.A N D N.Z.
J O U R N A I O F OBSTkTKICS A N D GYNATC.01 OCrY
Figure I(a). Four chamber view of the fetal heart at 30 weeks’ gestation illustrating hypertrophy of the right ventricular wall with diminished size of the cavity. The left ventricular size is normal. (LA: left atrium; LV left ventricle; IVS: interventricular septum; R V right ventricle; RA: right atrium).
Figure I(b). Pulsed Doppler examination confirming normal flow velocity across the mitral valve.
at a dose of 100 mg/day and fetal echocardiography was performed at 7-day intervals. Sixteen days after commencement of indomethacin the fetal heart appeared enlarged and there was mild dilatation of the right atrium and ventricle. The indomethacin dose was reduced to 25 mg given every 8 hours. One week later, the fetal ductus could not be demonstrated and was presumed to be constricted. The right ventricular enlargement and hypertrophy had increased and there was marked reduction in flow across the tricuspid valve with mild tricuspid incompetence. The right ventricular contractility appeared severely depressed. These findings were consistent with a poorly compliant and contractile right ventricle. Mild hepatic vein dilatation and a small pericardial effusion were present. Left heart function appeared entirely normal. Indomethacin therapy was ceased after a total of 23 days
Figure I(c). Pulsed Doppler examination of the same plane as shown in figure I(b) confirming very low flow velocity across the tricuspid valve secondary to prenatal constriction of the ductus arteriosus.
of administration. The amniotic fluid volume remained normal. Fifteen days following cessation of the indomethacin, at 32 weeks’ gestation, fetal echocardiography still failed to demonstrate flow across the ductus arteriosus and showed persistent right ventricular dilatation and hypertrophy, greater distension of the hepatic veins and inferior vena cava, and a definite pericardial effusion. The findings indicated right heart failure. Weekly fetal heart rate monitoring was commenced at 31 weeks’ gestation. At 32 weeks and 6 days gestation the fetal heart rate pattern indicated persistent nonreactivity with occasional late decelerations following spontaneous uterine contractions. Labour was induced by administration of extraamniotic prostaglandin F2 alpha followed by artificial rupture of the membranes and infusion of oxytocin. After a short but closely monitored labour a female infant, birth-weight 2,040 g was delivered, with Apgar scores of 7 and 9 at 1 and 5 minutes respectively; she developed mi[d respiratory distress and required supplemental oxygen for I day. Echocardiography on day 2 of postnatal life demonstrated marked right ventricular hypertrophy with flattening of the ventricular septum during systole consistent with elevated right ventricular pressure, bidirectional shunting across the foramen ovale, and normal tricuspid and pulmonary valve function. The ductus arteriosus was not patent. The appearances were of marked right ventricular hypertrophy with pulmonary hypertension (figure 1). The infant was subsequently shown to have severe hydronephrosis of a nonfunctioning left kidney and mild ureteropelvic junctional obstruction of an otherwise normally functioning right kidney. At one month of age she underwent a left nephrectomy and right-sided pyeloplasty and at 3 months of age she was well with no demonstrable abnormality of the cardiorespiratory system.
