The use of endoscopy in fetal medicine
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We aimed to review the state of affairs in the field of embryo–fetoscopy as well as its instrumental requirements. Today, endoscopic procedures of limited complexity are easily possible within the amniotic cavity. Embryoscopy is typically done for diagnostic purposes, such as the demonstration of external anomalies very early in pregnancy and/or obtaining embryonic tissues in recurrent miscarriages. Fetoscopy is the direct visualization of the amniotic cavity from the second trimester onwards. Its principal indications are complications of monochorionic twinning and severe congenital diaphragmatic hernia. There is level I evidence that fetoscopic laser surgery for twin–twin-transfusion syndrome is superior over amniodrainage. Fetoscopic endoluminal tracheal occlusion is done for severe diaphragmatic hernia. Whether tracheal occlusion yields better outcomes than expectant management during pregnancies is currently being investigated in a randomized trial. There are a number of less common procedures discussed as well. Overall, maternal risks of embryo–fetoscopy are minimal. The most frequent complication is rupture of the membranes and as a consequence preterm delivery. Fetal surgery seems safe and has, therefore, become a clinical reality. Although the stage of technical experimentation is over, most interventions remain investigational. Inclusion of patients into trials whenever possible should be encouraged, rather than building up casuistic experience.
KeywordsFetal surgery Fetoscopy Embryoscopy Prenatal diagnosis Missed abortion
Minimally invasive endoscopy became the gold standard for diagnosis as well as operative procedures in many fields of medicine during the last decades of the past century. Eventually, also the fetal patient does benefit today from this modality. Already in 1954, Bjorn Westin undertook the first attempts to visualize the human fetus with an endoscope . Only in the 1970s embryoscopy and fetoscopy evolved as a more common diagnostic and therapeutic technique throughout ongoing pregnancy. Fetoscopy was performed to demonstrate external malformations such as neural tube defects [2, 3], to gain fetal liver and skin biopsies [4, 5, 6], or to obtain fetal blood in the diagnosis of, e.g., hemoglobinopathies [6, 7]. It also allowed for interventions, such as intravascular transfusion under direct visual control . However, the invasiveness of the procedure, required skills, and a lack of suitable instruments lead to relatively high fetal loss rates. A report of the International Fetoscopy Group (1984) with pooled data of approximately 3,000 procedures in 24 programs reported an overall pregnancy loss rate prior to 28 weeks of 4% .
Indications for fetoscopic surgery
Rationale for in utero therapy
Reversal of pulmonary hypoplasia and prevention of pulmonary hypertension
Covering of exposed spinal cord, prevention of hydrocephaly and hindbrain herniation
Reversal of cardiac failure and prevention of polyhydramnios
Prevention of renal failure and pulmonary hypoplasia
Surgery on the placenta, cord, or membranes
Rationale for in utero therapy
Complicated MC pregnancies
Functional bichorionization or arrest of feto-fetal transfusion and its consequences
TRAP and other discordant anomalies
In some conditions (TTTS/TRAP), reversal of cardiac failure and polyhydramnios
In some conditions, selective feticide is a goal in itself
Prevention of deformities and functional loss
Prevention of cardiac failure, hydrops fetoplacentalis, and polyhydramnios
Reported risks for PROM following fetoscopic procedures in selected case series
Number of cases
Risk PROM (time point at assessment)
3 ports, largest 5.0 mm
Kohl (secondary laser) 
Van Schoubroeck (triplets only) 
28% (<34 weeks)
Yamamoto and Ville 
7% (<1 week)
5% (<28 weeks)
0% (<3 weeks)
2.3 or 3.3 mm
Lewi (bipolar/laser) 
Ville (laser) 
20% (<3 weeks)
Quintero (ligation ± transection/laser) 
16% (<3 weeks)
3.5 mm (1 or 2 ports)
Nakata (ligation/laser) 
Young (bipolar) 
5.0 mm (1 or 3 ports)
17% (<3 weeks)
Current embryo–fetoscopes come with a working length of 20–30 cm and a diameter of 1.0–3.8 mm. They are designed such that they are a compromise between the smallest diameter technically possible that still allows sufficient image quality. In some models, the standard eyepiece has been deported to reduce weight and allow for an ergonomic manipulation. Roughly spoken, two types are available, i.e., (a) rod lens endoscopes where the image itself is focused by a Hopkins rod lens system; (b) fiber endoscopes which use optical fibers for both light and image transmission. This way, they can be made in smaller diameters with a sufficient length and image quality. Fetoscopes are typically protected by a sheath, which may have additional operative channels for instruments or infusion.
