Amnioinfusion

Number: 0417

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses amnioinfusion.

1. Medical Necessity

   Aetna considers amnioinfusion medically necessary for any of the following indications:

   • Prophylactic treatment of oligohydramnios, or
   • Reduction of variable decelerations of the fetal heart rate because of cord compression during labor, or
   • Treatment of preterm premature rupture of membranes at 26 weeks' gestation or later.

2. Experimental, Investigational, or Unproven

   Aetna considers amnioinfusion experimental, investigational, or unproven for the following indications (not an all-inclusive list) because of insufficient evidence in the peer-reviewed literature:

   • Chorioamnionitis
   • Facilitation of external cephalic version
   • Preterm premature rupture of membranes before 26 weeks' gestation
   • Prevention of meconium aspiration syndrome
   • Prevention of post-partum hemorrhage
   • Reduction of risk of fetal neurologic injury during labor
   • Treatment of anhydramnios resulting from fetal bilateral renal agenesis
   • Treatment of second-trimester anhydramnios (amnioinfusion, however, may be indicated to improve ultrasound evaluation of the fetus)
   • Women with a singleton breech presentation and a previous failed external cephalic version.

   Aetna considers serial amnioinfusion experimental, investigational, or unproven for the treatment of pulmonary hypoplasia in fetuses with intrauterine renal failure or severe renal anomalies because its effectiveness for this indication has not been established.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
59070	Transabdominal amnioinfusion, including ultrasound guidance
Other CPT codes related to the CPB:
59412	External cephalic version, with or without tocolysis
ICD-10 codes covered if selection criteria are met:
O41.00x0 - O41.00x9	Oligohydramnios
O42.011 - O42.92	Premature rupture of membranes [only covered at 26 weeks gestation or later]
O69.0xx0 - O69.2xx9	Labor and delivery complicated by umbilical cord complications
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
O32.0xx0 - O32.9xx9	Maternal care for malpresentation of fetus
O35.00X0-35.09X9	Maternal care for (suspected) central nervous system malformation in fetus [reduction of risk of fetal neurologic injury during labor]
O35.8XX0 – O35.8XX9	Maternal care for other (suspected) fetal abnormality and damage [Pulmonary hypoplasia in fetuses with intrauterine renal failure or severe renal anomalies]
O36.8910 – O36.8919	Maternal care for other specified fetal problems [pulmonary hypoplasia in fetuses with intrauterine renal failure or severe renal anomalies
O41.1210 - O41.1299	Chorioamnionitis
O41.8X10-O41.8X99	Other specified disorders of amniotic fluid and membranes [anhydramnies]
O61.1	Failed instrumental induction of labor [singleton breech presentation and a previous failed external cephalic version]
O64.1xx1	Obstructed labor due to breech presentation, fetus 1 [singleton breech presentation and a previous failed external cephalic version]
O64.8xx1	Obstructed labor due to other malposition and malpresentation, fetus 1 [singleton breech presentation and a previous failed external cephalic version]
O72.0-O72.3	Postpartum hemorrhage [Prevention of post-partum hemorrhage]
P24.00 - P24.01	Meconium aspiration
Q60.1	Renal agenesis, bilateral [Treatment of anhydramnios resulting from fetal bilateral renal agenesis]

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Background

Amnioinfusion is a procedure in which normal saline or lactated Ringer's solution is infused into the uterine cavity to replace amniotic fluid.  It is used to treat problems known to be associated with decreased intra-amniotic volume, including prophylactic treatment of oligohydramnios and treatment of severe variable decelerations during labor.

Amnioinfusion has also been used to reduce the risk of meconium aspiration during labor in women with moderate or thick meconium fluid.  However, a multi-center randomized controlled clinical trial found no benefit to amnioinfusion for this indication.  In a prospective, multi-center, randomized controlled study (n = 1,975), Fraser et al (2005) examined if amnioinfusion in women who have thick meconium staining of the amniotic fluid reduces the risk of perinatal death, moderate or severe meconium aspiration syndrome, or both.  Women in labor at 36 or more weeks of gestation who had thick meconium staining of the amniotic fluid were stratified according to the presence or absence of variable decelerations in fetal heart rate and then randomly assigned to amnioinfusion or to standard care.  The composite primary outcome measure was perinatal death, moderate or severe meconium aspiration syndrome, or both.  Perinatal death, moderate or severe meconium aspiration syndrome, or both occurred in 44 infants (4.5 %) of women in the amnioinfusion group and 35 infants (3.5 % of women in the control group (relative risk [RR], 1.26; 95 % confidence interval [CI]: 0.82 to 1.95).  Five perinatal deaths occurred in the amnioinfusion group, and 5 in the control group.  The rate of cesarean delivery was 31.8 % in the amnioinfusion group and 29.0 % in the control group (RR, 1.10; 95 % CI: 0.96 to 1.25).  These investigators concluded that for women in labor who have thick meconium staining of the amniotic fluid, amnioinfusion did not reduce the risk of moderate or severe meconium aspiration syndrome, perinatal death, or other major maternal or neonatal disorders.

In an editorial that accompanied the article by Fraser et al, Ross (2005) stated that "Given the lack of benefit of amnioinfusion in the study by Fraser et al, what might the clinician do to prevent the meconium aspiration syndrome?  Although routine intrapartum oropharyngeal and nasopharyngeal suctioning of term infants born through meconium-stained amniotic fluid is a mainstay of current therapy, it has recently been shown not to prevent the meconium aspiration syndrome.  Better understanding of how the maturation of the motility of the fetal colon accounts for the timing of the passage of meconium and its stimulation by fetal stress (thought to be mediated, in part, by means of the hypoxia-induced release of placental corticotropin-releasing factor) ultimately may lead to future therapeutic interventions …. the article by Fraser et al provides strong evidence that amnioinfusion is not warranted to prevent this syndrome in women with thick meconium staining of the amniotic fluid".

The ACOG Committee on Obstetric Practice (2006) stated that based on available literature, routine prophylactic amnioinfusion for meconium-stained amniotic fluid is not recommended.  Prophylactic use of amnioinfusion for meconium-stained amniotic fluid should be performed only in the setting of additional clinical studies.  Data are not available on if amnioinfusion for fetal heart rate decelerations in the presence of meconium-stained amniotic fluid reduces meconium aspiration syndrome or other meconium-associated morbidities.  However, amnioinfusion remains a reasonable approach in the treatment of repetitive variable decelerations, regardless of amniotic fluid meconium status.

There is evidence supporting the use of amnioinfusion in pregnancies complicated by preterm premature rupture of membranes (pPROM).  In a randomized controlled study, Tranquilli et al (2005) assessed the role of transabdominal amnioinfusion in improving the perinatal outcomes of pregnancies complicated by pPROM.  Women with singleton pregnancies complicated by pPROM, between 24 + 0 and 32 + 6 weeks of gestation were randomized 24 hours after admission to the hospital, to expectant management with transabdominal amnioinfusion or expectant management only.  Main outcome measures were effects of transabdominal amnioinfusion on pPROM-delivery interval and on perinatal outcomes.  Of the 65 women with pPROM, 34 met the inclusion criteria.  Seventeen women were assigned to amnioinfusion (the amnioinfusion group), and the other 17 to expectant management.  Compared with the control group (median: 8 days; range of 3 to 14), the pPROM-delivery period was significantly longer in women who underwent amnioinfusion (median of 21 days; range of 15 to 29) (p < 0.05).  Women with amnioinfusion were less likely to deliver within 7 days since pPROM (RR: 0.18; range of 0.04 to 0.69, 95 % CI) or within 2 weeks (RR: 0.46; range of 0.21 to 1.02, 95 % CI).  In the amnioinfusion group the neonatal survival was significantly higher at each gestational age (p < 0.01, Yates's correction for Log Rank Test) with a reduction in pulmonary hypoplasia.  These researchers concluded that compared with standard expectant management, the treatment with transabdominal amnioinfusion after pPROM resulted in significant prolongation of pregnancy and better neonatal outcomes.

