Follow-Up after feToscopic sURgical intErventions: the FUTURE study

An increasing number of fetal diseases are being detected prior to birth and
some of them are amenable to fetal therapy1. Fetoscopic laser coagulation of
placental vascular anastomoses is nowadays widely accepted as the first-line
treatment for Twin to Twin Transfusion Syndrome (TTTS)2-6, while intrauterine
blood transfusion (IUT) is considered the mainstay of antenatal treatment for
Rhesus Hemolytic Disease (RHD)7;8. In addition, in-utero pulmonary drainage is
increasingly being advocated as the preferred treatment in hydropic fetuses
with primary hydrothoraces or congenital lung disease, such as congenital
cystic adenomatoid malformations (CCAM) 9;10.
Recent advances in fetal therapy, in particular endoscopic surgical
interventions, have led to a striking increase in fetal survival rate1;2;11. In
TTTS, overall perinatal survival rate with fetoscopic laser surgery is now
almost 80%, compared to 0-27% without intervention2. In RHD, a similar increase
in perinatal survival is reported after IUT treatment. Survival is almost 95%
in specialized centers, even in hydropic fetuses7. In fetuses with isolated
hydrothorax or congenital lung disease, treatment with thoraco-amniotic shunts
and thoracocentesis has led to an increase in perinatal survival from less than
10% to almost 65%9;10.
Most fetal interventions have become implemented without accurate and
systematic methodological evaluation. As with any therapeutic intervention, the
golden standard should be based on randomized controlled trials (RCT). To date,
only a handful of RCTs have been performed in vention3;12-14. We recently
initiated a multicenter RCT in TTTS, the Solomon study, to determine if a new
laser technique (the Solomon technique) is associated with a lower rate of
perinatal mortality and morbidity compared to the classic selective laser
technique.
The advancing techniques and corresponding survival rates necessitate a greater
knowledge on the impact of these interventions on long-term child development.
However, long-term follow-up after fetal therapy is scarce and based on a few
small studies15-20. Alongside perinatal survival rates, clinicians and, in
particular, parents are interested in the future quality of life of the child.
Is the child at risk for increased cognitive or behavioral problems? Will the
child be able to go to a regular school or will it need special assistance? How
will the child develop in terms of health related quality of life compared to a
*normal* peer or to children with a chronic condition like diabetes? Does
raising a child, following the stressful events during pregnancy and in light
of the yet unknown long-term outcome, entail additional parenting stress?
An increasing number of fetal diseases are being detected prior to birth of
which some are amenable to fetal surgical intervention1. Although the advances
in fetal surgery, in particular endoscopic surgical interventions, have led to
a striking increase in fetal survival rate, knowledge on long-term outcome is
scarce. To establish optimal fetal management and improve the quality of
antenatal parental counseling, a greater understanding of the impact of these
early interventions on child development is indispensable.
Recently, several reports of severe Retinopathy of Prematurity (ROP) in
monozygotic twins with TTTS have emerged, suggesting TTTS might contribute to
the development of ROP. ROP is defined as abnormal vessel growth in the
developing retina and is a potentially blinding disease in premature infants.
Major risk factors associated with the development of ROP are low gestational
age at birth, in particular less than 32 weeks, and birth weight of less than
1500 g. Many other risk factors have been reported such as excessive oxygen
use, long duration of artificial ventilation, postnatal cardiovascular and
inflammatory disease and multiple blood transfusions.

Both RCTs and long-term follow-up studies are required to establish optimal
fetal management and provide clinicians a better understanding of the impact of
these early interventions on child development in order to improve the quality
of antenatal parental counseling. The aim of the current project is: to
determine the incidence of developmental problems and neurodevelopmental
impairment (NDI), to examine risk factors for impairment and to assess Health
Related Quality of Life (HRQoL) as well as parenting stress levels after fetal
therapy.
Furthermore, the effect of TTTS and its treatment consisting of fetoscopic
laser surgery on the development of ROP in premature born infants < 32 weeks
will be evaluated retrospectively.

The design of the FUTURE study is divided into three parts, according to
methodology and subgroups.

Part 1: Solomon Randomized Controlled Trial Follow-up of all long-term
survivors from monochorionic (MC) twin pregnancies with TTTS included in the
Solomon RCT comparing two laser surgery techniques for the treatment of TTTS.

Part 2: Observational cohort study in 4 small study groups Follow-up of all
long-term survivors in the following 4 subgroups: Twin Anemia Polycythemia
Sequence (TAPS), Monochorionic Monoamniotic twin pregnancies (MCMA twins),
Primary Hydrothoraces/ Congenital Lung Disease and Lower Urinary Tract
Obstruction (LUTO).

Part 3: Observational cohort study with case-control design Follow-up of all
long-term survivors in the following 3 subgroups: Selective Feticide in MC
twins, selective Intra Uterine Growth Retardation (sIUGR) and Fetal/Neonatal
Alloimmune Thrombocytopenia (FNAIT). To validate outcomes against controls,
parents of children delivered consecutively in the LUMC between 2000 and 2011
will be contacted, at random, and asked for their participation.

Participants will be invited to the LUMC for: formal psychological testing of
cognitive development, a physical and neurological examination, an assessment
of developmental problems and a brief behavioral screening and questionnaires
on Health Related Quality of Life, parenting stress and ROP-status.
Participation does not result in any direct benefit.