In analogy to laparoscopy, access needs to be gained by a cannula (or port). This cannula enables the surgeon to change instruments during the intervention and, in theory, reduces membrane friction, however, at the expense of a larger diameter. The port can be inserted into the amniotic cavity using a stabbing trocar or over a guide wire and dilator (Seldinger technique) [29, 38, 39, 40]. Alternatively, the fetoscope sheath can be inserted directly, using a pyramidal obturator within. The amniotic cavity is spontaneously distended by the amniotic fluid. When that does not create enough working space, additional infusion or, in case of unclear fluid, substitution or exchange can be done. We use warmed, isotonic Hartmann solution, which has been proven to be safe in experimental and clinical conditions [41, 42]. Gas distension (CO2, N2O) may permit a clearer view, even in the presence of bleeding, yet interferes with the use of ultrasound and some fear fetal side effects [43, 44, 45, 46]. The camera system and light sources are no different from other endoscopic operations, though the light cables are smaller in diameter.
Most fetoscopic procedures are done under local anesthesia. An anesthetic is injected down to the myometrium at the anticipated cannula tract. This site is determined by the purpose of the procedure but should ideally be in an area devoid of placenta. For placental surgery, no fetal anesthesia is needed. For interventions on the fetus, both fetal analgesia and immobilization are required. Most use injection of fentanyl and pancuronium (or an analog), which are either injected intramuscular or intravenous in the appropriate dose, based on fetal weight estimation. Historically, interventions have been done under general anesthesia, but today, this is rarely necessary, except for open surgical procedures. In that case, no additional fetal analgesia is usually required .
Recently, transcervical embryoscopy has been revived in the evaluation of missed abortions before 12 weeks, in particular in recurrent miscarriages or fertility treatment programs . In the latter, failing pregnancies might be biochemically identified very early in their course and as such could be assessed electively. In that case, endoscopic equipment is introduced through the cervix, and the procedure may be completed with evacuation of the products of conception. For this, larger equipment is often used, consisting of 0° or 30° hysteroscope, housed within a double flow sheath allowing for exchange of irrigation fluid (at body temperature and a pressure 40–120 mmHg) [50, 51] and insertion of instruments (Bettocchi 3.6 mm 5 Ch operating sheath with 30° scope of 2 mm diameter, Karl Storz GmbH, Tuttlingen, Germany). The operator first localizes the gestational sac and surgically opens the chorionic membrane. At that time, the embryo can already be seen through the amnion. Further opening of the amniotic membrane with micro-scissors allows a closer look at the different fetal elements and from different sides. Also, the yolk sac and umbilical cord are inspected. Normal or anomalous evolution is usually described and dated in function of the crown-rump length as measured on ultrasound or described in the Carnegie stages . After that, direct sampling of chorionic villi is possible, as well as directed embryonic biopsies. Prior to 7 weeks, the embryo can usually be removed in toto. One can use ultrasound guidance, which in our experience facilitates localization of the gestational sac and the structures inside. In summary, next to external or phenotypic description, embryoscopy allows the prelevation of pure embryonic material, without maternal contamination, for further genetic testing. The procedure can be part of the formal evacuation of the products of conception and would lengthen that procedure only by 10 min. Also, the procedure-related complications are similar, i.e., bleeding, infection, and perforation.
Paschopoulos et al. leave the amnion intact and report on 42 patients with first trimester miscarriage . Ferro et al. work intra-amniotically and published data on 68 patients presenting with missed abortion in an IVF program. Compared to material obtained from curettage, cytogenetic analysis of embryoscopic prelevations was more informative in 22% of cases . Philipp et al. reported abnormal standard karyotyping with G-banding in as many as 75% of 233 missed abortions. Eighteen percent had a variety of abnormal phenotypic features, despite a normal karyotype. In 7%, no phenotypical or cytogenetic abnormalities could be found . The same group described the typical phenotype of triploidy with severe cranio-facial malformations, retarded limb development, delayed retinal pigment development, and neural tube defects . Monosomy 45X is associated with microcephaly, encephalocoele, and limb retardation . Obviously, those defects would not show up on curettage specimens nor would they be typically seen on high-definition ultrasound.