DIANEMOHENET AL
DISCUSSION This case has demonstrated the profound effect that indomethacin can have on amniotic fluid volume. In 48 hours, symptomatic polyhydramnios was reduced to an amniotic fluid volume which on clinical and sonographic criteria was entirely normal. The principal action on amniotic fluid volume is believed to be a reduction in fetal urine output which in late pregnancy is the major source of amniotic fluid. This effect on urine production after administration of indomethacin has been demonstrated both before and after birth (2,3). Indomethacin freely crosses the placenta and within 2 hours circulating levels in the fetus are one half those in the mother (6). Through inhibition of prostaglandin synthetase, indomethacin reduces prostaglandin E formation. This class of prostaglandins has been shown to antagonize the effects of vasopressin on the proximal tubule (7) and elevated vasopressin levels have been found after indomethacin has been administered to human infants (8). There is not an associated alteration in renal arterial vascular resistance, at least as can be assessed by Doppler waveform analysis (9). Lung liquid also contributes to amniotic fluid volume in late pregnancy. Indomethacin administered to chronically catheterized fetal sheep has been shown to reduce by two thirds the production of lung fluid (lo), to increase fetal breathing movements (1l), and possibly to reduce fetal swallowing (10). Together the combined effects of indomethacin on urine output and lung fluid production appear to have a potent ability to treat polyhydramnios and even to cause oligohydramnios (12). However, indomethacin may also constrict the ductus arteriosus. After birth, medical closure of the ductus arteriosus by administration of indomethacin has been in use for many years as a standard medical therapy (3) and a similar effect can also occur in utero. The mechanism is inhibition of synthesis of the prostaglandins which are required to maintain patency of the ductus arteriosus and pulmonary vessels (13). Prenatal patency of the ductus arteriosus is known t o be important because congenital absence of the ductus arteriosus as an isolated abnormality results in nonimmune hydrops and fetal death (14). Exposure t o indomethacin before birth in animal models can result in constriction of the ductus arteriosus and increased pulmonary vascular resistance (13) which in turn may lead to increased right ventricular pressure, subendocardial ischaemia and tricuspid insufficiency (15). These cardiopulmonary changes were observed in the case reported here, but in addition, with time the right ventricle became hypertrophied. In the presence of increased pulmonary vascular resistance the ventricle became less compliant with markedly diminished inflow and poor contractility, leading to cardiac failure. Other authors have also reported prenatal constriction of the ductus after exposure of human fetuses to indomethacin. Itskovitz and coworkers reported 3 cases in which it was believed that
245
indomethacin, administered to arrest preterm labour, had resulted in oligohydramnios, meconium passage and fetal death (12). When evaluated by serial fetal echocardiography, the rate of indomethacin induced constriction of the ductus arteriosus appears to be 30-50% (4,16). Of those in which there is ductal constriction, approximately one third will be of a severity sufficient to also develop tricuspid regurgitation. Most cases of ductal constriction have been shown to resolve in utero after discontinuation of the indomethacin (4,16); however, in the case reported here the ductus remained constricted and right heart failure was present 17 days after the drug was ceased, indicating that resolution will not always occur. Nevertheless, the consequences for the neonate of irreversible prenatal constriction of the ductus arteriosus appear small and in our case we did not observe any long-term untoward effects. The sequence of prenatal closure of the ductus arteriosus, fetal heart failure and perinatal demise must be considered a possible outcome when indomethacin is used during pregnancy. In addition, the consequences for the surviving infant of prenatal ductal constriction remain uncertain. Equally uncertain is whether the risk is dose-dependent and if the duration of treatment is critical. In the case outlined in this report the effect on amniotic fluid volume of indomethacin at a dose of 100 mg per day was dramatic. It is possible that a smaller dose of indomethacin may have had an equally beneficial effect on amniotic fluid volume but have been less likely to interfere with the fetal ductus arteriosus. Indomethacin is a useful treatment for severe polyhydramnios developing at gestational ages where it is desirable to prolong the pregnancy. However, the risks associated with its use dictate that close fetal monitoring, with particular attention to the fetal ductus arteriosus and heart function, be part of the overall management.
References 1. Cabrol D, Landesman R, Muller J, Uzan M, Sureau C, Saxena
BB. Treatment of polyhydramnios with prostaglandin synthetase inhibitor (indomethacin). Am J Obstet Cynecol 1987; 157: 422-426. 2. Kirshon B, Moise KJ, Wasserstrum N, Ou C, Huhta JC. Influence
3.
4. 5.
6.
of short-term indomethacin therapy o n fetal urine output. Obstet Gynecol 1988; 72: 51-53. Heymann MA, Rudolph AM, Silverman NH. Closure of the ductus arteriosus in premature infants by inhibition of prostaglandin synthesis. N Eng J Med 1976; 295: 530-535. Moise KJ, Huhta JC, Sharif DS et al. Indomethacin in the treatment of premature labor. New Eng J Med 1988; 319: 327-331. Golbus MS, Filly RA, Callen PW, Click PL, Harrison MR, Anderson RL. Fetal urinary tract obstruction: management and selection for treatment. Semin Perinatol 1985; 9: 91-97. Parks BR, Jordan RL, Rawson JE, Douglas BH. Indomethacin: studies of absorption and placental transfer. Am J Obstet Gynecol
1977; 129: 464-465. 7. Anderson R, Berl T, McDonald K et al. Evidence for an in vitro
antagonism between vasopressin and prostaglandin in the mammalian kidney. J Clin Invest 1975; 56: 420-426.
