1-s2.0-S0002937801474217-main

8/12/2019 1-s2.0-S0002937801474217-main

http://slidepdf.com/reader/full/1-s20-s0002937801474217-main 1/6

368

One in 154 pregnancies will be complicated by prema-

ture rupture of the membranes in the second trimester.

The median latency between rupture of the membranes

and delivery is 6.6 days, with 80% of patients delivering

within 7 days of rupture.1 In pregnancies that continue

the rate of “resealing” of the membranes is approximately

8%. Those pregnancies in which resealing does not occurare at significant risk for pulmonary hypoplasia, skeletal

abnormalities, perinatal morbidity and mortality, and ma-

ternal infectious morbidity. Furthermore, in a report by

Hadi et al,2 in patients with second-trimester rupture of

the membranes and persistent oligohydramnios, it was

found that only 9.4% of neonates survived. This led the

authors to conclude that women with premature rupture

of the membranes at 20 to 25 weeks’ gestation, with inad-

equate amniotic fluid volume (maximum vertical pocket,

<2 cm) “have a dismal chance for neonatal survival.” Even

in those infants who survive, there appears to be a signifi-

cant risk for developmental delay (22%-53%).3, 4

Fibrin tissue sealants were first described in the early

1900s as a potentially useful clinical tool. Since that time,

fibrin sealants have gained popularity for many uses, in-

cluding hemostasis, tissue healing, and the formation of

watertight seals. In a recent MEDLINE search >1000 pub-

lications were found that referred to the clinical use of fi-

brin sealants.

Fibrin sealants mimic the last step in the coagulationcascade, resulting in a semirigid fibrin clot. The fibrin

clot adheres to the application site, which results in a seal

against the passage of fluid or air. The main components

of fibrin sealants are fibrinogen, Factor XIII, and throm-

bin. Other components include calcium to provide acti-

vation of Factor XIII, fibronectin to aid in adhesion, and

an inhibitor of fibrinolysis to prolong fibrin clot life.

The use of a fibrin tissue sealant for preterm prema-

ture rupture of the membranes was first suggested by

Genz5 in 1979. Since that time there have been varying

degrees of success with this modality, with larger reports

finding success.6, 7 Unfortunately, techniques and out-

come parameters varied significantly between the studies.

Furthermore, there was a large variation in gestationalage at application, and the quantity of amniotic fluid was

not documented before or after the application of the fi-

brin sealant.

Fibrin sealants appear to have important functions

when applied to the cervix. Fibrin sealants may prevent

amniorrhea, resulting in an increase in amniotic fluid vol-

ume. The subsequent increase in amniotic fluid volume

may decrease the occurrence of pulmonary hypoplasia or

skeletal abnormalities, although the amount of amniotic

From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology,a and the Department of Pathology and Laboratory Medicine,b Christiana Care Health Services.Received for publication May 30, 2000; revised August 3, 2000;accepted September 20, 2000.Reprint requests: Anthony C. Sciscione, DO, Christiana Care Health Ser- vices, Maternal-Fetal Medicine Division, 4755 Ogletown-Stanton Rd,Newark, DE 19718.Copyright © 2001 by Mosby, Inc.0002-9378/2001 $35.00 + 0 6/1/111796 doi:10.1067/mob.2001.111796

Intracervical fibrin sealants: A potential treatment for early

preterm premature rupture of the membranes

Anthony C. Sciscione, DO,a James S. Manley, MD,a Marjorie Pollock, MSN, CRNP,a

Bridget Maas, BSN, RNC,a Philip A. Shlossman, MD,a Wadia Mulla, MD,a Mike Lankiewicz, MD,b

and Garrett H.C. Colmorgen, MDa

Newark, Delaware

OBJECTIVE: We report our experience with a transvaginally applied intracervical fibrin sealant at <24

weeks’ gestation.

STUDY DESIGN: This is an observational study of a referred patient population, with preterm premature rup-

ture of the membranes at <24 weeks’ gestation.

RESULTS: Twelve women consented to our protocol.The mean gestational age at preterm premature rup-

ture of membranes was 19 weeks 4 days (range, 13-23 weeks); the mean gestational age at treatment was

20 weeks 5 days (range, 17-23 weeks). All women had a diminution in the amount of amniotic fluid leakage

with an increase in amniotic fluid index. Among the 12 pregnancies (13 fetuses), there were 7 surviving

neonates.Two women had apparent “resealing” of the membranes.

