■ ORIGINAL ARTICLE ■ & Amniopatch for

MANAGEMENT OF OLIGOHYDRAMNIOS WITH ANTEPARTUM AMNIOINFUSION, AMNIOPATCH AND CERCLAGE

Ming Chen1,2*, Chang-Yao Hsieh2, Alan D. Cameron3, Jin-Chung Shih2, Chien-Nan Lee2, Hong-Nerng Ho2, Tze-Ho Chen1, Chih-Ping Chen4 1Department of and Gynecology, and Center for Medical Genetics, Changhua Christian Hospital, Changhua, 2Department of Obstetrics and Gynecology, National Taiwan University Hospital, 4Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan, and 3Department 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 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 treat- ment. 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 sequelae of oligohydramnios [1,2]. However, its safety worries others, especially the theoretical fear of the Antepartum amnioinfusion is a procedure under de- complications related to invasive procedures such as bate. Some authors claim that it can reduce the rate of infection, fetal loss, and even pulmonary hypoplasia, which is one of the main deadly [3]. A large randomized trial is lacking despite several large-scale case-control studies revealing that it seems to provide benefit to the , no matter whether the amniotic membranes are intact or ruptured, and does *Correspondence to: Dr. Ming Chen, Center for Medical Genetics, not induce more complications than conservative treat- Changhua Christian Hospital, 176, Chunghua Road, Changhua ment [2–4]. 500, Taiwan. The overall perinatal mortality after previable E-mail: [email protected] preterm premature rupture of membranes (PPROM), Received: September 2, 2005 Revised: September 6, 2005 if managed expectantly, is about 60%, regardless of Accepted: September 14, 2005 whether it is iatrogenic or spontaneous [5,6]. Several

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experimental therapies have been proposed to treat Exclusion criteria PPROM. Serial amnioinfusion or maternal adminis- We excluded women who were in active labor or had tration of vasopressin to induce fetal diuresis has been fever (maternal temperature > 38° C), maternal leuko- used to restore amniotic fluid volume [7,8]. However, cytosis (white blood cell count > 15,000/mL), a history the resulting amniorrhea often makes the effort point- of cervical incompetence, cervical length less than 4 less. Fetoscopic closure of the defect (amniograft) [9], cm by ultrasound at the time of diagnosis of oligohy- occlusion of the cervical canal with fibrin glue [10,11], dramnios, or maternal/placental problems including in situ cerclage [12], and instillation of platelets fol- hyperthyroidism, pregnancy-induced hypertension, lowed by cryoprecipitation (amniopatch) [13] were de- , or placental tumors. Patients vised to tackle the condition. Among these treatments, whose had bilateral renal agenesis, obstructive amniopatch appeared to be promising in the two small uropathy, or multiple anomalies at the time of diagnosis series reported to date in iatrogenic PPROM caused by of oligohydramnios, despite most of them undergoing genetic invasive diagnostic procedures or by fetoscopic one-time amnioinfusion to facilitate ultrasound diag- intervention [13,14]. nosis, were not included. In other words, we only enrolled Here, we present our experience of managing oligo- women with oligohydramnios caused by PPROM or hydramnios without concomitant intrauterine infection idiopathic oligohydramnios with the amniotic mem- using various treatment modalities including antepar- branes intact, to study the efficacy of amnioinfusion tum amnioinfusion (to treat oligohydramnios without without interference from confounding factors in the PPROM), antepartum amnioinfusion with or without fetuses or mothers. cerclage (for oligohydramnios with PPROM), and successful allogenic amniopatch to salvage a woman Interventions with oligohydramnios caused by spontaneous PPROM For amnioinfusion, varying amounts (200–500 mL) of who suffered from amniorrhea after amnioinfusion warm, sterile Ringer’s lactate or normal saline were together with emergency cerclage. This was a valuable slowly infused through an intravenous set originally success since amniopatch appears less effective in designed for blood transfusion after the conduit was women with spontaneous PPROM [13,14]. established with a 21-gauge spinal needle inserted into the amniotic cavity with the assistance of real- time ultrasound (Voluson® 730, GE Medical Systems, Methods Milwaukee, WI, USA). Patients were prescribed anti- biotics and tocolytics to prevent maternal infection and Patients and selection criteria preterm delivery before and after the invasive procedure. Eleven patients with oligohydramnios (amniotic fluid Patients were admitted for at least 24 hours’ hospitali- index, AFI, ) 5), singleton pregnancy, and normal karyo- zation to observe the immediate postoperative condition. type at less than 30 complete gestational weeks were In cerclage, the McDonald approach was used in recruited at National Taiwan University Hospital and patients with oligohydramnios caused by ruptured Changhua Christian Hospital for aggressive manage- membranes who showed no signs of infection before ment after informed consent was obtained with auto- amnioinfusion. nomy under the care of the same physician (M. Chen) Amniopatch was performed according to the pro- between October 2002 and May 2005. Enrollment was tocol devised by Quintero et al [13]: 100 mL warm nor- simultaneous at the two hospitals, both of which are mal saline was infused intra-amniotically under ultra- tertiary referral medical centers. Status of amniotic sound monitoring without knowing the exact site membranes (intact or ruptured), gestational age, and of rupture of the amniotic membranes. Cross-matched ethnic background were carefully examined and clas- allogenic platelets (0.5 units) were then infused, fol- sified. Karyotyping was performed by mid-trimester lowed by 0.5 units cryoprecipitate. Another 100 mL chorionic villus sampling (CVS), small-amount warm normal saline was then instilled to achieve the , or cordocentesis. Another 29 similar optimal deepest pocket of the amniotic fluid bag, that patients who received expectant and conservative is, about 5 cm of the maximal vertical pool depth in treatment were prospectively enrolled as the control our patient. group in 2003–2005 at the same two hospitals. Para- Elective cesarean section was chosen by all women meters including maternal age, gestational age at who wished to save the fetus at delivery. diagnosis, and the percentage of PPROM were match- controlled. All patients received prophylactic oral anti- Data biotic therapy. Maternal age, ethnic background, gestational age at