Stage-related outcome after laser therapy in TTTS
at least 1 survivor
Stage I (n = 29)
6.9 (0.8–22.8) (2/29)
17.2 (5.9–35.8) (5/29)
75.9 (56.5–89.7) (22/29)
93.1 (77.2–99.2) (27/29)
Stage II (n = 81)
17.3 (9.8–27.3) (14/81)
22.2 (13.7–32.8) (18/81)
60.5 (49.0–71.2) (49/81)
82.7 (72.7–90.2) (67/81)
Stage III (n = 80)
17.5 (9.9–27.6) (14/80)
28.7 (19.2–40.0) (23/80)
53.8 (42.2–65.0) (43/80)
82.5 (72.4–90.1) (66/80)
Stage IV (n = 10)
30 (6.7–65.2) (3/10)
20 (2.5–55.6) (2/10)
50 (18.7–81.3) (5/10)
70 (34.8–93.3) (7/10)
The procedure is completed by amnioreduction to normal levels. Complications are peritoneal irritation by amniotic fluid leakage through the uterine entry point, iatrogenic PPROM (7% within 1 week, 28% before 34 weeks), placental abruption (1%), as well as infection and hemorrhage in rare cases [27, 60]. An earlier drainage or stained liquid may hamper visualization, as well as an unfavorable placental location [25, 67]. For patients with anterior placentas, special techniques and instruments have been designed. These include a deflecting mechanism built in the sheath , side firing laser fibers through an additional insert , and even a laparoscopic-assisted posterior uterine access . So far, none of these techniques has been proven superior, and for that reason, we personally remain mostly with the use of curved scopes of the same diameter and lateral trocar insertion . Other groups achieve similar results by the consequent use of other techniques .
The superiority of laser over amniodrainage was proven in the Eurofoetus randomized trial . Laser treatment resulted in a later delivery (33.3 versus 29 weeks), a better survival rate at 6 months of age (at least one survivor in 76% compared to 51%), and less neurological impairment (intraventricular hemorrhage grades III or IV, 1% versus 6%; cystic periventricular leukomalacia, 6% versus 14%; infants alive without major complications at 6 months, 52% versus 31%). Later meta-analyses [72, 73] and a Cochrane review  confirmed this including other series; therefore, laser is the current standard of care.
A lower neurologic morbidity in survivors has been confirmed in other studies as well, but the studies giving these results were not designed with carefully selected controls. In a more recent follow-up study on infants born after laser surgery, 18% showed neurological impairment at age 2 years (cerebral palsy 6%, severe mental delay 7%, severe psychomotor delay 12%, bilateral blindness 1%, bilateral deafness 1%). Risk factors for neurodevelopmental impairment were an advanced GA at laser therapy, a low GA at birth, a low birth weight, and a more advanced stage at laser. Post-laser neurologic sequel do not differ in donor or recipient twin . However, some of the lesions may not be related to TTTS, as we recently showed a background neurologic impairment rate of 7% in apparently normal MC twins . As this is probably the most feared complication of TTTS, we routinely perform follow-up ultrasound as well as a fetal MRI around 30–32 weeks in pregnancy to rule out this condition as much as possible.
Another cause of morbidity are cardiac complications, which may be as high as 10% in recipients, who are prone to right ventricular outflow tract obstruction. On the other hand, the majority of recipients, who all have a vast cardiac overload, recover already in utero from cardiac dysfunction [77, 78].
Other complications of monochorionic pregnancies
MC twins are more prone to structural anomalies, more than 80% being discordant. They can even be discordant for aneuploidy . Parents may decide not to deliver such baby alive, and selective feticide avoids termination of the entire pregnancy. Another anomaly is twin-reversed-arterial-perfusion sequence (TRAP or acardiac fetus). Functionally spoken, the anomalous is perfused by the normal “pump” twin, which risks to develop congestive heart failure and hydrops in >50% . Fetal death puts the healthy one at risk, due to feto-fetal hemorrhage over the anastomoses.
Another not infrequent clinical scenario is that of selective intrauterine growth restriction (sIUGR), e.g., defined by a sonographic estimated fetal weight <10th percentile in the growth restricted fetus. However, different definitions are used and are discussed in detail by Russel et al. . sIUGR complicates around 7–15% of MC twins, and these pregnancies are extremely difficult to manage. There is no agreement what the criteria are to determine when a growth restricted fetus is at an extremely high risk for IUFD, but in that event, the MC status puts the other fetus at risk for fetal death or (neurological) morbidity [82, 83, 84] due to the anastomoses . For that reason, some have proposed to actively manage these pregnancies. In analogy to TTTS, laser bichorionization can be done, but technically, the procedure is more difficult because of the absent polyhydramnios, hence, more scalloped placenta. Also, the angioarchitecture is different. Another intervention that can be done in such circumstances is selective feticide to protect the other fetus [81, 86]. This concept is supported by a recent retrospective study on 135 MC pregnancies after single (spontanous, post cord occlusion, or laser bichorionization) IUFD. Brain injuries that were picked up by MRI were significantly less in the survivors of cord occlusion or laser intervention (3%) compared to spontaneous co-twin loss (22%) .