CONCLUSION: Fibrin sealants in midtrimester rupture of the membranes may lead to improved outcomes

and now warrant formal evaluation. (Am J Obstet Gynecol 2001;184:368-73.)

Key words: Premature rupture of the membranes, prematurity, neonatal outcomes

8/12/2019 1-s2.0-S0002937801474217-main


Volume 184, Number 3 Sciscione et al 369 Am J Obstet Gynecol

fluid necessary to accomplish this is unclear. Second, fi-

brin sealants may act as barriers to ascending infection.

In an effort to determine the utility of a fibrin tissue

sealant in women with previable, preterm premature rup-

ture of the membranes, we chose to apply the fibrinsealant in pregnancies that had a poor prognosis, <24

weeks with severe oligohydramnios. We describe the ex-

perience in our institution over a 5-year period.

Material and methods

This study was approved by the Institutional Review

Board of the Christiana Care Health System. Women

were offered placement of fibrin tissue sealants on a case-

by-case basis as a “heroic” treatment for preterm rupture

of the membranes at <24 weeks’ gestation. After rupture

of the membranes was confirmed by history, fluid ar-

borization, Nitrazine paper testing, and pooling, women

with reliable dating criteria at <24 weeks’ gestation with

no sign of chorioamnionitis or severe oligohydramnios

(maximum vertical pocket <2 cm and an amniotic fluid

index of <3 cm), with a structurally normal fetus on tar-

geted sonogram, were offered therapy after an in-hospital

observation period of 48 hours. All patients were offered

termination of the pregnancy.

To determine the optimal amount, concentration, and

position of the fibrin tissue sealant a pilot series of 5 patients

underwent evaluation; each fibrin tissue sealant compo-

nent was varied until the best and most stable fibrin clot was

formed. The desired components were then inserted

through the cervix and advanced to the internal os with ul-

trasonographic guidance. A double-lumen catheter was uti-

lized that allowed mixing of the components at the tip. Although all 5 pilot patients experienced a marked de-

crease in the amount of amniotic fluid leakage, no

woman had an appreciable reaccumulation of amniotic

fluid. If the patient agreed, a second procedure was per-

formed at least 24 hours after the first, and the compo-

nents and placement location were changed. In this pilot

series no pregnancies progressed beyond 24 weeks’ gesta-

tion, with no surviving infants (Table I).

After this pilot series a common protocol was instituted

and offered to all patients with ruptured membranes at

<24 weeks’ gestation. The protocol included admission to

the hospital for 48 hours of bed rest, intravenous hydra-

tion, and intravenous broad-spectrum antibiotic cover-

age. After 48 hours, if the patient did not show signs of labor or infection, ultrasonography was performed to re-

assess the amniotic fluid volume. If severe oligohydram-

nios was still present, the patient was offered the applica-

tion of the fibrin tissue sealant.

Initially, the fibrin tissue sealant was made from a donor

unit of cryoprecipitate along with 10,000 units of bovine

thrombin. After the seventh patient, a commercial fibrin

tissue sealant (Tisseel; Baxter, Glendale, Calif) became

available and was used for the remainder of the patients.

One syringe of this commercial preparation was filled with

cryoprecipitate and another with thrombin and ε-

aminocaproic acid. The component-filled syringes were at-

tached to the ends of a double-lumen catheter, and a suffi-

cient volume to assure adequate mixing at the tip wasinjected. After the vagina was prepared with iodine, with

ultrasonographic guidance through a partially filled blad-

der, the catheter tip was inserted through the cervix to the

level of the internal os. Approximately 1 to 2 mL of each

component was slowly injected until an ultrasonographi-

cally evident fibrin clot was seen. Once this was observed,

the catheter was slowly withdrawn but placement of fibrin

tissue sealant was continued until it filled the endocervical

canal. The clot was then trimmed flush with the exocervix

before removal of the speculum. The patient remained at

strict bed rest for 96 hours. Intravenous antibiotics were

continued, and the patient maintained a log of the amount

of amniotic fluid leakage from the vagina. A sonogram was

obtained at 24 to 48 hours and again at 96 hours. If there

was no appreciable increase in the amount of fluid, a re-

peat procedure was offered to the patient. This sequence

was repeated with a maximum of 5 reapplications. All pa-

tients were placed on a regimen of modified bed rest, with

complete blood cell counts obtained twice weekly and eval-

uation of amniotic fluid leakage performed daily, until

fluid reaccumulated or no further applications were indi-

cated. After this, the amniotic fluid volume was rechecked

weekly by ultrasonography until delivery.

