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Management of Oligohydramnios with Antepartum Amnioinfusion, Amniopatch and Cerclage
■ ORIGINAL ARTICLE ■
Amnioinfusion & Amniopatch for Oligohydramnios
MANAGEMENT OF OLIGOHYDRAMNIOS WITH ANTEPARTUM AMNIOINFUSION, AMNIOPATCH AND CERCLAGE 1,2
2
3
2
Ming Chen *, Chang-Yao Hsieh , Alan D. Cameron , Jin-Chung Shih , 2 2 1 4 Chien-Nan Lee , Hong-Nerng Ho , Tze-Ho Chen , Chih-Ping Chen 1
Department of Obstetrics and Gynecology, and Center for Medical Genetics, Changhua Christian Hospital, Changhua, 2 Department of Obstetrics and Gynecology, National Taiwan University Hospital, 4 Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan, and 3 Department of Fetal Medicine, Queen Mother’s Hospital, Glasgow, U.K.
SUMMARY Objective: To evaluate the efficacy and safety of aggressive management of oligohydramnios. Methods: Forty women with oligohydramnios (< 30 complete weeks), either because of preterm premature rupture of membranes or with intact membranes, were prospectively enrolled in this study. Eleven women were assigned to the treatment group and 29 to the control group. Transabdominal amnioinfusion was performed with warm Ringer’s lactate or normal saline in all 11 patients in the treatment group. In addition, cerclage was performed in patients with ruptured amniotic membranes. Amniopatch was used to salvage a patient with immediate amniorrhea (< 6 hours) after the above procedures. Results: Nine of the 11 patients prolonged their pregnancy for at least 3 weeks (81.8%), while all 29 patients in the control group delivered their babies within 3 weeks of diagnosis of oligohydramnios (p < 0.05). Signs of maternal infection were noted in two patients in the treatment group (18.2%). The newborns of eight patients in the treatment group survived beyond 1 month (72.7%), whereas this occurred in only six control patients (20.7%; p < 0.05). Conclusion: Aggressive management seemed to provide prolongation of pregnancy compared with no treatment. Amniopatch salvaged the immediate amniorrhea in our patient. [Taiwanese J Obstet Gynecol 2005;44(4): 347–352] Key Words: amnioinfusion, amniopatch, cerclage, oligohydramnios, preterm premature rupture of membranes
Introduction Antepartum amnioinfusion is a procedure under debate. Some authors claim that it can reduce the rate of pulmonary hypoplasia, which is one of the main deadly
*Correspondence to: Dr. Ming Chen, Center for Medical Genetics, Changhua Christian Hospital, 176, Chunghua Road, Changhua 500, Taiwan. E-mail: [email protected] Received: September 2, 2005 Revised: September 6, 2005 Accepted: September 14, 2005
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sequelae of oligohydramnios [1,2]. However, its safety worries others, especially the theoretical fear of the complications related to invasive procedures such as infection, fetal loss, and even amniotic fluid embolism [3]. A large randomized trial is lacking despite several large-scale case-control studies revealing that it seems to provide benefit to the fetus, no matter whether the amniotic membranes are intact or ruptured, and does not induce more complications than conservative treatment [2–4]. The overall perinatal mortality after previable preterm premature rupture of membranes (PPROM), if managed expectantly, is about 60%, regardless of whether it is iatrogenic or spontaneous [5,6]. Several
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experimental therapies have been proposed to treat PPROM. Serial amnioinfusion or maternal administration of vasopressin to induce fetal diuresis has been used to restore amniotic fluid volume [7,8]. However, the resulting amniorrhea often makes the effort pointless. Fetoscopic closure of the defect (amniograft) [9], occlusion of the cervical canal with fibrin glue [10,11], in situ cerclage [12], and instillation of platelets followed by cryoprecipitation (amniopatch) [13] were devised to tackle the condition. Among these treatments, amniopatch appeared to be promising in the two small series reported to date in iatrogenic PPROM caused by genetic invasive diagnostic procedures or by fetoscopic intervention [13,14]. Here, we present our experience of managing oligohydramnios without concomitant intrauterine infection using various treatment modalities including antepartum amnioinfusion (to treat oligohydramnios without PPROM), antepartum amnioinfusion with or without cerclage (for oligohydramnios with PPROM), and successful allogenic amniopatch to salvage a woman with oligohydramnios caused by spontaneous PPROM who suffered from amniorrhea after amnioinfusion together with emergency cerclage. This was a valuable success since amniopatch appears less effective in women with spontaneous PPROM [13,14].
Methods Patients and selection criteria Eleven patients with oligohydramnios (amniotic fluid index, AFI, ) 5), singleton pregnancy, and normal karyotype at less than 30 complete gestational weeks were recruited at National Taiwan University Hospital and Changhua Christian Hospital for aggressive management after informed consent was obtained with autonomy under the care of the same physician (M. Chen) between October 2002 and May 2005. Enrollment was simultaneous at the two hospitals, both of which are tertiary referral medical centers. Status of amniotic membranes (intact or ruptured), gestational age, and ethnic background were carefully examined and classified. Karyotyping was performed by mid-trimester chorionic villus sampling (CVS), small-amount amniocentesis, or cordocentesis. Another 29 similar patients who received expectant and conservative treatment were prospectively enrolled as the control group in 2003–2005 at the same two hospitals. Parameters including maternal age, gestational age at diagnosis, and the percentage of PPROM were matchcontrolled. All patients received prophylactic oral antibiotic therapy.