246
AUST.AND N.Z. JOURNALOF OBSTETRICS AND GYNAECOLOGY
8. Seyberth HW, Rascher W, Hackenthal R, Wille L. Effect of prolonged indomethacin therapy o n renal function and selected vasoactive hormones in very low birth weight infants with symptomatic ductus arteriosus. J Pediatr 1983; 103: 979-984. 9. Mari G, Moise KJ, Deter RL, Kirshon B, Carpenter RJ. Doppler assessment of the renal blood flow velocity waveform during indomethacin therapy for preterm labor and polyhydramnios. Obstet Gynecol 1990; 75: 199-201. 10. Wlodek ME, Harding R, Hooper SB, Thorburn GD. How does indomethacin cause oligohydramnios? Proceedings of 9th Annual Congress of the Australian Perinatal Society, Melbourne 1991; A33. 11. Kitterman JA, Liggins GC. Fetal breathing movements and inhibitors of prostaglandin synthesis. Semin Perinatol 1980; 4 97-100.
12. ltskovitz J, Abramovici H, Brandis JM. Oligohydramnios, meconium, and perinatal death concurrent with indomethacin treatment in human pregnancy. J Reprod Med 1980; 24: 137-140. 13. Heymann MA, Rudolph AM. Effects of acetylsalicylic acid on the ductus arteriosus and circulation in fetal lambs in utero. Circ Res 1976; 38: 418-422. 14. Harlass FE, Duff P, Brady K, Read J. Hydrops fetalis and premature closure of the ductus arteriosus: A review. Obstet Gynecol Surv 1989; 44: 541-543. 15. Turner GR, Levin DL. Prostaglandin synthesis inhibition in persistent pulmonary hypertension of the newborn. Clinic Perinatol 1984; 11: 581-589. 16. Kirshon B, Mari 0, Moise KJ, Wasserstrum N. Effect of indomethacin on the fetal ductus arteriosus during treatment of symptomatic polyhydramnios. J Reprod Med 1990; 35: 529-532.
Aust NZ J Obstet Gynaecol 1992; 32: 3: 246
Campylobacter Jejuni in Pregnancy J. Goh', MBBS and M. Flynn', MBBS Department of Obstetrics and Gynaecology, Mater Misericordiae Hospital, South Brisbane, Queensland EDITORIAL COMMENT: We accepted this paper for publication since it reinforces the message carried by the paper by D. 1 Farrell and M. 7: Harris (Aust NZ J Obstet Gynaecol 1992; 32: 172-174) that Campylobacter species can cause perinatal infection and deaths. Irma Kruszelnicki, the senior microbiologist at the Mercy Hospital for Women, provided the information that at this hospital faecal samples from patients presenting with clinical symptoms of diarrhoea are routinely screened for Campylobacter species using selective media. Specimens which are mucoid, bloody or purulent are examined by direct preparation microscopy since this often gives an indication of the presence of Campylobacter namely seeing numerous leucocytes and characteristically vibrantly-motilecurved organisms. Since 1982 there have been 8 cases of Campylobacter species isolated, 7from faeces (all Campylobacterjejuni) in patients (4 adults, 3 neonates) with clinical symptoms or signs of enteritisand one positive blood culture (Campylobacter fetussubspeciesfetus) from an infant who had clinicalfeatures of septicaemia andsurvived after treatment with gentamicin.
Summary: Case notes of pregnancies with proven Campylobacter jejuni infections were collected from 2 Queensland teaching hospitaIs and reviewed. Of these cases, 2 pregnancies (3 fetuses) resulted in stillbirths, 2 neonates required treatment with antibiotic therapy within 2 days of birth, while the remaining 2 pregnancies were treated at the time of the infection and were not associated with adverse outcome. Maternal Campylobacter infection should be actively sought for in the patient with suspected infectious diarrhoea.
1. Registrar.
Address for correspondence: Dr. J. Goh, Department of Obstetrics and Gynaecology, Mater Misericordiae Hospital, South Brisbane, Queensland.
