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Health of children conceived after preimplantation genetic diagnosis: A preliminary outcome study

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Health of children conceived after preimplantation genetic diagnosis: A preliminary outcome study

Abstract

A preliminary study was conducted on health of children conceived after preimplantation genetic screening and diagnosis (PGD). Forty-nine children were assessed with 66 matched naturally conceived (NC) controls. Primary outcome was neurodevelopmental screening, and secondary outcomes were evidence of other health problems and assessment of parent-child relationships. Study and control children were well matched across relevant socio-demographic variables. Growth parameters at mean age 18 months were normal. The mean Griffiths quotient was 102.7 (+/-13.1) (PGD) and 103.3 (+/-12.8) (NC), both of which were within the normal range, and did not differ significantly. PGD cases were more likely to be lighter, at <2500 g (12 children, 24.5% versus one child 1.5%, P < 0.0001) and born earlier than controls (38.2 +/- 2.6 versus 40.0 +/- 1.4 weeks; P < 0.0001), consistent with other similar studies. PGD families showed no evidence of excess stress in their relationship with their child. The PGD group had significantly higher scores on the warmth-affection sub-scale (P = 0.042), and significantly lower scores on the aggression-hostility and rejection sub-scales (P = 0.030) of the questionnaire. The study showed no major ill effects from PGD on the child health. A larger study is needed to confirm the validity of this conclusion.
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Dr Alastair Sutcliffe is a paediatrician who has conducted a series of studies from 1993
looking at the health of children born after interventions in early life. These include the
first on embryo cryopreservation outcome and twin–twin transfusion syndrome. He has
collaborated with researchers in Belgium, Denmark, Sweden, Greece, Australia and Germany
on ICSI outcome studies and is presently working on a study of oocyte cryopreservation
outcome with Italian collaborators. He is author of over 40 papers and two books. His work
has resulted in the ESHRE established clinician award (1999) and the Donald Patterson
prize (2003) from the Royal College of Paediatrics.
Dr Alastair Sutcliffe
I Banerjee1, M Shevlin2, M Taranissi3, A Thornhill4, H Abdalla5, O Ozturk6, J Barnes7, A Sutcliffe1,8
1Adolescent and General Paediatric Unit, Institute of Child Health, University College London, 250 Euston Road, 6th
Floor, London NW1 2PQ; 2Psychology Research Institute, School of Psychology, University of Ulster, Northland Road,
Londonderry, Co. Londonderry, BT48 7JL; 313 Upper Wimpole Street, London W1G 6LP; 4The London Bridge Fertility,
Gynaecology and Genetics Centre, 1 St Thomas Street, London SE1 9RY; 5Lister Fertility Clinic, Lister Hospital,
Chelsea Bridge Road, London SW1W 8RH; 6The Assisted Conception Unit, University College Hospital, The New
Wing, Eastman Dental Hospital, 256 Gray’s Inn Road, London WC1X 8LD; 7Institute for the Study of Children, Families
and Social Issues, Birkbeck, University of London, 7 Bedford Square, London WC1B 3RA, UK
8Correspondence: e-mail: a.sutcliffe@medsch.ucl.ac.uk
Abstract
A preliminary study was conducted on health of children conceived after preimplantation genetic screening and diagnosis
(PGD). Forty-nine children were assessed with 66 matched naturally conceived (NC) controls. Primary outcome was neuro-
developmental screening, and secondary outcomes were evidence of other health problems and assessment of parent–child
relationships. Study and control children were well matched across relevant socio-demographic variables. Growth parameters
at mean age 18 months were normal. The mean Grifths quotient was 102.7 (±13.1) (PGD) and 103.3 (±12.8) (NC), both of
which were within the normal range, and did not differ signicantly. PGD cases were more likely to be lighter, at <2500 g
(12 children, 24.5% versus one child 1.5%, P < 0.0001) and born earlier than controls (38.2 ± 2.6 versus 40.0 ± 1.4 weeks; P
< 0.0001), consistent with other similar studies. PGD families showed no evidence of excess stress in their relationship with
their child. The PGD group had signicantly higher scores on the warmth–affection sub-scale (P = 0.042), and signicantly
lower scores on the aggression–hostility and rejection sub-scales (P = 0.030) of the questionnaire. The study showed no major
ill effects from PGD on the child health. A larger study is needed to conrm the validity of this conclusion.
Keywords: children, health, neurodevelopmental, outcome, preimplantation genetic diagnosis; preimplantation genetic screening
The use of preimplantation genetic diagnosis (PGD) is
rapidly expanding as a diagnostic technique (Sermon et al.,
2007). As it involves in vitro fertiIisation (IVF) and usually
intracytoplasmic sperm injection (ICSI), the health of children
born after PGD is proposed to have similarities to those born
following conventional IVF and ICSI therapy. Indeed, this is
borne out by the limited literature on paediatric outcome, almost
entirely (uncontrolled) birth data from the European Society for
Human Reproduction and Embryology (ESHRE) consortium
(Sermon et al., 2007). A number of outcome studies (Sutcliffe
et al., 1995, 2001) have looked at possible treatment effects
of various types of assisted reproductive therapies and these
have been reviewed recently (Ludwig et al., 2006). However,
the data were limited regarding the potential risks of PGD. In
view of the paucity of data (Baruch et al., 2005) surrounding
any additional risk associated with PGD, this preliminary study
Article
Health of children conceived after
preimplantation genetic diagnosis: a
preliminary outcome study
Introduction
was conducted. Predictions were: that PGD children in this
study would be similar in overall health to IVF children (i.e.
