Groningen ART cohort study

The study

Background: in vitro fertilization


The first IVF-baby, Louise Brown was born in 1978. Nowadays, up to 2% of all children in the Netherlands are born following assisted reproductive technologies (ART) such as in vitro fertilization (IVF) with or without intracytoplasmic sperm injection (ICSI). Many studies addressed the outcome of children born following assisted conception, as assisted conception substantially differs from natural conception. In general, the literature suggests that outcome of children born following IVF is largely similar to that of their naturally conceived peers. But it also became clear that IVF children are slightly more often born prematurely, have lower birth weights and have slightly more birth defects than children that are born without IVF. Previous studies demonstrated that IVF itself is not associated with an increased risk of neurodevelopmental handicap. However, it is still unclear whether IVF affects developmental outcome at school age or beyond.


The Groningen ART cohort study


The Groningen ART cohort study aims to study development of children born following IVF (with or without ICSI). To this end, developmental outcome at various ages of three groups is compared. The first group (group 1) consists of children born to women who underwent IVF with hormonal treatment; the conventional form of IVF, in which the hormonal treatment aims to accelerate maturation of multiple eggs (‘oocytes’).  The second group (group 2) consists of children born to women who underwent IVF with minimal hormonal treatment; the egg that naturally developed to dominance was used for conception. The third group (group 3) consists of children born to women who did not receive fertility treatment, even though they had fertility problems. These women became pregnant while on the waiting list for fertility evaluation or treatment.
The three ART groups share the characteristic that the parents tried to achieve pregnancy for more than one year. These couples therefore are regarded as less fertile, or, in medical terms ‘subfertile’. Comparison of outcomes in the three ART groups provides insight in the effects of the hormonal treatment, the laboratory procedures and the combination of both. This is illustrated in the figure below. At some of the assessment ages we also assessed children of a ‘fertile’ control group (group 4). These children were born to parents who achieved pregnancy within a year and without medical assistance. Comparison of the ART children (group 1, 2 and 3) with the children of fertile couples (group 4) furnishes insight into the role of subfertility (see figure below)





Child development


In the Groningen ART cohort study we study a wide array of developmental outcomes. Special attention is paid to neurodevelopmental outcome: neurological, motor, cognitive and behavioural outcome. Neurological condition is evaluated with sensitive, age-specific tools, which include the observation of spontaneous motor behaviour. Cognition is tested with standardized tests and behaviour is evaluated with parental questionnaires.

Next to brain development, general physical development is assessed. This includes the evaluation of blood pressure, height, weight, circumference of specific body parts and skinfold thickness. In addition, we assessed at the age of 2 years the presence of congenital anomalies, such as a cleft palate and an extra finger or toe.

Results

 
Development up until the age of 4 years
Analysis of the data up until the age of 4 years has been completed. The data revealed the following:
  • Neurological, cognitive and behavioural development of the three ART groups was similar. This means that hormonal treatment and the laboratory procedures did not affect neurodevelopmental outcome up until 4 years.
  • Neurological, cognitive and behavioural condition of children born to subfertile parents was less optimal than that of children of fertile couples. Non-optimal neurological condition was especially related to time to pregnancy. This means that a longer time needed to achieve pregnancy was associated with higher chance of a non-optimal neurological condition at 4 years.
  • Dysmorphic features occurred equally frequent in the three ART groups. This means that the hormonal treatment and the laboratory procedures did not affect the chance of having dysmorphic features at 2 years. However, a positive association was found between the time to achieve pregnancy and clinically relevant birth defects, implying that a longer time to achieve pregnancy was associated with a higher chance of these congenital anomalies.
  • At the age of 4 years the children of group 1 (children born after IVF with conventional hormonal stimulation) had a slightly higher bloodpressure, slightly thicker skinfolds and somewhat more often asthma than children conceived without IVF. This may suggest that the conventional hormonal stiumulation of IVF has a slightly negative effect on the child's health. This finding urged us to re-assess the children at school age.
  • We compared health and development of the 4-year-old singletons of our cohort with that of 4-year-old twins born after IVF. The twins had a lower IQ, and they had a lower body weight and body length than the singletons. This negative effect could not be attributed to IVF, but to being a twin

Developmental outcome at 9 years
Recently the children have been re-assessed at the age of 9 years. The first results have been published, more will follow:
  • Neurological condition at the age of 9 years of the three ART groups was similar.
  • Neurological condition at 9 years of children born to subfertile couples was less optimal than that of children born to fertile couples.
  • Blood pressure and skinfolds at the age of 9 years of the three ART groups was similar. This means that the association between slightly adverse cardiometabolic health and hormonal treatment that we found at the age of 4 years could not be replicated.
  • Blood pressure at 9 years of children born to subfertile couples was slightly higher than that of children born to fertile couples.