Selective feticide in MC twins needs to be done with alternative techniques to potassium chloride injections because both fetal circulations are functionally one unit. This is achieved by surgical obliteration of both the arterial and venous flow, preferentially nearly simultaneous. Several techniques are available today. The largest experience is by ultrasound or sono-endoscopic guided bipolar cord coagulation, using forcepses of 2.4 or 3.0 mm, according to the cord size. Cord occlusion has a 78–84% survival rate [31, 88]. Pre- and perinatal losses of the healthy twin are mainly due to cord entanglement because of iatrogenic rupture of the intertwin membrane or consequences of early PPROM also responsible for 7% developmental problems in survivors. An effect of operator experience was demonstrated, showing decrease in PPROM and morbidity after 40 procedures . Alternative energy sources such as laser, monopolar, or radiofrequency energy may be used through 14–18 G needles [89, 90, 91]. They work effectively in TRAP where low-flow conditions are present and all energy modalities show comparable outcomes [30, 92]. A special scenario is found in discordant monoamniotic pregnancies. Here, cord occlusion should be combined with subsequent cord transsection .
Congenital diaphragmatic hernia
A later occlusion is proposed in moderate CDH (25% < O/E LHR <45%), where a lesser lung response might still allow survival, and where the intervention targets at a reduction of the oxygen need in the postnatal period [98, 99, 100]. Whether FETO is better than expectant management during pregnancy is currently being investigated in the TOTAL trial. Meanwhile, FETO has also been applied to fetuses at risk for severe lung hypoplasia due to persistent oligohydramnios . This more recent indication will require validation of selection criteria for lethal hypoplasia due to PPROM.
In myelomeningocoele (MMC), the spinal cord protrudes through a defect in the bone and usually through the skin as well. The condition also has remote effects on fetal development, such as cerebellar herniation and hydrocephalus due to abnormal dynamics in cerebrospinal fluid production. The subsequent handicaps associated with MMC include lower limb paralysis, sensory loss as well as bladder, bowel, and sexual dysfunction, but there may be cognitive impairment as well. The severity of MMC is dependent on the level and extent of the spinal defect. This is why most children with MMC have a normal intelligence quotient, walking abilities, and social continence. Ventriculo-peritoneal shunting is often required, a known additional risk factor for cognitive impairment [102, 103, 104].
Experimental and clinical data suggest that neurological impairment progresses throughout pregnancy. Hence, fetal therapy might favor long-term outcome by preventing exposure to the amniotic fluid as well as cerebrospinal fluid leakage. This should reduce the chance for hydrocephalus, hindbrain herniation, and result in lower shunt requirement after birth [40, 105]. Another theoretical advantage of fetal surgery is that the repair would be less prone to scarring, avoiding the so-called tethered cord syndrome , although adhesions between spinal cord and skin after fetal surgery have been reported [107, 108, 109].
The US-based Management of MMC study (MOMS), which started in 2003 in three centers, will determine whether prenatal (19–25 weeks) yields better results than postnatal closure. Recruitment is still ongoing, and results are eagerly awaited. In this trial, the operation is carried out by open access, after an initial pilot study using an endoscopic approach with poor results [19, 43]. The potential of robotic surgery  or alternative “sealing” of the defect with a patch through fetoscopy is currently being explored. The first fetoscopic applications of a patch failed as one out of three babies all born ≤30 weeks died from prematurity, and the two remaining ones required postnatal shunting, therefore, not meeting trial goals . In a more recent attempt, the same group tried a fetoscopic double patch (first patch is absorbable and covered by a non-absorbable second one) approach in two more infants. Although GA at delivery was 33 weeks now, and reversal of hindbrain herniation was seen in both cases, one child still struggled with prematurity effects, and the other one required shunting .
