Description of the condition
The increasing use of advanced ultrasound technologies, in combination with increased multiple pregnancy rates globally and the development of novel procedures to address fetal problems in utero has resulted in more invasive fetal procedures and surgeries being performed during pregnancy. Fetal conditions that may be suitable for in-utero interventions include fetal tumours, lung and airway lesions, cardiac abnormalities, urinary tract abnormalities and complications associated with monochorionic twin pregnancies. Increasing diagnosis of severe and life-threatening fetal conditions has also resulted in more frequent termination of pregnancy.
Fetal complications that may require in-utero intervention
Lower urinary tract obstruction (LUTO)
Congenital abnormalities of the urinary tract are relatively common (1/500 pregnancies) (Ruano 2011). Bilateral ureteric or bladder outflow obstruction carries a particularly poor prognosis. Without intervention, LUTO has a perinatal mortality rate of 90% and more than 50% of survivors require renal dialysis or transplantation (Ruano 2011). Therapeutic interventions include vesicocentesis (draining the fetal bladder with a needle), vesico-amniotic shunting (placing a tube from the bladder into the amniotic cavity) (Kilby 2013), and fetal cystoscopy (looking at the fetal bladder with a small camera), which can both diagnose and treat posterior urethral valves. Fetal cystoscopy requires maternal epidural or local anaesthesia combined with direct fetal administration of anaesthetic agents (Ruano 2011).
Fetal lung lesions
Fetal lung lesions, most commonly congenital cystic adenomatous malformations, bronchopulmonary sequestration or ‘hybrid’ lesions, occur in 1/10,000 to 35,000 pregnancies (Witlox 2011). While many of these may regress over the course of pregnancy, they may be associated with severe fetal compromise leading to the need for in utero procedures. These procedures include thoracocentesis (ultrasound-guided needle drainage), thoraco-amniotic shunting (placing a tube from the cyst cavity inside the chest to the amniotic cavity), ultrasound-guided laser coagulation of the arteries that supply the lesion and open surgical resection of severe lesions (Witlox 2011). Fetoscopic tracheal occlusion procedures (plugging of the fetal trachea) have been advocated to induce growth and expansion of the hypoplastic (underdeveloped) lung (Van de Velde 2012).
Fetal heart lesions that may be suitable for intracardiac intervention during pregnancy include stenotic valvular lesions (where there is a critical narrowing of the heart valve), in addition to some other more complicated structural anomalies. In utero interventions aim to facilitate both the growth and functioning of the heart (Artz 2011).
Fetal anaemia requiring fetal transfusion
Sampling of fetal blood via cordocentesis, also known as percutaneous umbilical blood sampling, allows increased diagnostic accuracy for many fetal conditions including fetal anaemia, hydrops, neonatal alloimmune thrombocytopenia and fetal genetic disorders. The ability to access fetal vasculature in utero may enable timely treatment during pregnancy, most commonly fetal red blood cell or platelet transfusions (Fox 2012).
Complications of monochorionic twin pregnancies
Monochorionic twin pregnancies share the same placental mass and due to vascular connections there may be discordance in blood supply to each twin, which can result in twin-to-twin transfusion syndrome (TTTS). TTTS occurs in up to 15% of monochorionic twin pregnancies, and untreated has a mortality rate of 90% (Chalouhi 2011). Treatment may involve selective laser coagulation of placental vessels, which involves performing an in utero procedure (Roberts 2008).
Fetal reduction and feticide for fetal anomalies and other fetal conditions
All types of multiple pregnancy are at risk for 'selective' structural and chromosomal anomalies. As mentioned, monochorionic twin pairs are at particular risk for TTTS and also selective growth restriction. In some of these situations one option for management might be to selectively 'reduce' the fetus with the poor or poorest prognosis in order to prolong pregnancy or to improve outcomes for the remaining fetus/es. Selective reduction procedures all require a fetal intervention and thus fetal immobilisation is an important part of such a procedure. In some settings, for example, late termination of pregnancy with a singleton fetus, feticide prior to induction of labour may be offered/performed.