Hicks (2005) noted that the benefit of amnioinfusion in women with previous cesarean deliveries is unclear.  Theoretically, rapid increases in intra-uterine volume would lead to a higher risk of uterine rupture.  The author concluded that the use of amnioinfusion in women with previous cesarean delivery who are undergoing a trial of labor may be a safe procedure, but confirmatory large, controlled prospective studies are needed before definitive recommendations can be made.

A Cochrane review (Hofmeyr, 2004) found no randomized controlled studies of transabdominal amnioinfusion for external cephalic version at term.  Adama van Scheltema and colleagues (2006) assessed the effectiveness of antepartum transabdominal amnioinfusion to facilitate external cephalic version after initial failure.  Women with a structurally normal fetus in breech lie at term, with a failed external cephalic version and an amniotic fluid index (AFI) less than 15 cm, participated in this study.  After tocolysis with indomethacin, a transabdominal amnioinfusion was performed with an 18-G spinal needle.  Lactated Ringers solution was infused until the AFI reached 15 cm, with a maximum of 1 liter.  External cephalic version was performed directly afterward.  A total of 7 women participated in the study.  The gestational age of the women was between 36(+4) weeks and 38(+3) weeks, and 3 women were primiparous.  The AFI ranged from 4 cm to 13 cm.  A median amount of 1,000 ml Ringers solution (range of 700 ml to 1,000 ml) was infused per procedure.  The repeat external cephalic versions after amnioinfusion were unsuccessful in any of the patients.  The authors concluded that amnioinfusion does not facilitate external cephalic version.

Xu et al (2007) evaluated if amnioinfusion (AI) reduces meconium aspiration syndrome (MAS) and other indicators of morbidity in babies born to women with meconium-stained amniotic fluid (MSAF).  Randomized trials comparing AI with no AI for women in labor with MSAF were reviewed.  Trial quality was evaluated using pre-established criteria.  The following morbidity indicators were assessed: MAS, 5-min Apgar score less than 7, arterial cord pH less than 7.2, and cesarean section.  Studies were stratified according to the level of peripartum surveillance (standard versus limited).  Typical RRs with their 95 % CI were calculated for each outcome using a random effects model.  In clinical settings with standard peripartum surveillance, no evidence that AI reduced the risk of MAS (RR 0.59, 95 % CI: 0.28 to 1.25), 5-min Apgar score less than 7 (RR 0.90, 95 % CI: 0.58 to 1.41), or cesarean delivery (RR 0.89, 95 % CI: 0.73 to 1.10) was found.  In clinical settings with limited peripartum surveillance, AI appeared to reduce the risk of MAS (RR 0.25, 95 % CI: 0.13 to 0.47).  The authors concluded that in clinical settings with standard peripartum surveillance, the evidence does not support the use of AI for MSAF.  In settings with limited peripartum surveillance, where complications of MSAF are common, AI appears to reduce the risk of MAS.  However, the authors stated that this finding requires confirmation by further studies.

Engel and colleagues (2008) evaluated the effect of intra-partum AI in the presence of MSAF.  Women with MSAF were assigned to receive AI (n = 93) or no-AI (n = 128).  The trials were evaluated for fetal distress syndrome, route of delivery, fetal acidemia, Apgar score at 1 and 5 mins, MAS, post-partum endometritis, as well as maternal hospital stays.  Amnioinfusion in cases of meconium-stained fluid did not improve the number of fetal distress symptoms during fetal heart rate monitoring.  Amnioinfusion was associated with a significant decrease of neonatal acidemia although it did not improve Apgar score.  The authors concluded that AI was not associated with reduction in the incidence of neonatal outcome and puerperial complications.

In a Cochrane review, Hofmeyr and Xu (2010) evaluated the effects of AI for meconium-stained liquor on perinatal outcome.  These investigators searched the Cochrane Pregnancy and Childbirth Group's Trials Register (May 2009).  Randomized trials comparing AI with no AI for women in labor with moderate or thick meconium-staining of the amniotic fluid were included.  Two review authors assessed eligibility and trial quality, and extracted data, independently.  A total of 13 studies of variable quality (4,143 women) were included.  Subgroup analysis was performed for studies from settings with limited facilities to monitor the baby's condition during labor and intervene effectively, and settings with standard peripartum surveillance.  For settings with standard peripartum surveillance, there was considerable heterogeneity for several outcomes.  There was no significant reduction in the primary outcomes MAS, perinatal death or severe morbidity, and maternal death or severe morbidity.  There was a reduction in cesarean sections (CSs) for fetal distress but not overall.  Meconium below the vocal cords diagnosed by laryngoscopy was reduced, as was neonatal ventilation or neonatal intensive care unit admission, but there was no significant reduction in perinatal deaths or other morbidity.  Planned sensitivity analysis excluding trials with greater risk of bias resulted in an absence of benefits for any of the outcomes studied.  Settings with limited peripartum surveillance: 2 studies (855 women) were included.  In the AI group there was a reduction in CS for fetal distress and overall; MAS (RR 0.25, 95 % CI: 0.13 to 0.47), and neonatal ventilation or neonatal intensive care unit admission; and a trend towards reduced perinatal mortality (RR 0.37, 95 % CI: 0.13 to 1.01).  In one of the studies, meconium below the vocal cords was reduced and, in the other, neonatal encephalopathy was reduced.  The authors concluded that AI is associated with substantive improvements in perinatal outcome only in settings where facilities for perinatal surveillance are limited.  It is unclear if the benefits are due to dilution of meconium or relief of oligohydramnios.  In settings with standard peripartum surveillance, some non-substantive outcomes were improved in the initial analysis, but sensitivity analysis excluding trials with greater risk of bias eliminated these differences.  Amnioinfusion is either ineffective in this setting, or its effects are masked by other strategies to optimize neonatal outcome.  The trials reviewed were too small to address the possibility of rare but serious maternal adverse effects of AI.

