Preventing Miscarriages/Autism using Progesterone? And Sex-Specific Fetal and Placental Responses to Adversity

 

Today’s post returns to the theme of reducing the incidence/severity of future autism and introduces another factor that helps explain why girls have some degree of protection from autism.

The focus today is on female hormones and progesterone in particular.

It does look like hormones can play a role in both triggering and potentially treating some autism, but it is not an area likely to be followed up on in the mainstream.

We have seen previously in this blog that some infertility experts find an association between miscarriage and autism. One US fertility doctor has a prevent miscarriages website and a prevent autism website, because his feeling is that by reducing miscarriage risk, you may also reduce autism risk. He was shocked by how many of his fertility patients have other offspring with autism.

This should really be common sense.

·        In-utero stress increases the chance of a miscarriage

·        In-utero stress increases the chance of autism

The common solution would be to reduce sources of in-utero stress.  Which sounds simpler than it is.

I have previously looked in some detail into therapies that improve outcomes in traumatic brain injury (TBI), because much damage done in a TBI from a car crash, or skiing accident, occurs after the accident, as the brain over-reacts to the trauma and this then causes irreparable damage. Both the female hormones estradiol and progesterone, if given promptly, improve the outcome in TBI.  Another highly neuroprotective drug is Atorvastatin, from my son’s Polypill therapy, which has also been shown to improve outcomes in TBI; we even know how this happens. Atorvastatin, given intravenously, can extinguish a cytokine storm. Cytokine storms even play a key role in severe Covid-19, when lungs and other organs are damaged by the over-response of the immune system.

I was pleased to see that progesterone has recently been adopted as an approved therapy to prevent miscarriages in the United Kingdom.  I am actually really surprised that they were allowed to make the necessary clinical trials.  I would have thought this would be seen as unethical and risky.

 

Progesterone recommended to prevent early miscarriage

One of those behind the Tommy's National Centre for Miscarriage Research research, Prof Arri Coomarasamy, from the University of Birmingham, said  "This is a very significant moment.  We have an intervention that works that can stop a miscarriage. This gives hope to thousands of couples throughout UK. But it's really important to appreciate that only some miscarriages can be prevented by progesterone. There are other causes for miscarriages. We still need to study them. We need to find other effective treatment. About one in four pregnancies ends in miscarriage - the vast majority in the first few months or trimester.” 

 

Progesterone could prevent 8,450 miscarriages a year, finds new research 

PRISM studied 4,153 women with early pregnancy bleeding at 48 hospitals in the UK and found there was a 5% increase in the number of babies born to those who were given progesterone who had previously had one or more miscarriages, compared to those given a placebo.

The benefit was even greater for the women who had previous ‘recurrent miscarriages’ (i.e., three or more miscarriages) – with a 15% increase in the live birth rate in the progesterone group compared to the placebo group.

 

A 5% increase does not sound much.

A 5% reduction in autism incidence probably would not be seen as statistically significant. 5% would not be a very high hurdle for an autism prevention therapy. With a package of therapies, I think you could do very much better. I would consider “good” to be at least a one third reduction in genuine cases. Of course, it would be more complex, since in reality you would be reducing severity of autism. Autism is not binary, more like shades of grey.

 

Would progesterone reduce the risk of future autism?

I do not think we will ever get the answer that question.

Preventing miscarriage is seen as much more important than preventing autism.

The evidence for immediate treatment with progesterone or atorvastatin, after a head injury, has not led to its widespread adoption.  Try explaining that one to Mrs Schumacher (wife of the Formula One racing star, who had a traumatic brain injury while skiing)

The key take away from the PRISM miscarriage study is that progesterone treatment in pregnant women is safe.  It is also inexpensive.

 

Prenatal Hormones in Autism

In a perfect world, you would study hormone levels in pregnant women and find clear associations with autism incidence in offspring. We do not live in such a world.

In the research, hormone levels are all over the place and vary from study to study.

This can be seen as good news, since the range is so wide you can very likely increase the level of certain hormones without any unintended consequences.

  

Foetal oestrogens and autism

Oestradiol, oestrone, oestriol and progesterone each related to autism in univariate analyses after correction with false discovery rate. A comparison of standardised odds ratios showed that oestradiol, oestrone and progesterone had the largest effects on autism likelihood. These results for the first time show that prenatal oestrogens contribute to autism likelihood,

 

When I look at the above graph my conclusion is that the fetal estradiol (oestradiol, in UK English) level is all over the place.  It is nonsense to conclude that high levels are associated with autism. 