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Exclusion criteria We excluded women who were in active labor or had fever (maternal temperature > 38° C), maternal leukocytosis (white blood cell count > 15,000/mL), a history of cervical incompetence, cervical length less than 4 cm by ultrasound at the time of diagnosis of oligohydramnios, or maternal/placental problems including hyperthyroidism, pregnancy-induced hypertension, gestational diabetes, or placental tumors. Patients whose fetuses had bilateral renal agenesis, obstructive uropathy, or multiple anomalies at the time of diagnosis of oligohydramnios, despite most of them undergoing one-time amnioinfusion to facilitate ultrasound diagnosis, were not included. In other words, we only enrolled women with oligohydramnios caused by PPROM or idiopathic oligohydramnios with the amniotic membranes intact, to study the efficacy of amnioinfusion without interference from confounding factors in the fetuses or mothers.
Interventions For amnioinfusion, varying amounts (200–500 mL) of warm, sterile Ringer’s lactate or normal saline were slowly infused through an intravenous set originally designed for blood transfusion after the conduit was established with a 21-gauge spinal needle inserted into the amniotic cavity with the assistance of realtime ultrasound (Voluson® 730, GE Medical Systems, Milwaukee, WI, USA). Patients were prescribed antibiotics and tocolytics to prevent maternal infection and preterm delivery before and after the invasive procedure. Patients were admitted for at least 24 hours’ hospitalization to observe the immediate postoperative condition. In cerclage, the McDonald approach was used in patients with oligohydramnios caused by ruptured membranes who showed no signs of infection before amnioinfusion. Amniopatch was performed according to the protocol devised by Quintero et al [13]: 100 mL warm normal saline was infused intra-amniotically under ultrasound monitoring without knowing the exact site of rupture of the amniotic membranes. Cross-matched allogenic platelets (0.5 units) were then infused, followed by 0.5 units cryoprecipitate. Another 100 mL warm normal saline was then instilled to achieve the optimal deepest pocket of the amniotic fluid bag, that is, about 5 cm of the maximal vertical pool depth in our patient. Elective cesarean section was chosen by all women who wished to save the fetus at delivery.
Data Maternal age, ethnic background, gestational age at
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onset of oligohydramnios, gestational age at delivery, latency period between diagnosis and delivery, number of serial amnioinfusions, rate of PPROM, neonatal survival, rate of cesarean delivery, rate of intrauterine fetal demise, number of patients whose latency period was more than 21 days, birth body weight, number of patients who underwent termination of pregnancy (TOP) of the viable fetus, number of patients who developed fever or leukocytosis after onset, and karyotype were carefully reviewed and tabulated. Pathology reports for the delivered placenta as well as dead fetuses were recorded, if available.
Statistical analysis Fisher’s exact test and two-tailed Student’s t test were used to analyze relevant data using STATA (Stata Corp, College Park, TX, USA) and Microsoft Excel software.
Results Seven of 11 women (63.6%) in the treatment group and 20 of the 29 control women (69.0%) were Taiwanese/ Chinese; the remaining subjects were women from Vietnam, Cambodia, or the Philippines married to a Taiwanese husband. Four women in the treatment group (36.4%) and 13 control women (44.8%) had PPROM (Table 1). There was no significant difference between the groups in maternal age (32 vs 33 years), gestational age at diagnosis (23 vs 23 weeks), and the percentage of PPROM. Seven women who had intact amniotic membranes received amnioinfusion only and four women with PPROM received amnioinfusion and cerclage. Two of the four PPROM women who had cerclage suffered
from amniorrhea within 6 hours after amnioinfusion, and one chose TOP when the fetus was still alive, after nondirective genetic counseling. The other woman decided to undergo another amnioinfusion and amniopatch after thorough discussion. She suffered from mild amniorrhea on the fourth day after amniopatch, but her AFI remained at the optimal level for her gestational age (10). Amniopatch was considered successful. The mean number of serial amnioinfusions was 3.9 (range, 1–8) (Table 2). Intrauterine fetal death (IUFD) was noted in one treated woman (9.1%) and 11 control women (37.9%). There was significant prolongation of the latency period in the treatment group compared with the control group (34 vs 9 days; p < 0.05) (Table 2). The neonatal survival rate was also significantly improved in the treatment group compared with the control group (72.7% vs 20.7%; p < 0.05). The birth weight was greater in the treatment group than the control group (1,400 vs 900 g; p < 0.05). No women showed signs of infection such as fever or leukocytosis, but two women in the treatment group (18.2%) and 12 in the control group (41.4%) developed fever or leukocytosis later. Karyotype was known and normal in all the women in the treatment group but for only 20 women in the control group, five of whom had an abnormal karyotype (Table 1). More women in the treatment group (9; 81.8%) than control group (6; 20.7%) had cesarean delivery. The number of pregnancies whose latency period was more than 21 days was significantly greater in the treatment group (9) than the control group (0). No serious maternal complication was noted in any of the subjects. Placental pathology showed no remarkable findings for any subjects who underwent this examination (treatment group, n = 11; control group, n = 27).