1992; 32: 3: 243
Indomethacin for the Treatment of Polyhydramnios: A Case of Constriction of the Ductus Arteriosus Diane Mohen:s4 MBBS, John P. Newnham:~~ MD, FRACOG, DDU and Luigi D’Orsogna:,5 MBBS, FRACP King Edward Memorial Hospital4 and Department of Paediatric Cardiology, Princess Margaret Hospital5, Subiaco, Western Australia
Summary: Prenatal administration of indomethacin for the treatment of polyhydramnios at 27 weeks’ gestation resulted in the rapid restoration of normal amniotic fluid volume. However, after 16 days therapy, fetal echocardiography revealed constriction of the fetal ductus arteriosus which did not reverse during the 17 days after the therapy was discontinued. The constriction resulted in right heart failure but no long-term effects on the infant after birth. Indomethacin is a powerful treatment for polyhydramnios but its use requires close monitoring of the fetal heart.
Polyhydramnios of any cause increases the risk of preterm labour and early birth. Surgical drainage of the fluid will reduce the uterine distension but often will precipitate placental separation and labour. Recently, indomethacin has been proposed as a medical treatment for polyhydramnios because of its known action on fetal urine output (1,2). However, enthusiasm for use of this drug in pregnancy is tempered by the possible side-effect of prenatal constriction of the ductus arteriosus (3,4). This side-effect has been observed in cases in which indomethacin was prescribed as a treatment to arrest preterm labour, but the constriction usually reverses after discontinuation of the drug (4). We report a case in which indomethacin was used successfully for the treatment of polyhydramnios but resulted in constriction of the ductus arteriosus which was displayed by prenatal echocardiography and did not reverse after the drug was ceased.
Case report A 28-year-old woman whose 2 previous pregnancies had resulted in the delivery of healthy infants.at term, presented at 24 weeks’ gestation with dyspnoea, abdominal discomfort and irregular, painful contractions. On examination the uterus was tense and the symphysialfundal height was 34 cm. Ultrasound imaging examination confirmed the presence of an increased amniotic fluid volume. Fetal growth as assessed by biparietal diameter and femur length measurements was approp1. Registrar. 2. Clinical Associate Professor. 3. Paediatric cardiologist.
Address for correspondence: John P. Newnham, Clinical Associate Professor, King Edward Memorial Hospital for Women, 374 Bagot Road, Subiaco, Western Australia, 6008.
riate for the gestational age of 24 weeks. The placenta appeared normal. A 7 cm dilatation of the fetal left renal pelvis was seen. The right kidney and bladder appeared normal. A provisional diagnosis of left ureteropelvic junctional obstruction was made. Another cause for polyhydramnios could not be identified. The woman was admitted to hospital for bed rest and corticosteroids were administered to enhance lung maturation. In order to confirm the origin of this cystic swelling and to investigate function of the kidney, the fluid was aspirated under ultrasound guidance; 130 ml of pale yellow urine were removed, biochemical analysis of which revealed a sodium concentration of 127 mmol/l and an osmolality of 250 mosm/l; these values were greater than would be expected for normal fetal urine and suggested impaired function of that kidney (5). Cordocentesis was performed and laboratory investigation of the fetal blood sample confirmed a female with normal karyotype and normal blood film. A glucose tolerance test revealed that the mother had mild gestational diabetes and her blood glucose levels thereafter were well controlled by alterations to her diet. Over the following days the left renal pelvis increased in size. Since the patient reported temporary symptomatic relief and reduced uterine activity following the previous renal aspiration, the procedure was repeated. However, by 27 weeks’ gestation the woman was in constant discomfort from the polyhydramnios and the maximum amniotic fluid pocket depth had increased to 11 cm; 170 ml of urine were aspirated after which a thorough examination of the fetal heart by colour and pulsed Doppler studies confirmed normal anatomy and a patent ductus arteriosus. Indomethacin was commenced at an oral dose of 25 mg every 6 hours. Over the next 48 hours the woman reported a copious urine output and the amniotic fluid volume decreased to normal levels, as assessed by both clinical and ultrasound examination. The indomethacin was continued
244
AUST.A N D N.Z.
