MoDi Twin Placental Imaging

Twin-twin transfusion syndrome (TTTS) is a pathology that can arise in monochorionic, diamniotic (MoDi) identical twins arising from the division of a single fertilized ovum at 4-8 days gestational age (GA), after the chorion has formed but before the amnion's formation. TTTS can also arise in monochorionic, monoamniotic (MoMo) twins when there is a division in the fertilized ovum between day 8-13 GA, also resulting in a single chorion but also a single amnion. The amnion is the tissue layer that will develop into the amniotic sac, while the single chorion in both MoDi and MoMo twins, made up of the cytotrophoblastic and syncytiotrophoblastic layers as well as the extraembryonic mesoderm tissue layers; eventually composing the fetal side of the placenta including the chorionic plate and villi.

The fetal side of the placenta is composed of low-resistance, higher-pressure vascular beds terminating in villous capillaries where deoxygenated blood can be easily exchanged with the lower-pressure, extra-vascular, maternal-side blood supply for oxygenated blood flowing through the chorionic and umbilical vein(s). The maternal and fetal blood supplies are not directly connected.

The placental vasculature is further broken down into 15-28 cotyledons, which are fed originally by each umbilical artery that branch into eight or more terminal chorionic plate arteries/'stem' arteries. These arteries then divide into first-order-branching truncal vessels which in turn divide into 4-8 horizontal cotyledonary vessels of the second-order. These horizontal cotyledonary vessels then branch further into third-order, villous branches of which there are 30-60 main branches per cotyledon, terminating in a vast network of even smaller capillaries.

As mentioned, arterial and venous blood flow should not directly be connected. However, in monochorionic twin pregnancies sharing a single placenta often unevenly, anastomoses [connections] artery to artery (AA), vein to vein (VV), and artery to vein (AV) can occur. AA and VV anastomoses often occur superficially on the placenta, with AA anastomoses being considered protective against TTTS. These AA and VV anastomoses tend to have bi-directional flow and are of less clinical concern.

In contrast, AV anastomoses usually flow in a unilateral manner and often shunt blood unevenly towards one twin and away from the other. This can be further complicated by one twin's vasculature dominating the majority of the placenta's vascular area and thus oxygen-CO2 exchange. These factors can lead to one twin with hypovolemia [lack of blood volume/flow], leading to renal hypoperfusion and stimulating the renin-angiotensin-aldosterone system (RAAS) which then induces potent vasoconstriction, water and sodium retention, increased blood pressure, and vascular resistance within the kidney. These factors, in turn, lead to oligouria, a low urine output by the fetus and oligohydramnios, a low volume of amniotic fluid, with increased collagen synthesis, hypertrophy [increased size] of the vascular media, and smooth-muscle hypertrophy following.

In contrast, the other twin receives too much blood flow causing hypervolemia, which in turn causes the cardiac muscle to stretch and release atrial and brain natriuretic peptides to lower fetal blood pressure. This in turn leads to polyuria and polyhydramnios, with atrioventricular valve insufficiency [incomplete closure of the mitral/tricuspid heart valves leading to regurgitation], diastolic dysfunction, pulmonary valve stenosis [a narrowing of the valve lumen], and pulmonary atresia [when the pulmonary valve & lumen does not form], following.

TTTS will affect approximately 8-10% of MoDi twins while 6% of MoMo twins will suffer with this condition. Considering twinning rates in pregnancy, this places the overall incidence of the pathology at 1-3 pregnancies per 10,000.