Table 1. Demographic and obstetric characteristics Treatment group (n = 11)
Control group (n = 29)
32 (23–41)0. 23+2 (17+3–26+0) 31+3 (24+2–33+4) 00 4 (36.4%) 11 00 04 03 04 00 00
33 (20–43)0. 23+4 (15+2–29+5) 26+2 (16+2–30+6) 00 13 (44.8%)0. 25 04 14 03 03 09 05
Maternal age, mean (range) (yr)* GA at diagnosis, mean (range) (wk)* GA at delivery, mean (range) (wk) Fever/leukocytosis at diagnosis* PPROM* GA ) 26 wk 26 wk < GA < 30 wk Karyotyping by amniocentesis Karyotyping by CVS Karyotyping by cordocentesis Karyotyping in postnatal period Abnormal karyotypes†
*No significant difference between the two groups; †abnormal karyotypes include 47,XX,+der(2), 45,X, 69,XXY, 47,XY,+21 and 47,XX,+13. CVS = chorionic villus sampling; GA = gestational age; PPROM = preterm premature rupture of membranes.
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Table 2. Intervention and delivery characteristics Treatment group (n = 11) Serial amnioinfusion, mean (range) Amnioinfusion Cerclage Amniopatch Amniorrhea < 6 hr after amnioinfusion Latency period, mean (range) (d)* Women with latency > 21 d* IUFD* TOP of viable fetus by induction Baby survived > 1 mo* Birth body weight (g)* Cesarean delivery Fever/leukocytosis after diagnosis*
Control group (n = 29)
3.9 (1–8)00 11 04 01 02 34 (11–59) 09 1 (9.1%) 1 (9.1%) 08 (72.7%) 01,400 (350–2,200) 09 (81.8%) 02 (18.2%)
9 11 12 6 0,900 6 12
0 0 0 0 0 (2–19)0 0 (37.9%)0 (41.4%)0 (20.7%) (190–1,300) (20.7%) (41.4%)0
*p < 0.05. IUFD = intrauterine fetal death; TOP = termination of pregnancy.
Discussion Selection bias and matched controls The difficulty of conducting such a controversial study rests mainly on the probable selection bias. Some may argue that the two groups we chose inherited different characteristics, which may confound our results. We tried to match parameters such as maternal age, gestational age at diagnosis, and the percentage of PPROM, and excluded confounding factors such as preexisting infection, fetal/maternal/placental pathology, and patients with the possibility of cervical incompetence. The major pitfall of this study is that it was not a randomized controlled trial, and the reasons for offering options in the treatment group and choosing not to treat in the control group are difficult to standardize. However, results obtained with randomized and strictly selected groups may have a limited value in clinical practice since most patients we encounter in clinical practice would deviate from such study groups. We believe our results are of some value even though this was not a randomized controlled trial. Furthermore, the prospective nature of our study enhances its applicability in the real situations encountered in practice.
Oligohydramnios Early onset oligohydramnios is not common and indicates poor fetal prognosis. Apart from PPROM, the most common etiology is fetal anuria caused by either obstructive uropathy or renal agenesis. Other etiologies mainly include maternal disease such as preeclampsia, hypertension, diabetes, hyperthyroidism, and others [15]. Oligohydramnios is associated with increased perinatal morbidity and mortality. PPROM
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before 25 gestational weeks with severe oligohydramnios for more than 14 days has a perinatal mortality of more than 90% [16]. Maternal chorioamnionitis and neonatal respiratory distress syndrome are also noted in more than half of patients [17]. Cerclage and amnioinfusion were universally offered to patients with PPROM in the treatment group, which further eliminated the interaction of both treatment modalities in these patients.
Amnioinfusion The efficacy and safety of intrapartum amnioinfusion have been proven in several prospective randomized studies, as summarized in an evidence-based metaanalysis [18]. However, antepartum amnioinfusion is still under debate, despite its safety and efficacy (in lengthening the latency between diagnosis and delivery, in reducing pulmonary hypoplasia, in increasing diagnostic accuracy of ultrasound, and in reducing perinatal mortality) reported in some studies [2,7,19, 20]. A large randomized controlled trial is lacking. It is difficult to study this topic because there are too many confounding factors such as various underlying fetal/ maternal pathologies and the difficulty controlling for pregnancy course across many variables. We, therefore, focused our study on singleton pregnancies complicated with oligohydramnios, regardless of intact or ruptured amniotic membranes, and no signs of infection, observing the latency period and neonatal survival and maternal infection rates. Other outcome measures such as birth body weight and the rate of cesarean delivery were considered unsuitable items for outcome assessment since any conclusion drawn from these markers may call for considerable speculation and have limited value.