 

Autism Spectrum Disorder Risk in Relation to Maternal Mid-Pregnancy Serum Hormone and Protein Markers from Prenatal Screening in California

Results from this large, population-based study suggest that prenatal levels of the hormones, estriol and a gonadotropin (hCG), as well as MSAFP are associated with altered risks of having a child who later develops autism. Consistently, the risk of ASD was increased at lower levels of uE3; modelled both categorically or continuously, and examining the distribution graphically, the curve seems shifted to the left for cases. Further, the risk of ASD was increased with higher levels of MSAFP, while the associations with hCG were with both low and high levels. Although associations were modest, the fact that our results are based on levels of these prenatal markers measured during a developmentally-relevant period, and account for potential confounders, p

 

Our results suggest that continued investigation of prenatal hormones and possible mechanisms for an association with ASD is warranted. The associations we report were not of a large magnitude, which may make replication of the findings difficult in other studies that do not have access to the large numbers and unique resources we used. The 90th percentiles reflect MoMs of 1.7–2.0, which are not particularly high, but approach prenatal screening risk cut-points currently in use for other conditions (usually 2.0–2.5 MoM). The 10th percentile of uE3 is about 0.75 MoM. Measurement of additional estrogens, as well as androgens, from blood samples collected during pregnancy would be an interesting avenue for future research, if available in large enough studies. In addition, studies of endocrine-disrupting chemicals and genes involved in steroid hormone metabolism may yield further clues to a hormonal etiology for autism. Though modest increases in risk were seen in this large study, converging evidence suggests that ASD has multiple causes, and thus, identifying factors with small associated risks may help to better understand ASD and potential mechanistic pathways.

  

The Prenatal Hormone Milieu in Autism Spectrum Disorder

Though the etiology of autism spectrum disorder (ASD) remains largely unknown, recent findings suggest that hormone dysregulation within the prenatal environment, in conjunction with genetic factors, may alter fetal neurodevelopment. Early emphasis has been placed on the potential role of in utero exposure to androgens, particularly testosterone, to theorize ASD as the manifestation of an “extreme male brain.” The relationship between autism risk and obstetric conditions associated with inflammation and steroid dysregulation merits a much broader understanding of the in utero steroid environment and its potential influence on fetal neuroendocrine development. The exploration of hormone dysregulation in the prenatal environment and ASD development builds upon prior research publishing associations with obstetric conditions and ASD risk. The insight gained may be applied to the development of chronic adult metabolic diseases that share prenatal risk factors with ASD. Future research directions will also be discussed.

 

Female placentas are “superior” to male placentas.  Note the placenta has the same sex as the fetus and yes, it is a binary choice.

  

Sex-Specific Fetal and Placental Responses to Adversity

Fetal growth, development, and HPA axis programming in the setting of obstetric adversity differ by fetal sex (173–175). These sex-specific responses serve as additional mechanisms in which to consider male ASD predominance (see Figure 2). As the placenta is derived from extra-embryonic tissues, the placenta has the same sex as the fetus (178). Evidence suggests that the placentas of male and female fetuses differ in response to adverse prenatal environments through modulation of steroid pathways, placental genes, and protein synthesis (176). Placental growth and structure differ by sex, with male placentas being smaller in size but more efficient at nutrient and oxygen delivery (179, 180). Fetal growth depends upon the limited capacity of the maternal-placental interface to deliver oxygen and nutrients. Thus, greater placental efficiency among males precipitates faster somatic growth while increasing vulnerability to in utero perturbations (179, 181). This may have deleterious neurodevelopmental consequences, as fetal brain development relies on the availability of oxygen and nutrients such as fatty acids, glucose, and amino acids (131, 182, 183). In contrast, female placentas may have superior ability to buffer and adapt to suboptimal prenatal conditions (180).

 

Sex-specific fetal and placental adaptations to maternal adversity. Placentas of male and female fetuses respond differently to mild forms of maternal adversity. In the placenta of female fetuses, multiple changes in glucocorticoid barrier enzyme activity, gene expression, and protein synthesis occur leading to decreased growth (176, 177). This is advantageous as it preserves fetal oxygen and nutrient delivery. In the placenta of male fetuses, minimal changes in gene and protein expression occur, and the male fetus continues to grow incurring increased vulnerability to adverse outcomes (176). 

Figure 3 links heightened in utero stress from inflammation, stressors, and metabolic disturbances to perturbation within the prenatal hormone milieu. Through pCRH stimulation, the placenta upregulates fetal HPA axis activity in response to in utero stress. Subsequently, the fetal adrenal glands increase DHEA(S) synthesis leading to elevated placental estradiol production. Higher placental estradiol and pCRH production promotes HPA axis maturation denoted by fetal adrenal de novo cortisol synthesis. In response to in utero stress, the placental also increases hCG production which stimulates fetal gonadal testosterone synthesis.

