How are the other 7 million IVF people doing?
7 million people and forty two year later, the questions remains as to how the people who ‘conceived’ through IVF are doing? In 1978, I was a resident at Johns Hopkins and the team of Georgeanna and Howard Jones were just leaving to start an IVF clinic in Virginia. Three years later, Elizabeth Carr was born, the first person conceived by IVF in the USA, This was only three years after the birth of Louise Brown, the world’s first IVF baby in the United Kingdom born on July 25, 1978.
At that time, one of my fellow residents came us to up on the OB deck and announced the success of Louise Brown’s birth. We were all in training to be reconstructive pelvic surgeons and expected to make our living doing surgery. At that time, we felt IVF was just an anomaly, a passing fad that would have no place in the treatment of infertility. Oh, how wrong we were.
So, besides the influx of babies and diapers since these two women were born through Assisted Reproductive Technology, how have the other millions fared?
Two recent articles highlight the continuing concern about the impact of IVF on the health of the individuals who are conceived through the use of IVF. One article evaluated school performance in third grade students conceived through IVF and compared them to those students conceived naturally. The results demonstrated no difference is the standardized achievement testing done for third graders in Texas. And this has been the results of most studies looking at the health of IVF conceived people. There appears to be no difference.
The second article looked at a phenomenon called imprinting in children born after assisted reproductive technologies and found no overall difference except for a syndrome called Beckwith- Wiedemann (not the first item this has been described). Imprinting has been a concern because some of the problems that result from imprinting do not appear until later in life. [The topic of imprinting will be addressed in a future posting at rinehartfertilitycenter.com] Since Louise Brown is only 42, it is unknown if this phenomenon will show up as IVF people age. So, what do we know?
Are there know differences between people conceived through IVF as compared to natural conception?
This question has been posed since the birth of Louise Brown. But a subtle variation on this question is who should the IVF conceived people be compared to? After all most people do not use IVF to conceive unless there is some reproductive problem. Should the comparison be between infertility patients not using IVF to those using IVF or should the comparison be between IVF conceived people and naturally conceived people? Kind of reminds one of the chicken or egg argument: did infertility cause any difference or did IVF cause a difference? The answer seems to be a little of each.
What differences have been identified?
Comparing IVF pregnancies to natural conception pregnancies, there is an increase in several areas including preterm birth, low birthweight, and small for gestational age. Maternal obstetric complications show an increased risk of hypertensive disorders of pregnancy, gestational diabetes, and placental complications. While this list seems ominous, the question is are these differences significant enough to have a negative impact on the health of the mothers or babies? A study from Nordic countries published in 2015 made an interesting observation in that many of the adverse outcomes had decreased in incidence over time. IVF itself has undergone considerable change since it was first introduced. Most significantly is the increase in the success of embryos implanting which has permitted the reduction in the number of embryos that needs to be transferred. This has decreased the risk of twins and thus considerably reduced the adverse outcomes. However, even for singleton pregnancies, there has been a decrease in many adverse outcomes. To put this in real numbers, preterm birth was defined as a birth 32-37 weeks, low birth weight was < 2500 g (5.5 lbs.), and small for gestational age was 2 standard deviations less than the average birth weight. Twenty-eight percent of the births from IVF pregnancies and 6% from spontaneous in 1988-1992 in Norway were preterm but by 2003-2007 the IVF rate had dropped to 8% while the spontaneous group remained constant at 6%. Small for gestational age occurred in 8% of IVF pregnancies and 4% of spontaneous pregnancies in 1988-1992 but by 2003 -2007 the percentage was the same at 3% for both. Finally, the rate of stillborn infants declined so that after 1990 there was no difference between spontaneously conceived and IVF pregnancies. The implication from this well- done study is that outcomes have improved over time and this needs to be taken into account when determining the incidence of adverse perinatal outcomes.
Admitting that there remain some differences between spontaneously conceived pregnancies and IVF pregnancies, the question remains: is the difference due to the diagnosis of infertility or due to the procedure. A well-constructed analysis published by Berntsen et al concludes with the following “In general, short-term health of singletons conceived by ART shows modestly increased risks of adverse outcomes, including LBW, PTB, and birth defects. The causes of the poorer outcomes seem to be a combination of parental subfertility and the ART techniques per se.”
Do the small differences impact the health of individuals conceived through IVF?
The recently published article by Luke et al looking at school performance in third graders provides reassuring evidence that IVF kids are doing just fine. The study was interesting because of the large number of individuals included in the data. In the US, IVF outcomes are reported to SART which provides a very large database for research concerning IVF outcomes.
Many states have standardized testing that is done periodically and thus also provides a large database. Of course, the problem arises when trying to match these databases to see which individuals were conceived using IVF and then their performance on the standardized testing. Texas provided just such a mechanism to merge the two sets of data. The outcome of the STAAR program for third graders was used. The third grade seems to be an important developmental time in the life of a child because it is at this age that a child switches from learning to read to reading to learn. The study included 27,050 children who had a math or reading score. The test results are reported as scaled scores with 1500 being the average score and the standard deviation being 140 points. Interestingly, singleton IVF children scored 16-19 points higher than the average and this was statistically significant.
While this is encouraging, the authors emphasize that this should not be over interpreted and their conclusion was that “children conceived with the use of IVF have an academic achievement in the third grade as good as those conceived spontaneously.”
One last example of the influence of IVF on the health of IVF conceived children is that of a study published by Halliday et al in 2019. The study compared individuals conceived through IVF with spontaneously conceived individuals. The study evaluated vascular structure, vascular function, metabolic markers, anthropomorphic measurements, and respiratory function. The conclusion of the study was” This study…. found no evidence of increased vascular or cardiometabolic risk, or growth or respiratory problems in the ART group compared to the non- ART group.” Interestingly, diastolic blood pressure was lower in IVF males. The IVF group did report an increase in having asthma, but the respiratory flow rates were the same as spontaneously conceived individuals.
There is much to be learned about the influence of IVF upon the health of the individuals created through the use of IVF. Louise Brown is only 42 years old and has another half of her life to live. How IVF will affect age- related disease is unknown. But as of now IVF children seem to be OK- just as goofy as their parents.
I will close with a personal story. As a statistician, I am loath to reports of individual cases but as a step- parent I would like to share one. In the early 1990s my wife, a nurse, and I worked in our practice and had the privilege of helping a close relative conceive a daughter. My stepdaughter was about the same age, so we have had the opportunity to see how they grew. They are incredibly similar which on any given day can be a blessing or a challenge since they are both attractive, intelligent, and stubborn…Imagine that! Louise Brown must be proud.
1 Henningsen et al Tren30:710ds in perinatal health after assisted reproduction: a Nordic study from the CoNARTs group 2015 Hum. Reprod.
2 Berntsen et al The health of children conceived by ART: “the chicken or the egg?” 2019 Hum. Reprod. Update 25:137
3 Luke b et al Third grade academic achievement among children conceived with the use of in vitro fertilization: a population- based study in Texas 2020 Fertil. Steril. 113 (June): 1242
4 Halliday J et al Health of adults aged 22-35 years conceived by assisted reproductive technology 2019 Fertil. Steril. 112:130