Description of the intervention
Fetal interventions performed during pregnancy may involve open fetal surgery with maternal laparotomy, obstetric endoscopy (fetoscopy), and ultrasound-guided needling techniques. During these procedures described above, movement of the foetus increases the technical difficulty of the procedure and may contribute to trauma, as well as increasing the required operating time. Whilst there is much debate surrounding the perception of pain in the fetus, pain transmission can be demonstrated in controlled settings from approximately 16 weeks' gestation, and these pathways are completely developed from 26 weeks. With the recognition of a fetal stress response in response to procedures and in particular to noxious stimuli, effective fetal anaesthesia and analgesia may modify the fetal response, improve fetal outcome and possibly limit preterm labour (Anand 2001; Brusseau 2013).
Various methods and routes of administration have been utilised to aid in fetal immobilisation and analgesia, including transplacental routes (maternal general anaesthesia and other maternal medications), and combined spinal epidural and local anaesthesia with direct fetal administration of analgesic medications (intravenous (IV), intramuscular (IM) or intra-amniotic) (Fink 2011). To date, although the literature describes various routes of administration, their relative advantages and disadvantages and commonly used doses of medication, little is known about short- and long-term safety for the fetus after such medications are given (Brusseau 2013). Even simple pharmacokinetic profiles are poorly described for most agents, with the volatile agents best described, for example, isoflurane levels in the fetus reach 70% of maternal levels after 60 minutes of administration (Brusseau 2013). At this time in clinical practice, the choice of anaesthetic and analgesic agents, their dose and the mode of administration are ultimately determined by the procedure performed, clinical experience and the medical condition of the fetus.
Open fetal surgery
Open fetal surgery is used for repair of severe fetal lung lesions, and severe spine and spinal cord lesions (such as myelomeningocoele (Adzick 2011) and sacral teratomas) (Schwarz 2003). It requires maternal general anaesthesia (with or without epidural anaesthesia), and fetal anaesthesia, which can be achieved by placental transfer of anaesthetic agents administered to the mother, or additional administration of fetal opioids and muscle relaxants (Van de Velde 2012). There appears to be little consensus on the most appropriate agents for maternal general anaesthesia. Epidural anaesthesia and IV induction agents (thiopental, propofol, etomidate and ketamine), as well as volatile anaesthetics (inhaled gases, e.g. halothane and isoflurane) have all been used in pregnancy. Newer volatile agents (desflurane, seroflurane) have not yet been studied but it has been hypothesised that they will undergo rapid placental transfer to the fetus (Tran 2010). Other agents that are used for their ability to induce both maternal and fetal anaesthesia include thiopental, propofol, diazepam, morphine, remifentanil, and midazolam (Tran 2010).
Fetoscopic surgery and ultrasound-guided procedures
Most fetoscopic surgery is well tolerated under maternal local anaesthesia, although maternal regional anaesthesia (spinal, epidural or combined spinal epidural) is often used for complex procedures. Combined spinal and epidural anaesthesia provide neither fetal immobilisation or anaesthesia, so additional agents are required (IV maternal agents, or fetal IM/IV opioids and muscle relaxants) (Van de Velde 2012). Agents that have been studied in this setting include remifentanil (a short-acting potent opioid), diazepam or propofol administered to the woman. Alternative strategies involve the direct administration of anaesthetic agents to the fetus, including fentanyl and pancuronium (either IM or IV into the umbilical vein) (Ruano 2011). For situations that require complete fetal immobilisation, direct fetal administration of fentanyl, vecuronium and atropine is often required.
How the intervention might work
Successful fetal anaesthesia and analgesia reduce fetal movements, which in turn may result in a reduction in fetal trauma during surgery, reduced surgical technical difficulty with increased surgical success, and shorter operating times. Furthermore, fetal anaesthesia and analgesia may reduce the fetal stress response to painful stimuli, and may prevent long-term adverse neurodevelopmental and behavioural responses to pain (Fink 2011).
Why it is important to do this review
The increasing frequency of fetal surgery and other interventions during pregnancy requires the identification of the optimal method for achieving fetal immobilisation and the safest and most effective means of fetal anaesthesia and analgesia.
To compare the fetal, neonatal and maternal outcomes with different types of anaesthetic and analgesic medication for fetal immobilisation when fetal surgery or intervention is required.
Criteria for considering studies for this review
Types of studies
Randomised and quasi-randomised controlled trials that compare different methods of achieving fetal immobilisation or trials that compare fetal immobilisation with no immobilisation. Trials using a cross-over design will not be included. We plan to include studies presented as abstracts if enough information is presented for us to make an assessment.