Chorioamnionitis was diagnosed by a maternal tem-

perature ≥38°C, with at least two of the following criteria:

fetal tachycardia (>160 beats/min) for >10 minutes), ma-

ternal tachycardia (>100 beats/min), uterine contrac-tions, uterine tenderness, or an elevated maternal leuko-

cyte count (>15 × 103). If a patient met criteria for

chorioamnionitis or active labor developed, delivery was

immediately instituted. Postpartum endomyometritis was

defined as uterine tenderness with a maternal fever

(≥38°C), documented two times 4 hours apart.

Results

In total, 17 patients have been treated with fibrin tissue

sealants, 5 as part of the pilot study to maximize the fibrin

tissue sealant concentration and 12 as part of the clinical

protocol. Only the 12 protocol patients are included in

this report. The pregnancy data for the patients are pre-

sented in Table II. The majority were multiparous, with amedian gravidity of 3.0 pregnancies per patient. The

mean gestational age at rupture of the membranes was 19

weeks 4 days, and the mean gestational age at treatment

was 20 weeks 5 days. The mean number of applications

was 1.7 (Table II). One patient had a twin gestation in

which both sacs appeared ruptured, with resultant oligo-

hydramnios surrounding both fetuses.

All patients reported an initial cessation of leakage of

amniotic fluid, but this did not correlate with ultrasono-

8/12/2019 1-s2.0-S0002937801474217-main


370 Sciscione et al February 2001

Am J Obstet Gynecol

graphic findings. The amniotic fluid indices are pre-

sented and charted in Fig 1. Two patients (17%) had

complete cessation of amniotic fluid leakage within 48

hours of application of a fibrin tissue sealant and a con-

comitant increase in amniotic fluid index, which re-

turned to normal. One of these patients was delivered at

32 weeks’ gestation, after an episode of premature labor.The other was delivered at term without complications.

Table III describes the outcomes of the pregnancies for

which we obtained consent to our protocol. The mean

gestational age at delivery was 27 weeks 4 days, and the

mean latency (time of rupture to delivery) was 48.1 days

with a median of 57 days. Potential viability was reached

in 9 of 12 (75%) patients at 24 weeks, and 4 of them

(33%) progressed to ≥32 weeks’ gestation. Most patients

had spontaneous labor as the reason for delivery. Only 1

patient experienced chorioamnionitis, and no other pa-

tient had any isolated symptoms or signs of chorioam-

nionitis. Seven of 13 (54%) neonates survived. After de-

livery of the presenting twin, 1 patient (patient 4) opted

for expectant management of the second twin. The first twin was premature but ultimately did well. The second

twin was delivered 13 days after delivery of the first twin

and died shortly after birth of a gram-negative sepsis. One

patient (patient 10) left the hospital shortly after applica-

tion of the fibrin tissue sealant. The patient was lost to fol-

low-up until she was seen at 30 weeks’ gestation in labor;

she was delivered of a fetus who died shortly after birth of

a diaphragmatic hernia. All of the surviving infants had

sequelae of prematurity, except the infant of patient 9.

There were no maternal local or systemic reactions

from the fibrin tissue sealant, and all patients remain

well, without any apparent side effects from the sealant

placement. There was no evidence of adhesions in any

fetus, fetal swallowing of the sealant, or disturbance in the

fetal coagulation system. All of the living children are

well, without any apparent adverse effects from the fibrinsealant.

Comment

We report the use of a fibrin tissue sealant in 17 women

who had preterm premature rupture of the membranes

with severe oligohydramnios at <24 weeks’ gestation.

Neonatal survival has previously been dismal in this

group of patients. In a 6-year prospective trial by Hadi et

al,2 the survival in pregnancies with preterm premature

rupture of membranes and a maximum vertical fluid

pocket <2 cm was only 9.4%. With the fibrin sealant we

decreased amniotic fluid leakage, and 2 women had com-

plete cessation of leakage with apparent resealing of the

amniotic membranes. In our limited experience we havehad 7 neonatal survivors in 12 pregnancies (13 fetuses),

resulting in an overall survival rate of 53.8%.