J O U R N A I O F OBSTkTKICS A N D GYNATC.01 OCrY
Figure I(a). Four chamber view of the fetal heart at 30 weeks’ gestation illustrating hypertrophy of the right ventricular wall with diminished size of the cavity. The left ventricular size is normal. (LA: left atrium; LV left ventricle; IVS: interventricular septum; R V right ventricle; RA: right atrium).
Figure I(b). Pulsed Doppler examination confirming normal flow velocity across the mitral valve.
at a dose of 100 mg/day and fetal echocardiography was performed at 7-day intervals. Sixteen days after commencement of indomethacin the fetal heart appeared enlarged and there was mild dilatation of the right atrium and ventricle. The indomethacin dose was reduced to 25 mg given every 8 hours. One week later, the fetal ductus could not be demonstrated and was presumed to be constricted. The right ventricular enlargement and hypertrophy had increased and there was marked reduction in flow across the tricuspid valve with mild tricuspid incompetence. The right ventricular contractility appeared severely depressed. These findings were consistent with a poorly compliant and contractile right ventricle. Mild hepatic vein dilatation and a small pericardial effusion were present. Left heart function appeared entirely normal. Indomethacin therapy was ceased after a total of 23 days
Figure I(c). Pulsed Doppler examination of the same plane as shown in figure I(b) confirming very low flow velocity across the tricuspid valve secondary to prenatal constriction of the ductus arteriosus.
of administration. The amniotic fluid volume remained normal. Fifteen days following cessation of the indomethacin, at 32 weeks’ gestation, fetal echocardiography still failed to demonstrate flow across the ductus arteriosus and showed persistent right ventricular dilatation and hypertrophy, greater distension of the hepatic veins and inferior vena cava, and a definite pericardial effusion. The findings indicated right heart failure. Weekly fetal heart rate monitoring was commenced at 31 weeks’ gestation. At 32 weeks and 6 days gestation the fetal heart rate pattern indicated persistent nonreactivity with occasional late decelerations following spontaneous uterine contractions. Labour was induced by administration of extraamniotic prostaglandin F2 alpha followed by artificial rupture of the membranes and infusion of oxytocin. After a short but closely monitored labour a female infant, birth-weight 2,040 g was delivered, with Apgar scores of 7 and 9 at 1 and 5 minutes respectively; she developed mi[d respiratory distress and required supplemental oxygen for I day. Echocardiography on day 2 of postnatal life demonstrated marked right ventricular hypertrophy with flattening of the ventricular septum during systole consistent with elevated right ventricular pressure, bidirectional shunting across the foramen ovale, and normal tricuspid and pulmonary valve function. The ductus arteriosus was not patent. The appearances were of marked right ventricular hypertrophy with pulmonary hypertension (figure 1). The infant was subsequently shown to have severe hydronephrosis of a nonfunctioning left kidney and mild ureteropelvic junctional obstruction of an otherwise normally functioning right kidney. At one month of age she underwent a left nephrectomy and right-sided pyeloplasty and at 3 months of age she was well with no demonstrable abnormality of the cardiorespiratory system.