Types of participants
Women with fetal conditions undergoing invasive fetal interventions or fetal surgery including fetal blood sampling and transfusion, fetal bladder drainage and stenting, fetal pleural effusion drainage and stenting, fetoscopy for laser ablation to treat twin-to-twin transfusion syndrome, fetal tracheal occlusion, fetal spina bifida repair and EXIT procedure.
Types of interventions
Different types of medication for fetal immobilisation compared with each other (including medications given to the mother and directly to the fetus), and medication for fetal immobilisation compared with no medication.
Types of outcome measures
- Degree of fetal immobilisation as defined by trial authors.
- Technically successful procedure as defined by trial authors.
- Clinically effective procedure as defined by trial authors.
- Time taken to perform the planned procedure.
- Fetal bradycardia or significant heart rate changes during or immediately after the procedure.
- Preterm birth at less than 28 completed weeks of gestation.
- Preterm birth at less than 34 completed weeks of gestation.
- Preterm birth at less than 37 completed weeks of gestation.
- Preterm pre labour ruptured membranes (defined as less than 37 weeks' gestation).
- Fetal growth restriction.
- Perinatal mortality defined as stillbirth (death prior to birth of a fetus of at least 20 weeks' gestation or at least 400 g) and neonatal death (death of a live born child up to 28 days after delivery).
- Any death of a fetus after the procedure and less than 20 weeks or less than 400 g (i.e. those deaths that do not meet the criteria for stillbirth).
- Death of a fetus during the procedure.
- Death of a fetus within 48 hours of the procedure.
- Death of a fetus within four weeks of the procedure.
- Death of a fetus more than four weeks after the procedure.
- Maternal respiratory depression as defined by trial authors or measured using intraoperative maternal arterial oxygen saturation and maternal respiratory rate.
- Maternal sedation measured using sedation scores as defined by trial authors.
- Maternal blood loss (defined as mean maternal blood loss measured in mL, and occurrence of postpartum haemorrhage defined by blood loss 600 mL or greater than 1500 mL, with and without treatment).
- Maternal pain scores as defined by trial authors.
- Maternal psychological well being and anxiety as defined by trial author.
Search methods for identification of studies
We will contact the Trials Search Co-ordinator to search the Cochrane Pregnancy and Childbirth Group’s Trials Register.
The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co-ordinator and contains trials identified from:
- monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
- weekly searches of MEDLINE;
- weekly searches of Embase;
- handsearches of 30 journals and the proceedings of major conferences;
- weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.
Details of the search strategies for CENTRAL, MEDLINE and Embase, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.
Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co-ordinator searches the register for each review using the topic list rather than keywords.
Searching other resources
We plan to search reference lists of retrieved studies.
We will not apply any language restrictions.
Data collection and analysis
Selection of studies
Two review authors will independently assess for inclusion all the potential studies we identify as a result of the search strategy. We will resolve any disagreement through discussion or, if required, we will consult a third author.
Data extraction and management
We will design a form to extract data. For eligible studies, at least two review authors will extract the data using the agreed form. We will resolve discrepancies through discussion or, if required, we will consult a third author. We will enter data into Review Manager software (RevMan 2012) and check for accuracy.
When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to provide further details.
Assessment of risk of bias in included studies
Two review authors will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreement by discussion or by involving a third assessor.
(1) Random sequence generation (checking for possible selection bias)
We will describe for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.
We will assess the method as:
- low risk of bias (any truly random process, e.g. random number table; computer random number generator);
- high risk of bias (any non-random process, e.g. odd or even date of birth; hospital or clinic record number);
- unclear risk of bias.
(2) Allocation concealment (checking for possible selection bias)
We will describe for each included study the method used to conceal allocation to interventions prior to assignment and will assess whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.
We will assess the methods as:
- low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
- high risk of bias (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);
- unclear risk of bias.
(3.1) Blinding of participants and personnel (checking for possible performance bias)
We will describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We will consider that studies are at low risk of bias if they were blinded, or if we judge that the lack of blinding would be unlikely to affect results. We will assess blinding separately for different outcomes or classes of outcomes.
We will assess the methods as:
- low, high or unclear risk of bias for participants;
- low, high or unclear risk of bias for personnel.
(3.2) Blinding of outcome assessment (checking for possible detection bias)
We will describe for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or classes of outcomes.
We will assess methods used to blind outcome assessment as:
- low, high or unclear risk of bias.
(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)
We will describe for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported, or can be supplied by the trial authors, we will re-include missing data in the analyses which we undertake.