Breech presentation is associated with increased complications.  Turning a breech baby to head-first presentation using external cephalic version (ECV) attempts to reduce the chances of breech presentation at birth, and reduce the adverse effects of breech vaginal birth or caesarean section.  Tocolytic drugs and other methods have been used in an attempt to facilitate ECV.  In a Cochran review, Cluver et al (2012) evaluated interventions such as tocolysis, fetal acoustic stimulation, regional analgesia, trans-abdominal amnioinfusion or systemic opioids on ECV for a breech baby at term.  These investigators searched the Cochrane Pregnancy and Childbirth Group's Trials Register (September 30, 2011) and the reference lists of identified studies.  Randomized and quasi-randomized trials comparing the above interventions with no intervention or other methods to facilitate ECV at term were selected for analysis.  These researchers assessed eligibility and trial quality.  Two review authors independently assessed for inclusion all potential studies identified as a result of the search strategy and independently extracted the data using a designed data extraction form.  The author included 25 studies, providing data on 2,548 women.  They used the random-effects model for pooling data due to clinical heterogeneity in the included studies in the various comparisons.  The overall quality of the evidence was reasonable, but a number of assessments had insufficient data to provide an answer with any degree of assurance.  Tocolytic drugs, in particular beta stimulants, were effective in increasing cephalic presentations in labor (average risk ratio (RR) 1.38, 95 % confidence interval (CI): 1.03 to 1.85, 8 studies, 993 women) and in reducing the number of caesarean sections (average RR 0.82, 95 % CI: 0.71 to 0.94, 8 studies, 1,177 women).  No differences were identified in fetal bradycardias (average RR 0.95, 95 % CI: 0.48 to 1.89, 3 studies, 467 women) although the review was under-powered for assessing this outcome.  These investigators identified no difference in success, cephalic presentation in labor and caesarean sections between nulliparous and multiparous women.  There were insufficient data comparing different groups of tocolytic drugs.  Sensitivity analyses by study quality agreed with the overall findings.  Regional analgesia in combination with a tocolytic was more effective than the tocolytic alone in terms of increasing successful versions (assessed by the rate of failed ECVs, average RR 0.67, 95 % CI: 0.51 to 0.89, 6 studies, 550 women) but there was no difference identified in cephalic presentation in labor (average RR 1.63, 95 % CI: 0.75 to 3.53, 3 studies, 279 women) nor in caesarean sections (average RR 0.74, 95 % CI: 0.40 to 1.37, 3 studies, 279 women) or fetal bradycardia (average RR 1.48, 95 % CI: 0.62 to 3.57, 2 studies, 210 women).  There were insufficient data on the use of vibro-acoustic stimulation, amnioinfusion or systemic opioids.  The authors concluded that t beta stimulants, to facilitate ECV, increased cephalic presentation in labor and birth, and reduced the caesarean section rate in both nulliparous and multiparous women, but there were insufficient data on adverse effects.  Calcium channel blockers and nitric acid donors had insufficient data to provide good evidence.  The authors recommended betamimetics for facilitating ECV.  There is scope for further research.  The possible benefits of tocolysis to reduce the force required for successful version and the possible risks of maternal cardiovascular side effects, need to be addressed further.  Further trials are needed to compare the effectiveness of routine versus selective use of tocolysis, the role of regional analgesia, fetal acoustic stimulation, amnioinfusion and the effect of intravenous or oral hydration prior to ECV.  Although randomized trials of nitroglycerine are small, the results are sufficiently negative to discourage further trials.

Roberts et al (2014) stated that fetal survival is severely compromised when the amniotic membrane ruptures between 16 and 24 weeks of pregnancy.  Reduced amniotic fluid levels are associated with poor lung development, whereas adequate levels lead to better perinatal outcomes.  Restoring amniotic fluid by means of ultrasound-guided AI may be of benefit in improving perinatal and long-term outcomes in children of pregnancies with this condition.  The AI in preterm premature rupture of membranes (AMIPROM) pilot study was conducted to assess the feasibility of recruitment, the methods for conduct and the retention through to long-term follow-up of participants with very early rupture of amniotic membranes (between 16 and 24 weeks of pregnancy).  It was also performed to assess outcomes and collect data to inform a larger, more definitive, clinical trial.  This study was a prospective, non-blinded RCT; a computer-generated random sequence using a 1:1 ratio was used.  Randomization was stratified for pregnancies in which the amniotic membrane ruptured between 16(+0) and 19(+6) weeks' gestation and 20(+0) and 24(+0) weeks' gestation.  The randomization sequence was generated in blocks of 4.  Telephone randomization and intention-to-treat analysis were used.  Women with confirmed pPROM between 16(+0) and 24(+0) weeks' gestation were include in this study; women with multiple pregnancies, resultant fetal abnormalities or obstetric indication for immediate delivery were excluded.  Participants were randomly allocated to either serial weekly trans-abdominal AI or expectant management (Exp) until 37 weeks of pregnancy, if the deepest pool of amniotic fluid was less than 2 cm.  Short-term maternal, pregnancy and neonatal outcomes and long-term outcomes for the child were studied.  Long-term respiratory morbidity was assessed using validated respiratory questionnaires at 6, 12 and 18 months of age and infant lung function was assessed at approximately 12 months of age.  Neurodevelopment was assessed using Bayley's Scale of Infant Development II at a corrected age of 2 years.  A total of 58 women were randomized and 2 were excluded from the analysis owing to termination of pregnancy for lethal anomaly, leaving 56 participants (28 serial AI, 28 Exp) recruited between 2002 and 2009, with annual recruitment rates varying between 2 and 14.  Recruitment to the study improved significantly from 2007 with National Institute for Health Research (NIHR) funding.  There was no significant difference in perinatal mortality [19/28 versus 19/28; (RR 1.0; 95 % CI: 0.70 to 1.43], maternal morbidity or neonatal morbidity.  The overall chance of surviving without long-term respiratory or neurodevelopmental disability is 4/56 (7.1 %): 4/28 (14.3 %) in the AI arm and 0/28 in the expectant arm (0 %) (RR 9.0; 95 % CI: 0.51 to 159.70).  The authors concluded that this pilot study found no major differences in maternal, perinatal or pregnancy outcomes.  The study was not designed to show a difference between the arms and the number of survivors was too small to draw any conclusions about long-term outcomes.  It did signal, however, that a larger, definitive, study to evaluate AI for improvement in healthy survival is indicated.  The results suggested that, with appropriate funding, such a study is feasible.  They stated that a larger, definitive, study with full health economic analysis and patient perspective assessment is needed to show whether AI can improve the healthy survivor rate.

An UpToDate review on "External cephalic version" (Hofmeyr, 2016) states that "To our knowledge, no randomized trials have been performed to determine the effectiveness of amnioinfusion for enhancing ECV success. Two small uncontrolled studies reported discordant results.  In one, 6 women with failed ECV had a successful repeat attempt following transabdominal amnioinfusion with 700 to 900 ml warmed saline.  In the other, however, none of 7 cases was successful".

An UpToDate review on "Prevention and management of meconium aspiration syndrome’ (Garcia-Prats, 2016) states that "Amnioinfusion, the instillation of isotonic fluid into the amniotic cavity, has been advocated to improve neonatal outcome in women laboring with thick meconium in the amniotic fluid. The proposed benefits of amnioinfusion include dilution of thick clumps of meconium by the instilled fluid, and possible prevention or relief of cord compression.  However, amnioinfusion is not beneficial in reducing meconium-related neonatal morbidity, with the possible exception of settings with limited facilities to monitor the fetus during labor.  As a result, amnioinfusion is not recommended as a routine approach for mothers with meconium-stained amniotic fluid (MSAF)".

Bilateral Renal Agenesis

Bienstock and associates (2014) reported a case of bilateral renal agenesis treated with serial amnioinfusion in which the newborn survived the newborn period and was able to undergo peritoneal dialysis as a bridge to planned renal transplantation.  A 34-year old woman, gravida 1 para 0, presented at 23 1/7 weeks of gestation with a diagnosis of anhydramnios and bilateral renal agenesis.  The patient underwent weekly serial amnioinfusion with the goal of improving fetal pulmonary development.  At 28 weeks of gestation, the patient delivered a live newborn who required minimal respiratory support.  The neonate is currently 9 months old and is undergoing daily peritoneal dialysis.  The authors concluded that serial amnioinfusion appeared to have mitigated the severe pulmonary compromise that has, in the past, led to the death of newborns with bilateral renal agenesis.

