By fertility experts from Spain.
Obesity is surely one of the most important public health issues in the world today. In this webinar, Dr José Bellver, MD, Attending Gynecologist at IVI Clinic Valencia, explains the effect of female obesity on both spontaneous and assisted conception as well as its influence on pregnancy and the postnatal life of an offspring.
The definition of obesity is based on the body mass index (BMI). It is the relationship between weight and height in kilograms per square meter. A normal weight is considered to be up to BMI of 25. A BMI of over 25 to 30 is considered overweight. A BMI of 30 and above is considered obese and thus, a pathological condition.
The medical world knows a lot of studies showing the relation between female obesity and an increased risk of both subfertility and infertility. While the former means that the time to achieve pregnancy is longer than expected, the latter describes the fact of not having any pregnancy at all. At the beginning of his presentation, Dr José Bellver introduces the study showing that the presence of obesity during adolescence is related to an increased risk of not having any pregnancy during lifetime or – if it eventually happens – no desired live birth because of several complications during pregnancy.
For many years, it has been believed that the exclusive mechanism related to subfertility and infertility in obese women is the presence of ovulatory disorders. However, there are studies suggesting that even in obese women with regular menstruations and normal ovulation, there is a significant reduction in spontaneous conception. Dr José Bellver admits that the deleterious effect on fertility is much stronger when both female and male obesity are combined and affecting the chances of a spontaneous conception. Unfortunately, it is quite common as both partners generally share the same lifestyle behaviours.
As obese women present an increased risk of infertility, they are more prone to undergo treatments of assisted conception. However, they may encounter a few challenges along the assisted reproductive technologies (ART) route as well. According to Dr José Bellver, the first problem in case of obesity is the fact ovarian response to any kind of medication administered is reduced. It happens so due to several mechanisms. One of them is the higher volume of distribution of the drug, meaning that less amount of the drug reaches the target organ. Dr Bellver says that ovarian response to ovulation-stimulating drugs, such as gonadotropins and clomiphene citrate, is negatively correlated with the body mass index of the patient.
However, it is not the only problem. What’s even more important is the fact that obese women see much poorer results of IVF treatment. One decade ago, Dr José Bellver and his colleagues published a study on how obesity reduces uterine receptivity and influences the effects of IVF. In their study – which turned out to be the largest single centre study performed – they analysed 6,500 cycles of IVF. If the body mass index of the patient was higher than 30, there was a significant reduction in all the parameters of the outcome, meaning implantation rate, pregnancy rates and live birth rates. In other words: the higher the body mass index of the patient, the higher the chances of not having a clinical intrauterine gestation. Similarly, there have been studies proving that the presence of male obesity in IVF contributes to reducing clinical pregnancy and live birth rates, too.
It is a solid fact that pregnancy outcomes decline with increasing BMI. In order to learn if female obesity affects more the egg or the uterus, it is best to analyse ovum/egg donation treatments. In the ovum donation model, oocytes/eggs are taken from a donor, they are fertilised with the sperm of the partner and then the embryo that is obtained is introduced into the uterus of the recipient. Dr Bellver says that if the donor is normal weight and the recipient is obese, it is possible to observe the clinical effect of the obesity on the uterus. On the other hand, if the donor is overweight or obese and the recipient is normal weight, one can see what the clinical effect of obesity on the oocyte is. According to the available studies, if the donor has BMI between 25 and 34 (which means either overweight or obesity), there is a significant reduction in the clinical pregnancy rate in the recipient – which means there is a negative impact on the oocyte quality. However, if the donor is normal weight and there is female obesity in the recipient (from BMI of 30 to BMI of 40), pregnancy outcomes are declining as well. It means that female obesity in the recipient is altering the endometrial receptivity. That’s why, from a clinical point of view, obesity is affecting both oocytes and the uterus.