more likely to be premature and lighter birth weight compared
with matched naturally conceived children); that PGD children
would have no other signicant health risks, including being
neurodevelopmentally normal; and that there was evidence of
stress in the parentchild relationships (Barnes et al., 2004) due
to the PGD and associated processes. The latter prediction is
particularly in the context of the extra putative stress of PGD
per se in couples who had either a previously conceived ill
child or difculties with standard IVF conception (Sutcliffe and
Ludwig, 2007).
Materials and methods
A population controlled, cross-sectional, study was conducted.
Centres with established PGD programmes in London were
contacted for agreement to participate. Of these ve centres,
four agreed to help recruit patients. The fth had an already
established (uncontrolled) nurse follow-up assessment ongoing
but unreported. Ethical approval was given by the Joint
University College London (UCL)/UCL Hospital Committees
on the Ethics of Human Research (Committee A).
The parents were contacted rst by their PGD clinic to preserve
condentiality, and asked to write to the researchers indicating
willingness to participate. Children who were aged up to 4
years and their parents were assessed by a single observer (IB)
blinded to their conception status in a child friendly outpatient
setting. The main outcome measure was neurodevelopmental
status, and thus children who would qualify for assessment
using the Grifths Scales of Mental Development (08 years)
(Grifths, 1996) were approached.
Naturally conceived children were recruited from local
nurseries for the control group. The London-based Multiple
Birth Foundation was approached for recruitment of twin
controls. Children who had emigrated, who were born at less
than 32 weeks gestation, or whose mother tongue was not
English were not approached. Control children were matched
for age, sex, multiplicity, ethnicity, maternal educational level
and socioeconomic status.
Primary outcome measure was neurodevelopmental scoring
and the secondary outcome measures were family functioning,
and any (initial) evidence of growth problems or other physical
abnormalities.
All children were assessed in accordance with an identical
protocol that included medical history, physical examination
and psychometric scoring using the Grifths Scales of Mental
Development. Family Functioning/Child Socio-emotional
development was assessed using the maternal General Health
Questionnaire (Goldberg and Hillier, 1979) for maternal mental
health status, the Toddler Temperament Scales (Carey, 2005) for
child behaviour, Parental Acceptance Rejection Questionnaire
(Rohner and Khaleque, 2005) and Parenting Stress Index
(short form) (Abidin, 1990) for parental attitudes to the child.
Parental information included age, social class, and educational
attainment. Social class was determined based on occupation
and grouped as being Class IV or below, or III M or above.
Educational attainment was based on highest educational
qualication achieved and grouped as school matriculation or
less, and degree level or higher.
Blinding was achieved by a separate researcher approaching
families for recruitment. The informed consent process also
involved forewarning families not to reveal their conception
status to the paediatrician. Analyses were also performed (by
M.S.) blind to the conception status.
Statistical analyses were conducted using Statistics Package
for Social Sciences (SPSS) for Windows 15.0. Between-group
differences on continuous variables were analysed using t-tests,
and means and standard deviations are reported. Chi-squared
tests were used for categorical variables, and frequencies and
percentages are reported. Where continuous variables were
expected to be highly related, such as separate subscales,
multivariate analysis of variance (MANOVA) was used and
the between-groups effects were reported. MANOVA was used
to for the analysis of the subscales of the Grifths Scale, the
Parenting Stress Index, the Parental Acceptance–Rejection
Questionnaire, and the Toddler Temperament Questionnaire.
Results
A total of 49 children was recruited (70% participation rate,
four pairs of twins and 41 singletons) who had been born after
embryo biopsy at the 8–10-cell stage. Thirty-nine children were
born after PGD for aneuploidy screening (preimplantation
genetic screening; PGS) and 10 children for known genetic
disorders in their families. Of these 10 families, four had
chromosomal translocation, three had Down syndrome occur
in a previous pregnancy and three had a family history of
myotonic dystrophy. In addition, 66 control children were
assessed (four pairs of twins and 58 singletons). There was no
signicant difference between the study and control groups in
terms of infant age at evaluation (mean PGD = 18.4 months,
mean control = 18.3 months) and the age of evaluation ranged
from 3 to 56 months.
For ethical reasons, it was not possible to determine the
participation rate in the control group. Controls were recruited
on an opt-in basis after matching, and it was not permitted to ask
reasons for non-participation. Nevertheless, close matching was
achieved for factors relevant to neuro-developmental outcome
(Table 1). The PGD mothers were signicantly older than the
natural conception group (P = 0.0001). This is not surprising in
view of the history of infertility in these women who underwent
PGD for aneuploidy screening (PGS).