An UpToDate review on "Prenatal diagnosis of renal agenesis" (Ozcan, 2017) states that "Utility of amnioinfusion – Poor visualization of fetal anatomy due to absence of amniotic fluid is the main obstacle to accurate diagnosis of bilateral renal agenesis.  Diagnostic amnioinfusion has been used in an attempt to surmount this limitation.  As an example, one study reported successful fluid replacement was possible in 95 % of diagnostic procedures and suspected fetal anomalies were confirmed in 27/30 patients; the diagnosis of bilateral renal agenesis was excluded in 3 fetuses after amnioinfusion.  However, it is not clear whether amnioinfusion improves the diagnostic accuracy for bilateral agenesis when a careful color Doppler examination of the renal artery has been performed …. Early serial amnioinfusion is a potential life-saving intervention for some affected fetuses, but only anecdotal information is available.  In a single case report, serial amnioinfusion was associated with the birth of a preterm neonate (29 weeks) with appropriate lung volume and no stigmata of Potter sequence.  At 9 months of age she was meeting her gestational age-adjusted milestones and growing appropriately on daily home peritoneal dialysis, with plans for renal transplantation at 12 to 24 months of age.  However, most of her first 9 months of life was spent in the hospital due to problems related to prematurity and/or dialysis.  More information is needed about complication rates and short- and long-term outcomes, including quality of life, before this procedure can be considered a reasonable intervention for treatment of bilateral renal.  Caution is advised interpreting the results of this single case.  Although meta-analysis of observational studies suggests serial amnioinfusion may decrease the risk of pulmonary hypoplasia, randomized trials do not show a difference compared with expectant management.  Serial amnioinfusion may also be associated with chorioamnionitis and abruption, which increase the risk of preterm delivery.  Finally, amnioinfusion does not eliminate the need for renal transplantation for long-term survival".

Thomas and colleagues (2017) stated that not much data are available on the natural history of bilateral renal agenesis, as the medical community does not typically offer aggressive obstetric or neonatal care as bilateral renal agenesis has been accepted as a lethal condition.  These researchers provided an evidence-based, ethically justified approach to counseling pregnant women about the obstetric management of bilateral renal agenesis.  They performed a systematic literature search using multiple databases, and deployed an ethical analysis of the results of the literature search on the basis of the professional responsibility model of obstetric ethics.  A total of 18 articles met the inclusion criteria for review.  With the exception of a single case study using serial amnioinfusion, there has been no other case of survival following dialysis and transplantation documented.  Live-born babies died during the neonatal period.  Counseling pregnant women about management of pregnancies complicated by bilateral renal agenesis should be guided by beneficence-based judgment informed by evidence about outcomes.  The authors conclude that based on the ethical analysis of the results from this review, without experimental obstetric intervention, neonatal mortality rates will continue to be 100 %.  They stated that serial amnioinfusion therefore should not be offered as treatment, but only as approved innovation or research.

Chorioamnionitis

In a Cochrane  review, Hofmeyr and Kiiza (2016) examined the effect of amnioinfusion on clinical and sub-clinical chorioamnionitis, fetal well-being, fetal heart rate characteristics and perinatal and maternal morbidity and mortality.  These investigators searched the Cochrane Pregnancy and Childbirth Group's Trials Register (July 6, 2016), PubMed, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (July 6, 2016) and reference lists of retrieved studies; RCTs of amnioinfusion (treatment group) versus no amnioinfusion in women with chorioamnionitis were selected for analysis.  These investigators would have also considered trials comparing amnioinfusion with sham amnioinfusion; different types or volumes of amnioinfusion fluid but none was identified.  Cluster-RCTs and quasi-RCTs were eligible for inclusion but none was identified.  They identified 1 study published in abstract form but it did not contain any numerical data and has therefore been excluded.  Studies using a cross-over design were not an appropriate study design and thus were not eligible for inclusion in this review.  Two review authors independently assessed potential studies for inclusion and assessed trial quality.  Both review authors independently extracted data and data were checked for accuracy.  They included 1 small trial (with data from 34 participants) comparing transcervical amnioinfusion with no amnioinfusion.  The trial was considered to be at a high risk of bias overall, due to small numbers, inconsistency in the reporting and lack of information on blinding.  Meta-analysis was not possible.  Transcervical amnioinfusion was with room temperature saline at 10 ml/min for 60 minutes, then 3 ml/min until delivery versus no amnioinfusion.  All women received intra-uterine pressure catheter, acetaminophen and antibiotics (ampicillin or, if receiving Group B beta streptococcal prophylaxis, penicillin and gentamycin).  The authors did not identify any trials that used transabdominal amnioinfusion.  Compared to no amnioinfusion, transcervical amnioinfusion had no clear effect on the incidence of post-partum endometritis (RR 1.50, 95 % CI: 0.29 to 7.87; absolute risk 176/1,000 (95 % CI: 34 to 96) versus 118/1,000; low-quality evidence).  Nor was there a clear effect in the incidence of neonatal infection (RR 3.00, 95 % CI: 0.13 to 68.84; absolute risk 0/1,000 (95 % CI: 0 to 0) versus 0/1,000; low-quality evidence).  The outcome of perinatal death or severe morbidity (such as neonatal encephalopathy, intra-ventricular hemorrhage, admission to intensive/high care) was not reported in the included trial.  In terms of this review's secondary outcomes, the rate of caesarean section was the same in both groups (RR 1.00, 95 % CI: 0.35 to 2.83; absolute risk 294/1,000 (95 % CI: 103 to 832) versus 294/1,000; low-quality evidence).  There was no clear difference in the duration of maternal antibiotic treatment between the amnioinfusion and no amnioinfusion control group (mean difference (MD) 16 hours, 95 % CI: -1.75 to 33.75); nor in the duration of hospitalization (MD 3.00 hours, 95 % CI: -15.49 to 21.49).  The study did not report any information about how many babies had a low Apgar score at 5 minutes after birth.  Women in the amnioinfusion group had a lower temperature at delivery compared to women in the control group (MD -0.38°C, 95 % CI: -0.74 to -0.02) but this outcome was not pre-specified in the protocol for this review.  The majority of this review's secondary outcomes were not reported in the included study.

The authors concluded that there is insufficient evidence to fully evaluate the effectiveness of using transcervical amnioinfusion for chorioamnionitis and to evaluate the safety of this intervention or women's satisfaction.  These researchers did not identify any trials that used transabdominal amnioinfusion.  The evidence in this review can neither support nor refute the use of transcervical amnioinfusion outside of clinical trials.  They included 1 small study that reported on a limited number of outcomes of interest in this review.  The numbers included in this review were too small for meaningful assessment of substantive outcomes, where reported.  For those outcomes the authors assessed using GRADE (post-partum endometritis, neonatal infection, and caesarean section), they down-graded the quality of the evidence to low – with down-grading decisions based on small numbers and a lack of information on blinding.  The included study did not report on this review's other primary outcome (perinatal death or severe morbidity).  The reduction in pyrexia, though not a pre-specified outcome of this review, may be of relevance in terms of benefits to the fetus of reduced exposure to heat.  The authors postulated that the temperature reduction found may be a direct cooling effect of amnioinfusion with room temperature fluid, rather than reduction of infection.  They stated that larger trials are needed to confirm and extend the findings of the trial reviewed here.  These should be RCTs; participants, women with chorioamnionitis; interventions, amnioinfusion; comparisons, no amnioinfusion; outcomes, maternal and perinatal outcomes including neurodevelopmental measures.  They also stated that further research is justified to determine possible benefits or risks of amnioinfusion for chorioamnionitis, and to investigate possible benefits of reducing temperature in fetuses considered at risk of neurological damage.  Research should include randomized trials to examine transcervical or transabdominal amnioinfusion compared with no infusion for chorioamnionitis and examine outcomes listed in the methods of this review.