Dr José Bellver makes it clear: the presence of female and male obesity is deleterious for both spontaneous and assisted conception. Of course, it has to be noted that the role of women is more important here because it is female obesity that has the effect on all the following elements: oocytes, the uterus and pregnancy. In case of men, it is only the sperm that is affected. Knowing all of this, one has to determine the exact damage that obesity is exerting on both reproductive gametes, embryos and uterine receptivity.
Dr Bellver admits that the clinical studies aimed at determining if sperm quality is altered in obese men, have not reached a consensus. Some of them have shown that in obese men, there are sperm alterations in terms of number, motility and morphology. The others, on the contrary, did not prove any alterations at all. The same refers to the relation between the men’s body mass index and embryo quality – there were no significant differences observed. When it comes to women, many studies have tried to ascertain if female obesity alters oocyte and embryo quality or not – but with no results. Despite the fact that there was a significant reduction in implantation, pregnancy and live birth rates when a patient’s BMI exceeded 30, the studies didn’t find any correlation between the body mass index and the embryo quality. Dr Bellver draws a conclusion that the methods used for determining gametes’ quality in the lab were simply not enough.
That’s the reason why new analysis techniques have emerged, such as e.g. embryo morphokinetics. Thanks to it, it has been observed that the embryo function was different in case of embryos coming from obese patients and normal weight patients. Dr Bellver says that from a morphological point of view, the culture media of embryos coming from obese women presented some differences in the metabolites, such as e.g. reduction in the percentage of saturated fatty acids. It means that, depending on a patient’s BMI, the same morphology embryos are working in a different way – and this results in various reproductive outcomes.
Similarly, attempts were made to determine what was happening in the endometrial receptivity due to female obesity. Having analysed the pattern of gene expression at the moment in which the embryo implanted, it has been observed that in obese women with PCOS, the expression is similar to other refractory conditions of the endometrium, such as the presence of a intrauterine device used for contraceptive purposes. Basing on the results of the endometrial receptivity array (ERA) test, Dr Bellver and his team determined whether the percentage of non-receptive ERA test was in any way related to the presence of female obesity. It turned out that the presence of endocrine and metabolic disturbances in the body of obese women was altering the expression of the endometrial genes related to the embryo implantation.
Unfortunately, obese women may not only have problems with achieving pregnancy but also with keeping it. According to Dr José, in pregnancy of obese women there is an increased risk of miscarriage during the first semester. And it has been shown both in natural conception and in assisted conception after IVF. The main origin of first semester miscarriages is generally aneuploidy (the presence of embryos with chromosomal abnormalities) – but, in case of female overweight, a higher embryo aneuploidy is not being observed. However, the fact remains that even after transferring embryos with normal chromosomes, there was a significant increase in the clinical miscarriage rate in case of patients with high BMI. The explanation given by Dr Bellver is as follows: obese women present an increased risk of miscarriage not because of excessive chromosomal abnormalities in the embryos but due to the abnormal environment in which their embryos develop. This is the same reason why, in obese women, there is an increased risk of fatal and maternal complications during the three trimesters of pregnancy, including an increased risk of congenital anomalies. Additionally, due to the exposure to the abnormal environment with endocrine, metabolic and inflammatory alterations, the offspring of overweight or obese mothers is subjected to a number of chronic diseases in their postnatal life, such as e.g. type 2 diabetes, cardiovascular disorders, osteoporosis or asthma.
It is obvious that obesity increases the risk of developing a whole lot of diseases. As Dr Bellver has proved in this webinar, its adverse effect on fertility and pregnancy outcomes should not be underestimated. It has been proven that obesity not only impairs natural and assisted conception but also increases pregnancy complications and offspring diseases. That’s why the best measure to prevent or at least to minimise all the problems related to it is weight reduction before conception – as well as its reasonable management during pregnancy.
The best way to reduce weight is by the so-called lifestyle therapy. A lifestyle therapy is a combination of different parts with a multidisciplinary team. Of course, the reduction of calories by the nutritionist is important but this has to be compensated with a specific training for the patient, psychological support and a close endocrinology follow-up for the patient. The only programs that have shown to be beneficial for improving fertility in women with obesity by reducing weight are those in which there is a combination of all these specialists: psychologists, nutritionists, a personal trainer and an endocrinologist.