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Amnioinfusion & Amniopatch for Oligohydramnios
Amniopatch The mechanism of amniopatch is still unclear. The authors who devised the method speculated that the platelet/cryoprecipitate plug might seal the amniotic membranous defect by artificial activation of platelet and fibrin adhesion at the site of rupture because fetal membranes are avascular and incapable of eliciting spontaneous platelet activation, fibrin deposition, and therefore wound healing. Amniotic membrane is thought to seal during genetic amniocentesis due to the adherence of amniotic membranes to the underlying chorionic membranes. Quintero et al documented the detachment of amniotic membranes from chorionic membranes in iatrogenic PPROM cases as well as reattachment of the successful amniopatched cases by ultrasound [13]. Lewi et al documented blood clot in successful amniopatched cases with ultrasound [14]. Both groups of authors considered amniopatch to be more effective for treating iatrogenic PPROM than spontaneous PPROM. Spontaneous PPROM may follow a different natural history because the hole is usually larger, less demarcated, and more often situated in the lower uterine segment than that of iatrogenic PPROM. Amniopatch has been tried in 11 cases up to 2004 and carries a favorable outcome when used to treat iatrogenic PPROM [13,14,21, 22]. There were no serious maternal complications in these 11 women, but IUFD was noted in some cases [14]. The hypotension and bradycardia induced by the platelet transfusion, as well as the similar intrinsic serotonin effect of the indigo carmine used to document amniorrhea, were thought to be the etiologies [14]. We, therefore, did not use indigo carmine in our oligohydramnios patients. The good response of the only patient in our study salvaged with amniopatch seemed a very rare and interesting success in treating spontaneous PPROM by amniopatch.
Efficacy and safety of amnioinfusion/amniopatch/ cerclage In our small series, aggressive management of oligohydramnios, regardless of intact or ruptured amniotic membranes, seemed to lengthen the latency period and improve neonatal survival, but not to increase the rate of maternal infection. Birth weights in the treatment group seemed to increase more than those in the control group, while IUFD seemed more frequent in the control group. Our study appears to be one of the very few reports of amnioinfusion in an East Asian population [23,24] and of amniopatch worldwide [13,14,21,22]. The amniopatch case appears to be the first such successful case reported from East Asia.
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Acknowledgments This study was partially funded by National Taiwan University Hospital (NTUH-93N10) and Changhua Christian Hospital (CCH-9282). The authors would like to thank Professor Chia-Li Yu, Professor Fon-Jou Hsieh, and Professor Song-Nan Chow of National Taiwan University Hospital, as well as Professor Bao-Tyan Wang, Dr. Kuo-Cherng Lin, Dr. Pan-Hsin Chou, and Dr. TsungChe Hsieh of Changhua Christian Hospital, for their support in conducting the study. The authors would also like to thank Ms. Li-Wen Chen, Ms. Mei-Hui Lee, Ms. Ming-Jung Tsai, and many other colleagues for their assistance.
References 1. Vergani P, Locatelli A, Strobelt N, Mariani S, Cavallone M, Arosio P, Ghidini A. Amnioinfusion for prevention of pulmonary hypoplasia in second-trimester rupture of membranes. Am J Perinatol 1997;14:325–9. 2. Gramellini D, Fieni S, Kaihura C, Faiola S, Vadora E. Transabdominal antepartum amnioinfusion. Int J Gynaecol Obstet 2003;83:171–8. 3. Fisk NM, Ronderos-Dumit D, Soliani A, Nicolini U, Vaughan J, Rodeck CH. Diagnostic and therapeutic transabdominal amnioinfusion in oligohydramnios. Obstet Gynecol 1991;78: 270–8. 4. De Santis M, Scavo M, Noia G, Masini L, Piersigilli F, Romagnoli C, Caruso A. Transabdominal amnioinfusion treatment of severe oligohydramnios in preterm premature rupture of membranes at less than 26 gestational weeks. Fetal Diagn Ther 2003;18:412–7. 5. Bengtson JM, VanMarter LJ, Barss VA, Greene MF, Tuomala RE, Epstein MF. Pregnancy outcome after premature rupture of the membranes at or before 26 weeks’ gestation. Obstet Gynecol 1989;73:921–7. 6. Beydoun SN, Yasin SY. Premature rupture of the membranes before 28 weeks: conservative management. Am J Obstet Gynecol 1986;155:471–9. 7. Locatelli A, Vergani P, Di Pirro G, Doria V, Biffi A, Ghidini A. Role of amnioinfusion in the management of premature rupture of the membranes at < 26 weeks’ gestation. Am J Obstet Gynecol 2000;183:878–82. 8. Ross MG, Cedars L, Nijland MJ, Ogundipe A. Treatment of oligohydramnios with maternal 1-deamino-[8-D-arginine] vasopressin-induced plasma hypoosmolality. Am J Obstet Gynecol 1996;174:1608–13. 9. Quintero RA, Morales WJ, Bornick PW, Allen M, Garabelis N. Surgical treatment of spontaneous rupture of membranes: the amniograft—first experience. Am J Obstet Gynecol 2002; 186:155–7. 10. Baumgarten K, Moser S. The technique of fibrin adhesion for premature rupture of the membranes during pregnancy. J Perinat Med 1986;14:43–9. 11. Sciscione AC, Manley JS, Pollock M, et al. Intracervical fibrin
