Cesarean section association with autism and attention deficit?

30 Sep

A recent New York Times headline stated “Children born by cesarean section may have important differences that affect their neurodevelopment”, based on a recent JAMA article1. The neurodevelopmental outcomes that were correlated were autism and attention deficit disorder.

The article goes on to explain that this is an association not a cause, and that conditions requiring a Cesarean section could cause the association, rather than the procedure itself. The article is a meta-analysis and does not subgroup Cesarean sections, for example, those done for non-reassuring fetal heart tracings. I think this is an important piece of missing data. My concern is that experimental evidence has demonstrated that very minimal hypoxic stress to a pregnant animal can cause pontosubicular neuronal necrosis in the fetus. I will discuss the specifics of the lesion below, but the importance is that relatively mild episodes of hypoxia/ischemia in the infant brain can cause loss of specific groups of neurons. In the typical sheep experiment, this lesion occurs after just 10 minutes of complete umbilical cord occlusion2-4. It is not a stretch to suggest that some of the infants undergoing emergency Cesarean sections have equivalent episodes of hypoxia.

Pontosubicular neuronal necrosis is a pathological lesion in which individual neurons in the basis pontis and in the subiculum show karyorrhexis (breaking apart) of the cell nucleus. In both experimentally produced lesions and in autopsy tissue, the karyorrhectic neurons demonstrate evidence of apoptosis5-8. These neurons are responding to the hypoxic event with basically programmed cell death, or as sometimes put, cell suicide. The cell death is not the direct result of hypoxia or acidosis. As discussed in my blog pages on primate models and particularly on Ron Myers model, neuronal necrosis occurs in a stereotyped pattern of progressively recruited areas of the brain the longer the infant monkey is completely hypoxic. This is a different pattern from the extensive coagulation necrosis seen in the white and gray matter with partial hypoxia. This latter pattern is typical of cerebral palsy. Myers proposed that the sequence of areas reflected damage starting with the most metabolic active areas progressing to less active areas. These studies evaluated neuronal necrosis starting at 14 minutes of total asphyxia, and did not include pontosubicular necrosis, but the appearance of the more advanced lesions is very similar to those in the pons and subiculum.

As a pathologist, I have often seen pontosubicular necrosis in stillborn infants in which an anatomic cause of death was not found (Fig 1).

fig 6927

This photomicrograph from the region near CA1 of the hippocampus shows numerous karyorrhectic neurons (arrows) H&E 40x

In these cases it is not unreasonable to speculate that the lesion reflects as recurrent or persistent hypoxic event prior to the final lethal event. Others have published on the finding of neuronal necrosis in stillbirth9,10. Since even apoptosis takes time, the lesion was not likely the result of the immediate episode that caused death. Interestingly, the lesion is found in neonates with more chronic causes of hypoxic (and hyperoxic) episodes and must be part of an ongoing process11. The dead cells are then removed without inflammation or scarring. The scattered, necrotic, cells that I see as a pathologist would not be detectable by the usual clinical imaging techniques. We simply have no way of knowing if pontosubicular necrosis has occurred in a living infant.

It is unclear if neurons are later replaced after pontosubicular necrosis or if a specific population of cells is permanently reduced. In my examination of the slides, the karyorrhectic cells appear to be in Sommer’s sector (CA1) of the hippocampus, the anatomic area adjacent to the subiculum, but I am not a neuropathologist, and the brains are very small. In either location, this is an area that appears to be important in correlating positional information with other cues12. Its role in memory and emotion is likely complex. Uncal lesions in the monkey brain lead to a lack of response to social cues (The uncus is in physical continuity with the hippocampus.)13. A reasonable hypothesis is that loss of certain neurons could influence attention and response to environmental clues. Mostly as an aside, the evolutionary basis if any of cell apoptosis in the developing brain to hypoxic stimuli is curious, but we know that the developing brain is in some sense a competitive environment for neurons, and perhaps apoptotic pathways may be hijacked by the external fetal hypoxic event.

