Summary: My son was stillborn and I don't know why. My wife and I would like to have another child, but would very much not like to try if the probability of this occurring again is above a certain threshold (of which we have already settled on one). All 3 doctors I have consulted were unable to give a definitive cause of death, nor were any willing to give a numerical estimate of the probability (whether for reasons of legal risk, or something else) that our next baby will be stillborn. I am likely too mind-killed to properly evaluate my situation and would very much appreciate an independent (from mine) probability estimate of what caused my son to die, and given that cause, what is the recurrence risk?

Background: V (L and my only biologically related living son) had no complications during birth, nor has he showed any signs of poor health whatsoever. L has a cousin who has had two miscarriages, and I have an aunt who had several stillbirths followed by 3 live births of healthy children. We know of no other family members that have had similar misfortunes.

J (my deceased son) was the product of a 31 week gestation. L (my wife and J's mother) is 28 years old, gravida 2, para 1. L presented to the physicians office for routine prenatal care and noted that she had not felt any fetal movement for the last five to six days. No fetal heart tones were identified. It was determined that there was an intrauterine fetal demise. L was admitted on 11/05/2015 for induction and was delivered of a nonviable, normal appearing, male fetus at approximately 1:30 on 11/06/2015.

Pro-Con Reasoning: According to a leading obstetrics textbook¹, causes of stillbirth are commonly classified into 8 categories: obstetrical complications, placental abnormalities, fetal malformations, infection, umbilical cord abnormalities, hypertensive disorders, medical complications, and undetermined. Below, I'll list the percentage of stillbirths in each category (which may be used as prior probabilities) along with some reasons for or against.

Obstetrical complications (29%)

• Against: No abruption detected. No multifetal gestation. No ruptured preterm membranes at 20-24 weeks.

Placental abnormalities (24%)

• For: Excessive fibrin deposition (as concluded in the surgical pathology report). Early acute chorioamnionitis (as conclused in the surgical pathology report, but Dr. M claimed this was caused by the baby's death, not conversely). L has gene variants associated with deep vein thrombosis (AG on rs2227589 per 23andme raw data).
• Against: No factor V Leiden mutation (GG on rs6025 per 23andme raw data and confirmed via independent lab test). No prothrombin gene mutation (GG on l3002432 per 23andme raw data and confirmed via independent lab test). L was negative for prothrombin G20210A mutation (as determined by lab test). Anti-thrombin III activity results were within normal reference ranges (as determined by lab test). Protein C activity results were withing normal reference ranges (as determined by lab test). Protein S activity results were within normal reference ranges (as determined by lab test). Protein S antigen (free and total) results were within normal references ranges (as determined by lab test).

Infection (13%)

• For: L visited a nurse's home during the last week of August that works in a hospital we now know had frequent cases of CMV infection. CMV antibody IgH, CMV IgG, and Parvovirus B-19 Antibody IgG values were outside of normal reference ranges.
• Against: Dr. M discounted the viral test results as the cause of death, since the levels suggested the infection had occurred years ago, and therefore could not have caused J's death. Dr. F confirmed Dr. M's assessment.

Fetal malformations (14%)

• Against: No major structural abnormalities. No genetic abnormalities detected (CombiSNP Array for Pregnancy Loss results showed a normal male micro array profile).

Umbilical cord abnormalities (10%)

• Against: No prolapse. No stricture. No thrombosis.

Hypertensive disorder (9%)

• Against: No preeclampsia. No chronic hypertension.

Medical complications (8%)

• For: L experienced 2 nights of very painful abdominal pains that could have been contractions on 10/28 and 10/29. L remembers waking up on her back a few nights between 10/20 and 11/05 (it is unclear if this belongs in this category or somewhere else).
• Against: No antiphospholipid antibody syndrome detected (determined via Beta-2 Glycoprotein I Antibodies [IgG, IgA, IgM] test). No maternal diabetes detected (determined via glucose test on 10/20).

Undetermined (24%)

What is the most likely cause of death? How likely is that cause? Given that cause, if we choose to have another child, then how likely is it to survive its birth? Are there any other ways I could reduce uncertainty (additional tests, etc...) that I haven't listed here? Are there any other forums where these questions are more likely to get good answers? Why won't doctors give probabilities? Help with any of these questions would be greatly appreciated. Thank you.

If your advice to me is to consult another expert (in addition to the 2 obstetricians and 1 high-risk obstetrician I already have consulted), please also provide concrete tactics as to how to find such an expert and validate their expertise.

