Periodic Reporting for period 2 - ART-HEALTH (Conception by artificial reproductive technologies and offspring health)
Période du rapport: 2023-06-01 au 2024-11-30
The problem that ART-HEALT is addressing:
Infertility is common. It affects 1 in 6 people who are trying to get pregnant. Assisted reproductive technologies (ART), which include vitro fertilisation (IVF), and intracytoplasmic sperm injection (ICSI), are used to enable pregnancy in those with infertility. ART is increasingly used worldwide,. Since the first ART birth in 1978, research has largely focused on methods to improve live-birth rates, with the result that 25-40% of ART now result in a live-birth. Now-a-days ART is considered to be a routine effective treatment for infertility. With the widespread use of ART, concerns have been raised about its potential effect on future health. Some evidence suggests that that people conceived and born by ART are more likely to be obese and have high blood pressure, cholesterol levels, type 2 diabetes and heart disease.
Why is this important?:
We need to know if ART is causing these health problems and if it is whether there are specific types of ART that cause the problems. For example if some ways of stimulating a woman’s hormones to produce an egg are part of the problem or if any type of ART might cause these problems. If any or some types of ART cause these problems it is then we might be able reduce the problem with existing treatments for e.g. reducing blood pressure.. If, on the other hand we show that ART does not cause theses problems, then we can reassure people considering ART and those who have already been born with it that they are not at increased risk.
It is difficult to determine if ART causes health problems. This is because it is difficult to be able to tell whether an association of ART conception with such problems is because the ART causes these adverse outcomes or because the association is due to bias giving us the wrong answer, or is explained by confounding. Confounding occurs when we assume something is causal but we are in fact being fooled (confounded) into thinking that, by other things that produce the association. For example, most couples who need ART are likely to be infertile, and it might be the cause of their infertility (which is more likely in older people, those who smoke and those who are obese) that causes the offspring obesity ad heart disease than the ART.
Objectives of ART-HEALTH.
Our overall goal is to used state-of-the-art methods to determine whether conception by ART results in increased risk of adverse pregnancy and later life health problems. We are doing this through the following objectives
1. We are brining together three types of studies and applying different novel analysis methods to these different study times. One type of study brings birth cohorts from across the world together. These studies follow people from when they were in the womb during their mothers pregnancy, through birth, childhood and into adulthood. The strengths f this collaboration of birth cohorts is that we do not select on whether someone is conceived by ART or not. This means that those conceived by ART or natural conception are treated the same, with all the same measures on both groups. We can also look at whether any effect of ART changes over time as people get older. : The down side of the birth cohorts they often do not have detailed information on exactly how the ART was done. The second type of study is large electronic health record studies of whole populations. These have the advantages that they are very large, cover the whole population, such as the whole of the UK over many years, and are less likely to suffer from selection bias. They will have more details on the types of ART that were used compared to the birth cohorts. The down side of these is that they have less information on confounders than the birth cohorts. Lastly we are suing data from clinical cohort that has collected very detailed information on the whole ART process on 500 couples and for those who become pregnant comparing their pregnancy health and offspring later life health with a cohort of people from the same city who have the same measures from birth onwards. This will enable us to look at different aspects of the ART treatment, with much more detail than either of the first two. Across all three types of study we will use different types of analyses that have different biases. If se see similar results across the different study types and analysis types this gives us greater confidence that those results are the correct causal answer.
2. We are using the above data and methods to determine the effect of ART on pregnancy health and cardiovascular health.
3. We are using the above data and methods to explore biological mechanisms for any effects on pregnancy and cardiovascular health.
Infertility is common. It affects 1 in 6 people who are trying to get pregnant. Assisted reproductive technologies (ART), which include vitro fertilisation (IVF), and intracytoplasmic sperm injection (ICSI), are used to enable pregnancy in those with infertility. ART is increasingly used worldwide,. Since the first ART birth in 1978, research has largely focused on methods to improve live-birth rates, with the result that 25-40% of ART now result in a live-birth. Now-a-days ART is considered to be a routine effective treatment for infertility. With the widespread use of ART, concerns have been raised about its potential effect on future health. Some evidence suggests that that people conceived and born by ART are more likely to be obese and have high blood pressure, cholesterol levels, type 2 diabetes and heart disease.
Why is this important?:
We need to know if ART is causing these health problems and if it is whether there are specific types of ART that cause the problems. For example if some ways of stimulating a woman’s hormones to produce an egg are part of the problem or if any type of ART might cause these problems. If any or some types of ART cause these problems it is then we might be able reduce the problem with existing treatments for e.g. reducing blood pressure.. If, on the other hand we show that ART does not cause theses problems, then we can reassure people considering ART and those who have already been born with it that they are not at increased risk.
It is difficult to determine if ART causes health problems. This is because it is difficult to be able to tell whether an association of ART conception with such problems is because the ART causes these adverse outcomes or because the association is due to bias giving us the wrong answer, or is explained by confounding. Confounding occurs when we assume something is causal but we are in fact being fooled (confounded) into thinking that, by other things that produce the association. For example, most couples who need ART are likely to be infertile, and it might be the cause of their infertility (which is more likely in older people, those who smoke and those who are obese) that causes the offspring obesity ad heart disease than the ART.
Objectives of ART-HEALTH.
