INeS Follow-up;Medically assisted reproduction techniques: do they influence the offspring*s growth, health and neurodevelopment?
Follow-up of a randomized controlled trial

Subfertility, defined as the inability to conceive a child after 12 months of
unprotected intercourse, affects millions of couples worldwide. Since the birth
of the first test-tube baby in 1978, millions of these couples have been aided
to conceive a child with medically assisted reproduction (MAR), such as
ovulation induction, ovarian stimulation, intrauterine insemination (IUI), in
vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI).

On the short term, Children conceived by MAR are more often born with low birth
weight (<2,500g) or pre-term (<27 weeks* gestation). IVF pregnancies have been
associated with a higher risk of complications and adverse perinatal outcomes.
For example, the risk of major congenital malformations was slightly higher
with ICSI versus general populations [7]. A difference of 200g in birth weight
was found between two commonly used culture media for IVF treatment. A similar
difference in birth weight is seen between smoking and non-smoking pregnancies.
In a Dutch cohort study, offspring birth weight and gestational age were lower
after hormone stimulation [10]. Also MAR singletons seem to have a longer
length of stay during the birth-admission.

On the longer term, parameters as BMI, cancer risk, respiratory disorders,
cognitive functioning and motor development seems to be similar in MAR and
naturally conceived children. However, there are indications that IVF-conceived
children have higher peripheral fat, higher growth velocity in early life,
higher blood pressure and higher fasting glucose concentrations than naturally
conceived children.

MAR techniques correspond on the fact that they impose a drastically different
environment on the earliest development of the embryo from in vivo. The altered
early environment common to all types of MAR conception may result in changes
in organ growth, endocrine function, physiology and metabolism leaving the
developing embryo at greater risk of poor perinatal outcome, and poorer health
in later life.

To date, studies to assess the health risks of MAR-conceived children have
remained inconsistent, especially regarding the long-term outcomes.
Furthermore, MAR consists of a multifaceted approach, which may involve hormone
stimulation (with different regimens), mechanical damage to the oocyte during
retrieval, differential circumstances in embryo culture media, and duration of
embryo culture, each of which may be contributors to offspring outcomes. On the
other hand, previous studies have also been challenged by the fact that poor
offspring outcomes may be the result of non-procedure-related factors,
including parental health, factors underlying the subfertility, age, smoking,
BMI, chromosomal disorders, pregnancy complications, or a combination of these.

By following up children born after parents with a uniform diagnosis of
unexplained or mild male factor infertility were randomized to fertility
treatment with IUI-COH, IVF-SET or IVF-MNC, the present study aims to
disentangle the contribution of each of these aspects of MAR on outcomes in
childhood.

The INeS Follow-up study will study the effect of type of MAR on offspring*s
health. More specifically, which features of assisted conception (IVF-MNC,
IVF-SET and IUI-COH) or natural conception affect child*s general health,
growth, body composition, cardiometabolic health, development and behavior.

Prospective long term follow-up cohort study of children born to participants
in a multicenter RCT (INeS-study).

Participants will be contacted three times for measurements. Parents will be
asked to fill out age apropriate questionnaires concerning demographics, growth
trajectory, general health, development and behavior (CBCL and BRIEF) of their
child. Filling out the questionnaires will take approximately one hour. During
the second stage two members of the research staff will visit participants
close to their homes in a mobile research vehicle. In this vehicle a set of
non-invasive measures, such as anthropometry and blood pressure, will be
obtained. This visit will take between one and one and a half hours. A
specialized nurse will perform a blood-draw in a separate visit at the
participant*s home. The blood-draw is optional and parents give explicit
consent. This will be done in the morning after an overnight fast. This visit
will approximately take 15 minutes. Children will be measured when they are
between 4-6 years old.