In a recent review of the literature the overall “success”

of fibrin sealants in patients with premature rupture of

membranes has been reported to be between 60% and

100%.8 However, there have been varying definitions for

success, including cessation of amniotic fluid leakage,9 a

live birth,5-7, 10-13 neonatal survival, or birth at term.14

Whereas intact survival is the ultimate goal of treatment,

Table I. Patient data and outcomes in first 5 patients

Gestational age Gestational age No. of Gestational age Patient No. at rupture at treatment placements at delivery (wk) Latency (d) Complication Survival

1 18 wk 2 d 20 wk 2 24 wk 2 d 23 Twins; chorioamnionitis No2 23 wk 1 d 23 wk 5 d 1 24 wk 2 d 7 Voluntary termination of pregnancy No3 16 wk 5 d 19 wk 3 d 1 20 wk 6 d 10 Chorioamnionitis No4 19 wk 4 d 22 wk 2 d 1 22 wk 6 d 4 Spontaneous labor No5 21 wk 5 d 21 wk 6 d 1 22 wk 6 d 3 Spontaneous labor No

Table II. Antenatal data on patients submitting to protocol

Gestational age Gestational age No. of Patient No. Age (y) Gravidity Parity at rupture at treatment applications Complication

1 34 2 1-0-0-1 12 wk 4 d 22 wk 6 d 1 None2 37 1 0-0-0-0 17 wk 4 d 17 wk 6 d 1 None3 20 4 0-0-3-0 20 wk 2 d 20 wk 4 d 1 None4 26 2 1-0-0-1 22 wk 1 d 22 wk 3 d 1 Twins5 30 4 0-0-3-0 18 wk 4 d 18 wk 6 d 1 None

6 32 5 0-0-4-0 17 wk 17 wk 3 d 5 None7 35 2 0-0-1-0 13 wk 5 d 20 wk 6 d 2 Uterine anomaly 8 35 5 0-0-4-0 15 wk 2 d 19 wk 5 d 3 None9 40 1 0-0-0-0 23 wk 4 d 23 wk 6 d 2 None

10 20 2 1-0-0-1 21 wk 21 wk 2 d 1 Left hospital11 32 4 1-0-1-2 21 wk 5 d 22 wk 4 d 1 None12 26 3 1-1-0-2 22 wk 1 d 22 wk 6 d 1 None

8/12/2019 1-s2.0-S0002937801474217-main



it is difficult to compare this outcome between studies of

early preterm premature rupture of membranes because

of the confounding effect of gestational age. Many previ-

ous studies evaluating fibrin tissue sealant have included

cases with rupture at ≥28 weeks’ gestation, when the

neonatal survival rate already approaches 100%. Success

defined as cessation of fluid leakage is not an adequate

end point, because we have found that women often can-not accurately determine if fluid is leaking from the

vagina. Fluid volume may be used as a marker of immedi-

ate success, but an objective assessment such as the amni-

otic fluid index should be utilized. Whereas this index

has inaccuracies,15 it is one of the more reliable indica-

tors of fluid leakage and objectively documents changes

in amniotic fluid volume over time.

Fibrin tissue sealants have been shown to increase the

postrupture latency period. Masson16 compared 10 pa-

tients between 16 and 30 weeks’ gestation who had a fi-

brin sealant placed with 10 control subjects. He found a

mean delay of 14 days from diagnosis to delivery in the

control group, versus a 59-day delay in those who re-

ceived the sealant. No intra-amniotic infections were

noted in the group that received the fibrin sealant. Fur-

thermore, he found significant cost savings with the ap-

plication of fibrin sealant. The increase in latency withthe use of fibrin sealants was further confirmed by Cata-

lano and Zardini7 in 47 patients with preterm premature

rupture of the membranes between 20 and 35 weeks’ ges-

tation. In the group that was expectantly managed, the

mean delay in delivery was 2.6 days versus 29 days in the

group that had a fibrin sealant application. Survival was

also significantly increased from 43% in the expectantly

managed group to 80% in the group receiving the fibrin

sealant.

Fig 1. Amniotic fluid indices (AFI) in patients 1 to 12.

8/12/2019 1-s2.0-S0002937801474217-main


8/12/2019 1-s2.0-S0002937801474217-main



REFERENCES

1. Taylor JD, Garite TJ. Premature rupture of the membranes be-fore fetal viability. Obstet Gynecol 1984;64:615-20.

2. Hadi HA, Hodson CA, Strickland RT. Premature rupture of themembranes between 20 and 25 weeks’ gestation: role of amni-

otic fluid volume in perinatal outcome. Am J Obstet Gynecol1994;170:1139-44.

3. Beydoun SN, Yasin SY. Premature rupture of the membranes be-fore 28 weeks: conservative management. Am J Obstet Gynecol1986;155:471-9.