Our overall goal is to used state-of-the-art methods to determine whether conception by ART results in increased risk of adverse pregnancy and later life health problems. We are doing this through the following objectives
1. We are brining together three types of studies and applying different novel analysis methods to these different study times. One type of study brings birth cohorts from across the world together. These studies follow people from when they were in the womb during their mothers pregnancy, through birth, childhood and into adulthood. The strengths f this collaboration of birth cohorts is that we do not select on whether someone is conceived by ART or not. This means that those conceived by ART or natural conception are treated the same, with all the same measures on both groups. We can also look at whether any effect of ART changes over time as people get older. : The down side of the birth cohorts they often do not have detailed information on exactly how the ART was done. The second type of study is large electronic health record studies of whole populations. These have the advantages that they are very large, cover the whole population, such as the whole of the UK over many years, and are less likely to suffer from selection bias. They will have more details on the types of ART that were used compared to the birth cohorts. The down side of these is that they have less information on confounders than the birth cohorts. Lastly we are suing data from clinical cohort that has collected very detailed information on the whole ART process on 500 couples and for those who become pregnant comparing their pregnancy health and offspring later life health with a cohort of people from the same city who have the same measures from birth onwards. This will enable us to look at different aspects of the ART treatment, with much more detail than either of the first two. Across all three types of study we will use different types of analyses that have different biases. If se see similar results across the different study types and analysis types this gives us greater confidence that those results are the correct causal answer.
2. We are using the above data and methods to determine the effect of ART on pregnancy health and cardiovascular health.
3. We are using the above data and methods to explore biological mechanisms for any effects on pregnancy and cardiovascular health.
During the current period we have set up the international birth cohort collaboration, which includes 158 066 participants (4329 conceived by ART) born between 1984 and 2018. We have established a UK wide electronic health record study consisting of 63,877997 babies born by AART between 1997 and 2009 (, their naturally conceived siblings (n=11,343) born and matched naturally conceived population controls (n=127,544), all born in the same time period. We have also worked with colleagues on a large electronic record linkage study of births between 1988 and 2025, consisting of 4,510,790 births, of which 78,095 from ART with fresh-embryo, and 17,990 ART with from frozen-embryo transfer.
Using these data we have shown that compared to naturally conceived siblings or the general population of unrelated people, conception by ART increases the risk of preterm birth (baby born early). Compared to sibling or general population natural conception, being born by ART using fresh embryo transfer increases the risk of being small for gestational age, whereas frozen embryo transfer increases the risk of being large for gestational age. Lastly, we have shown that previous studies suggesting that conception by ART reduced stillbirth and death of a baby in early life were biased.
Our findings so far in relation cardiovascular health are reassuring. In the birth cohort collaboration we find that levels of body fatness, blood pressure, cholesterol, glucose and inflammation are similar in those conceived by ART compared to those naturally conceived from infancy to adolescence. In the electronic record linkage data we see similar levels of hospital admissions for obesity and cardiovascular diseases between those conceived by ART compared to sibling or general population natural conceptions. Because the first baby born by ART was in 1978 and research of in large numbers has only been possible since the late 1980s, we cannot explore effects into mid-life. We will do that in the next period of ART-HEALTH.
Using these data we have shown that compared to naturally conceived siblings or the general population of unrelated people, conception by ART increases the risk of preterm birth (baby born early). Compared to sibling or general population natural conception, being born by ART using fresh embryo transfer increases the risk of being small for gestational age, whereas frozen embryo transfer increases the risk of being large for gestational age. Lastly, we have shown that previous studies suggesting that conception by ART reduced stillbirth and death of a baby in early life were biased.
Our findings so far in relation cardiovascular health are reassuring. In the birth cohort collaboration we find that levels of body fatness, blood pressure, cholesterol, glucose and inflammation are similar in those conceived by ART compared to those naturally conceived from infancy to adolescence. In the electronic record linkage data we see similar levels of hospital admissions for obesity and cardiovascular diseases between those conceived by ART compared to sibling or general population natural conceptions. Because the first baby born by ART was in 1978 and research of in large numbers has only been possible since the late 1980s, we cannot explore effects into mid-life. We will do that in the next period of ART-HEALTH.
We have developed novel methods that are beyond he state of the art that enable us to determine causal effects of ART for the first time. These suggest some increased risk of adverse pregnancy outcomes such as the baby being born early and either smaller or larger that naturally conceived children. Importantly, we have shown that ART does not protect against stillbirth or neonatal death as had been previously described.
Our findings that conception by ART does not increase obesity or cardiovascular disease risk factors up to adolescence is important and reassuring.
In the next period to the end of the project, we will have extended the electronic health record study so that we can explore hospital admissions for cardiovascular and other diseases in offspring conceived by ART (compared to natural conception) up to being aged mid- to late-40s.
We will also determine the effects of ART on biological molecular paths and whether any effects on these biological paths explain any effects of ART on pregnancy and future health.
Our findings that conception by ART does not increase obesity or cardiovascular disease risk factors up to adolescence is important and reassuring.
In the next period to the end of the project, we will have extended the electronic health record study so that we can explore hospital admissions for cardiovascular and other diseases in offspring conceived by ART (compared to natural conception) up to being aged mid- to late-40s.
We will also determine the effects of ART on biological molecular paths and whether any effects on these biological paths explain any effects of ART on pregnancy and future health.