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onset of oligohydramnios, gestational age at delivery, from amniorrhea within 6 hours after amnioinfusion, latency period between diagnosis and delivery, number and one chose TOP when the fetus was still alive, after of serial amnioinfusions, rate of PPROM, neonatal nondirective genetic counseling. The other woman de- survival, rate of cesarean delivery, rate of intrauterine cided to undergo another amnioinfusion and amnio- fetal demise, number of patients whose latency period patch after thorough discussion. She suffered from was more than 21 days, birth body weight, number of mild amniorrhea on the fourth day after amniopatch, patients who underwent termination of pregnancy but her AFI remained at the optimal level for her (TOP) of the viable fetus, number of patients who de- gestational age (10). Amniopatch was considered veloped fever or leukocytosis after onset, and karyotype successful. The mean number of serial amnioinfusions were carefully reviewed and tabulated. Pathology reports was 3.9 (range, 1–8) (Table 2). for the delivered placenta as well as dead fetuses were Intrauterine fetal death (IUFD) was noted in one recorded, if available. treated woman (9.1%) and 11 control women (37.9%). There was significant prolongation of the latency peri- Statistical analysis od in the treatment group compared with the control Fisher’s exact test and two-tailed Student’s t test group (34 vs 9 days; p < 0.05) (Table 2). The neonatal were used to analyze relevant data using STATA (Stata survival rate was also significantly improved in the treat- Corp, College Park, TX, USA) and Microsoft Excel soft- ment group compared with the control group (72.7% ware. 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 Results as fever or leukocytosis, but two women in the treat- ment group (18.2%) and 12 in the control group (41.4%) Seven of 11 women (63.6%) in the treatment group and developed fever or leukocytosis later. Karyotype was 20 of the 29 control women (69.0%) were Taiwanese/ known and normal in all the women in the treatment Chinese; the remaining subjects were women from group but for only 20 women in the control group, five Vietnam, Cambodia, or the Philippines married to a Tai- of whom had an abnormal karyotype (Table 1). More wanese husband. Four women in the treatment group women in the treatment group (9; 81.8%) than control (36.4%) and 13 control women (44.8%) had PPROM group (6; 20.7%) had cesarean delivery. The number of (Table 1). There was no significant difference between whose latency period was more than 21 the groups in maternal age (32 vs 33 years), gestational days was significantly greater in the treatment group age at diagnosis (23 vs 23 weeks), and the percentage of (9) than the control group (0). No serious maternal PPROM. Seven women who had intact amniotic mem- complication was noted in any of the subjects. Placental branes received amnioinfusion only and four women pathology showed no remarkable findings for any with PPROM received amnioinfusion and cerclage. Two subjects who underwent this examination (treatment of the four PPROM women who had cerclage suffered group, n = 11; control group, n = 27).

Table 1. Demographic and obstetric characteristics Treatment group (n = 11) Control group (n = 29) Maternal age, mean (range) (yr)* 32 (23–41)0. 33 (20–43)0. GA at diagnosis, mean (range) (wk)* 23+2 (17+3–26+0)23+4 (15+2–29+5) GA at delivery, mean (range) (wk) 31+3 (24+2–33+4)26+2 (16+2–30+6) Fever/leukocytosis at diagnosis* 00 00 PPROM* 4 (36.4%) 13 (44.8%)0. GA ) 26 wk 11 25 26 wk < GA < 30 wk 00 04 Karyotyping by amniocentesis 0414 Karyotyping by CVS 03 03 Karyotyping by cordocentesis 04 03 Karyotyping in postnatal period 00 09 Abnormal karyotypes† 00 05 *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) Control group (n = 29) Serial amnioinfusion, mean (range) 3.9 (1–8)00 0 Amnioinfusion 11 0 Cerclage 040 Amniopatch 010 Amniorrhea < 6 hr after amnioinfusion 020 Latency period, mean (range) (d)* 34 (11–59) 9 (2–19)0 Women with latency > 21 d* 090 IUFD* 1 (9.1%) 11 (37.9%)0 TOP of viable fetus by induction 1 (9.1%) 12 (41.4%)0 Baby survived > 1 mo* 08 (72.7%) 6 (20.7%) Birth body weight (g)* 01,400 (350–2,200) 0,900 (190–1,300) Cesarean delivery 09 (81.8%) 6 (20.7%) Fever/leukocytosis after diagnosis* 02 (18.2%) 12 (41.4%)0 *p < 0.05. IUFD = intrauterine fetal death; TOP = termination of pregnancy.