4. Morretti M, Sibai B. Maternal and perinatal outcome of expec-tant management of premature rupture of membranes in themidtrimester. Am J Obstet Gynecol 1988;159:390-6.

5. Genz HJ. [Treatment of premature rupture of the fetal mem-branes by means of fibrin adhesion.] Med Welt 1979;30:1557-9.

6. Baumgarten K, Moser S. The technique of fibrin adhesion forpremature rupture of the membranes during pregnancy. J Peri-nat Med 1986;14:43-9.

7. Catalano A, Zardini E. La rottura intempestiva delle membrane:Evoluzione spontanea dell’evento e suo approccio terapeuticomediante una colla di fibrina umana. Minerva Ginecol1994;46:675-80.

8. Delzano G, Gaudiano L. Impiego di colla di fibrina nella rottura

prematura delle membrane. Minerva Ginecol 1994;46:495-7.9. Kurz CS, Huch A. Fibrin sealing: an advanced therapy in dealing with premature rupture of membranes? J Perinat Med1982;10:66-7.

10. Genz HJ, Ludwig H. Weitere Erfahrungen mit der Fibrinkle-bung bei schwangeren Frauen und vorzeitigem Blasensprung.Blut 1981;42:122-5.

11. Genz HJ, Ludwig H. Weitere Ergebnisse mit der Fibrinklebungbei schwangeren Frauen und vorzeitigem Blasensprung. In:Blfimel G, Haas S, editors. Mikrocirculation und Prostaglandin-stoffwechsel. Neues fiber Fibrin und Fibrinkleber. Stuttgart:Schattauer-Verlag; 1981.

12. Genz HJ, Ludwig H, Metzger H, Rosenthal E, Gerlach H. Antibi-otikahaltiger Fibrinkleber zur Behandlung des vorzeitigen

Blasensprungs in Perinatale Medizin. In: Dudenhausen JW, Sal-ing E, editors. Perinatale Medizin. Stuttgart: Georg Thieme Ver-lag; 1982.

13. Genz HJ. Möglichkeiten der konservierenden Behandlung des vorzeitigen Blasensprungs. In: Ludwig H, Heilmann L, editors.

Ergebnisse des Hexoprenalinsymposiums Wehenhemmung.Berlin: Springer-Verlag; 1982.

14. Garite TJ, Freeman RK, Linzey EM, Braly PS, Dorchester WL.Prospective randomized study of corticosteroids in the manage-ment of premature rupture of the membranes and the prema-ture gestation. Am J Obstet Gynecol 1981;141:508-15.

15. Chauhan SP, Magann EF, Morrison JC, Whitworth NS, HendrixNW, Nevve LD. Ultrasonographic assessment of amniotic fluiddoes not reflect actual amniotic fluid volume. Am J Obstet Gy-necol 1997;177:291-6.

16. Masson M. Fibrin sealing by tissucol in premature rupture of thefetal membranes. In: Hans-Werner P, Waclawiczek J, editors.Progress in fibrin sealing. Berlin: Springer-Verlag; 1989. p. 41-8.

17. Dvorak HF, Harvey VS, Estrella P, Brown LF, McDonagh J, Dvo-rak AM. Fibrin containing gels induce angiogenesis. Implica-tions for tumor stroma generation and wound healing. Lab In- vest 1987;57:673-86.

18. Matras H. Fibrin seal: the state of the art. J Oral Maxillofac Surg

1995;54:570-3.19. Kram HB, Nathan RC, Mackabee JR, Klein S, Shoemaker WC.

Clinical uses of non-autologous fibrin glue. Am J Surg1988;35:633-5.

20. Watanabe T, Araki M, Mimuro J, Tamada T, Sakata Y. Fibrinolyticcomponents in fetal membranes and amniotic fluid. Am J Ob-stet Gynecol 1993;168:1283-9.

21. Quintero RA, Romero R, Dzieczkowski J, Mammen E, Evans M.Sealing of ruptured amniotic membranes with intra-amnioticplatelet-cryoprecipitate plug. Lancet 1996;347:1117.

22. Louis-Sylvestre C, Rand JH, Gordon RE, Salafia C, Berkowitz RL.In vitro studies of the interactions between platelets and amnioticmembranes: a potential treatment for preterm premature rup-ture of the membranes. Am J Obstet Gynecol 1988;178:287-93.

Documents

1-s2.0-S0002937801474217-main