DIANEMOHENET AL
DISCUSSION This case has demonstrated the profound effect that indomethacin can have on amniotic fluid volume. In 48 hours, symptomatic polyhydramnios was reduced to an amniotic fluid volume which on clinical and sonographic criteria was entirely normal. The principal action on amniotic fluid volume is believed to be a reduction in fetal urine output which in late pregnancy is the major source of amniotic fluid. This effect on urine production after administration of indomethacin has been demonstrated both before and after birth (2,3). Indomethacin freely crosses the placenta and within 2 hours circulating levels in the fetus are one half those in the mother (6). Through inhibition of prostaglandin synthetase, indomethacin reduces prostaglandin E formation. This class of prostaglandins has been shown to antagonize the effects of vasopressin on the proximal tubule (7) and elevated vasopressin levels have been found after indomethacin has been administered to human infants (8). There is not an associated alteration in renal arterial vascular resistance, at least as can be assessed by Doppler waveform analysis (9). Lung liquid also contributes to amniotic fluid volume in late pregnancy. Indomethacin administered to chronically catheterized fetal sheep has been shown to reduce by two thirds the production of lung fluid (lo), to increase fetal breathing movements (1l), and possibly to reduce fetal swallowing (10). Together the combined effects of indomethacin on urine output and lung fluid production appear to have a potent ability to treat polyhydramnios and even to cause oligohydramnios (12). However, indomethacin may also constrict the ductus arteriosus. After birth, medical closure of the ductus arteriosus by administration of indomethacin has been in use for many years as a standard medical therapy (3) and a similar effect can also occur in utero. The mechanism is inhibition of synthesis of the prostaglandins which are required to maintain patency of the ductus arteriosus and pulmonary vessels (13). Prenatal patency of the ductus arteriosus is known t o be important because congenital absence of the ductus arteriosus as an isolated abnormality results in nonimmune hydrops and fetal death (14). Exposure t o indomethacin before birth in animal models can result in constriction of the ductus arteriosus and increased pulmonary vascular resistance (13) which in turn may lead to increased right ventricular pressure, subendocardial ischaemia and tricuspid insufficiency (15). These cardiopulmonary changes were observed in the case reported here, but in addition, with time the right ventricle became hypertrophied. In the presence of increased pulmonary vascular resistance the ventricle became less compliant with markedly diminished inflow and poor contractility, leading to cardiac failure. Other authors have also reported prenatal constriction of the ductus after exposure of human fetuses to indomethacin. Itskovitz and coworkers reported 3 cases in which it was believed that
245
indomethacin, administered to arrest preterm labour, had resulted in oligohydramnios, meconium passage and fetal death (12). When evaluated by serial fetal echocardiography, the rate of indomethacin induced constriction of the ductus arteriosus appears to be 30-50% (4,16). Of those in which there is ductal constriction, approximately one third will be of a severity sufficient to also develop tricuspid regurgitation. Most cases of ductal constriction have been shown to resolve in utero after discontinuation of the indomethacin (4,16); however, in the case reported here the ductus remained constricted and right heart failure was present 17 days after the drug was ceased, indicating that resolution will not always occur. Nevertheless, the consequences for the neonate of irreversible prenatal constriction of the ductus arteriosus appear small and in our case we did not observe any long-term untoward effects. The sequence of prenatal closure of the ductus arteriosus, fetal heart failure and perinatal demise must be considered a possible outcome when indomethacin is used during pregnancy. In addition, the consequences for the surviving infant of prenatal ductal constriction remain uncertain. Equally uncertain is whether the risk is dose-dependent and if the duration of treatment is critical. In the case outlined in this report the effect on amniotic fluid volume of indomethacin at a dose of 100 mg per day was dramatic. It is possible that a smaller dose of indomethacin may have had an equally beneficial effect on amniotic fluid volume but have been less likely to interfere with the fetal ductus arteriosus. Indomethacin is a useful treatment for severe polyhydramnios developing at gestational ages where it is desirable to prolong the pregnancy. However, the risks associated with its use dictate that close fetal monitoring, with particular attention to the fetal ductus arteriosus and heart function, be part of the overall management.
References 1. Cabrol D, Landesman R, Muller J, Uzan M, Sureau C, Saxena
BB. Treatment of polyhydramnios with prostaglandin synthetase inhibitor (indomethacin). Am J Obstet Cynecol 1987; 157: 422-426. 2. Kirshon B, Moise KJ, Wasserstrum N, Ou C, Huhta JC. Influence
3.
4. 5.
6.
of short-term indomethacin therapy o n fetal urine output. Obstet Gynecol 1988; 72: 51-53. Heymann MA, Rudolph AM, Silverman NH. Closure of the ductus arteriosus in premature infants by inhibition of prostaglandin synthesis. N Eng J Med 1976; 295: 530-535. Moise KJ, Huhta JC, Sharif DS et al. Indomethacin in the treatment of premature labor. New Eng J Med 1988; 319: 327-331. Golbus MS, Filly RA, Callen PW, Click PL, Harrison MR, Anderson RL. Fetal urinary tract obstruction: management and selection for treatment. Semin Perinatol 1985; 9: 91-97. Parks BR, Jordan RL, Rawson JE, Douglas BH. Indomethacin: studies of absorption and placental transfer. Am J Obstet Gynecol
1977; 129: 464-465. 7. Anderson R, Berl T, McDonald K et al. Evidence for an in vitro
antagonism between vasopressin and prostaglandin in the mammalian kidney. J Clin Invest 1975; 56: 420-426.