 

Linking in utero stress to increased fetal steroidogenic activity and ASD biomarkers at mid-gestation.

 

In utero stress we see raises estradiol in the mother, but also increases testosterone in the males fetus.

The stress hormone, cortisol is elevated in the fetus.

You might imagine that less testosterone and more estradiol would be neuroprotective.

We know that progesterone is neuroprotective and now we know that its use is safe.

 

Conclusion 

Nature does sometimes stumble short of perfection and this is inevitable.  Going too far preventing miscarriages would not be wise, but improving the outlook of a viable fetus looks like a good idea.

Miscarriage is defined as pregnancy loss before 23 weeks’ gestation.

More than 80% of miscarriages occur before the 12th week, and the rate decreases rapidly thereafter.

Chromosomal anomalies cause at least half of these early miscarriages; for example, male fetuses with Rett Syndrome.  This is nature’s way of dealing with a non-viable fetus.  Only girls with Rett Syndrome can survive, since they have one good copy of the the MECP2 gene, males have none. MECP2 is on the X chromosome (girls have XX and boys have XY).

A little helping hand from Progesterone looks like a wise idea.

But, how slowly things move in medical science. The paper below is from 2013.

Use of progestagens during early pregnancy

“During the past 50 years several trials investigated the use of progestagens for the prevention of miscarriage. Actually the therapeutic value of progestagens remains to be established. This might be due to the poor design of the studies which evaluated hormone effectiveness”

 

The issue with using any hormone to prevent/minimize autism is the potential for harm.  This did not seem to worry people in 60 years of trials in miscarriage.

I think we can conclude that progesterone for the prevention/reduction in severity of autism is very likely entirely safe.  Would it be beneficial?

We know that women with Polycystic ovary syndrome (PCOS), a condition in which the ovaries produce an abnormal amount of androgens (male hormones), have an increased chance of producing children with autism.  They might be a good place to start with a clinical trial.

The fact that female placentas give more protection against adversity during pregnancy is interesting and another contributing factor to the lower prevalence of autism in girls.  It is only certain types of autism where girls have protection. In the case of severe autism, girls are more likely to have detectable genetic anomalies than boys, making whole exome sequencing (WES) well worthwhile. It looks like girls are protected somewhat from multifactorial autism, which I think makes sense; they might just end up with some dyslexia or sub-clinical autism.

Multifactorial autism should be the type that you can minimize, by lightening the contributing adverse burdens.  This itself requires a multifactorial approach.

Averting Autism - Antenatal Antioxidants? But Male, Female or Both?

 

 Salem College

 

Today’s post is the first of two new ones about preventing/minimizing future autism.  The second post will be about Dr Ramaekers’ idea of using Calcium Folinate, which he has already put into use in human parents seeking to avoid autism in their next child. 

Before we start, I should point out that while readers of this blog, and it seems Dr Ramaekers, likely wish that autism and its symptoms did not exist, there are some people, well paid to research autism, who think autism is a good thing. I really do wonder why such people receive any public funding and wonder what kind of University would employ such people. It is like researching deafness, but not wanting to treat it - better they stay home.

https://www.sciencedaily.com/releases/2020/08/200824091958.htm

Simon Baron-Cohen, PhD, Director of the Autism Research Centre at Cambridge, who co-led the study, added, "Some people may be worried that basic research into differences in the autistic and typical brain prenatally may be intended to 'prevent,' 'eradicate,' or 'cure' autism. This is not our motivation, and we are outspoken in our values in standing up against eugenics and in valuing neurodiversity. Such studies will lead to a better understanding of brain development in both autistic and typical individuals."

Even more odd is that Baron-Cohen's sister had a rare mutation of the GNAQ gene that led to intellectual disability and a reduced lifespan. Why would you not want to treat/prevent that?  Treating your sister would not have meant you did not value her, it would have been another sign that you loved her. 

A positive example is another autism researcher, Manuel Casanova, and his family, who set up a research effort for people who have a disorder related to the gene NGLY1.  Sadly, Manuel's grandson passed away, but the research goes on.   

If you can escape from intellectual disability, someone should make it happen.  That someone might be you.

 

I must admit I had never heard of Salem College.  It is an all-female college in Winston-Salem, North Carolina.  It is the source of another idea to avert autism, this time treating the future father with an anti-oxidant like NAC.  NAC was already on my list for future mothers.  When it comes to autism, it looks like little Salem College is going to be more useful than stuffy old Cambridge University.

I am rather surprised there still are all female colleges, but in the US, there are many.

My mother went to an all-female college at Cambridge University, back then they had no mixed colleges.  Only after 1948 could women even receive a degree at the end of their studies. Cambridge University still has three all-female colleges.