It has been shown that the lost of weight can be significant after three months if the patient goes to the clinic to visit all these specialists at least twice a week. Sometimes the problem we have is that the exercises performed by the patient are not good for her reducing weight in a personalised way. It is so because the way to reduce weight depends on the situation and the physical condition of each patient or sometimes the exercise is not enough to compensate for the calories that the patient is taking in.
So the combination of calories reduction and an increase in expenditure of energy is the best way to loose weight. But it needs to be guided by a specialist and with psychological support because as you know, many women tend to have high weight due to anxiety and other problems. They tend to eat not for hunger but in order to comfort themselves. So my advice is to go to a multidisciplinary team with a close follow-up. It means at least two visits per week with personal trainers, nutritionists and psychologists and a control visit with the endocrinologist at least every 15 days or three weeks – in order to know that there is no negative implication of the approach to your metabolism.
Yes. For instance, in our clinic we have a program like this one and we perform the visits one after the other on the same day. The reason is that there are studies that have shown that weight reduction before IVF is useful for having a higher live-birth rate and there are other studies which have shown that it is not useful. The difference between these studies is that in the first ones, with better IVF results after weight reduction, there was a close follow-up of the patient by a multidisciplinary team every week for at least 12 weeks.
Only in these cases it has been detected that the weight reduction is significant and can improve the result of IVF. On the contrary, in other studies, in which the patient was seen once a month or only by phone but without a close follow-up or with a follow-up by a non-specialist, such as a resident of gynaecology instead of a nutritionist or a personal trainer, the program has failed to produce significant weight reduction. It did not improve the chances of conception after IVF either. So only a close follow-up by a multidisciplinary team has shown to be beneficial in reducing weight for fertility purposes – especially, when a patient has a very high body mass index (BMI).
The thyroid plays a big role, especially in hypothyroidism, when it is not regulated. But once the thyroid function is regulated, its role is really marginal. So if you detect a woman with obesity and severe hypothyroidism and you control hypothyroidism, the role of thyroid in her weight is really marginal.
I can reply to this question but it is not related to obesity. Carrier testing is an option to avoid monogenetic diseases – this means rare diseases that are due to the presence of the same mutation in the same gene in both members of the couple. Of course, it is really good because if you detect that both members of the couple present the same mutation, you know that the risk of having the disease in the offspring is around 25% – as in case of all the autosomal recessive diseases. So if you detect this situation, you can analyse the embryo after in vitro fertilisation, but before the embryo transfer, to discard the embryos with a disease. And it is the only way today to avoid the disease in the offspring. The only problem is problem of money.
Testing all the couples that want to have a pregnancy – not only by assisted reproduction but also by spontaneous conception (because the risk is exactly the same) – is really expensive. So from a point of view of public health, it is not possible today. From the point of view of private settings, it is possible but it’s an amount of money that the patient has to add to the money that they have to pay for an IVF cycle. And sometimes this is the problem because a complete testing of all the possible mutations – today there are more than 500 of them – costs around 1,000 to 1,300 Euros per person.
So it’s expensive and sometimes the reason why some patients do not want to perform the test is the problems of cost. But if the test is cheaper in the future, it is always advisable in patients in order to cut all the rare diseases that can occur not only in an assisted conception but also in a spontaneous one.
Yes, it depends on the number of diseases that you discard. In Spain, it is the same. There are different prices because it is not the same to discard 50 diseases and 100 or 300 diseases. In Spain, it costs around 1000 Euros when you discard more than 500 diseases.
As far as I know, the problem is that epigenetics cannot be tested in any patient. While genetics describes the DNA sequences in our genes, epigenetics means the way these genes are expressed. Sometimes the genes that don’t have to be expressed are expressed and can induce a disease. Or just the opposite: some genes that have to be expressed are not expressed. The way these genes are expressed or not depends on the environment in which the embryo and the fetus develop.