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sealants: a potential treatment for early preterm premature rupture of the membranes. Am J Obstet Gynecol 2001;184: 368–73. 12. McElrath TF, Norwitz ER, Lieberman ES, Heffner LJ. Perinatal outcome after preterm premature rupture of membranes with in situ cervical cerclage. Am J Obstet Gynecol 2002;187: 1147–52. 13. Quintero RA, Morales WJ, Allen M, Bornick PW, Arroyo J, LeParc G. Treatment of iatrogenic previable premature rupture of membranes with intra-amniotic injection of platelets and cryoprecipitate (amniopatch): preliminary experience. Am J Obstet Gynecol 1999;181:744–9. 14. Lewi L, Van Schoubroeck D, Van Ranst M, et al. Successful patching of iatrogenic rupture of the fetal membranes. Placenta 2004;25:352–6. 15. Cunningham FG, Gant NF, Leveno KJ, Gilstrap LC III, Havth JC, Wenstrom KD. Abnormalities of the fetal membranes and amniotic fluid. In: Cunningham FG, Gant NF, Leveno KJ, Gilstrap LC III, Havth JC, Wenstrom KD, eds. Williams Obstetrics, 21st edition. New York: McGraw-Hill, 2001:821–3. 16. Kilbride HW, Yeast J, Thibeault DW. Defining limits of survival: lethal pulmonary hypoplasia after midtrimester premature rupture of membranes. Am J Obstet Gynecol 1996;175: 675–81. 17. Cox SM, Williams ML, Leveno KJ. The natural history of pre-
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term ruptured membranes: what to expect of expectant management. Obstet Gynecol 1988;71:558–62. 18. Hofmeyr GJ. Amnioinfusion for meconium-stained liquor. Curr Opin Obstet Gynecol 2000;12:129–32. 19. Ogunyemi D, Thompson W. A case controlled study of serial transabdominal amnioinfusions in the management of second trimester oligohydramnios due to premature rupture of membranes. Eur J Obstet Gynecol Reprod Biol 2002;102:167–72. 20. Turhan NO, Atacan N. Antepartum prophylactic transabdominal amnioinfusion in preterm pregnancies complicated by oligohydramnios. Int J Gynaecol Obstet 2002;76:15–21. 21. Quintero RA, Romero R, Dzieczkowski J, Mammen E, Evans MI. Sealing of ruptured amniotic membranes with intraamniotic platelet-cryoprecipitate plug. Lancet 1996;347:1117. 22. Young BK, Roque H, Abdelhak YE, Poiolek D, Demopulos R, Lockwood CJ. Minimally invasive endoscopy in the treatment of preterm premature rupture of membranes by application of fibrin sealant. J Perinat Med 2000;28:326–30. 23. Wang CC, Rogers MS. Lipid peroxidation in cord blood: a randomised sequential pairs study of prophylactic saline amnioinfusion for intrapartum oligohydramnios. Br J Obstet Gynaecol 1997;104:1145–51. 24. Sakamoto S, Takeda Y, Nakabayashi M. Advances in perinatal medical care—from our experience. Int J Gynaecol Obstet 1998; 63(Suppl 1):S107–14.
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Amnioinfusion & Amniopatch for Oligohydramnios
MANAGEMENT OF OLIGOHYDRAMNIOS WITH ANTEPARTUM AMNIOINFUSION, AMNIOPATCH AND CERCLAGE 1,2
2
3
2
Ming Chen *, Chang-Yao Hsieh , Alan D. Cameron , Jin-Chung Shih , 2 2 1 4 Chien-Nan Lee , Hong-Nerng Ho , Tze-Ho Chen , Chih-Ping Chen 1
Department of Obstetrics and Gynecology, and Center for Medical Genetics, Changhua Christian Hospital, Changhua, 2 Department of Obstetrics and Gynecology, National Taiwan University Hospital, 4 Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan, and 3 Department of Fetal Medicine, Queen Mother’s Hospital, Glasgow, U.K.
SUMMARY Objective: To evaluate the efficacy and safety of aggressive management of oligohydramnios. Methods: Forty women with oligohydramnios (< 30 complete weeks), either because of preterm premature rupture of membranes or with intact membranes, were prospectively enrolled in this study. Eleven women were assigned to the treatment group and 29 to the control group. Transabdominal amnioinfusion was performed with warm Ringer’s lactate or normal saline in all 11 patients in the treatment group. In addition, cerclage was performed in patients with ruptured amniotic membranes. Amniopatch was used to salvage a patient with immediate amniorrhea (< 6 hours) after the above procedures. Results: Nine of the 11 patients prolonged their pregnancy for at least 3 weeks (81.8%), while all 29 patients in the control group delivered their babies within 3 weeks of diagnosis of oligohydramnios (p < 0.05). Signs of maternal infection were noted in two patients in the treatment group (18.2%). The newborns of eight patients in the treatment group survived beyond 1 month (72.7%), whereas this occurred in only six control patients (20.7%; p < 0.05). Conclusion: Aggressive management seemed to provide prolongation of pregnancy compared with no treatment. Amniopatch salvaged the immediate amniorrhea in our patient. [Taiwanese J Obstet Gynecol 2005;44(4): 347–352] Key Words: amnioinfusion, amniopatch, cerclage, oligohydramnios, preterm premature rupture of membranes
Introduction Antepartum amnioinfusion is a procedure under debate. Some authors claim that it can reduce the rate of pulmonary hypoplasia, which is one of the main deadly
*Correspondence to: Dr. Ming Chen, Center for Medical Genetics, Changhua Christian Hospital, 176, Chunghua Road, Changhua 500, Taiwan. E-mail: [email protected] Received: September 2, 2005 Revised: September 6, 2005 Accepted: September 14, 2005