The importance of noting the risk of subtle neuronal necrosis is important. If neuronal necrosis is causing neurodevelopmental disease with relatively mild fetal hypoxia, then anti-apoptotic therapy may be better. In the experimental worm, C. elgans mutations of the insulin/ insulin growth factor homolog DAF-2 can help prevent apoptosis 14. Identifying similar mutations in humans that could influence susceptibility to neuronal necrosis might allow more aggressive obstetrical care. More information on the mechanism and outcome of pontosubicular necrosis is needed. Further investigation of subtle neuronal necrosis following brief fetal hypoxia may provide insight into one possible lesion for a link between Cesarean section and neurodevelopmental pathology of autism and attention deficit.

 

 

References:

  1. Zhang T, Sidorchuk A, Sevilla-Cermeno L, et al. Association of Cesarean Delivery With Risk of Neurodevelopmental and Psychiatric Disorders in the Offspring: A Systematic Review and Meta-analysis. JAMA Netw Open 2019;2:e1910236.
  2. Mallard C, Gunn A, Williams C, Johnston B, Gluckman P. Transient umbilical cord occlusion causes hippocampal damage in the fetal sheep. Am J Obstet Gynecol 1992;167:1423-30.
  3. Keunen H, Deutz NE, Reempts JL, Hasaart TH. Transient umbilical cord occlusion in late-gestation fetal sheep results in hippocampal damage but not in cerebral arteriovenous difference for nitrite, a stable end product of nitric oxide [In Process Citation]. J Soc Gynecol Investig 1999;6:120-6.
  4. Fujii EY, Takahashi N, Kodama Y, Roman C, Ferriero DM, Parer JT. Hemodynamic changes during complete umbilical cord occlusion in fetal sheep related to hippocampal neuronal damage. Am J Obstet Gynecol 2003;188:413-8.
  5. Rossiter JP, Anderson LL, Yang F, Cole GM. Caspase-3 activation and caspase-like proteolytic activity in human perinatal hypoxic-ischemic brain injury. Acta Neuropathol 2002;103:66-73.
  6. van Landeghem FK, Felderhoff-Mueser U, Moysich A, et al. Fas (CD95/Apo-1)/Fas ligand expression in neonates with pontosubicular neuron necrosis. Pediatr Res 2002;51:129-35.
  7. Stadelman C, Mews I, Srinivasan A, Deckwerth TL, Lassmann H, Bruck W. Expression of cell death-associated proteins in neuronal apoptosis associated with pontosubicular neuron necrosis. Brain Pathol 2001;11:273-81.
  8. Takizawa Y, Takashima S, Itoh M. A histopathological study of premature and mature infants with pontosubicular neuron necrosis: neuronal cell death in perinatal brain damage. Brain Res 2006;1095:200-6.
  9. Mito T, Kamei A, Takashima S, Becker LE. Clinicopathological study of pontosubicular necrosis. Neuropediatrics 1993;24:204-7.
  10. Grafe MR, Kinney HC. Neuropathology associated with stillbirth. Semin Perinatol 2002;26:83-8.
  11. Ahdab-Barmada M, Moossy J, Painter M. Pontosubicular necrosis and hyperoxemia. Pediatrics 1980;66:840-7.
  12. Bilkey DK. Neuroscience. In the place space. Science 2004;305:1245-6.
  13. Dicks D, Myers RE, Kling A. Uncus and amiygdala lesions: effects on social behavior in the free-ranging rhesus monkey. Science 1969;165:69-71.
  14. Scott BA, Avidan MS, Crowder CM. Regulation of hypoxic death in C. elegans by the insulin/IGF receptor homolog DAF-2. Science 2002;296:2388-91.

 

A new page on Villitis of Unknown Etiology

27 Aug

This is another segment of a chapter. I hope it usefully shares some of my experience looking at this entity under the microscope.

Comments on Spiral Artery

27 Jun

Dr. Peilin Zhang has submitted some interesting comments to this blog. Dr. Zhang suggests that we try to evaluate the early stages of trophoblast remodeling by measuring smooth muscle antigens from damaged media in maternal blood.

He also suggests that we try to pool pregnancy information on patients with the genetic defect, MonoMac or Emberger’s syndrome in which NK cells, monocytes and B-cells are absent or low due to GATA2 mutations.

Thank you Dr. Zhang!

Go to the end of the Spiral Artery page to see his comments.