Of course, there are conditions in which there are clearly epigenetic modifications. For instance, if a mother takes drugs or alcohol, there is the induction of some epigenetic modifications in the embryo genome that can increase the risk of diseases in the offspring. Obesity is one of such situations.
It has been established that the risk of offspring diseases in obese women is due to the epigenetic modifications that the abnormal metabolic and endocrine environment of the uterus can induce. So there is only thing that we can do today: if we know that one condition can induce epigenetic modifications, the solution is not to treat the genes or their expression but to avoid the situation that can induce these modifications.
If you know that alcohol, drugs, obesity, etc. can induce epigenetic modifications, the only thing that you can do is to avoid these conditions during pregnancy. So you should stop alcohol, stop drugs and reduce weight. We cannot, for instance, maintain obesity and somehow change the expression of the genes. The only way to avoid this abnormal expression of the genes is to avoiding obesity.
One thing is that with BMI of 43, there is enough reason to have a failure in any kind of treatment – because the endometrial receptivity is really altered, even in ovum donation. This doesn’t mean it is impossible to achieve a pregnancy but the chances of pregnancy are really reduced.
As you know, in ovum donation, if we have a good uterus, good morphology and good receptivity – that in this case can be altered by obesity – the chances are really high. But if the uterus is not okay from an anatomical point of view or from a problem of receptivity – in your case probably induced by the body mass index – the results are poorer. If the only problem that you had was your BMI, the advice is to go ahead with new ovum donation and you don’t need more tests.
The problem is the following: as you know, AMH (anti-Müllerian hormone) is a marker of the number of oocytes that you have inside your ovaries. What this clear is that if you have higher BMI, despite having the same level of AMH as another woman, you will have a lower ovarian response. On the other hand, AMH in obese women usually represents lower values than real values.
There are some conditions that can vary the level of AMH by reducing it. One of these conditions is taking contraceptive pills. Another condition is obesity. So if you want to see what your AMH is – after weight reduction and with your age – my advice is to measure it again. If AMH was low because of false reduction induced by your weight, it will be higher.
But if your AMH was low simply because of your age – because sometimes even while being younger you can have low AMH – its level will be as low as before. So the only way to know it is to repeat it. However, repeating AMH makes sense only if you want to go ahead with your own oocytes. Because if it’s ovum donation, then it doesn’t really matter.
Yes, but as you said, it was when you had very high BMI. I think that now you can have an opportunity. I’d perform the AMH test and if the level is not so low and you are 38, you can have an opportunity with your own oocytes.
The body mass index is not related to miscarriages but to the chances of conception. If your donor has a high BMI, pregnancy rates can be reduced. This is clear. The risk cut-off is from 25 to 30. It is a situation of overweight and sometimes the quality of the oocytes can also be reduced – but this has not been proven. In our clinic, we decided some years ago not to admit any donor with a body mass index higher than 25. But while with BMI between 25 and 30 there are still doubts, it is sure that no clinic in the world would admit a donor with BMI of over 30 – surely not with the information that we have today.
Yes, from 30. Of course BMI of 30 is only an isolated measurement. When we assess a patient, we look at the distribution of fat (if it’s a central distribution), we look if there is an implication in lipids, in glucose, we look at the age of the patient and so on. So BMI is an isolated parameter. But of course, all the studies have agreed that BMI of 30 is when the problems really start. And it happens in a dose-dependent manner: if BMI increases, all the problems that I have shown you are increased, too.
I need my calculator and I’ll tell you. Your body mass index (BMI) is 31 so you have obesity plus 1 – but it is just in the limit. The weight that you have to lose to stay out of the obese definition will probably be only 5 kilograms. Then you will have BMI of 29 that is overweight. But as I have told you before, this is not really negative for reproduction. So you will be okay with loosing only 5 kilograms. Of course, if you lose 10 or 15 kilos, it’s even better – but with only 5, you will be out of the risk as well.