Furthermore, UpToDate reviews on "Intra-amniotic infection (clinical chorioamnionitis or triple I)" (Tita, 2017), "Intrapartum fever" (Chen, 2017), and "Overview of second-trimester pregnancy termination" (Hammond, 2017) do not mention amnioinfusion as a management tool.

Treatment of Second-Trimester Anhydramnios

Io and colleagues (2018) noted that second-trimester anhydramnios, which is primarily caused by ruptured membranes, placental dysfunction, or congenital renal malformations, is associated with high perinatal morbidity and mortality.  Although amnioinfusion temporarily increases amniotic fluid volume, it does not generally provide a fundamental solution.  These investigators described a case of second-trimester anhydramnios with an umbilical cord factor, wherein single amnioinfusion may have successfully broken a vicious circle involving non-reassuring fetal status.  A 34-year old primigravid woman was referred to the authors’ hospital because of anhydramnios at 22 weeks' gestation.  Single amnioinfusion improved the fetal circulatory failure, and the patient delivered a healthy full-term newborn.  The authors concluded that single amnioinfusion may be a therapeutic approach to improve the prognosis of pregnancy when second-trimester anhydramnios resulted from umbilical cord factors.

Tchirikov and associates (2018) stated that mid-trimester preterm premature rupture of membranes (PPROM), defined as rupture of fetal membranes prior to 28 weeks of gestation, complicates approximately 0.4 % to 0.7 % of all pregnancies.  This condition is associated with a very high neonatal mortality rate as well as an increased risk of long- and short-term severe neonatal morbidity.  The causes of the mid-trimester PPROM are multi-factorial.  The management of the PPROM requires balancing the potential neonatal benefits from prolongation of the pregnancy with the risk of intra-amniotic infection and its consequences for the mother and infant.  Close monitoring for signs of chorioamnionitis (e.g., body temperature, cardiotocography (CTG), C-reactive protein [CRP], leucocytes, interleukin-6 [IL-6], procalcitonine, amniotic fluid examinations) is necessary to minimize the risk of neonatal and maternal complications.  In addition to delayed delivery, broad spectrum antibiotics of penicillin or cephalosporin group and/or macrolide and corticosteroids have been show to improve neonatal outcome [reducing risk of chorioamnionitis (average RR = 0.66), neonatal infections (RR = 0.67) and abnormal ultrasound scan of neonatal brain (RR = 0.67)].  The positive effect of continuous amnioinfusion through the subcutaneously implanted perinatal port system with amniotic fluid like hypo-osmotic solution in "classic PPROM" less than 28/0 weeks' gestation shows promise but must be proved in future prospective randomized studies.  Systemic antibiotics administration in "pre-PPROM" without infection and hospitalization are also of questionable benefit and needs to be further evaluated in well-designed randomized prospective studies to evaluate if it is associated with any neonatal benefit as well as the relationship to possible adverse effect of antibiotics on to fetal development and neurological outcome.

Furthermore, an UpToDate review on "Amnioinfusion" (Goldfarb, 2018) states that "Transabdominal amnioinfusion has been described for the evaluation and diagnosis of fetal anomalies in the setting of second-trimester oligohydramnios and to facilitate external cephalic version.  However, these are not standard indications and supporting data are sparse.  Amnioinfusion to aid ultrasound diagnosis is generally only performed in specialty practices".

In a nationwide, multi-center, open-label RCT, van Kempen and colleagues (2019) examined the effectiveness of amnioinfusion in women with second-trimester pPROM.  These researchers performed the PPROM: Expectant Management versus Induction of Labor-III (PPROMEXIL-III) trial, in women with singleton pregnancies and pPROM at 16 0/7 to 24 0/7 weeks of gestation with oligohydramnios (single deepest pocket less than 20 mm).  Participants were allocated to trans-abdominal amnioinfusion or no intervention in a 1-to-1 ratio by a web-based system.  If the single deepest pocket was less than 20 mm on follow-up visits, amnioinfusion was repeated weekly until 28 0/7 weeks of gestation.  The primary outcome was peri-natal mortality.  These investigators needed 56 women to show a reduction in peri-natal mortality from 70 % to 35 % (β error 0.20, 2-sided α error 0.05).  Between June 15, 2012, and January 13, 2016, these researchers randomized 28 women to amnioinfusion and 28 to no intervention; 1 woman was enrolled before the trial registration date (June 19, 2012).  Peri-natal mortality rates were 18 of 28 (64 %) in the amnioinfusion group vs 21 of 28 (75 %) in the no intervention group (RR 0.86, 95 % CI: 0.60 to 1.22, p = 0.39).  the authors concluded that in women with second-trimester pPROM and oligohydramnios, they found no reduction in peri-natal mortality following amnioinfusion.

de Ruigh and colleagues (2021) examined the effect of trans-abdominal amnioinfusion or no intervention on long-term outcomes in children born after second-trimester PROM (between 16+0/7 to 24+0/7 weeks) and oligohydramnios.  This trial was a follow-up of infants of women who participated in the RCT: PPROMEXIL-III (NTR3492).  Surviving infants were invited for neurodevelopmental assessment up to 5 years of corrected age using a Bayley Scales of Infant and Toddler Development or a Wechsler Preschool and Primary Scale of Intelligence.  Parents were asked to complete several questionnaires.  Neurodevelopmental outcomes were measured.  Mild delay was defined as -1 standard deviation (SD), severe delay as -2 SD.  Healthy long-term survival was defined as survival without neurodevelopmental delay or respiratory problems.  In the amnioinfusion group, 18/28 children (64 %) died versus 21/28 (75 %) in the no intervention group (RR 0.86; 95 % CI: 0.60 to 1.22).  Follow-up data were obtained from 14/17 (82 %) children (10 amnioinfusion, 4 no intervention).  In both groups, 2/28 (7.1 %) had a mild neurodevelopmental delay; no severe delay was observed.  Healthy long-term survival occurred in 5/28 children (17.9 %) after amnioinfusion versus 2/28 (7.1 %) after no intervention (odds ratio [OR] 2.50; 95 % CI: 0.53 to 11.83).  When analyzing data for all assessed survivors, 10/14 (71.4 %) survived without mild neurodevelopmental delay and 7/14 (50 %) were classified healthy long-term survivor.  The authors concluded that in this small sample of women suffering second-trimester PROM and oligohydramnios, amnioinfusion did not improve long-term outcomes.  Overall, 71 % of survivors had no neurodevelopmental delay.

Amnioinfusion for Women with a Singleton Breech Presentation and a Previous Failed External Cephalic Version

In an open RCT, Diguisto and colleagues (2018) evaluated the effectiveness of amnioinfusion for a second attempt at external cephalic version (ECV).  This study was planned with a sequential design.  Women at a term of greater than or equal to 36 weeks of gestation with a singleton fetus in breech presentation and a first unsuccessful ECV were recruited in 2 level-3 maternity units.  They were randomly allocated to trans-abdominal amnioinfusion with a 500-ml saline solution under ultrasound (US) surveillance or no amnioinfusion before the second ECV attempt.  Trained senior obstetricians performed all procedures.  The primary outcome was the cephalic presentation rate at delivery.  Analyses were conducted according to intention-to-treat.  Recruitment difficulties led to stopping the trial after a 57-month period, 119 women were randomized: 59 allocated to amnioinfusion + ECV and 60 to ECV only.  Data were analyzed without applying the sequential feature of the design.  The rate of cephalic presentation at delivery did not differ significantly according to whether the second version attempt was or was not preceded by amnioinfusion (20 % versus 12 %, p = 0.20); PROMs occurred for 15 % of the women in the amnioinfusion group.  The authors concluded that amnioinfusion before a second attempt to external version did not significantly increase the rate of cephalic presentation at delivery.