Variables of pregnancy and birth in the PGD and natural
conception babies are presented in Table 2. The PGD group had
a signicantly lower gestational age at birth (38.2 ± 2.6 versus
40.0 ± 1.4 weeks; P = 0.0001), more preterm births (<37 weeks;
14.3 versus 1.5%; P = 0.009), lower birth weight (3122 ± 905
versus 3440 ± 453 g; P = 0.030), and higher number of births
with a birth weight <2500 g (24.5 versus 1.5%; P = 0.0001).
Two children born after PGS had congenital anomalies, one with
mild hypospadias and another with a minor ear deformity. Both
of these children would be classied as having major anomalies
according to denitions used in previous studies (Bonduelle et
al., 2005). In this study, a major malformation was dened as one
in which surgery or ongoing medical monitoring was needed.
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Growth parameters were within the normal range assessed at
a mean age of 18 months (Table 3). An overview of previous
growth patterns in the parent-held child health records by the
single (blinded) observer showed no evidence of ‘catch up
growth’ or other abnormal growth patterns.
The Grifths Scale was used for the assessment of all children.
The mean Grifths quotient was 102.7 (±13.1) for the PGD
group and 103.3 (±12.8) for the naturally conceived group,
which were both in the normal range, and did not differ
signicantly (Table 4). The only signicant differences were
for the Locomotor (PGD signicantly lower; 101.0 ± 14.2
versus 111.4 ± 14.4; P = 0.0001) and Hearing and Language
subscale (PGD signicantly higher; 106.4 ± 15.1 versus 99.9 ±
6.5; P = 0.030).
No signicant differences were found on the three Parental
Stress Index subscales (Table 5).
Differences in the parentchild relationship were assessed by
means of Parental AcceptanceRejection Questionnaire (Table
6). The PGD group had a signicantly higher scores on the
warmth–affection sub-scale (27.5 ± 7.9 versus 25.1 ± 4.3; P
= 0.042), and signicantly lower scores on the aggression–
hostility (19.5 ± 5.2 versus 21.8 ± 5.8; P = 0.030) and rejection
sub-scales (11.4 ± 2.8 versus 13.3 ± 3.7; P = 0.005) than the
control group.
Differences between child temperaments were assessed by
means of the Toddler Temperament Scales. All tests of group
differences were non-signicant (Table 7).
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Table 1. Social class and educational attainment of the parents of children
conceived after preimplantation genetic diagnosis (PGD) and those
conceived naturally.
PGD (n = 49) Natural
conception
(n = 66)
Mother
Agea 40.4 ± 3.7 35.4 ± 4.3
Social class IV or lower (%) 0 (0) 3 (4.5)
Education: school matriculation or less (%) 9 (18.0) 8 (12.1)
GHQ total 3.0 ± 4.1 3.34 ± 4.5
Father
Age 41.3 ± 5.4 38.5 ± 10.0
Social class IV or lower (%) 0 (0) 3 (4.6)
Education: school matriculation or less (%) 8 (16.3) 9 (13.6)
Values are mean ± SD or number (%).
GHQ = general health questionnaire. For denitions of social class and education see Materials
and methods.
aAge at 1st January 2007 was signicantly higher in the PGD group (P = 0.0001).
Table 2. Pregnancy and birth information of babies conceived after
preimplantation genetic diagnosis (PGD) or conceived naturally.
Babies PGD (n = 49) Natural P-value
conception
(n = 66)
Boys (%) 28 (57.1) 32 (48.5) NS
Gestational age (weeks) 38.2 ± 2.6 40.0 ± 1.4 0.0001
Gestation <37 weeks (%) 7 (14.3) 1 (1.5) 0.009
Birth weight (g) 3122 ± 915 3440 ± 453 0.030
Birth weight <2500 g (%) 12 (24.5) 1 (1.5) 0.0001
Needed resuscitation (%) 4 (8.2) 6 (9.1) NS
Neonatal unit admission (%) 8 (16.3) 7 (10.6) NS
Values are mean ± SD or number (%). NS = not statistically signicant.
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Table 3. Physical development of children conceived after
preimplantation genetic diagnosis (PGD) or conceived
naturally at time of evaluation.
PGD Natural
conception
Height (cm) 77.5 ± 17.1 81.1 ± 6.8
Weight (kg) 11.3 ± 3.3 11.8 ± 2.0
Head circumference (cm) 47.8 ± 6.4 47.8 ± 2.1
Values are mean ± SD. There were no statistically signicant differences between
the two groups.
Table 4. Group differences on the overall and subscale scores on the Grifths
Mental Development Scales for children conceived after preimplantation genetic
diagnosis (PGD) or conceived naturally.
PGD mean Natural conception P-value
score mean score
Locomotor subscale 101.0 ± 14.2 111.4 ± 14.4 0.0001
Personal social subscale 100.3 ± 18.9 103.7 ± 16.6 NS
Hearing language subscale 106.4 ± 15.1 99.9 ± 6.5 0.03
Eye–hand subscale 100.7 ± 15.5 102.6 ± 16.3 NS
Performance subscale 104.0 ± 16.5 100.8 ± 19.7 NS
Grifths General quotient 102.7 ± 13.1 103.3 ± 12.8 NS
Values are mean ± SD. NS = not statistically signicant.