An Obstetrical Care Research Center

8 Feb

 

These are just some preliminary ideas. It is not a proposal to start all at once, nor is it a thought out blueprint. Possible funding is guess work All of this would take a lot of leg work.

1. Emergency team for abnormal FHR:

Experience: I have reviewed over 600 “bad baby” cases.

Insights:A. An obstetrician with a difficult decision based on fetal monitoring might benefit by real time consultation with a team that works on this specific management problem all the time.

  1. I don’t think (tell me if I am wrong) that the obstetrician usually knows anatomically what is causing the abnormal heart rate. It is not enough to know that there are deep variables, I would want to know how is the cord compressed.

Response:1. Team MFM and Nursing that keeps up with the literature, reviews hospital cases, but also legal cases, and is on call by phone to look at tracings, and manage in consultation with obstetricians including hospitalists.

  1. Develop research protocols such as immediate imaging options to identify cord compression or fetal risk such as NMR of brain pH to better evaluate new therapeutic options for in utero rescue.

Goals:A. Prevent low Apgars while still reducing C-sections for non-reassuring heart tracings.

  1. Convince liability insurers to reduce our rates because of the program

Funding:Liability insurers, NICHD

 

2. Improved stillbirth care:

Experience: I have preformed around 2000 perinatal autopsies. I have participated on and off in FIMR since its beginning.

Insights: A. The precise cause of death is often unknown. The autopsy in cases of unknown cause often shows features that are the same as those found in deaths due to known causes of asphyxia.

  1. Parents often don’t truly understand what we do or don’t know after the autopsy.

Response: A. Develop research protocols that include offering an MRI of the stillborn infant before delivery. B. Create a stillbirth team that can be consulted for patient interview at the time of discovery of the death and post autopsy review that included the parents, caregivers and pathologist with training similar to that of Dr. Orsini for newborn deaths.

Goals: A. Learn information that may improve prevention of stillbirth

  1. Improve the caring part of obstetrical care.

Funding:Parent groups like Star Legacy (I am currently working on a meta-review on umbilical cord with Dr. Heazell in Manchester England funded by the group); NICHD

 

 

4. Placenta diagnostic utility to maximize value:

Experience:I have examined more than 50,000 placentas. I have organized many studies of placenta pathology clinical correlation, but 2 stand out (see foot note *). I participated in the just published monograph of the international consensus on placental pathology. (Pathology of the Placenta, a Practical Guide, editors Khong et.al., Springer)

Insight:Placental diagnostic examination requires better standardization, and better understanding of its diagnostic implication by both clinicians and pathologists. Criteria for submitting placentas to pathology are still subjective, and not based on clinical utility.

Response: The use of the placenta examination needs to be critically reviewed by a maternal fetal medicine specialist, pathologist, and neonatologist team, to develop guidelines for submission and interpretation.

Goals:A. To reduce unnecessary placental examination, and to better utilize placental examinations that are performed.

Funding:Medical Insurers, NICHD

 

5. Research into how to meet the logistical needs of patients:

Experience:Observation of the obstetrical care of my wife for 4 daughters, and for my 8 grandchildren.

Insight:Problems with transportation, baby sitting, communication, finances, etc. have a large impact on the quality of care received and the patient’s evaluation of the institutional experience.

Response: A team to review patient concerns and problems with the aim of developing and testing creative solutions.

Goals:Better patient care and better perception of the hospital system as a caring place for obstetrics.

Funding:Hospital funding, State funding

 

6 . A center for improved obstetrical technology:

Experience:Submission of a proposal for a device to detect preterm labor for Coulter grant. (see footnote **)

Insight:There is a need for a center to focus on sophisticated obstetrical technology, for example devices to detect and monitor early signs of and progression of labor and of fetal well being. There is a need for new diagnostic tests, for example to detect molecules in cord blood to detect timing of brain injury or identify pathogens quickly.

Response:To create a group of obstetricians, engineers, and pathologists to meet regularly to discuss potential technical solutions to problems in obstetrics. The goal would then be to develop those ideas into useful tests or devices.

Goals:To develop patentable devices that would improve patient care and generate income for the participating parties.