Serial Amnioinfusion for the Treatment of Pulmonary Hypoplasia in Fetuses with Intrauterine Renal Failure or Severe Renal Anomalies

In a systematic review, Warring and colleagues (2020) examined the effect of serial amnioinfusion therapy (SAT) for pulmonary hypoplasia in lower urinary tract obstruction (LUTO) or congenital renal anomalies (CRAs); introduced patient selection criteria; and presented the findings of a case of SAT in bilateral renal agenesis.  These investigators carried out a search of the Medline, Embase, Web of Science, and Scopus databases for articles published from database inception to November 10, 2017.  A total of 8 studies with 17 patients (7 LUTO, 8 CRA, and 2 LUTO + CRA) were included in the study.  The median age of the mothers was 31 years (n = 9; interquartile range [IQR], 29 to 33.5 years), the total number of amnioinfusion was 7 (n = 17; IQR, 4.5 to 21), gestational age at 1st amnioinfusion was 23 weeks and 4 days (n = 17; IQR, 21 to 24.07), gestational age at delivery was 32 weeks and 2 days (n = 17; IQR, 30 weeks to 35 weeks and 6.5 days), birthweight of newborns was 3.7 kg (n = 9; IQR, 2.7 to 3.7 kg), Apgar score at 1 min was 2.5 (n = 8; IQR, 1 to 6.5), and Apgar score at 5 mins was 5.5 (n = 8; IQR, 0 to 7.75).  The authors concluded that SAT may provide fetal pulmonary palliation by reducing the risk of newborn pulmonary compromise secondary to oligohydramnios.  Moreover, these researchers stated that multi-disciplinary research efforts are needed to further determine treatment and counseling guidelines.  These investigators proposed a multi-disciplinary pre-natal management classification system based on fetal disease severity that can be used as a guideline to inform patient selection in clinical trials examining SAT for mothers of fetuses with LUTO.  With strong evidence lacking for this fetal intervention, a clinical trial is needed to further examine the long-term outcomes of this intervention in cases of severe fetal renal dysfunction.

The authors stated that a drawback of this study was the lack of consistent patient selection criteria that hindered their ability to conduct a statistical outcomes analysis given the widely varying severities of disease.  The philosophy and criteria guiding which patients were selected for SAT were not fully described in the studies; thus, these researchers could not account for selection bias or potential confounding factors when reviewing survival outcomes.  Moreover, these researchers stated that further clinical trials to examine feasibility, safety, and efficacy of SAT in mothers with fetuses diagnosed as having severe LUTO (stage III and IV) and CRA need to be completed in order to better determine the advantages and risks of SAT.  Optimal procedure protocol, possible prognostic factors, and detailed quality-of-life (QOL) outcomes should be published before SAT can be adopted as routine practice.

Riddle and associates (2020) noted that bilateral renal agenesis (BRA) is a lethal diagnosis, specifically meaning that natural survival beyond birth is not expected secondary to pulmonary hypoplasia.  Limited contemporary data are available regarding intervention and the impact of restoring amniotic fluid volume in relation to the risk for lethal pulmonary hypoplasia and other factors that might influence survival in cases of fetal BRA.  These investigators reported the largest series of patients undergoing fetal intervention and post-natal care for BRA at a single comprehensive fetal center.  All patients with fetal BRA were reviewed from January 2004 to November 2017.  Maternal and neonatal data were collected in an institutional review board (IRB)-approved retrospective review.  From 2014 to 2017, a total of 20 singleton pregnancies with isolated fetal BRA were evaluated and 14 had amnioinfusion; 8 had serial infusions.  Of those, there were 6 neonatal deaths.  There were 2 neonatal survivors beyond 30 days; however, both died of sepsis on dialysis.  One of these survivors received amnioinfusion by percutaneous approach and 1 via amnio-port.  There were no survivors to transplantation.  The authors concluded that fetal intervention via amnioinfusion may promote pulmonary survivorship after birth; however, post-natal survival remains poor.  These researchers stated that future studies must place an emphasis on standardizing the post-natal approach to this patient population.

In a meta-analysis, Celik et al (2023) examined the effect of serial transabdominal amnioinfusion (TAI) on short-term and long-term perinatal outcomes in mid-trimester PPROM.  These investigators carried out literature searches of PubMed, Web of Sciences, Scopus, and Cochrane Library from their inception to April 2022.  Studies comparing conventional treatment with serial TAI in women with proven PPROM at less than 26 + 0 weeks of gestation with oligohydramnios were included.  Studies that included oligohydramnios due to other reasons such as fetal growth retardation or renal anomalies were excluded.  Risk of bias in observational studies was assessed using the tool of the Cochrane Review group identified as risk of bias in non-randomized studies - of interventions.  The risk of bias assessments for RCTs were performed according to the Cochrane risk-of-bias tool for randomized trials.  An I2 score was used to assess the heterogeneity of included studies.  The analyses were performed by using random-effect model, and the results were expressed as RR or MD with 95 % CIs.  A total of 8 relevant studies including 5 observational studies (n = 252; 130 women allocated to the intervention) and 3 RCTs (n = 183; 93 women allocated to the intervention) were eligible.  The pooled latency period was 21.9 days (95 % CI: 13.1 to 30.8) and 5.8 days (95 % CI: -11.6 to 23.2) longer in the TAI group in the observational studies and RCTs, respectively.  The perinatal mortality rate was reduced in the intervention group when tested in observational studies (RR 0.68; 95 % CI: 0.51 to 0.92), but not in RCTs (RR 0.79; 95 % CI: 0.56 to 1.13).  The rate of long-term healthy survival was higher in the children whose mothers were treated with the TAI (35.7 %) than those were treated with the standard management (28.6 %) (RR 1.30, 95 % CI: 0.47 to 3.60, "best case scenario").  The authors concluded that the effectiveness of serial TAI on early PPROM associated morbidity and mortality was not attested.  These researchers stated that additional RCTs with adequate power and multi-center collaboration are needed to demonstrate the utility of serial TAI in routine care

The authors stated that the main of this of this meta-analysis entailed heterogeneity in the quality of studies regarding the high risk of biases and assessment of outcomes.  Another drawback was the low number of participants, both in observational studies as well as RCTs.  Lastly, there was heterogeneity in terms of the protocol and assessment of outcomes.

Amnioinfusion for the Treatment of Preterm Premature Rupture of Membranes Before 26 Weeks of Gestation

In a Cochrane review, Van Teeffelen et al (2013) evaluated the effectiveness of trans-abdominal amnioinfusion in improving perinatal outcome in women with oligohydramnios secondary to rupture of fetal membranes before 26 weeks.  These investigators searched the Cochrane Pregnancy and Childbirth Group's Trials Register (April 30, 2013).  All randomized controlled trials (RCTs) comparing trans-abdominal amnioinfusion with no trans-abdominal amnioinfusion were selected for analysis.  Cluster- or quasi-randomized trials were not eligible for inclusion.  In cases where only an abstract was available, these researchers attempted to find the full articles.  Two review authors assessed trials for inclusion.  No eligible trials were identified.  The authors concluded that there is currently no evidence to evaluate the use of trans-abdominal amnioinfusion in women with oligohydramnios secondary to rupture of fetal membranes before 26 weeks for improving perinatal outcome.  They stated that further research examining the effects of this intervention is needed; 2 RCTs are ongoing but final data have not yet been published.