Table 5. Group differences on the overall and subscale scores on the
Parenting Stress Index for parents of children conceived after preimplantation
genetic diagnosis (PGD) or conceived naturally.
PGD mean Natural
± SD score conception
mean ± SD score
Parental distress 23.7 ± 7.2 25.0 ± 7.8
Parent–child dysfunctional interaction 16.0 ± 3.7 15.9 ± 5.1
Difcult child 20.7 ± 5.6 22.3 ± 6.4
Total score 60.4 ± 13.4 62.4 ± 16.4
There were no statistically signicant differences between the two groups.
Article -
Health of children conceived after PGD - I Banerjee et al.
Discussion
This preliminary study is the rst detailed study published on
children born beyond their newborn period following PGD, and
provides provisional reassurance that these children do not have
any overt problems over and above those known to be a risk
from conception through assisted reproduction. The blinding of
the paediatrician was a strength of the study.
This preliminary study showed that its methodology is
potentially viable to assess a larger group of children. Although
the study was not adequately powered for denite conclusions,
it was nevertheless reassuring that there was no evidence in
these children of major health concerns, effects on the mother–
child relationship or neurodevelopment scoring following
PGD. Indeed, these ndings were contrary to one of the initial
hypotheses, but consistent with an earlier major European
study, which showed that assisted reproduction families had
higher levels of warmth and lower levels of hostility towards
their children (Barnes et al., 2004). Thus, so far contrary to
expectations, parents seem to cope with the extra stresses of
PGD without evidence of ill effects on these relationships.
The PGD children were more likely to be premature and of
lower birth weight, consistent with other studies of assisted
reproduction outcome (Ludwig et al., 2006; Sutcliffe and
Ludwig, 2007). It could be argued that PGD is closer to natural
conception, in the context of the reproductive health of the
parents; however, the majority of the present cases were from
PGS (39/49), in which parents bear closer risk/resemblance to
other assisted reproduction conceiving couples. Thus, the lower
birth weight in the PGD/PGS group was unsurprising. However,
they were growing well with no major health concerns at mean
age of 18 months. Notably, growth parameters that are a good
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Table 6. Group differences on the overall and subscale scores on the Parental
Acceptance Rejection Questionnaire (PARQ) where children were conceived
after preimplantation genetic diagnosis (PGD) or conceived naturally.
PGD mean Natural P-value
± SD score conception
mean ± SD score
PARQ warmth–affection 27.5 ± 7.9 25.1 ± 4.3 0.042
PARQ aggression–hostility 19.5 ± 5.2 21.8 ± 5.8 0.03
PARQ neglect–indifference 17.7 ± 4.1 18.8 ± 4.0 NS
PARQ rejection 11.4 ± 2.8 13.3 ± 3.7 0.005
NS = not statistically signicant.
Table 7. Group differences on the overall and subscale
scores on the Toddler Temperament Questionnaire for
children conceived after preimplantation genetic
diagnosis (PGD) or conceived naturally.
PGD mean Natural
± SD score conception
mean ± SD score
Activity 4.0 ± 0.7 4.0 ± 0.6
Rhythmicity 2.7 ± 0.8 2.6 ± 0.7
Approach 2.5 ± 0.9 2.8 ± 1.0
Adaptability 2.9 ± 0.8 3.0 ± 0.8
Intensity 3.7 ± 0.8 4.0 ± 0.7
Mood 2.7 ± 0.6 2.9 ± 0.7
Persistence 3.3 ± 1.0 3.4 ± 0.7
Distractibility 3.6 ± 1.2 3.8 ± 0.9
Threshold 3.7 ± 0.8 3.6 ± 0.8
There were no statistically signicant differences between the two groups.
‘bioassay of wellbeing’ were normal compared with control
children. Developmentally, children were doing well as assessed
by the Grifths scales (Grifths, 1996). The analyses did not
distinguish between PGD for known genetic problems and
PGD for aneuploidy screening (PGS), due to the small sample
size. A larger study with adequate power for sub-group analysis
will be a worthwhile enquiry. Another renement, although
problematic from a control recruitment perspective, would be
to match for maternal age in the larger proposed study.
It is worth noting that families who participated in this
preliminary study expressed gratitude and were grateful that
their child had been formally assessed, indicating an unfullled
medical need that is likely to provide an acceptable participation
rate for larger studies, which is always a challenge in research
of this nature.
In conclusion, this study demonstrated preliminary evidence
that PGD children under 4 years of age born at four London
centres have health and development that is comparable
with naturally conceived control children. Families had no
identiable difculties, and if anything enjoyed warmer
parentchild relationships. A larger study is now planned.
Acknowledgements
We would like to thank participating families and also the
Multiple Birth Foundation. We would like to thank Professor
Gedis Grudzinskas and Professor Alan Handyside at the Bridge
Fertility Centre and Mary Power at the Lister Hospital. We also
thank Dr Richard Tozer, Dr Katya Johnson and Audrey Soo,
who helped with recruitment.
