Treatment of Iatrogenic Previable PROM with the Amniopatch:
Information for Healthcare Professionals

Iatrogenic preterm premature rupture of membranes (iatrogenic PPROM ) occurs in approximately 1.2% of patients after genetic amniocentesis, 3-5% after diagnostic fetoscopy, and in approximately 5-8% of patients after operative fetoscopy. The membranes may seal spontaneously in this setting, however, patients may continue to leak fluid per vagina, and are at risk for pregnancy loss.

Successful prolongation of pregnancy after iatrogenic PPROM is complicated by the fact that the invasive procedure responsible for the complication is typically performed early in pregnancy. Although the natural history of PPROM may differ between spontaneous and iatrogenic PPROM, the overall perinatal mortality of pre-viable PPROM managed expectantly is 60%. Nearly one third of these deaths occur in utero. Pulmonary hypoplasia occurs in 50% of cases diagnosed prior to 19 weeks. Serious sequelae in surviving infants include blindness, chronic lung disease, and cerebral palsy.

Background

Until our first report in 1996, there was no treatment available for iatrogenic PPROM. Still, to this date, management of patients with iatrogenic PPROM before 23 weeks gestation often consists of induction of labor in view of the risk of serious maternal infection and the low likelihood of neonatal survival.

In 1996 we described the first successful treatment of iatrogenic PPROM with the intraamniotic injection of platelets and cryoprecipitate. The idea stemmed from the blood patch, described by Gormley in 1960 for the treatment of headache after spinal anesthesia. The rationale for the technique was to allow platelets to identify the area of injury and stabilize the clot with cryoprecipitate. The concentration of fibrinogen in cryoprecipitate ranges from 800-1200 mg/dL, a much higher concentration than in fresh blood. Under ultrasound guidance, we injected one unit of autologous platelets and cryoprecipitate in a free pocket of amniotic fluid. The patient, who had been leaking amniotic fluid for 3 weeks after operative fetoscopy, had no further leakage of fluid, the amniotic fluid volume normalized, and she was delivered electively at term. We called this technique "the amniopatch." Sener et al subsequently reported another successful case by injecting whole blood into the chorionic space in a patient with iatrogenic PPROM after genetic amniocentesis.

Amniopatch Technique

Patients with iatrogenic PPROM after 16 weeks' gestation without clinical evidence of intraamniotic infection are considered eligible for therapy. PPROM is confirmed with sterile speculum examination showing vaginal pooling of fluid, ferning, and a positive nitrazine test. The maximum vertical pocket of amniotic fluid is measured sonographically. Patients are typically placed on intravenous antibiotics and bed rest for one week to allow for spontaneous sealing of the membranes. If spontaneous sealing does not occur, one unit each of autologous platelets and cryoprecipitate are prepared, if the patient is eligible for autologous donation. Otherwise, donor platelets and cryoprecipitate are prepared.

After informed consent is obtained, an amniocentesis is performed using a 22-gauge needle. The needle is directed into an available pocket of fluid, regardless of the site of the previous invasive procedure. A K-51 tubing extension attached to a 3-way stopcock is connected to the hub of the needle. Platelets are administered first, followed by cryoprecipitate. In the original protocol, one whole unit of platelets was injected. We have subsequently reduced the dose of platelets to ½ unit, because of unexplained fetal demise, an adverse effect, probably due to sudden activation of a large number of platelets.

Clinical Experience with the Amniopatch

In a series of 28 patients treated with the amniopatch at our institution, the average gestational age at the time of the procedure was 19.3 weeks. The average gestational age at delivery in those patients that did not have an intrauterine fetal demise was 33.4 weeks. Genetic or therapeutic amniocentesis was responsible for PPROM in 10/28 cases (35.7 %), one case due to transvaginal CVS and the rest were due to operative fetoscopy. Overall, membrane sealing occurred in 19/28 ( 67.9 %). Of the 28 patients treated, 11 had a large membrane detachment but no overt leakage of fluid. The detachment of the membrane occurred from fluid escaping the amniotic cavity through the membrane defect causing dissection of the chorionic cavity. In this group, only the chorion separates this fluid from leaking grossly through the vagina. In these patients, the amniopatch was successful in resealing the amniotic membrane in 7 / 11 (63.6 %).