Contact Information: If you would like to contact me, but don't want to create an account here, you can do so at deprimita.patro@gmail.com.

^{[1] Cunningham, F. (2014). Williams obstetrics. New York: McGraw-Hill Medical.}

EDIT 1: Updated to make clear that both V and J are mine and L's biological sons.

EDIT 2: Updated to add information on family history.

EDIT 3: On PipFoweraker's advice, I added contact info.

EDIT 4: I've cross-posted this on Health Stack Exchange.

EDIT 5: I've emailed the list of authors of the most recent meta-analysis concerning causes of stillbirth. Don't expect much.

(Oops. I forgot this was moved to Discussion.)

TL;DR:  When people read a journal article that concludes, "We have proved that it is not the case that for every X, P(X)", they generally credit the article with having provided at least weak evidence in favor of the proposition ∀x !P(x).  This is not necessarily so.

 

Authors using statistical tests are making precise claims, which must be quantified correctly.  Pretending that all quantifiers are universal because we are speaking English is one error.  It is not, as many commenters are claiming, a small error.  ∀x !P(x) is very different from !∀x P(x).

 

A more-subtle problem is that when an article uses an F-test on a hypothesis, it is possible (and common) to fail the F-test for P(x) with data that supports the hypothesis P(x).  The 95% confidence level was chosen for the F-test in order to count false positives as much more expensive than false negatives.  Applying it therefore removes us from the world of Bayesian logic.  You cannot interpret the failure of an F-test for P(x) as being even weak evidence for not P(x).

Yesterday, my mother (not a rationalist) told me that she had recently heard somewhere (most likely on a popular television program) that, as simple as it sounds, an effective cancer treatment is cutting back on glucose intake. According to her story, cancer cells can only efficiently use glucose as fuel, and will be unable to multiply (or will starve, or something like that) if you don't consume any. Meanwhile, normal cells can convert other forms of energy into glucose inside their membranes, and then will continue functioning normally.

My first two thoughts:

Reality just can't be that nice.

Hey, wait a second, doesn't the body just convert everything into glucose before it's released into the bloodstream, anyways?

So I did some Googling and I found out that what my mother was referring to is called a ketogenic diet (from Wikipedia):

The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet that in medicine is used primarily to treat difficult-to-control (refractory) epilepsy in children. The diet forces the body to burn fats rather than carbohydrates. Normally, the carbohydrates contained in food are converted into glucose, which is then transported around the body and is particularly important in fuelling brain function. However, if there is very little carbohydrate in the diet, the liver converts fat into fatty acids and ketone bodies. The ketone bodies pass into the brain and replace glucose as an energy source. An elevated level of ketone bodies in the blood, a state known as ketosis, leads to a reduction in the frequency of epileptic seizures.

So, prima facie, my second objection was dealt with. More Googling led me to discover these two references to what my mother had mentioned:

• http://blogs.timesofindia.indiatimes.com/one-healthy-day-at-a-time/entry/ketogenic-diet-effective-against-metastatic-cancer
• The paper mentioned in the blog post, "The Ketogenic Diet and Hyperbaric Oxygen Therapy Prolong Survival in Mice with Systemic Metastatic Cancer".

According to the paper:

Abnormal energy metabolism is a consistent feature of most tumor cells across all tissue types [14]. In the 1930 s, Otto Warburg observed that all cancers expressed high rates of fermentation in the presence of oxygen [15]. This feature, known as The Warburg Effect, is linked to mitochondrial dysfunction and genetic mutations within the cancer cell [14], [16], [17]. These defects cause cancers to rely heavily on glucose for energy, a quality that underlies the use of fluorodeoxyglucose-PET scans as an important diagnostic tool for oncologists [18]. Ketogenic diets are high fat, low carbohydrate diets that have been used for decades to treat patients with refractory epilepsy [19]. Ketogenic diets also suppress appetite naturally thus producing some body weight loss [19], [20], [21], [22]. Dietary energy reduction (DER) lowers blood glucose levels, limiting the energy supply to cancer cells, while elevating circulating blood ketone levels [6]. Ketone bodies can serve as an alternative energy source for those cells with normal mitochondrial function [23], [24], but not for cancer cells [25]. DER has been shown to have anti-tumor effects in a variety of cancers, including brain, prostate, mammary, pancreas, lung, gastric, and colon [14], [26], [27], [28], [29], [30], [31], [32], [33], [34]. DER produces anti-cancer effects through several metabolic pathways, including inhibition of the IGF-1/PI3K/Akt/HIF-1α pathway which is used by cancer cells to promote proliferation and angiogenesis and inhibit apoptosis [35], [36], [37], [38], [39], [40], [41], [42]. Additionally, DER induces apoptosis in astrocytoma cells, while protecting normal brain cells from death through activation of adenosine monophosphate kinase (AMPK) [43].