Declaration
This study was funded by intramural funds with no explicit
external sponsor. There are no nancial or commercial conicts
of interests related to any authors of the paper.
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... The need for a cell biopsy and the effect of this biopsy on the (mental) health and cognitive development of the children has also been a point of concern ever since PGD treatment was instigated (Banerjee et al., 2008;Desmyttere et al., 2009;Liebaers et al., 2010). To date, studies focusing on children born after ART have mostly included children born after IVF and/or ICSI. ...
... To date, only a few systematic studies have assessed the cognitive and socio-emotional development of children born after PGD. Internationally, data from five PGD cohorts have been published (Banerjee et al., 2008;Nekkebroeck et al., 2008aNekkebroeck et al., , 2008bNekkebroeck et al., , 2011Thomaidis et al., 2012;Sacks et al., 2015;Winter et al., 2014Winter et al., , 2015. ...
... With regards to the constitution of the PGD group, only Winter et al. (2014Winter et al. ( , 2015, Thomaidis et al. (2012) and Sacks et al. (2015) focused solely on PGD and compared them with either an ICSI and/or NC control group, though this latter control group consisted of families without a known genetic disorder, or they did not include a control group at all. The other studies included children born after PGD as well those born after PGS (Banerjee et al., 2008;Nekkebroeck et al., 2008a;2008b, or PGS solely (Middelburg et al., 2011;Schendelaar et al., 2013). A cell biopsy is required for both PGD and PGS, however, the indications differ; PGS is a form of aneuploidy screening used to optimize pregnancy rates after IVF treatment, whereas PGD is a diagnostic test for couples with an increased risk of offspring with a genetic disorder. ...
Article
Study question: Does PGD increase the risk on adverse cognitive and socio-emotional development? Summary answer: The cognitive and socio-emotional development in children born after PGD seems to be normal when compared to control groups. What is known already: A limited number of studies with small sample sizes indicate that the cognitive and socio-emotional development of (pre)school-aged children born after either PGD or PGS seem to be comparable to those of children born after IVF/ICSI and to naturally conceived (NC) children from the general population. Study design, size, duration: For this study we invited 72 5-year-old PGD children, 128 5-year-old IVF/ICSI children and 108 5-year-old NC children from families with a genetic disorder. All children were invited between January 2014 and July 2016. Participants/materials, setting, methods: In total, 51 PGD children, 52 IVF/ICSI children and 35 NC children underwent neuropsychological testing (WPPSI-III-NL and AWMA). The children's parent(s) and teachers filled in questionnaires evaluating children's executive functioning (Behaviour Rating Inventory of Executive Functions; BRIEF) and socio-emotional development (Child Behaviour Checklist; CBCL and Caregiver-Teacher Report Form; C-TRF). Main results and the role of chance: The mean full-scale intelligence quotient scores (P = 0.426) and performance on the AWMA Listening Span task (P = 0.873) and Spatial Span task (P = 0.458) were comparable between the three groups. Regarding socio-emotional development, the teachers' scores revealed more externalizing (P = 0.011) and total problem (P = 0.019) behaviour in PGD children than for IVF/ICSI children; both groups did not differ significantly from the NC children (P = 0.11). More children (13%) with an affected first-degree family member (mostly parent) were included in the PGD group than in the NC group. Scores in all groups fell within the normal population range and should be considered normal. Limitations, reasons for caution: The number of NC children from families with a genetic disorder was relatively small. Furthermore, the fathers' CBCL results were based on small samples. Wider implications of the findings: PGD children show levels of cognitive and socio-emotional development at 5 years that are within the normal range, despite the biopsy involved in PGD and the potential extra psychological burden associated with the presence of a genetic disorder in the family. Study funding/competing interest(s): This study was funded by ZonMw (70-71300-98-106). None of the authors have any competing interests to declare. Trial registration number: NCT 02 149485.
... Some of these children were also studied at the age of 6 and compared with children born after ICSI (9). Banerjee et al. (10) reported on the health, height, and weight of 10 children born after PGD with a mean age of 18.4 months. Some studies on the neurological development of children born after PGD and PGS report an increased use of medical diagnostics in these children and question their psychomotor development when compared with children born after natural conception (NC) (8,(11)(12)(13)(14). ...
... Another study reported that lower birth weight and prematurity are more common in children born after PGD/PGS than in children born after NC (10). Both studies included more children born after PGS than after PGD (60% and 80% born after PGS, respectively) making it difficult to assess whether the biopsy or the intrinsic parental characteristics causes the lower weights. ...
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Objective: To evaluate the growth, health, and motor development of children born after preimplantation genetic diagnosis (PGD). Design: Observational cohort study and comparison of 5-year-old children born after PGD to similar aged children born after IVF/intracytoplasmic sperm injection (ICSI) and children from families with a genetic disorder born after natural conception (NC). Setting: University hospital. Patient(s): One hundred three children were included in the PGD group. The two control groups consisted of 90 children born after IVF/ICSI and 58 children born after NC. Intervention(s): PGD. Main outcome measure(s): We measured height, weight, body circumferences, body mass index, and blood pressure and performed a dysmorphological and neurological examination. We also collected data about the children's medical history, health care consultations, and motor milestones. Result(s): The mean height, weight, and body mass index were comparable for all groups. Six (5.8%) PGD, four (4.4%) IVF/ICSI, and five (8.6%) NC children had a major congenital abnormality. The incidence of acute and chronic illnesses was similar in all groups. Motor milestones were achieved on time, but the IVF/ICSI group had a slightly younger mean sitting age. None of the children had severe neurological problems. Conclusion(s): Five-year-old children born after PGD show normal growth, health, and motor development when compared with children born after IVF/ICSI and NC children from families with a genetic disorder. Trial registration number: NCT02149485.