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sequelae of oligohydramnios [1,2]. However, its safety worries others, especially the theoretical fear of the complications related to invasive procedures such as infection, fetal loss, and even amniotic fluid embolism [3]. A large randomized trial is lacking despite several large-scale case-control studies revealing that it seems to provide benefit to the fetus, no matter whether the amniotic membranes are intact or ruptured, and does not induce more complications than conservative treatment [2–4]. The overall perinatal mortality after previable preterm premature rupture of membranes (PPROM), if managed expectantly, is about 60%, regardless of whether it is iatrogenic or spontaneous [5,6]. Several
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experimental therapies have been proposed to treat PPROM. Serial amnioinfusion or maternal administration of vasopressin to induce fetal diuresis has been used to restore amniotic fluid volume [7,8]. However, the resulting amniorrhea often makes the effort pointless. Fetoscopic closure of the defect (amniograft) [9], occlusion of the cervical canal with fibrin glue [10,11], in situ cerclage [12], and instillation of platelets followed by cryoprecipitation (amniopatch) [13] were devised to tackle the condition. Among these treatments, amniopatch appeared to be promising in the two small series reported to date in iatrogenic PPROM caused by genetic invasive diagnostic procedures or by fetoscopic intervention [13,14]. Here, we present our experience of managing oligohydramnios without concomitant intrauterine infection using various treatment modalities including antepartum amnioinfusion (to treat oligohydramnios without PPROM), antepartum amnioinfusion with or without cerclage (for oligohydramnios with PPROM), and successful allogenic amniopatch to salvage a woman with oligohydramnios caused by spontaneous PPROM who suffered from amniorrhea after amnioinfusion together with emergency cerclage. This was a valuable success since amniopatch appears less effective in women with spontaneous PPROM [13,14].
Methods Patients and selection criteria Eleven patients with oligohydramnios (amniotic fluid index, AFI, ) 5), singleton pregnancy, and normal karyotype at less than 30 complete gestational weeks were recruited at National Taiwan University Hospital and Changhua Christian Hospital for aggressive management after informed consent was obtained with autonomy under the care of the same physician (M. Chen) between October 2002 and May 2005. Enrollment was simultaneous at the two hospitals, both of which are tertiary referral medical centers. Status of amniotic membranes (intact or ruptured), gestational age, and ethnic background were carefully examined and classified. Karyotyping was performed by mid-trimester chorionic villus sampling (CVS), small-amount amniocentesis, or cordocentesis. Another 29 similar patients who received expectant and conservative treatment were prospectively enrolled as the control group in 2003–2005 at the same two hospitals. Parameters including maternal age, gestational age at diagnosis, and the percentage of PPROM were matchcontrolled. All patients received prophylactic oral antibiotic therapy.
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Exclusion criteria We excluded women who were in active labor or had fever (maternal temperature > 38° C), maternal leukocytosis (white blood cell count > 15,000/mL), a history of cervical incompetence, cervical length less than 4 cm by ultrasound at the time of diagnosis of oligohydramnios, or maternal/placental problems including hyperthyroidism, pregnancy-induced hypertension, gestational diabetes, or placental tumors. Patients whose fetuses had bilateral renal agenesis, obstructive uropathy, or multiple anomalies at the time of diagnosis of oligohydramnios, despite most of them undergoing one-time amnioinfusion to facilitate ultrasound diagnosis, were not included. In other words, we only enrolled women with oligohydramnios caused by PPROM or idiopathic oligohydramnios with the amniotic membranes intact, to study the efficacy of amnioinfusion without interference from confounding factors in the fetuses or mothers.
Interventions For amnioinfusion, varying amounts (200–500 mL) of warm, sterile Ringer’s lactate or normal saline were slowly infused through an intravenous set originally designed for blood transfusion after the conduit was established with a 21-gauge spinal needle inserted into the amniotic cavity with the assistance of realtime ultrasound (Voluson® 730, GE Medical Systems, Milwaukee, WI, USA). Patients were prescribed antibiotics and tocolytics to prevent maternal infection and preterm delivery before and after the invasive procedure. Patients were admitted for at least 24 hours’ hospitalization to observe the immediate postoperative condition. In cerclage, the McDonald approach was used in patients with oligohydramnios caused by ruptured membranes who showed no signs of infection before amnioinfusion. Amniopatch was performed according to the protocol devised by Quintero et al [13]: 100 mL warm normal saline was infused intra-amniotically under ultrasound monitoring without knowing the exact site of rupture of the amniotic membranes. Cross-matched allogenic platelets (0.5 units) were then infused, followed by 0.5 units cryoprecipitate. Another 100 mL warm normal saline was then instilled to achieve the optimal deepest pocket of the amniotic fluid bag, that is, about 5 cm of the maximal vertical pool depth in our patient. Elective cesarean section was chosen by all women who wished to save the fetus at delivery.