Note what the sentence with ten citations says. Why have I never heard of this? If the basic claims being made are true, we seem to have an effective way of at least preventing cancer from progressing further (if not killing it off), and it's not even dangerous (at least compared to the alternatives, as far as I am aware of...however, I realize I know next to nothing in this field...that's the reason for this post)! Is there some reason this isn't being sung about on Reddit as a huge victory for science? What is the counterevidence? Or are we still waiting for more research to be done?

For genetic reasons and because humans often engage in motivated reasoning, I am skeptical. I am querying the Less Wrong community for more information...perhaps some of you have already heard of a ketogenic diet being used as a cancer treatment, or would like to do more research than I've done now that I've introduced you to it. The following books may also serve as helpful, albeit expensive, references:

• Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer by Thomas Seyfried.  I think this would be the "standard" reference here.
• The Cantin Ketogenic Diet: For Cancer, Type I Diabetes & Other Ailments by Elaine Cantin.
• Ketogenic Diets by Dr. Eric H. Kossoff (and others).

I just read this article (which is well worth reading for anyone interested in cryonics).  One of the important things that the article points out is that, while it takes some time for the memory structures of the brain to degrade due to ischemia, one of the more rapid effects is blood clotting in the fine capillaries of the brain after fairly brief ischemia.  This reduces the flow of cryoprotectant, and causes large swathes of neural tissue to be frozen, instead of vitrified, which would be catastrophic for personal identity.  While this is not a problem for best-case 'standby' cryonics, it is a problem for those who cannot afford a standby team, or are simply hit by cars.

Being an engineer, my first thought is that this is ridiculous, and there has to be a better solution to the problem.  It may be possible to build a device, maybe the size of a shoe box, which can be deployed in the field by a minimally-trained amateur (like a defibrillator), and perfuses the brain with cold saline and anti-coagulants -- or even a synthetic oxygen carrier).  I'm picturing a cylinder of fluid, large needles with sterilizing caps for tapping the jugular and carotid arteries, and a gas cylinder to provide pressure.  You'd simply break a chemical cold pack, put a plastic neck brace in place and insert the needles, and press a button.

Such a device could even be useful to non-cryonicists, as a way to prevent ischemic injury in people found medically dead at the scene of an accident, during transport to the hospital.  

Does anyone with more of a medical background know if such a machine would be at all feasible?  I can't imagine it would be expensive to construct.      

Those of us who have found the arguments for stagnation in our near future by Peter Thiel and Tyler Cowen pretty convincing, usually look only to the information and computer industries as something that is and perhaps even can keep us afloat. On the excellent West Hunters blog (which he shares with Henry Harpending) Gregory Cochran speculates that there might be room for progress in a seemingly unlikely field.

Low-hanging fruit

In The Great Stagnation, Tyler Cowen discusses a real problem – a slowdown in technical innovation,  with slow economic growth as a consequence..   I think his perspective is limited, since he doesn’t know much about the inward nature of innovation. He is kind enough to make absolutely clear how little he knows by mentioning Tang and Teflon as spinoffs of the space program, which is  of course wrong. It is unfair to emphasize this too strongly, since hardly anybody in public life knows jack shit about technology and invention. Try to think of a pundit with a patent.

Anyhow, it strikes me that a certain amount of knowledge  may lead to useful insights. In particular, it may help us find low-hanging-fruit, technical innovations that are tasty and relatively easy – the sort of thing that seems obvious after someone thinks of it.

If we look at cases where an innovation or discovery was possible – even easy – for a long time before it was actually developed, we might be able to find patterns that would help us detect the low-hanging fruit  dangling right in front of us today.

For now, one example.  We know that gastric and duodenal ulcer, and most cases of stomach cancer, are caused by an infectious organism, helicobacter pylori.  It apparently causes amnesia as well. This organism was first seen in 1875 – nobody paid any attention.

Letulle showed that it induced gastritis in guinea pigs, 1888. Walery Jaworski rediscovered it in 1889, and suspected that it might cause gastric disease. Nobody paid any attention.  Krienitz associated it with gastric cancer in 1906.  Who cares?