In general, there are some stillbirths with unknown origin. Sometimes there is no apparent reason because after the analysis of the baby, the placenta is all okay. Sometimes it is a compression of the umbilical cord etc., but in the vast majority of situations, as you have said, the cause is a metabolic condition: diabetes, preeclampsia – because there is a thrombophilic problem that blocks the vessels that supply the blood flow to the fetus.
Sometimes there are situations of chronic diseases in which there is a subclinical inflammation of vessels that finally alters the blood supply to the fetus. And this is, for instance, the reason why in obese women there is an increased risk of a stillbirth. But as I have already told you, there are some cases of a stillbirth in which, after the study of the baby and the chromosomes and discarding infections or chronic diseases, there is no apparent reason and we don’t know what has happened.
In some of these cases, the problem may be a compression of the umbilical cord. Sometimes the umbilical cord is around the arm or around the leg and it can be the reason. But if in your case the placenta was large, it is probably an unknown cause. But when there is no apparent reason, the good news is that the risk of recurrence is really low. So usually the problem does not repeat in a future pregnancy.
Yes, in fact the increased body mass index during pregnancy and out of pregnancy can induce what is called comorbidities. Comorbidities are metabolic situations that can appear due to obesity. They can be before in the patient but they are increased with obesity. And this is why these situations are sometimes improved or even avoided when we reduce weight in obese women. It’s clear obesity increases all types of metabolic disturbances that can appear in women but this occurs out and in the pregnancy.
Some years ago it was believed that hypothyroidism is when you have high TSH and low T4 (thyroid hormone) and symptoms were related to the problems in the growth of the fetus and in the neural development. This is why this problem was related to mental retardation. But since some years ago, there’s a new problem that is the subclinical hypothyroidism. There are women without symptoms and the only way to determine if TSH and thyroid hormone are normal is by performing analysis. So what happens is that in an adult person, a level of TSH can be normal, from 4.5 up to 4.6 – according to different labs.
So for your functions as an adult, there is no problem. But during the first weeks of pregnancy – the first 16 weeks more or less – your fetus does not produce thyroid hormone (T4) that is essential for the neurological development of the brain. So the hormone comes exclusively from the mother. And if the level of T4 is normal but in the lower range, sometimes the neurological development is not as good as it can be.
So these problems are not related to mental retardation. These problems can be related to the so-called school retardation with attention-deficit/hyperactivity syndrome. So if you have a lower level of T4 – even in the normal range – you can have a baby with these problems. It has been established by endocrinologists that when TSH is lower than 2.5, it is because T4 is at the level that is good for your pregnancy. But if the level of TSH is higher, it is because T4 is lower. And the same as with folic acid that we give to every woman to prevent spina bifida (that is the only malformation that can be prevented today) – no matter if she wants to get pregnant spontaneously or via assisted reproduction – we perform the TSH test to everyone.
If the TSH test is more than 2.5, after checking T4 and T3, etc., we give low doses of thyroid hormone in order to prevent these mild alterations in the brain development of the fetus.
I have a neighbour with three car accidents that is still alive. It’s the same example. What I want to tell you is that a risk factor does not mean that something is impossible. Obesity is a risk factor for having fertility and pregnancy complications. So if infertility occurs in 15% of general population, when there is a risk factor, it is e.g. tripled up to 45%. In women that are really obese, you can have even 80% risk of infertility. But you still have that 20% of normal fertility. Not everybody that smokes has a lung cancer. I have friends that smoke a lot and do not have lung cancer. But this does not mean that tobacco is not related to lung cancer, right? I hope I have answered your question correctly.
The level that you have is not really high. And when the level is not really high, we usually suggest to repeat it. It’s because sometimes you can have isolated peaks of TSH. Anyway, if the level persists over 2.5, we usually give thyroxine, that is T4. It is usually given in low doses. I think 25 or 50 micrograms per day is enough in your case. But if this is an isolated level of TSH, my advice is to repeat the test in order to be sure that it is maintained over time.
T4 is a more stable hormone in order to determine the function of the thyroid gland. If endocrinologists see that TSH and T4 are normal, they usually don’t consider the level of T3.