In a retrospective study, Gozdziewicz and colleagues (2021) examined the effectiveness of long-term amnioinfusion on perinatal outcomes in patients with PPROM before 26 weeks' gestation.  A total of 31 patients with PPROM at a peri-viable gestational age (21 + 0-25 + 0 weeks) were enrolled.  Long-term amnioinfusion was carried out in 22 patients, and 9 patients did not receive amnioinfusion.  Data were collected retrospectively from 2 clinical sites between January 2017 and March 2019.  In the medical management group, there was a significantly higher rate of chorioamnionitis compared to the long-term amnioinfusion group (89 % versus 15 %, p = 0.001).  The latency period between PPROM and delivery was higher in the amnioinfusion group (median of 5.5 weeks versus 3 weeks, p = 0.04).  The frequency of bronchopulmonary dysplasia (BPD) was higher in the control group compared to the amnioinfusion group (89 % versus 40 %, p = 0.03).  The rates of other neonatal complications were similar in both groups.  The authors concluded that long-term amnioinfusion via an intra-uterine catheter in PPROM before 26 weeks' gestation may improve pregnancy and newborn outcomes.

The authors stated that this study had several drawbacks, which included a small study group (n = 22 in the amnioinfusion group), the possible effects of bias on the results, and being a retrospective analysis.  These researchers stated that in the future, RCTs are needed to confirm these retrospective findings.  Furthermore, the use of an artificial amniotic fluid solution (e.g., Amnion Flush Solution; Serumwerk AG, Bernburg, Germany) during amnioinfusion may protect the fetus from the possible adverse effects of NaCl.

de Ruigh et al (2022) noted that mid-trimester pre-labor rupture of membranes (PROM) between 16 and 24 weeks of gestational age is a major obstetric complication with high rates of peri-natal morbidity and mortality.  Amnioinfusion has been proposed in women with mid-trimester PROM to target oligohydramnios and subsequently enhance pulmonary development and peri-natal outcomes.  In a systematic review and meta-analysis, these investigators examined amnioinfusion versus no intervention in women with PROM between 16+0 and 24+0 weeks of gestational age.  Databases Central, Embase, Medline, ClinicalTrials.gov and references of identified articles were searched from inception of database to December 2021.  The primary outcome was peri-natal mortality.  Secondary outcomes included neonatal, maternal, and long-term developmental outcomes as defined in the core outcome set for preterm birth studies.  Summary measures were reported as pooled RR or MD with corresponding 95 % CI.  A total of 2 studies (112 patients, 56 in the amnioinfusion group and 56 in the no intervention group) were included in this review.  Pooled peri-natal mortality was 66.1 % (37/56) in the amnioinfusion group compared with 71.4 % (40/56) in no intervention group (RR 0.92, 95 % CI: 0.72 to 1.19).  Other neonatal and maternal core outcomes were similar in both groups, although due to the relatively small number of events and wide CIs, there was a possibility that amnioinfusion could be associated with clinically important benefits and harms.  Long-term healthy survival was observed in 35.7 % (10/28) of children evaluated for follow-up and treated with amnioinfusion versus 28.6 % (8/28) after no intervention (RR 1.30, 95 % CI: 0.47 to 3.60, "best case scenario").  The authors concluded that based on these findings, the benefits of amnioinfusion for mid-trimester PROM of less than 24 weeks of gestational age were unproven, and the potential harms remained undetermined.  Moreover, these researchers stated that it must be noticed that patient numbers in this meta-analysis were small; thus, these findings and conclusions should be interpreted with care.  They stated that the findings of this review justify the need for additional research and especially adequately powered RCTs to demonstrate a smaller but clinically relevant effect, before this therapy can be considered for routine clinical use.  These researchers stated that performing an international, multi-center study may be the only way to achieve this large sample size.

Prevention of Post-Partum Hemorrhage

Zloto et al (2025) noted that although amnioinfusion lowers the rate of uterine atony, its effect on post-partum hemorrhage (PPH) is uncertain.  In a retrospective study, these researchers examined if amnioinfusion would reduce the risk of PPH in laboring women.  This trial included laboring singletons at a tertiary center between January 2013 and December 2022 at 34 weeks or greater gestation.  Individuals with known major fetal anomalies, still-births, or missing delivery records were excluded; the primary outcome was PPH.  Neonatal and secondary maternal outcomes were also explored.  Adjusted OR (aOR) were estimated using multi-variable regression models.  Out of 113,816 deliveries during the study period, 83,152 (77.1 %) fulfilled inclusion criteria, and among them 4,597 (4.03 %) had amnioinfusion.  Laboring women with amnioinfusion were more commonly nulliparous, had more polyhydramnios, oligohydramnios, pre-eclampsia, gestational diabetes, and fetal growth restriction.  In addition, women with amnioinfusion had a higher rate of labor induction (54.54 % versus 27.8 %; p < 0.01) and a higher cesarean rate (36.9 % versus 9.5 %; p < 0.01).  Following multi-variable regression, there was no significant difference in the rate of PPH among individuals who had an amnioinfusion (2.6 %) versus those who did not (3.1 %; aOR 0.95, 95 % CI: 0.87 to 1.27).  The rates of endometritis (aOR 1.4; 95 % CI: 1.04 to 1.89) and post-partum fever (aOR 1.70; 95 % CI: 1.36 to 2.12), were higher in those who had amnioinfusion compared to those who did not.  The authors concluded that among laboring women with gestation of 34 weeks or longer, intrapartum amnioinfusion was not associated with a reduction in the rate of PPH and was associated with a higher likelihood of infectious morbidity.

Reduction of Risk of Fetal Neurologic Injury During Labor

Polnaszek et al (2024) stated that therapeutic cooling for neonates with hypoxic-ischemic encephalopathy (HIE) reduces morbidity and mortality.  Given that HIE can be attributed to intra-uterine insult, therapeutic cooling may be more beneficial when initiated before delivery via an amnioinfusion.  Incidentally, amnioinfusion has also been shown to reduce intra-uterine temperatures (IUTs); therefore, amnioinfusion may provide a method for initiating intra-uterine therapeutic hypothermia treatment for HIE before delivery.  However, intra-uterine hypothermia must be carefully studied to avoid harm and show clear benefit.  In the setting of emergent events, such as placental abruption, expedited delivery remains the primary prevention for neurologic injury in fetuses.  In a pilot study, these researchers examined the feasibility and preliminary effects of continuous room temperature amnioinfusion on fetuses at increased risk of neurologic injury during labor who do not qualify for emergent delivery.