Discussion before 25 gestational weeks with severe oligohydram- nios for more than 14 days has a perinatal mortality of Selection bias and matched controls more than 90% [16]. Maternal and The difficulty of conducting such a controversial study neonatal respiratory distress syndrome are also noted rests mainly on the probable selection bias. Some may in more than half of patients [17]. Cerclage and amnio- argue that the two groups we chose inherited differ- infusion were universally offered to patients with ent characteristics, which may confound our results. PPROM in the treatment group, which further eliminated We tried to match parameters such as maternal age, the interaction of both treatment modalities in these gestational age at diagnosis, and the percentage of patients. PPROM, and excluded confounding factors such as preexisting infection, fetal/maternal/placental pa- Amnioinfusion thology, and patients with the possibility of cervical The efficacy and safety of intrapartum amnioinfusion incompetence. The major pitfall of this study is that have been proven in several prospective randomized it was not a randomized controlled trial, and the rea- studies, as summarized in an evidence-based meta- sons for offering options in the treatment group and analysis [18]. However, antepartum amnioinfusion is choosing not to treat in the control group are difficult still under debate, despite its safety and efficacy (in to standardize. However, results obtained with ran- lengthening the latency between diagnosis and deliv- domized and strictly selected groups may have a limited ery, in reducing pulmonary hypoplasia, in increasing value in clinical practice since most patients we en- diagnostic accuracy of ultrasound, and in reducing counter in clinical practice would deviate from such perinatal mortality) reported in some studies [2,7,19, study groups. We believe our results are of some value 20]. A large randomized controlled trial is lacking. It is even though this was not a randomized controlled trial. difficult to study this topic because there are too many Furthermore, the prospective nature of our study confounding factors such as various underlying fetal/ enhances its applicability in the real situations en- maternal pathologies and the difficulty controlling for countered in practice. pregnancy course across many variables. We, therefore, focused our study on singleton pregnancies complicated Oligohydramnios with oligohydramnios, regardless of intact or ruptured Early onset oligohydramnios is not common and in- amniotic membranes, and no signs of infection, ob- dicates poor fetal prognosis. Apart from PPROM, serving the latency period and neonatal survival and the most common etiology is fetal anuria caused by maternal infection rates. Other outcome measures such either obstructive uropathy or renal agenesis. Other as birth body weight and the rate of cesarean delivery etiologies mainly include maternal disease such as pre- were considered unsuitable items for outcome assess- , hypertension, diabetes, hyperthyroidism, ment since any conclusion drawn from these markers and others [15]. Oligohydramnios is associated with may call for considerable speculation and have limited increased perinatal morbidity and mortality. PPROM value.

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Amniopatch Acknowledgments The mechanism of amniopatch is still unclear. The authors who devised the method speculated that the This study was partially funded by National Taiwan platelet/cryoprecipitate plug might seal the amniotic University Hospital (NTUH-93N10) and Changhua membranous defect by artificial activation of platelet Christian Hospital (CCH-9282). The authors would like and fibrin adhesion at the site of rupture because fetal to thank Professor Chia-Li Yu, Professor Fon-Jou Hsieh, membranes are avascular and incapable of eliciting and Professor Song-Nan Chow of National Taiwan spontaneous platelet activation, fibrin deposition, and University Hospital, as well as Professor Bao-Tyan Wang, therefore wound healing. Amniotic membrane is thought Dr. Kuo-Cherng Lin, Dr. Pan-Hsin Chou, and Dr. Tsung- to seal during genetic amniocentesis due to the adher- Che Hsieh of Changhua Christian Hospital, for their ence of amniotic membranes to the underlying chorionic support in conducting the study. The authors would membranes. Quintero et al documented the detachment also like to thank Ms. Li-Wen Chen, Ms. Mei-Hui Lee, of amniotic membranes from chorionic membranes in Ms. Ming-Jung Tsai, and many other colleagues for iatrogenic PPROM cases as well as reattachment of their assistance. the successful amniopatched cases by ultrasound [13]. Lewi et al documented blood clot in successful amnio- patched cases with ultrasound [14]. Both groups of References authors considered amniopatch to be more effective for treating iatrogenic PPROM than spontaneous 1. Vergani P, Locatelli A, Strobelt N, Mariani S, Cavallone M, PPROM. Arosio P, Ghidini A. 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