Data Maternal age, ethnic background, gestational age at
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Amnioinfusion & Amniopatch for Oligohydramnios
onset of oligohydramnios, gestational age at delivery, latency period between diagnosis and delivery, number of serial amnioinfusions, rate of PPROM, neonatal survival, rate of cesarean delivery, rate of intrauterine fetal demise, number of patients whose latency period was more than 21 days, birth body weight, number of patients who underwent termination of pregnancy (TOP) of the viable fetus, number of patients who developed fever or leukocytosis after onset, and karyotype were carefully reviewed and tabulated. Pathology reports for the delivered placenta as well as dead fetuses were recorded, if available.
Statistical analysis Fisher’s exact test and two-tailed Student’s t test were used to analyze relevant data using STATA (Stata Corp, College Park, TX, USA) and Microsoft Excel software.
Results Seven of 11 women (63.6%) in the treatment group and 20 of the 29 control women (69.0%) were Taiwanese/ Chinese; the remaining subjects were women from Vietnam, Cambodia, or the Philippines married to a Taiwanese husband. Four women in the treatment group (36.4%) and 13 control women (44.8%) had PPROM (Table 1). There was no significant difference between the groups in maternal age (32 vs 33 years), gestational age at diagnosis (23 vs 23 weeks), and the percentage of PPROM. Seven women who had intact amniotic membranes received amnioinfusion only and four women with PPROM received amnioinfusion and cerclage. Two of the four PPROM women who had cerclage suffered
from amniorrhea within 6 hours after amnioinfusion, and one chose TOP when the fetus was still alive, after nondirective genetic counseling. The other woman decided to undergo another amnioinfusion and amniopatch after thorough discussion. She suffered from mild amniorrhea on the fourth day after amniopatch, but her AFI remained at the optimal level for her gestational age (10). Amniopatch was considered successful. The mean number of serial amnioinfusions was 3.9 (range, 1–8) (Table 2). Intrauterine fetal death (IUFD) was noted in one treated woman (9.1%) and 11 control women (37.9%). There was significant prolongation of the latency period in the treatment group compared with the control group (34 vs 9 days; p < 0.05) (Table 2). The neonatal survival rate was also significantly improved in the treatment group compared with the control group (72.7% vs 20.7%; p < 0.05). The birth weight was greater in the treatment group than the control group (1,400 vs 900 g; p < 0.05). No women showed signs of infection such as fever or leukocytosis, but two women in the treatment group (18.2%) and 12 in the control group (41.4%) developed fever or leukocytosis later. Karyotype was known and normal in all the women in the treatment group but for only 20 women in the control group, five of whom had an abnormal karyotype (Table 1). More women in the treatment group (9; 81.8%) than control group (6; 20.7%) had cesarean delivery. The number of pregnancies whose latency period was more than 21 days was significantly greater in the treatment group (9) than the control group (0). No serious maternal complication was noted in any of the subjects. Placental pathology showed no remarkable findings for any subjects who underwent this examination (treatment group, n = 11; control group, n = 27).
Table 1. Demographic and obstetric characteristics Treatment group (n = 11)
Control group (n = 29)
32 (23–41)0. 23+2 (17+3–26+0) 31+3 (24+2–33+4) 00 4 (36.4%) 11 00 04 03 04 00 00
33 (20–43)0. 23+4 (15+2–29+5) 26+2 (16+2–30+6) 00 13 (44.8%)0. 25 04 14 03 03 09 05
Maternal age, mean (range) (yr)* GA at diagnosis, mean (range) (wk)* GA at delivery, mean (range) (wk) Fever/leukocytosis at diagnosis* PPROM* GA ) 26 wk 26 wk < GA < 30 wk Karyotyping by amniocentesis Karyotyping by CVS Karyotyping by cordocentesis Karyotyping in postnatal period Abnormal karyotypes†
*No significant difference between the two groups; †abnormal karyotypes include 47,XX,+der(2), 45,X, 69,XXY, 47,XY,+21 and 47,XX,+13. CVS = chorionic villus sampling; GA = gestational age; PPROM = preterm premature rupture of membranes.
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Table 2. Intervention and delivery characteristics Treatment group (n = 11) Serial amnioinfusion, mean (range) Amnioinfusion Cerclage Amniopatch Amniorrhea < 6 hr after amnioinfusion Latency period, mean (range) (d)* Women with latency > 21 d* IUFD* TOP of viable fetus by induction Baby survived > 1 mo* Birth body weight (g)* Cesarean delivery Fever/leukocytosis after diagnosis*
Control group (n = 29)
3.9 (1–8)00 11 04 01 02 34 (11–59) 09 1 (9.1%) 1 (9.1%) 08 (72.7%) 01,400 (350–2,200) 09 (81.8%) 02 (18.2%)
9 11 12 6 0,900 6 12
0 0 0 0 0 (2–19)0 0 (37.9%)0 (41.4%)0 (20.7%) (190–1,300) (20.7%) (41.4%)0
*p < 0.05. IUFD = intrauterine fetal death; TOP = termination of pregnancy.