We will assess methods as:
- low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);
- high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation);
- unclear risk of bias.
(5) Selective reporting (checking for reporting bias)
We will describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.
We will assess the methods as:
- low risk of bias (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);
- high risk of bias (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
- unclear risk of bias.
(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)
We will describe for each included study any important concerns we have about other possible sources of bias.
We will assess whether each study was free of other problems that could put it at risk of bias:
- low risk of other bias;
- high risk of other bias;
- unclear whether there is risk of other bias.
(7) Overall risk of bias
We will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Cochrane Handbook (Higgins 2011). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. We will explore the impact of the level of bias through undertaking sensitivity analyses - see Sensitivity analysis.
Measures of treatment effect
For dichotomous data, we will present results as summary risk ratio with 95% confidence intervals.
For continuous data, we will use the mean difference if outcomes are measured in the same way between trials. We will use the standardised mean difference to combine trials that measure the same outcome, but use different methods.
Unit of analysis issues
We will not include cluster-randomised trials in this review as it is unlikely they would be an appropriate method of investigation and unlikely that a sufficient number of units would be randomised to ensure an even distribution of potential confounders among groups.
Trials including women with multiple pregnancies
Where trials have included women with a twin pregnancy, we will use cluster-randomised trial methods outlined in section 16.3 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) to account for non-independence of infants from multiple pregnancies.
Dealing with missing data
For included studies, we will note levels of attrition. We will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.
For all outcomes, we will carry out analyses, as far as possible, on an intention-to-treat basis, i.e. we will attempt to include all participants randomised to each group in the analyses, and all participants will be analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial will be the number randomised minus any participants whose outcomes are known to be missing.
Assessment of heterogeneity
We will assess statistical heterogeneity in each meta-analysis using the T², I² and Chi² statistics. We will regard heterogeneity as substantial if the I² is greater than 30% and either the T² is greater than zero, or there is a low P value (less than 0.10) in the Chi² test for heterogeneity.
Assessment of reporting biases
If there are 10 or more studies in the meta-analysis, we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually. If asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate it.
We will carry out statistical analysis using the Review Manager software (RevMan 2012). We will use fixed-effect meta-analysis for combining data where it is reasonable to assume that studies are estimating the same underlying treatment effect: i.e. where trials are examining the same intervention, and the trials’ populations and methods are judged sufficiently similar. If there is clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if substantial statistical heterogeneity is detected, we will use random-effects meta-analysis to produce an overall summary, if an average treatment effect across trials is considered clinically meaningful. The random-effects summary will be treated as the average range of possible treatment effects and we will discuss the clinical implications of treatment effects differing between trials. If the average treatment effect is not clinically meaningful, we will not combine trials.
If we use random-effects analyses, the results will be presented as the average treatment effect with 95% confidence intervals, and the estimates of T² and I².
Subgroup analysis and investigation of heterogeneity
If we identify substantial heterogeneity, we will investigate it using subgroup analyses and sensitivity analyses. We will consider whether an overall summary is meaningful, and if it is, use random-effects analysis to produce it.
We plan to carry out the following subgroup analyses:
- type of procedure performed;
- gestational age at the time the procedure was performed;
- singleton pregnancy versus multiple pregnancy;
- different drug doses for each specific drug used;
- different routes of administration – for example, fetal intramuscular injection versus fetal umbilical vein injection.
The following outcome will be used in subgroup analysis.
- Degree of fetal immobilisation as defined by trial authors.
We will assess subgroup differences by interaction tests available within RevMan (RevMan 2012). We will report the results of subgroup analyses quoting the χ
We will carry out sensitivity analysis to explore the effects of trial quality all potential risk of bias components, by omitting studies rated as 'high risk of bias' on overall assessment. We will restrict this to the primary outcome. In particular, as quasi-randomised trials are eligible to be included, we plan to perform a sensitivity analysis on the basis of excluding such trials.
As part of the pre-publication editorial process, this protocol has been commented on by three peers (an editor and two referees who are external to the editorial team) and the Group's Statistical Adviser.
Contributions of authors
A Le Blanc and R Grivell developed the idea for this review. The initial protocol was drafted by A Le Blanc with assistance from R Grivell and review by J Dodd and K Andrewartha.
Declarations of interest
Sources of support
- No sources of support supplied
- NHMRC, Australia.Practitioner Fellowship and Early Career Fellowship for JD and RG respectively