Clearly male post-conception antioxidant supplementation is not going to help.

We have already seen in the research that the future father can damage the DNA he passes on to his offspring.  This was done via epigenetic tags on his DNA caused by things like recreational drug use, or smoking tobacco.

The author of today’s paper look’s exclusively at autism risk from the father, but exactly the same therapy during pregnancy can reduce risk from the mother.  The maternal immune activation model is one of the most studied in autism. We also know that emotional stress during pregnancy increases autism risk.  Emotional stress leads to oxidative stress.

The only issue I had with this preventative approach is whether there are any negative effects from antioxidants during pregnancy.  There may well be none, since the body just adjusts production of its own antioxidants.

There was an interesting experiment I mentioned a while back about giving antioxidant or “detox” juices to healthy young people.  The anti-oxidants from the fruits just made the body reduce its own production of GSH/glutathione, so the net result of the detox juice was actually negative.  People in oxidative stress benefit from anti-oxidant therapy, everyone else is wasting their money.

There are highly conflicting reports as to whether autism tends to come from the mother’s half of the child’s DNA or from the father’s half.  In reality it does not matter, it can from either, both or neither.  What is important is to take whatever simple safe steps you can to avert future autism. 

Future parents taking NAC and Calcium Folinate, might as well join the idea of keeping pets at home during pregnancy to get exposure to the evolutionarily expected bacteria that are needed to calibrate the immune system of the fetus/baby. Humans have been living with dogs, and very importantly their bacteria, for 11,000 years.  Only very recently did humans come up with the idea of trying to kill 99.9% of bacteria in their homes. 

Dogs are humans' oldest companions, DNA shows

I really do not see anyone doing a placebo controlled clinical trial on any of this.  Nobody who agrees to participate will accept the risk of being in the placebo group.  You would have to create a control group out of people who did not want to join the trial.  The people who join the trial are self-selected and are more likely to be health conscious, or have a family history of autism or dys-something else.

Male preconception antioxidant supplementation may lower autism risk: a call for studies

Current research indicates that a sizable number of autism spectrum disorder (ASD) cases arise from de novo mutations (DNMs) occurring within the paternal germline, usually in an age-dependent manner. Andrologists have reported that somatic cells and gametes share the same pathologies that generate these DNMs—specifically, DNA hypomethylation caused by oxidative nucleoside base damage. Because many ASD researchers seek to identify genetic risk factors, teams are developing methods of assessing aberrant DNA patterns, such as parental gonadal mosaicism. Several studies propose antioxidant supplementation as a strategy to lower autism risk, and/or suggest connections between childhood neurodevelopmental disorders such as autism and paternally-derived DNMs. Actual data, however, are currently not available to determine whether male preconception antioxidant supplementation effectively lowers autism risk. The purpose of this paper is to (1) explore the mechanisms causing DNMs, specifically DNA hypomethylation; (2) explain how antioxidant supplementation may lower the risk of having a child with ASD; and, (3) advocate for the implementation of large prospective studies testing (2). These studies may very well find that male preconception supplementation with antioxidants prevents neurodevelopmental disorders in offspring, in much the same way that female prenatal consumption of folate was found to decrease the risk of birth defects. If this is indeed the case, the alarming rise in autism prevalence rates of the past few decades will slow—or even cease—upon the initiation of public awareness campaigns.

  

Antenatal antioxidants to avert autism?

Paternally derived de novo mutations (DNMs) caused by oxidative stress (OS) have been implicated in the development of autism spectrum disorders (ASDs). Whether preconception antioxidant supplementation can reduce the incidence of ASDs by reducing OS is an area of uncertainty and potentially important future scientific investigation.

The recently completed double blind, multicenter, randomized controlled Males, Antioxidants, and Infertility (MOXI) trial by the Reproductive Medicine Network (RMN), funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), investigated whether antioxidants improve male fertility, as measured by semen parameters and sperm DNA integrity at 3 months and pregnancy by 6 months of treatment [11]. The RMN investigators found that antioxidant treatment of the male partner does not improve semen parameters, sperm DNA integrity, or in vivo pregnancy rates in couples with male factor infertility, prompting the question whether antioxidant therapy should no longer be routinely recommended for infertile men [12]. It would be intriguing to evaluate the offspring from the participant couples of the MOXI trial for ASD. However, with only 13 live births in the antioxidant group and 21 live births in the placebo arm, the study would be vastly underpowered to demonstrate a benefit of antioxidants in the prevention of a condition with an incidence of 1 in 54 children.

The next post is about Dr Ramaeker's clinical trial of calcium folinate in children with autism and his comments about their parents and future siblings.