Gross leakage of fluid from either transvaginal CVS, amniocentesis or operative fetoscopy occurred in 17 patients. Successful sealing of the cavity occurred in 12 / 17 (70.6 %). However, spontaneous intrauterine fetal demise or pregnancy loss occurred in 4 / 17 patients. The first demise was probably due to a large infusion of platelets. The other demise occurred from an incompetent cervix associated with twin-twin transfusion syndrome, the third demise a bladder obstruction, and the fourth was a severe chorioamnionitis. Therefore, the overall successful pregnancy outcome for patients with gross leakage of fluid was 10 / 17 patients (58.8%).

Conclusions on Treatment of Iatrogenic PPROM

Our preliminary experience shows that the amniotic cavity can in fact be sealed with an intraamniotic injection of platelets and cryoprecipitate, and that the pregnancy may continue uneventfully thereafter. Knowledge of the site of rupture is not necessary for the amniopatch. In our first case, the original trocar insertion (and thus the site of membrane defect) was at the uterine fundus. However, the only available pocket of fluid at the time of the amniopatch was in the lower left portion of the uterus. Thus, the material seems to find its way within the amniotic cavity to the defect and seal it. This may in fact be taking place, as documented passage of the injected material from the amniotic cavity into the extraamniotic space in patients in whom membrane detachment has occurred.

The precise mechanism by which the amniopatch may work is unknown. Presumably, platelet activation at the site of rupture and fibrin formation would initiate the healing process and allow the membranes to seal. From our own in vitro work, we know that amnion cells are capable of restoring the integrity of an amnion monolayer after iatrogenic injury, though at much slower rate than endothelial cells. Platelets and fibrin may provide the necessary scaffold for amnion cells and fibroblasts to restore the integrity of the membrane, overcoming the adverse effect of the intraamniotic fluid pressure. Because of the avascular nature of the fetal membranes, the amnion is incapable of eliciting spontaneous platelet activation, fibrin deposition and wound healing. The artificial administration of platelets and cryoprecipitate through the amniopatch may overcome this natural limitation.

Detachment of the amnion from the subjacent chorion, with dissection of the extraamniotic space by amniotic fluid, may be involved in the mechanism of iatrogenic PPROM in all cases. This may explain the increased risk of PPROM in first trimester amniocentesis, at a time when the membranes may not have fused yet. Membrane detachment is also present in patients with spontaneous PPROM, as we recently documented endoscopically. As a corollary, the ability of amniotic membranes to heal after invasive procedures is probably due to their strong attachment to the underlying chorion. Indeed, membrane reattachment may be an essential operative step in the ability of the amniopatch to seal the membranes. Whether an inherent or acquired lack of adhesiveness of the amnion to the chorion is present in some patients (such as may occur after a subchorionic bleed), or whether technical reasons related to the original invasive procedure are responsible for the rupture of the membranes is unclear at this point.

The cause of spontaneous fetal demise in three of our initial patients was most likely due to sudden activation of a large amount of platelets. Severe bradycardia and hypotension has been described with platelet transfusion through the release of serotonin, adenosine diphosphate (ADP), platelet activating factor (PAF), and bradykinin. Although this etiology had not been apparent in the first two cases, our third demise occurred after injection of 150 cc of platelets obtained through plasmapheresis (three times the previous amniopatch dose). The fetus developed severe bradycardia within minutes of the procedure and died despite intrauterine resuscitative efforts. Surgical pathology showed a significant amount of fibrin formation but the umbilical cord was intact. Hypotension and bradycardia have also been described with intravenous injection of indigo carmine. These effects are presumably attributed to the similarities of the molecule to serotonin, which causes similar cardiovascular effects. Due to these complications, we have modified our protocol to include no more than 25 cc of platelets and we have discontinued the use of indigo carmine.

Successful treatment of iatrogenic PPROM is an important step in the understanding of amniotic membrane integrity and pregnancy preservation in the human. In this small series, despite inherent additional complications such as twin-twin transfusion syndrome or acardiac twin, the survival rate was remarkable (3/7, or 42.8%), considering that most of these pregnancies would have been lost to PPROM. Though the appropriate dose of platelets and cryoprecipitate needs to be established, the amniopatch may allow iatrogenic PPROM no longer to be considered a devastating complication of pregnancy.

Please contact us to fax the Amniopatch Evaluation/Screening Form to your office. For further information, feel free to contact us.

Phone Toll Free: 1-877-FETAL-77
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