Treatment for TTTS is necessary, with the donor or 'pump' twin having around an 80% chance of death without medical intervention. Interventions to date have included septostomy, where the septum or membrane separating the two amniotic fluid sacs is cut, amnioreduction, where a volume of amniotic fluid is removed from the sac with polyhydramnios, and fetoscopic laser photocoagulation surgery, where a fetoscope and a 600 micrometer laser fiber is inserted via trocar & cannula placed in the abdomen and ablates pathologically communicating vessels on the placental surface. A large, systematic & metareview of the Cochrane Pregnancy and Childbirth Group's Trials Register (April 2007) and the Cochrane Central Register of Controlled Trials found that "laser coagulation resulted in less overall death (48% vs. 59%; relative risk (RR), 0.81; 95% CI, 0.65-1.01 adjusted for clustering; two trials, 364 fetuses), perinatal death (26% vs. 44%; RR, 0.59; 95% CI, 0.40-0.87 adjusted for clustering; one trial, 284 fetuses) and neonatal death (8% vs. 26%; RR, 0.29; 95% CI, 0.14-0.61 adjusted for clustering; one trial, 284 fetuses) when compared with amnioreduction. There was no difference in perinatal outcome between amnioreduction and septostomy. More babies were alive without neurological abnormality at the age of 6 months in the laser group than in the amnioreduction group (52% vs. 31%; RR, 1.66; 95% CI, 1.17-2.35 adjusted for clustering; one trial). There was no difference in the proportion of babies alive at 6 months that had undergone treatment for major neurological abnormality between the laser coagulation and the amnioreduction groups (4% vs. 7%; RR, 0.58; 95% CI, 0.18-1.86 adjusted for clustering; one trial). The results suggest that endoscopic laser coagulation of anastomotic vessels should be considered in the treatment of all stages of TTTS to improve perinatal and neonatal outcome. The study also notes that further research is needed to fully ascertain the ideal treatment modality in different stages of TTTS."

Even with intervention, the above results still show a very high overall mortality rate in TTTS, with a 48% fetal mortality rate with laser coagulation; rates of neurological complications, periventricular leukomalacia (PVL) [death of white matter in the brain], intracerebral hemorrhage, deafness, blindness, motor deficits, and other symptoms, are also very high in this population, even with treatment. These rates demonstrate an urgent need for not only more research to support a clear, ideal treatment protocol for TTTS, but a need to improve the current treatment modalities themselves. Additionally, there is no current clinical imaging that allows direct visualization of the placental microvasculature.

Recently, there has been growing enthusiasm toward developing non-invasive placental imaging technologies. Superb microvascular imaging (SMI) is an emerging sonographic placental imaging method that has been shown to be useful for evaluating placenta vascularization. Compared to conventional blood-flow imaging methods, SMI uses advanced techniques to reduce motion artifacts and allows the visualization of low-velocity blood flow in small vessels. While SMI demonstrates the power of microvascularity imaging, this method is only available from a single ultrasound vendor (Toshiba Medical Systems, Tokyo, Japan) and has its own limitations.

Ultrafast power Doppler imaging (uPDI) relies on the use of revolutionary ultrafast ultrasound techniques to image the blood flow with a high spatial-temporal resolution simultaneously and at several locations, providing previously unavailable information about flow behavior. uPDI has shown tremendous success in imaging organs such as the kidney and has also shown promise for placental imaging by providing enhanced sensitivity to placental blood flow and the fine, small vessels of the placental surface and cotyledons. The technology may allow for much superior vascular mapping on and within the placenta and may in the future allow identification of pathologically anastomosed vessels in TTTS. This improved vascular mapping may, in turn, lead to a superior visualization and fetoscopic laser ablation treatment in a TTTS population.

Due to the limited number of human subjects research studies utilizing uPDI for placental vascular mapping, the present study is a proof-of-concept and feasibility, non-significant risk device study utilizing the FDA Grade-I, investigational, non-FDA-approved device, the Verasonics Vantage 256 uPDI ultrasound platform, to demonstrate the ability of the technology to create a detailed, high-quality, high-resolution image of the placental vasculature in healthy MoDi and MoMo twins without TTTS. The Verasonics device is exempt from requiring a 510(k) or IDE due to its low-risk classification but is an FDA-regulated device subject to general controls.

Quality, resolution, detail, and other comparisons of the Verasonics uPDI images with those of a standard-of-care Phillips ultrasound machine used for routine prenatal care at Carilion Clinic will also occur.

Results of this study may support a future interventional, randomized clinical trial to determine whether the Verasonics Vantage 256 uPDI platform and uPDI technology in general, may offer superior visualization of placental vasculature and anastomoses during minimally invasive laser photocoagulation procedures in monochorionic twins requiring treatment for TTTS, as well as whether this improved visualization may benefit detection, diagnosis, and treatment of TTTS.

Procedure:

Prescreening: Potential participants within the Carilion Clinic Maternal Fetal Medicine and other Carilion OBGYN schedules will be prescreened by IRB-approved, study team members for eligibility.

Informed Consent Discussion: If a patient viewed during prescreening appears to meet study eligibility criteria, the treating physician will be approached by a study team member(s) during or prior to the potential participant's routine Carilion appointment. The physician, if they agree that the patient may be a good candidate for the study procedure, will approach the patient to ask whether they would be willing to speak to the research team member about a research study. If the potential participant verbally agrees, the study team member will then take the potential participant to a private place for them to share the informed consent form and conduct the informed consent discussion.