Treatment of Anhydramnios Resulting from Bilateral Renal Agenesis

Miller et al (2023) noted that early anhydramnios during pregnancy, resulting from fetal bilateral renal agenesis, results in lethal pulmonary hypoplasia in neonates.  Restoring amniotic fluid via serial amnioinfusion may promote lung development and enable survival.  In a prospective, non-randomized clinical trial, these researchers examined neonatal outcomes of serial amnioinfusion initiated before 26 weeks' gestation to mitigate lethal pulmonary hypoplasia.  This study was carried out at 9 U.S. fetal therapy centers between December 2018 and July 2022.  Outcomes were reported for 21 maternal-fetal pairs with confirmed anhydramnios as a consequence of isolated fetal bilateral renal agenesis without other identified congenital anomalies.  Enrolled subjects initiated US-guided percutaneous amnioinfusion of isotonic fluid before 26 weeks' gestation, with frequency of infusions individualized to maintain normal amniotic fluid levels for gestational age.  The primary end-point was post-natal infant survival to 14 days of life or longer with dialysis access placement.  The trial was stopped early based on an interim analysis of 18 maternal-fetal pairs given concern regarding neonatal morbidity and mortality beyond the primary end-point despite demonstration of the effectiveness of the intervention.  There were 17 live-births (94 %), with a median gestational age at delivery of 32 weeks, 4 days (IQR, 32 to 34 weeks).  All subjects delivered before 37 weeks' gestation.  The primary outcome was achieved in 14 (82 %) of 17 live-born infants (95 % CI: 44 % to 99 %).  Factors associated with survival to the primary outcome included a higher number of amnioinfusion (p = 0.01), gestational age greater than 32 weeks (p = 0.005), and higher birth-weight (p = 0.03).  Only 6 (35 %) of the 17 neonates born alive survived to hospital discharge while receiving peritoneal dialysis at a median age of 24 weeks of life (range of 12 to 32 weeks).  The authors concluded that serial amnioinfusion mitigated lethal pulmonary hypoplasia but were associated with preterm delivery.  The lower rate of survival to discharge highlighted the additional mortality burden independent of lung function.  Moreover, these researchers stated that additional long-term data are needed to fully characterize the outcomes in surviving neonates and evaluate the morbidity and mortality burden.  They noted that because additional long-term data are needed to more fully characterize the outcomes in surviving neonates and evaluate the morbidity and mortality burden, this intervention is best offered with careful, multi-disciplinary prenatal counseling in centers with collaborative multi-disciplinary teams, including palliative care, with the capability to provide neonatal intensive care as well as kidney replacement therapy, and in the context of ongoing research.

The authors stated that this study had several drawbacks.  First, there was a notable lack of diversity among participants enrolled in the RAFT (Renal Anhydramnios Fetal Therapy) Trial.   Zero participants identified as Black or African American, 11 % with Hispanic ethnicity, and 94 % as White.  This lack of diversity in participants limited the generalizability of the findings.  Two potential socio-economic barriers to enrollment include a requirement for adequate insurance coverage and the requirement to have both pre-natal as well as post-natal care provided at 1 of the 9 RAFT centers, which in many cases required family flexibility and resources to relocate for participation.  Second, small sample size.  Although the initial target for recruitment was 35 maternal-fetal pairs with bilateral renal agenesis, enrollment was halted at 18.  The trial was not powered to evaluate the secondary outcomes, including survival to hospital discharge and pediatric morbidities of end-stage kidney disease.  Third, the limits of pre-natal phenotyping should be acknowledged.  Families considering amnioinfusion must be counseled that any additional organ system anomalies will further complicate already complex post-natal care.  If additional abnormalities were identified postnatally, shared decision-making with parents may be necessary to determine if aggressive management of end-stage kidney disease should continue.  Fourth, post-natal management of neonates was purposefully not standardized across the study sites for multiple reasons, including center differences in neonatal surgical approaches to placement of dialysis access and available modes of hemodialysis when needed.  Advances in neonatal hemodialysis have occurred since the start of the trial; thus, this impact on survival could not be estimated.  Because all centers had multi-disciplinary teams with the capability to provide neonatal intensive care and kidney replacement therapy, results of this trial should not be generalized to centers without these capabilities or to patients that do not meet eligibility criteria.  Fifth, collection of longitudinal QOL data from infants who survive to initial hospital discharge is ongoing in both groups of the RAFT Trial and will be examined in future reports; however, because infants must survive to hospital discharge before these data were collected, data available to-date remained limited.

Lammert et al (2024) noted that the Renal Anhydramnios Fetal Therapy (RAFT) Trial was a study of serial amnioinfusions to prevent lethal neonatal pulmonary hypoplasia from early renal anhydramnios.  The authors stated that infant neurologic outcomes were not originally evaluated.  They described the high incidence of stroke observed among infants in the treatment arm of the trial at their center.

On behalf of the LUTO Working Group, Mustafa et al (2024) reached an international expert consensus on the diagnosis, prognosis and management of fetal lower urinary tract obstruction (LUTO) by means of a Delphi procedure, and employed this to define a core outcome set (COS).  A 3-round Delphi procedure was carried out among an international panel of experts in fetal LUTO.  The panel was provided with a list of literature-based parameters to consider for the diagnosis, prognosis, management and outcomes of LUTO.  A parallel procedure was carried out with patient groups during the development of the COS.  A total of 168 experts were approached, of whom 99 completed the 1st round; and 80/99 (80.8 %) completed all 3 rounds of the study questionnaires.  Consensus was reached that, in the 1st trimester, an objective measurement of longitudinal bladder diameter of 7 mm or larger should be used to suspect LUTO.  In the 2nd trimester, imaging parameters suggestive of LUTO could include enlarged bladder, keyhole sign, bladder wall thickening, bilateral hydronephrosis, bilateral hydroureteronephrosis and male sex.  There was 79 % agreement that the current prognostic scoring systems in the literature should not be used clinically.  However, experts agreed on the value of amniotic fluid volume (at less than 24 weeks) to predict survival and that the value of fetal intervention is to improve the chance of neonatal survival.  Experts endorsed sonographic parameters suggestive of renal dysplasia, at least 1 vesicocentesis, and renal biochemistry for prognosis and counseling; however, these items did not reach a consensus for determining candidacy for fetal intervention.  On the other hand, imaging parameters suggestive of LUTO, absence of life-limiting structural or genetic anomalies, GA of 16 weeks or longer and oligohydramnios (defined as deepest vertical pocket  of less than 2 cm) should be used as candidacy criteria for fetal intervention based on expert consensus.  If bladder refill was evaluated, it should be assessed subjectively.  Vesicoamniotic shunt should be the 1st-line of fetal intervention.  In the presence of suspected fetal renal failure, serial amnioinfusion should be offered only as an experimental procedure under research protocols.  A COS for future LUTO studies was agreed upon.  The authors concluded that international consensus on the diagnosis, prognosis and management of fetal LUTO, as well as the COS, should inform clinical care and research to optimize peri-natal outcomes.

Furthermore, an UpToDate review on “Oligohydramnios: Etiology, diagnosis, and management in singleton gestations” (Beloosesky and Ross, 2025) lists serial amnioinfusion as one of the “Investigational therapies to achieve a long-term increase in AFV [amniotic fluid volume]”.  This UTD review states that “The Renal Anhydramnios Fetal Therapy (RAFT) Trial evaluated serial amnioinfusions for pregnancies with early anhydramnios due to fetal bilateral renal agenesis.  Fourteen of the 17 live-born infants (82 %) survived to 14 days with dialysis access, but only 6 (35 %) survived to hospital discharge.  Serial amnioinfusions reduced lethal pulmonary hypoplasia but were linked to preterm birth.  The trial was stopped early due to concerns about neonatal morbidity and mortality.  A follow-up study of stroke in infants enrolled in the treatment arm of the RAFT trial at one institution reported 8 of 10 participants experienced stroke and 4 participants experienced recurrent stroke.  Four of the 8 infants had bilateral renal agenesis, 2 had bilateral multicystic kidney disease, and 2 had a combination of unilateral renal agenesis and multicystic kidney disease.  Punctate strokes occurred in the perinatal to very early childhood period during critical illness while quadrantal strokes occurred in 6 of 8 infants that survived past 2 months of age and presented between 2 and 11 months of age.  These findings highlight the need for further long-term outcome data before serial amnioinfusions can be considered for prevention of pulmonary hypoplasia in such cases”.

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References