... Follow-up research does not show a higher degree of major abnormalities in children born after PGT in comparison with IVF or ICSI only (Banerjee et al., 2008;Nekkebroeck et al., 2008;Desmyttere et al., 2009;Liebaers et al., 2009;Heijligers et al., 2018Heijligers et al., , 2019. Although children born following PGT-M and PGT-SR in combination with blastomere biopsy do have an increased risk of adverse obstetric and neonatal outcomes, these seem mainly related to underlying parental conditions, except for an increased risk of placenta previa (Bay et al., 2016). ...
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The field of reproductive medicine has been criticized for introducing ARTs without systematic research on possible safety risks and for failing to meet the standards of evidence-based innovation held elsewhere in medicine. In this paper, firstly, we ask whether 'responsible innovation' has been a concern for the field, and if so, how it has understood the practical implications of this idea for the development and introduction of potentially risky new ARTs. Secondly, we consider whether the field has indeed fallen short of its responsibilities in this respect, and if so, how things can be improved. To answer these questions, we present three case studies involving the introduction of a new reproductive technology: ICSI, preimplantation genetic testing and mitochondrial replacement therapy. As a framework for analyzing these cases, we used Per Sandin's account of the four dimensions of dealing with risks (threat, uncertainty, action, command) that are central to debates about the possible role of the so-called precautionary principle. We conclude that, although offspring safety concerns have been on the agenda of the debate about bringing the relevant technologies to the clinic, systematic safety and effectiveness studies were not always conducted. As professionals in assisted reproduction have a responsibility to take account of the welfare of the children they are creating, we suggest a policy of proceeding with systematic caution. Legal measures may be needed to ensure that professional guidance is followed in practice. Finally, an open question concerns the threshold for acceptable risk in the context of introducing new ARTs. Multiple stakeholders, including professional societies and patient organizations, should have a role in the urgent debate about this.
... Consequently, the safety of PGD is an issue that needs constant scrutinizing, the more since the number of pregnancies after PGD is increasing over the years [5]. Since the first PGD treatment was performed in the early 1990s [6], clinical studies on PGD pregnancies and children born after PGD did not report a higher rate of major congenital malformations when compared to IVF-ICSI children [7][8][9][10][11][12]. The results of these studies raise concerns about adverse perinatal and neonatal outcome, like prematurity rate, the incidence of low, and very low birth weight as well as the incidence of perinatal mortality. ...
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PurposeWe aim to evaluate the safety of PGD. We focus on the congenital malformation rate and additionally report on adverse perinatal outcome. Methods We collated data from a large group of singletons and multiples born after PGD between 1995 and 2014. Data on congenital malformation rates in live born children and terminated pregnancies, misdiagnosis rate, birth parameters, perinatal mortality, and hospital admissions were prospectively collected by questionnaires. ResultsFour hundred thirty-nine pregnancies in 381 women resulted in 364 live born children. Nine children (2.5%) had major malformations. This percentage is consistent with other PGD cohorts and comparable to the prevalence reported by the European Surveillance of Congenital Anomalies (EUROCAT). We reported one misdiagnosis resulting in a spontaneous abortion of a fetus with an unbalanced chromosome pattern. 20% of the children were born premature (< 37 weeks) and less than 15% had a low birth weight. The incidence of hospital admissions is in line with prematurity and low birth weight rate. One child from a twin, one child from a triplet, and one singleton died at 23, 32, and 37 weeks of gestation respectively. Conclusions We found no evidence that PGD treatment increases the risk on congenital malformations or adverse perinatal outcome. Trial registration numberNCT 2 149485
Article
BACKGROUND Preimplantation genetic testing (PGT) includes methods that allow embryos to be tested for severe inherited diseases or chromosomal abnormalities. In addition to IVF/ICSI and repeated freezing and thawing of the embryos, PGT requires a biopsy to obtain embryonic genetic material for analysis. However, the potential effects of PGT on obstetric and neonatal outcomes are currently uncertain. OBJECTIVE AND RATIONALE This study aimed to investigate whether pregnancies conceived after PGT were associated with a higher risk of adverse obstetric and neonatal outcomes compared with spontaneously conceived (SC) pregnancies or pregnancies conceived after IVF/ICSI. SEARCH METHODS PubMed, EMBASE, MEDLINE, Web of Science and The Cochrane Library entries from January 1990 to January 2021 were searched. The primary outcomes in this study were low birth weight (LBW) and congenital malformations (CMs), and the secondary outcomes included gestational age, preterm delivery (PTD), very preterm delivery (VPTD), birth weight (BW), very low birth weight (VLBW), neonatal intensive care unit (NICU) admission, hypertensive disorders of pregnancy (HDP), gestational diabetes, placenta previa and preterm premature rupture of membranes (PROM). We further pooled