Sacrococcygeal teratoma (SCT) is the most frequent tumor in neonates with an estimated prevalence of one in 40,000 . It is easily diagnosed before birth with ultrasound, Doppler, and MRI providing detailed information about location, size, and functional impact. Long-term outcome after standard therapy including postnatal tumor removal and follow-up for malignancy is usually excellent. Yet, a subgroup of SCT are large, fast-growing, and highly vascularized tumors, which set the fetus at risk for anemia and cardiac failure due to arterial–venous fistulas. Fetal hydrops and placentomegaly are accepted indicators for fetal intervention [112, 113, 114, 115]. Causative approaches comprise open fetal tumor resection or debulking, which was published in eight cases with a mean GA of 28 weeks (range 26–29) and four survivors [116, 117, 118]. There is casuistic experience with less-invasive interventions such as thermocoagulation, radiofrequency ablation, embolization, and laser surgery [115, 119, 120, 121]. The London group treated four hydropic fetuses with laser; only one survived after preterm birth at 32 weeks, two died in utero, and one as a neonate after preterm delivery at 28 weeks . In an earlier case report, Hecher et al.  describe successful partial SCT ablation via fetoscopic laser at 20 weeks of gestation. However, this fetus was not hydropic, and decision for fetal intervention was made based on polyhydramnios. The concurrent fetal anemia may need to be addressed as well, perhaps prior to surgery.
Uncommon fetoscopic interventions
Placental chorioangiomas are benign tumors that cause fetal heart failure due to a vascular steal mechanism. When treatment cannot wait until birth (e.g., in case of fetal hydrops), fetoscopic devascularization can be done, using an equipment that is the same as for laser therapy. Alternatives are embolization of the vascular plexus, either by alcohol or coils. The condition is too rare to reasonably assess as to which is the best technique [123, 124, 125, 126, 127].
Amniotic bands may lead to progressive constrictive lesions and amputate fetal body parts. The first one to describe a fetoscopic-guided lysis of such bands was Quintero , and several case reports were published since. Instrumentation consists of a 1.3-mm fetoscope, which is inserted into a special sheath ending up in scissors. This allows fetoscopic control of the section of the bands. Alternatively, laser can be used, but that can cause collateral damage [22, 23]. It might be very difficult to section the bands entirely as they get entrapped within edematous surrounding structures.
Endoscopy is also used in the exploration of urinary tract lesions. Particularly male fetuses can develop complete lower urinary tract obstruction. This leads to two problems: one is secondary renal failure but the subsequent oligohydramnios-induced pulmonary hypoplasia is life-threatening. So far, the standard prenatal intervention that salvages the lungs, and in well-selected cases also kidney function, is urinary diversion. Vesicoamniotic shunting is a palliative intervention that allows further repair after birth. They can also dislodge or become unfunctional in 20–40% of cases, requiring reinsertion [128, 129, 130, 131]. The material used for fetal shunting is of comparable diameter to that of fetoscopic instruments. This means that with a similar access port, one can try to also assess the lower urinary tract by inserting an endoscope and perform fetal cystoscopy. It was Quintero who should be credited for performing the first percutaneous fetal urethral valve ablation [132, 133], i.e., a causative intervention. Alternatively, hydro- or laser ablation of urethral valves or antegrade catheterization can be done [20, 134]. However, so far, the reported successful experience remains casuistic, and also, the role of diagnostic fetal cystoscopy remains to be determined.
Fetoscopic surgery has become a clinical reality in selected large fetal medicine units. The equipment is nothing but purpose-designed miniaturized variants of conventional endoscopic hardware. A number of indications for minimally invasive surgery within the womb have been established, and several more are under investigation. Fetoscopic surgery has proven its superiority in laser surgery of the placenta, and at present, its place in the prenatal treatment of CDH is being investigated within a European trial. The less invasive nature has made fetoscopic surgery more acceptable for parents and clinicians. However, a few more complex fetal surgical interventions remain impossible with current equipment. Fetoscopy is an invasive technique, with inherent consequences. Whereas PPROM, and subsequent preterm delivery, seems less frequent than with open surgery, it still is limiting current applications. Its increasing application and mediagenicity has triggered the interest to embark on fetal surgical therapy although the complexity as well as the overall rare indications are a limitation to sufficient experience on an individual basis. Therefore, these procedures may probably only be done properly when sufficient volume is available. Also, further advance in this field will only be possible by inclusion of patients into trials whenever possible, rather than building up casuistic experience.
The European Commission supports fetoscopy in Europe through different funding mechanisms (EuroSTEC, 6th Framework, LSHC-CT-2006-037409; Marie Curie Early Stage Research Training MEST CT2005 019707), and provided the doctoral grants for VB, LG. The Flemish Regional Government (IWT/ 070715) supports our local fetoscopy program for Congenital Diaphragmatic Hernia and the stipend of PDK. JDP is a “clinical researcher” for the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (1.8.012.07.N.02). AP and TVM are supported by a grant of the University Hospitals Leuven (KOOR fonds and strategic projects). Kathleen Albert and Vital Noppen are thanked for their help with the acquisition of images of fetoscopic instruments.