246
AUST.AND N.Z. JOURNALOF OBSTETRICS AND GYNAECOLOGY
8. Seyberth HW, Rascher W, Hackenthal R, Wille L. Effect of prolonged indomethacin therapy o n renal function and selected vasoactive hormones in very low birth weight infants with symptomatic ductus arteriosus. J Pediatr 1983; 103: 979-984. 9. Mari G, Moise KJ, Deter RL, Kirshon B, Carpenter RJ. Doppler assessment of the renal blood flow velocity waveform during indomethacin therapy for preterm labor and polyhydramnios. Obstet Gynecol 1990; 75: 199-201. 10. Wlodek ME, Harding R, Hooper SB, Thorburn GD. How does indomethacin cause oligohydramnios? Proceedings of 9th Annual Congress of the Australian Perinatal Society, Melbourne 1991; A33. 11. Kitterman JA, Liggins GC. Fetal breathing movements and inhibitors of prostaglandin synthesis. Semin Perinatol 1980; 4 97-100.
12. ltskovitz J, Abramovici H, Brandis JM. Oligohydramnios, meconium, and perinatal death concurrent with indomethacin treatment in human pregnancy. J Reprod Med 1980; 24: 137-140. 13. Heymann MA, Rudolph AM. Effects of acetylsalicylic acid on the ductus arteriosus and circulation in fetal lambs in utero. Circ Res 1976; 38: 418-422. 14. Harlass FE, Duff P, Brady K, Read J. Hydrops fetalis and premature closure of the ductus arteriosus: A review. Obstet Gynecol Surv 1989; 44: 541-543. 15. Turner GR, Levin DL. Prostaglandin synthesis inhibition in persistent pulmonary hypertension of the newborn. Clinic Perinatol 1984; 11: 581-589. 16. Kirshon B, Mari 0, Moise KJ, Wasserstrum N. Effect of indomethacin on the fetal ductus arteriosus during treatment of symptomatic polyhydramnios. J Reprod Med 1990; 35: 529-532.
Aust NZ J Obstet Gynaecol 1992; 32: 3: 246
Campylobacter Jejuni in Pregnancy J. Goh', MBBS and M. Flynn', MBBS Department of Obstetrics and Gynaecology, Mater Misericordiae Hospital, South Brisbane, Queensland EDITORIAL COMMENT: We accepted this paper for publication since it reinforces the message carried by the paper by D. 1 Farrell and M. 7: Harris (Aust NZ J Obstet Gynaecol 1992; 32: 172-174) that Campylobacter species can cause perinatal infection and deaths. Irma Kruszelnicki, the senior microbiologist at the Mercy Hospital for Women, provided the information that at this hospital faecal samples from patients presenting with clinical symptoms of diarrhoea are routinely screened for Campylobacter species using selective media. Specimens which are mucoid, bloody or purulent are examined by direct preparation microscopy since this often gives an indication of the presence of Campylobacter namely seeing numerous leucocytes and characteristically vibrantly-motilecurved organisms. Since 1982 there have been 8 cases of Campylobacter species isolated, 7from faeces (all Campylobacterjejuni) in patients (4 adults, 3 neonates) with clinical symptoms or signs of enteritisand one positive blood culture (Campylobacter fetussubspeciesfetus) from an infant who had clinicalfeatures of septicaemia andsurvived after treatment with gentamicin.
Summary: Case notes of pregnancies with proven Campylobacter jejuni infections were collected from 2 Queensland teaching hospitaIs and reviewed. Of these cases, 2 pregnancies (3 fetuses) resulted in stillbirths, 2 neonates required treatment with antibiotic therapy within 2 days of birth, while the remaining 2 pregnancies were treated at the time of the infection and were not associated with adverse outcome. Maternal Campylobacter infection should be actively sought for in the patient with suspected infectious diarrhoea.
1. Registrar.
Address for correspondence: Dr. J. Goh, Department of Obstetrics and Gynaecology, Mater Misericordiae Hospital, South Brisbane, Queensland.
![[Premature constriction of the ductus arteriosus].](/assets/img/hold.png)