the results of PGT singleton pregnancies. Subgroup analyses included preimplantation genetic diagnosis (PGD), preimplantation genetic screening (PGS), cleavage-stage biopsy combined with fresh embryo transfer (CB-ET) and blastocyst biopsy combined with frozen-thawed embryo transfer (BB-FET). OUTCOMES This meta-analysis included 15 studies involving 3682 babies born from PGT pregnancies, 127 719 babies born from IVF/ICSI pregnancies and 915 222 babies born from SC pregnancies. The relative risk (RR) of LBW was higher in PGT pregnancies compared with SC pregnancies (RR = 3.95, 95% confidence interval [CI]: 2.32–6.72), but the risk of CMs was not different between the two groups. The pooled results for the risks of LBW and CMs were similar in PGT and IVF/ICSI pregnancies. The risks of PTD (RR = 3.12, 95% CI: 2.67–3.64) and HDP (RR = 3.12, 95% CI: 2.18–4.47) were significantly higher in PGT pregnancies compared with SC pregnancies. Lower gestational age (mean difference [MD] = −0.76 weeks, 95% CI −1.17 to −0.34) and BW (MD = −163.80 g, 95% CI: −299.35 to −28.24) were also noted for PGT pregnancies compared with SC pregnancies. Nevertheless, compared with IVF/ICSI pregnancies, the risks of VPTD and VLBW in PGT pregnancies were significantly decreased by 41% and 30%, respectively, although the risk of HDP was still significantly increased by 50% in PGT pregnancies compared with IVF/ICSI pregnancies. The combined results of obstetric and neonatal outcomes of PGT and IVF/ICSI singleton pregnancies were consistent with the overall results. Further subgroup analyses indicated that both PGD and PGS pregnancies were associated with a higher risk of PTD and a lower gestational age compared with SC pregnancies. WIDER IMPLICATIONS This meta-analysis showed that PGT pregnancies may be associated with increased risks of LBW, PTD and HDP compared with SC pregnancies. The overall obstetric and neonatal outcomes of PGT pregnancies are favourable compared with those of IVF/ICSI pregnancies, although PGT pregnancies were associated with a higher risk of HDP. However, because the number of studies that could be included was limited, more randomised controlled trials and prospective cohort studies are needed to confirm these conclusions.
Article
Research Question Despite the increasing use of Preimplantation Genetic Testing (PGT) for aneuploidy and monogenic diseases, for children conceived using PGT there is limited follow up beyond two years of age. We examined the health, wellbeing and development of school-aged children (aged 5-8 years old) conceived following PGT. Design Retrospective cohort study of children conceived after in-vitro fertilisation (IVF) with PGT (exposed cohort) and children conceived after IVF without PGT (unexposed cohort) at two IVF clinics in Melbourne, born between 2000 and 2008, recruited with a 1:2 ratio. Mothers of the children completed a questionnaire asking child-specific questions regarding health and wellbeing, mental health, development, educational achievement and family-specific questions regarding family functioning and parent-child attachment. Results We recruited 155 participants in the PGT cohort and 303 participants in the IVF-only cohort. There were no differences between the two cohorts with regards to maternal characteristics, birth defect frequency, and pregnancy characteristics, apart from delivery by caesarean section which was more frequent in PGT singletons (55%) compared to IVF-only singletons (36%). While no significant differences between the PGT and IVF-only cohorts were found for the majority of general health and psychological scales, there were differences when compared with population data. Children in the exposed cohort appeared to have more positive outcomes in many of the measures. Conclusion The data from this study suggest that PGT does not cause adverse outcomes in children. However, the nature (self-report) and small sample size of the study must be taken into consideration when interpreting the data.
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Chapter
The first PGD cycles were carried out in late 1989 in a series of couples at risk of X-linked disease and involved cleavage-stage embryo biopsy. Theoretically, PGD can be accomplished at any developmental stage between the mature oocyte and blastocyst, but to date, only three discrete stages have been proposed: polar body, cleavage-stage, and blastocyst. Clearly, each of these stages is biologically different, and thus, the strategic considerations have both advantages and disadvantages. However, cleavage-stage biopsy has remained the most widely practiced form of embryo biopsy worldwide according to the ESHRE PGD Consortium, accounting for approximately 90% of all reported PGD cycles to date. Currently, this embryo biopsy strategy requires the removal of one or more cells from each embryo, making it comparable to amniocentesis or CVS at fetal stages since the primary aim is the removal of sufficient embryonic tissue to allow diagnosis. Cleavage-stage embryo biopsy is a two-step micromanipulation process involving the penetration or removal of part of the zona pellucida surrounding the oocyte or embryo followed by removal of one or more cells. Many of the biopsy techniques currently in use for human embryos were pioneered in animal models, notably the mouse. While the total number of human embryos biopsied in clinical cases is vast, relatively little work has been published to define the relative merits of different biopsy methods and their safety and efficacy in clinical application. This chapter will focus on cleavage-stage embryo biopsy since the majority of PGD centers and clinical cases reported have employed this technique.