31 is not really considered a high body mass index in relation to three spontaneous pregnancies and three miscarriages. So probably your level of BMI is not a reason for having recurrent miscarriages. Polycystic ovary syndrome (PCOS) is probably not the reason either. In polycystic ovary syndrome, there is a controversy whether it’s related to miscarriages or not – that is not clear. What happens in PCOS is that you can usually have a higher number of oocytes. Many of them are not good but the remaining oocytes are good – so finally we have good embryos. It means that if in a woman without polycystic ovary syndrome we obtain 8 oocytes and 4 embryos, in a woman with PCOS we can have 20 oocytes and finally 4 embryos, too.
That’s why when there is a comparison between the results in terms of clinical pregnancy rate and live birth rates between polycystic and non polycystic ovary syndrome women, the results are exactly the same. The women with PCOS produce more bad oocytes, but there are still the good ones in the cohort of all oocytes that we take. So I think that neither PCOS nor your BMI are the reasons of your miscarriages – but if you are 46, this is the reason.
If we discard any other problems, such as uterine problems, thrombophilia, chronic diseases, etc., the reason is your age. Last year you were 45 and if miscarriages occur over 40 years old, the age is probably the reason. So you have two things to do: one thing is to perform in vitro fertilisation with preimplantation genetic testing to discard abnormal embryos – but with your age, probably all of them will be abnormal. And the second option that I will advise is to perform ovum donation as the problem are your oocytes – due to your age.
If your husband has no symptoms, it is not a problem. Of course, if he has symptoms, he has to be treated as everyone else. But there is no clear relationship with the quality of sperm, if hypo- or hyperthyroidism is not really severe. So if your husband has no symptoms, it is ok. There is no reason to measure TSH as such level is of no importance.
Yes, it affects. But as I have shown in my presentation, the alteration is difficult to be seen by the conventional methods of sperm analysis because there is no clear effect in sperm concentration, motility and morphology. But eventually, the results are poorer in men. However, as you know, the sperm is not as important as all the components from the woman’s side. The body of the embryo is the oocyte, the chromosomal complement of the embryo is altered in women earlier than in men and finally, the uterus is yours and the pregnancy is yours as well.
So probably the contribution of the sperm to all the process is 10% and 90% is a woman’s part. This is why when we have an obese man with a normal-weight woman, the effect is mitigated. However, on the contrary, it is not. Of course, it is the best situation if both members of the couple are of normal weight.
The combination of obesity in both is related to reduced chances of a conception, even in a spontaneous conception. So the answer is: yes, high male BMI has a negative effect but when taking into account all the components that contribute to the achievement of a pregnancy, the aspect of the sperm is the least important.
Of course. If you perform preimplantation genetic testing for discarding chromosomal abnormalities, remember that these abnormalities can appear in any chromosome. Obviously, there are some chromosomes that are more frequently altered by different conditions, such as e.g. advanced age – but sometimes other less frequently affected chromosomes can be affected as well.
The problem of chromosomes is that sometimes we are focusing on those chromosomes that are more related to miscarriages or to Down syndrome, such as chromosome 15, 16, 18, 13 or 21. But there are other chromosomes that, when reduced in number (e.g. monosomy instead of trisomy) can be related to infertility and the lack of implantation. So if you perform preimplantation genetic testing, the advice today is to analyse all of them because each one can induce a different problem: no pregnancy, a miscarriage or a baby with some alteration.
The technology today can give us the analysis of all of them – at the same time and with a similar price. However, in young donors, there is no reason to perform preimplantation genetic testing.
For instance, in Spain we cannot do it because by law, all the donors are below 35. Recently, there has been a study published in which one group of randomised young women below 35 had preimplantation genetic testing performed while the other group of young women didn’t undergo it and had the embryos directly transferred without any prior analysis. And the results were exactly the same.
So there’s no reason to perform preimplantation genetic testing in young woman. Of course, you can discard Down syndrome but the risk of Down syndrome in young women is really low. So there is no reason to pay for it and there is no reason to do it because you are not going to improve the result.