Discussion Selection bias and matched controls The difficulty of conducting such a controversial study rests mainly on the probable selection bias. Some may argue that the two groups we chose inherited different characteristics, which may confound our results. We tried to match parameters such as maternal age, gestational age at diagnosis, and the percentage of PPROM, and excluded confounding factors such as preexisting infection, fetal/maternal/placental pathology, and patients with the possibility of cervical incompetence. The major pitfall of this study is that it was not a randomized controlled trial, and the reasons for offering options in the treatment group and choosing not to treat in the control group are difficult to standardize. However, results obtained with randomized and strictly selected groups may have a limited value in clinical practice since most patients we encounter in clinical practice would deviate from such study groups. We believe our results are of some value even though this was not a randomized controlled trial. Furthermore, the prospective nature of our study enhances its applicability in the real situations encountered in practice.
Oligohydramnios Early onset oligohydramnios is not common and indicates poor fetal prognosis. Apart from PPROM, the most common etiology is fetal anuria caused by either obstructive uropathy or renal agenesis. Other etiologies mainly include maternal disease such as preeclampsia, hypertension, diabetes, hyperthyroidism, and others [15]. Oligohydramnios is associated with increased perinatal morbidity and mortality. PPROM
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before 25 gestational weeks with severe oligohydramnios for more than 14 days has a perinatal mortality of more than 90% [16]. Maternal chorioamnionitis and neonatal respiratory distress syndrome are also noted in more than half of patients [17]. Cerclage and amnioinfusion were universally offered to patients with PPROM in the treatment group, which further eliminated the interaction of both treatment modalities in these patients.
Amnioinfusion The efficacy and safety of intrapartum amnioinfusion have been proven in several prospective randomized studies, as summarized in an evidence-based metaanalysis [18]. However, antepartum amnioinfusion is still under debate, despite its safety and efficacy (in lengthening the latency between diagnosis and delivery, in reducing pulmonary hypoplasia, in increasing diagnostic accuracy of ultrasound, and in reducing perinatal mortality) reported in some studies [2,7,19, 20]. A large randomized controlled trial is lacking. It is difficult to study this topic because there are too many confounding factors such as various underlying fetal/ maternal pathologies and the difficulty controlling for pregnancy course across many variables. We, therefore, focused our study on singleton pregnancies complicated with oligohydramnios, regardless of intact or ruptured amniotic membranes, and no signs of infection, observing the latency period and neonatal survival and maternal infection rates. Other outcome measures such as birth body weight and the rate of cesarean delivery were considered unsuitable items for outcome assessment since any conclusion drawn from these markers may call for considerable speculation and have limited value.
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Amnioinfusion & Amniopatch for Oligohydramnios
Amniopatch The mechanism of amniopatch is still unclear. The authors who devised the method speculated that the platelet/cryoprecipitate plug might seal the amniotic membranous defect by artificial activation of platelet and fibrin adhesion at the site of rupture because fetal membranes are avascular and incapable of eliciting spontaneous platelet activation, fibrin deposition, and therefore wound healing. Amniotic membrane is thought to seal during genetic amniocentesis due to the adherence of amniotic membranes to the underlying chorionic membranes. Quintero et al documented the detachment of amniotic membranes from chorionic membranes in iatrogenic PPROM cases as well as reattachment of the successful amniopatched cases by ultrasound [13]. Lewi et al documented blood clot in successful amniopatched cases with ultrasound [14]. Both groups of authors considered amniopatch to be more effective for treating iatrogenic PPROM than spontaneous PPROM. Spontaneous PPROM may follow a different natural history because the hole is usually larger, less demarcated, and more often situated in the lower uterine segment than that of iatrogenic PPROM. Amniopatch has been tried in 11 cases up to 2004 and carries a favorable outcome when used to treat iatrogenic PPROM [13,14,21, 22]. There were no serious maternal complications in these 11 women, but IUFD was noted in some cases [14]. The hypotension and bradycardia induced by the platelet transfusion, as well as the similar intrinsic serotonin effect of the indigo carmine used to document amniorrhea, were thought to be the etiologies [14]. We, therefore, did not use indigo carmine in our oligohydramnios patients. The good response of the only patient in our study salvaged with amniopatch seemed a very rare and interesting success in treating spontaneous PPROM by amniopatch.
Efficacy and safety of amnioinfusion/amniopatch/ cerclage In our small series, aggressive management of oligohydramnios, regardless of intact or ruptured amniotic membranes, seemed to lengthen the latency period and improve neonatal survival, but not to increase the rate of maternal infection. Birth weights in the treatment group seemed to increase more than those in the control group, while IUFD seemed more frequent in the control group. Our study appears to be one of the very few reports of amnioinfusion in an East Asian population [23,24] and of amniopatch worldwide [13,14,21,22]. The amniopatch case appears to be the first such successful case reported from East Asia.
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Acknowledgments This study was partially funded by National Taiwan University Hospital (NTUH-93N10) and Changhua Christian Hospital (CCH-9282). The authors would like to thank Professor Chia-Li Yu, Professor Fon-Jou Hsieh, and Professor Song-Nan Chow of National Taiwan University Hospital, as well as Professor Bao-Tyan Wang, Dr. Kuo-Cherng Lin, Dr. Pan-Hsin Chou, and Dr. TsungChe Hsieh of Changhua Christian Hospital, for their support in conducting the study. The authors would also like to thank Ms. Li-Wen Chen, Ms. Mei-Hui Lee, Ms. Ming-Jung Tsai, and many other colleagues for their assistance.
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