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Over a million children have been born from assisted conception worldwide. Newer techniques being introduced appear less and less 'natural', such as intracytoplasmic sperm injection (ICSI), but there is little information on these children beyond the neonatal period. 540 ICSI conceived 5-year-old children from five European countries were comprehensively assessed, along with 538 matched naturally conceived children and 437 children conceived with standard IVF. Of the 540 ICSI children examined, 63 (4.2%) had experienced a major congenital malformation. Compared with naturally conceived children, the odds of a major malformation were 2.77 (95% CI 1.41-5.46) for ICSI children and 1.80 (95% CI 0.85-3.81) for IVF children; these estimates were little affected by adjustment for socio-demographic factors. The higher rate observed in the ICSI group was due partially to an excess of malformations in the (boys') urogenital system. In addition, ICSI and IVF children were more likely than naturally conceived children to have had a significant childhood illness, to have had a surgical operation, to require medical therapy and to be admitted to hospital. A detailed physical examination revealed no further substantial differences between the groups, however. Singleton ICSI and IVF 5-year-olds are more likely to need health care resources than naturally conceived children. Assessment of singleton ICSI and IVF children at 5 years of age was generally reassuring, however, we found that ICSI children presented with more major congenital malformations and both ICSI and IVF children were more likely to need health care resources than naturally conceived children. Ongoing monitoring of these children is therefore required.
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The sixth report of the ESHRE PGD Consortium is presented, relating to cycles collected for the calendar year 2003 and follow-up of the pregnancies and babies born up to October 2004. Since the beginning of the data collections, there has been a steady rise in the number of cycles, pregnancies and babies reported. For this report, 50 centres participated, reporting on 2984 cycles, 501 pregnancies and 373 babies born. Five hundred and twenty-nine cycles were reported for chromosomal abnormalities, 516 cycles were reported for monogenic diseases, 137 cycles were reported for sexing for X-linked diseases, 1722 cycles were reported for preimplantation genetic screening (PGS) and 80 cycles were reported for social sexing. Data VI is compared to the cumulative data for data collections I–V.
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In-vitro fertilisation has been done for nearly 30 years; in developed countries at least 1% of births are from assisted reproductive therapies (ART). These children now represent a substantial proportion of the population but little is known about their health. Some of the morbidity associated with ART does not result from the techniques but from the underlying health risks of being subfertile. Much of the amplified risk associated with ART is related to high birth order. However, risk of intrauterine and subsequent perinatal complications is enhanced after ART, and urogenital malformations can be present in boys, even in singleton infants. No increase in discord or other difficulties within families has been recorded. Long-term follow-up of children born after ART to reproductive age and beyond is necessary.
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SYNOPSIS This study reports the factor structure of the symptoms comprising the General Health Questionnaire when it is completed in a primary care setting. A shorter, 28-item GHQ is proposed consisting of 4 subscales: somatic symptoms, anxiety and insomnia, social dysfunction and severe depression. Preliminary data concerning the validity of these scales are presented, and the performance of the whole 28-item questionnaire as a screening test is evaluated. The factor structure of the symptomatology is found to be very similar for 3 independent sets of data.
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Preimplantation genetic diagnosis (PGD), the genetic testing of embryos developed through IVF is one of the fastest growing techniques in reproductive medicine and IVF. Some suggest that PGD will become part of every IVF cycle in the future. The growing popularity of PGD has highlighted the fact that there are no comprehensive data available about the use of PGD, its accuracy, or the health outcomes of babies born following PGD. For patients, practitioners, and policymakers alike, such information is critical. To address the gaps in knowledge, a working group of the leading experts in the development and practice of PGD and IVF has begun to design a database to collect information about PGD as practised in the United States.
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Long-term follow-up studies on the health and the development of children conceived by assisted reproduction (ART) are mandatory to assess the safety of ART. Meanwhile, different aspects of health of these children have been studied. To put these results together, we performed a systematic review of these publications. A Pubmed search and a hand-search of the abstract books from the annual meeting of the European Society of Human Reproduction and Embryology and the American Society of Reproductive Medicine were performed for controlled studies on the developmental outcome of children after ART, which include a matching for plurality of gestation. Regarding general health, growth, mental and psychomotor development IVF children do not differ from spontaneously conceived (SC) children. An increased need for surgical interventions may be due to an increase in the malformation rate. However, a lower birth weight and lower gestational age compared to matched controls may contribute to some health problems observed. The increased risk of neurological problems found in some large registry-based studies can partly be explained by the higher frequency of twins born, by low birth weight, and by low gestational age also found in singletons. But an effect of IVF, the parents' infertility or other factors not adjusted for in the studies cannot be excluded. In addition to this reporting bias caused by concerned parents cannot be excluded, either. To conclude, children born after assisted reproductive techniques are generally healthy and are developmentally similar to children born after SC. However, low birth weight and prematurity contributes to health care problems. An increase of neurological problems by IVF cannot be excluded. Further prospective studies on the neurological outcome are needed.