Ultrasound Procedure: Enrolled participants will have a single research ultrasound of their placenta performed. This research ultrasound will occur immediately after or during their routine-care appointment. There will not be separate research visits for this study though some participants may choose to sign the informed consent form during one appointment date/time and have the research ultrasound scan performed at a different appointment date/time, due to their scheduling needs.

The participant will be taken to a designated ultrasound exam room within the Maternal Fetal Medicine suite with a certified ultrasonographer who has also been trained to operate the research ultrasound machine, a Verasonics Vantage 256, per manufacturer and PI instructions. The participant will lay on an exam bench and be appropriately draped, then have warmed ultrasound coupling gel applied to their abdomen. An ultrasound transducer will then be applied to the participant's abdomen and multiple images of the placenta [from different angles/lateralities] will be taken. After all desired images are captured, a clean washcloth will be used to wipe the ultrasound coupling gel off the participant's abdomen. The research ultrasound exam will take approximately 10-15 minutes.

Results: Participants are not expected to be contacted following the single research ultrasound visit, except by phone or in-person at a future Carilion appointment, should the research scan identify incidental findings pertinent to the participant's health or safety, as well as the health and safety of the fetus. Participants may also express during this meeting that they'd like their OBGYN or another provider informed about the findings; this oral request will be documented in their Carilion medical record. Except where pertinent incidental findings are discovered, individual results of the placental scans will not be given to participants, though they may be summarized across all participants and presented at academic conferences, in medical journals, or through other appropriate professional mediums.

The Device: The Verasonics Vantage 256 research ultrasound machine will utilize uPDI imaging techniques applied to the placenta to evaluate health of the placenta and blood flow visualized by the colored Doppler imaging. This device is not FDA approved and is considered experimental. uPDI utilizes an ultra-high frame rate and clutter filtering to increase the Doppler imaging sensitivity. Traditional Doppler ultrasound displays color onto the normally greyscale ultrasound where blood flow is seen by the machine. However, traditional ultrasound with Doppler has difficulty in detecting blood flow within smaller vessels, such as the smallest spiral arteries of the placenta which provide nutrition to both the placenta and fetus. It is therefore believed uPDI can better visualize these and other small areas of blood flow or pooled blood within the placenta, providing the sonographer with improved indications of placental tissue perfusion, health, as well as allowing vascular mapping of the placenta. In the future, this technology may be useful for better and more precisely guiding minimally invasive procedures to separate blood flow that is pathologically anastomosed [joined] in multiple pregnancy patients with twin-twin transfusion syndrome (TTTS). This study hopes to demonstrate the feasibility of mapping the placental vasculature in monochorionic, diamniotic or monoamniotic, healthy twins, not diagnosed with TTTS.

Routine-care images from an FDA-approved, standard-of-care Phillips ultrasound machine may also be used for research, allowing comparison of the two devices' resolutions, sensitivity to fine vasculature, ability to visualize the placental cotyledonary vascular, etc. 'Color Doppler' mode may be turned on for one additional scan with this machine, which will take under 1 minute to collect and will be performed immediately after the routine-care scans. This is a standard-of-care mode used clinically for many indications. Additional data collection into a research electronic database will occur from information in the medical record that was originally obtained for routine care of participants.

Inclusion criteria

• Subject is 18 to 45 years of age at screening
• Non-anomalous, monochorionic, diamniotic (MoDi) or monochorionic, monoamniotic (MoMo) twin gestation without suspected genetic disorders
• Low-risk aneuploidy screening, if performed
• Intention to deliver at Carilion Roanoke Memorial Hospital (CRMH) or Carilion New River Valley Medical Center (CNRVMC)
• Anatomical survey has been performed
• 18 - 26 weeks gestational age

• Subject willing and able to provide/re-provide informed consent

Exclusion criteria

• Suspected fetal genetic disorder(s)
• Suspected fetal infection(s), twin-twin transfusion syndrome (TTTS), twin reversed arterial perfusion sequence (TRAPS), or maternal vascular disease
• Non-English reading and speaking
• Unstable housing or transportation
• Any other criterion which, in the clinical judgement of the investigator, would make the subject unsuitable for study enrollment