Collaborators

Mijna Hadders-Algra, MD, PhD
professor of developmental neurology, UMCG

Maaike L. Haadsma, MD, PhD
resident clinical genetics, UMCG

Maas Jan Heineman, MD, PhD
professor of obstetrics & gynaecology, AMC

Marjon Hendriks, MD
ophthalmologist, Martini Hosp

Derk Kuiper, MD/PhD student
Developmental Neurology, UMCG

Sacha la Bastide-van Gemert, Ph.D
mathematician, UMCG

Tessa J. Rosenboom, PhD
medical biologist, AMC

Pamela Schendelaar, MD, PhD

Jorien Seggers, MD, PhD
general practitioner in training, UMCG

Key publications

  • Middelburg KJ, Heineman MJ, Bos AF, Hadders-Algra M. Neuromotor, cognitive, language and behavioural outcome in children born following IVF or ICSI – a systematic review. Hum Reprod Update 2008; 14: 219-31.
  • Middelburg KJ, Heineman MJ, Bos AF, Pereboom M, Fidler V, Hadders-Algra M. The Groningen ART cohort study: ovarian hyperstimulation and the in vitro procedure do not affect neurological outcome in infancy. Hum Reprod 2009; 24: 3119-26.
  • Middelburg KJ, Haadsma ML, Heineman MJ, Bos AF, Hadders-Algra M. Ovarian hyperstimulation and the in-vitro procedure do not influence early neuromotor development, a history of subfertility does.  Fertil Steril 2010; 93: 544-53.
  • Schendelaar P, Middelburg KJ, Bos AF, Heineman MJ, Jongbloed-Pereboom M, Hadders-Algra M. The Groningen ART-cohort study: the effects of ovarian hyperstimulation and the IVF laboratory procedures on neurological condition at 2 years. Hum Reprod 2011; 26: 703-12.
  • Jongbloed-Pereboom M, Middelburg KJ, Heineman MJ, Bos AF, Hadders-Algra M. The Groningen assisted reproductive technologies cohort study: developmental status and behavior at 2 years. Fertil Steril 2011; 95: 2283-9.
  • Seggers J, Haadsma ML, Bos AF, Heineman MJ, Keating  P, Middelburg KJ, Van Hoften JC, Veenstra-Knol HE, Kok JH, Cobben JM, Hadders-Algra M. Dysmorphic features in 2-year-old IVF/ICSI offspring. Early Hum Dev 2012; 88: 823-9.
  • Seggers J, Schendelaar P, Bos AF, Heineman MJ, Middelburg KJ, Haadsma ML, Hadders-Algra M. Increased time to pregnancy is associated with suboptimal neurological condition of 2-year-olds. Arch Dis Child Fetal Neonatal Ed 2013; 98: F434-6.
  • Schendelaar P, Heineman KR, Heineman MJ, Jongbloed-Pereboom M, La Bastide-Van Gemert S, Middelburg K, Van den Heuvel E, Hadders-Algra M. Movement variation in infants born following IVF/ICSI with and without ovarian hyperstimulation. Early Hum Dev 2013;89:507–13.
  • Seggers J, Haadsma ML, La Bastide-Van Gemert S, Heineman MJ, Middelburg KJ, Roseboom TJ, Schendelaar P, Van den Heuvel ER, Hadders-Algra M. Is ovarian hyperstimulation associated with higher blood pressure in 4-year-old IVF offspring? Part 1, multivariable regression analysis. Hum Reprod 2014;29:502-9.
  • La Bastide-Van Gemert S, Seggers J, Haadsma ML, Heineman MJ, Middelburg KJ, Roseboom TJ, Schendelaar P, Hadders-Algra M, Van den Heuvel ER. Is ovarian hyperstimulation associated with higher blood pressure in 4-year-old IVF offspring? Part II: a causal inference approach. Hum Reprod 2014;29:510-7
  • Schendelaar P, Van den Heuvel ER, Heineman MJ, La Bastide-Van Gemert S, Middelburg KJ, Seggers J, Hadders-Algra M. Increased time to pregnancy is associated with less optimal neurological condition in 4-year-old singletons, in vitro fertilization itself is not. Hum Reprod 2014;29:2773-86.
  • Kuiper DB, Seggers J, Schendelaar P, Haadsma ML, Roseboom TJ, Heineman MJ, Hadders-Algra M. Asthma and the use of asthma medication in 4-year-old offspring of subfertile couples. Reprod Biomed Online 2015, 31:711-4.
  • Schendelaar P, La Bastide-Van Gemert S, Heineman MJ, Middelburg KJ, Seggers J, Van den Heuvel ER, Hadders-Algra M. Subfertility factors rather than assisted conception factors affect cognitive and behavioural development of 4-year-old singletons. Reprod Biomed Online 2016; 33: 752-62.
  • Kuiper D, Bennema A, La Bastide-van Gemert S, Seggers J, Schendelaar P, Haadsma M, Hoek A, Heineman MJ, Hadders-Algra M. Neurodevelopmental and cardiometabolic outcome in 4-year-old twins and singletons born after IVF. Reprod Biomed Online 2017; 34: 659-67.
  • Kuiper D, Hoek A, la Bastide-van Gemert S, Seggers J, Mulder DJ, Haadsma M, Heineman MJ, Hadders-Algra M. Cardiovascular health of 9-year-old IVF offspring: no association with ovarian hyperstimulation and the in vitro procedure. Hum Reprod 2017; 32: 2540-8.
  • Drenth Olivares M, Kuiper D, Haadsma ML, Heineman KR, Heineman MJ, Hadders-Algra M. IVF-procedures are not, but subfertility is associated with neurological condition of 9-year-old offspring. Early Hum Dev 2019; 129: 38-44.
  • Kuiper D, La Bastide-van Gemert S, Hoek A, Seggers J, Haadsma M, Heineman MJ, Hadders-Algra M. Parental subfertility is associated with higher blood pressure in offspring. Acta Paediatr, 2019;108: 373-74.

Sponsors

  • Behavioural and Cognitive Neurosciences
  • Cornelia stichting
  • Junior Scientific Masterclass
  • Universitair Medisch Centrum Groningen

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