Around 1940, some American researchers rediscovered it, found it more common in ulcerated stomachs,  and published their results.  Some of them thought that this might be the cause of ulcers – but Palmer, a famous pathologist,  couldn’t find it when he looked in the early 50s, so it officially disappeared again. He had used the wrong stain.  John Lykoudis, a Greek country doctor noticed that a heavy dose of antibiotics coincided with his ulcer’s disappearance, and started treating patients with antibiotics – successfully.   He tried to interest pharmaceutical companies – wrote to Geigy, Hoechst, Bayer, etc.  No joy.   JAMA rejected his article. The local medical society referred him for disciplinary action and fined him

The Chinese noticed that antibiotics could cure ulcers in the early 70s, but they were Commies, so it didn’t count.

Think about it: peptic and duodenal ulcer were fairly common, and so were effective antibiotics, starting in the mid-40s. . Every internist in the world – every surgeon – every GP was accidentally curing ulcers  – not just one or twice,  but again and again.  For decades. Almost none of them noticed it, even though it was happening over and over, right in front of their eyes.  Those who did notice were ignored until the mid-80s, when Robin Warren and Barry Marshall finally made the discovery stick. Even then,  it took something like 10 years for antibiotic treatment of ulcers to become common, even though it was cheap and effective. Or perhaps because it was cheap and effective.

This illustrates an important point: doctors are lousy scientists, lousy researchers.  They’re memorizers, not puzzle solvers.  Considering that Western medicine was an ineffective pseudoscience – actually, closer to a malignant pseudoscience  – for its first two thousand years, we shouldn’t be surprised.    Since we’re looking for low-hanging fruit,  this is good news.  It means that the great discoveries in medicine are probably not mined out. From our point of view, past incompetence predicts future progress.  The worse, the better!

Link to post.

I think Greg is underestimating the slight problems of massive over-regulation and guild-like rent seeking that limits medical research and providing medical advice quite severely. He does however make a compelling case for there to still be low hanging fruit there which with a more scientific and rational approach could easily be plucked. I also can't help but wonder if investigating older, supposedly disproved, treatments and theories together with novel research might bring up a few interesting things.

Many on LessWrong share Greg's estimation of the incompetence of the medical establishment, but how many share his optimism that our lack of recent progress isn't just the result of dealing with a really difficult problem set? It may be hard to tell if he is right.

From Quora:

"Now Mr. Jobs always was a free thinker, a strong believer in spirituality, a vegetarian and a known skeptic of conventional medicine. He chose to reject conventional medicine altogether. He's not alone in that. We come across many people like this and we all know someone in our midst that uses homeopathy or has this known fear of anything "chemical" (to those I always say that everything is chemical, if you think dihydrogen oxide sounds scary you should stop drinking water). Individual freedom of thought and choice is a cornerstone of our modern society and the medical world makes no exception."

The placebo effect (benefit in groups receiving fake pills) and nocebo effect (detriment in those same groups) have frequently been the bane of medical research. They are usually explained in terms of psychology: because people receiving placebos believe they have been treated, they get psychosomatic effects that cure symptoms and create side effects. This explanation is supported by the fact that the placebo effect is strongest when the effect being studied is subjective - eg, tests of painkillers and antidepressants. This explanation is neat, tidy, and in my opinion, altogether unsatisfying.

I have an alternative theory. Most people in medical studies take more than one medication; in addition to the drug being studied, they take unrelated drugs and supplements, usually including a multivitamin and often including other things they were prescribed. However, many people take their pills inconsistently; they miss or mistime some fraction of their doses. This is especially true of depressed people. Prescribing a placebo, however, fixes this; when they take their placebo pill in the morning, they are reminded to take everything else they should be taking. In addition to making pill-taking more salient, being prescribed a placebo may also cause some people to fix the organization and affordances they have for taking pills.

I suspect that many of the benefits attributed from placebos may in fact be due to increased compliance with unrelated prescriptions and correction of vitamin and mineral deficiencies. Arranging a study to test this should be fairly straightforward; simply measure the rate at which unrelated prescriptions are refilled in two groups, one of which receives sugar pills and one of which does not.

A feature in Scientific American magazine casts some light on the troubled state of modern medicine.

Health Care Myth Busters: Is There a High Degree of Scientific Certainty in Modern Medicine?

Short excerpt:

We could accurately say, "Half of what physicians do is wrong," or "Less than 20 percent of what physicians do has solid research to support it." Although these claims sound absurd, they are solidly supported by research that is largely agreed upon by experts.

Scientific American often gates its online articles after some time has passed, so I don't know how long it will be available.