Funding: Industry, NICHD

 

Footnotes:

 

 

*When I first started in obstetrical pathology I initiated and completed a project that asked obstetricians to check on a list what they hoped to learn from the placenta examination. The placenta pathology reports were then analyzed in a conference with the MFM fellow (Dart Mostello) MFM (Menachem Miodovnik) and Neonatologist (Uma Kotagal) as to whether the question was answered, but even more importantly whether the exam was useful for clinical care of the patient in the current or future pregnancies, for potential quality control value, for teaching value, for medico legal value, research or of no value. The results showed very disappointing utility. I forget how many we did or the exact numbers, but clinical utility was close to zero. I submitted the paper to AJOG who trashed it as non-scientific. I foolishly gave up trying to get it published. Wind the clock ahead thirty five years and I did the PROOF study here based in part on Dr. Stan Gall’s contention that all placentas should be looked at since they might contain information that we could not at the current time appreciate. I went a step further and suggested two hypotheses that I thought had a strong chance of showing utility of the placental examination, yet did not necessarily have any clinical signs. These were severe villitis as a predictor of the risk of autoimmune disease and small placental separations as impacting neurologic outcome. The study demonstrated that at least up to age 7 years, the lesions were not predictive of disease.

 

**A few years back I worked with Dr. Harnett from the U of L engineering school to try to apply for a Coulter grant for a device that measured cervical changes. It was a simple grid on a silicon rubber band that fit over the cervix and generated a signal without a battery if the band was distorted. It works well on the skin surface, but the signal did not penetrate to the outside when we put it around the cervix of a dead sheep. But there is no reason that it could not be made to work, and could probably also detect softening as well, and signal this to a smart phone or watch.

Another example of useful technology occurred to me as I watched a nurse spend the majority of her time repositioning the fetal heart beat sensor over the two heartbeats of my daughter’s twins. If the sensor had servomotors and could follow the signal strength by angling the sensor, it could save a lot of nursing time and produce a more reliable tracing.

 

New page on fetal cells

18 Oct

Most of the pages posted on this cite had been prepared with the idea of writing a textbook on obstetrical pathology, and as noted before, being unable to find a publisher. I thought it might be helpful to add the original chapter numbers to try to create some order to the posted pages. Chapter 7 was primarily in the first section of the book on fetal asphyxia, and would have dealt primarily with nucleated red cells. However, I had prepared material on other uncommon findings in fetal blood cells and posted them on this site long ago. I copied that material to the end of this chapter directly from that blog.

TIPPS: The International Placental Pathology Study Group?

11 Sep

 

Some years ago, I had initiated a group, MAPS,  (MidAmerica Placenta Study group) with the idea that it would encompass placental pathologists who could easily get together to meet. I sent out a newsletter with placental slides for discussion. We had 2 meetings. One locally in which the pathologists came more or less locally, from St. Louis, Detroit, Cleveland, Chicago, and Birmingham Alabama. Kurt Benirschke came from San Diego. The next meeting was in Toronto preceding the SPP meeting and by then we had members from all over as far away as Australia. Given the capability of the internet for rapid communication, I think we should form The International Placental Pathology Study Group, (TIPPS Group).

 

I am going to use a recent paper to provide an example/argument for the value of an online interactive placental/perinatal pathology group (1). The paper reviews the association of a blood clot received with the placenta with finding basal plate myofibers on microscopic examination.  The logic of the study is that if a placenta has focal adherence to the myometrium, it will not separate immediately after postpartum contraction of the uterus. However, a portion will separate, and beneath that separated area of retained placenta there will be decidual hemorrhage. Recent reports that basal plate myofibers are a marker of increased risk for placental accreta in subsequent pregnancies, makes improved criteria for finding the lesion clinically important.

 

As with many papers as I read them I have questions I wish I could ask the authors. I had trouble understanding how the placentas were selected. The N for the study is 156 “routine placentas”. They represented 11% of 1,471 “placenta cases”.  To me this could mean two different things. Either there were 156 placentas submitted to pathology from 1,471 placentas delivered, or 156 placentas were selected for the study presumably because they had been grossed by a specially trained pathology assistant and then evaluated by a board certified pediatric pathologist. There was no review of the clinical charts, and certainly no prospective attempt to obtain information about type of delivery, vaginal bleeding, length of third stage of labor, manual extraction, history of prior Cesarean deliveries, location of the placenta in the uterus. Some information however was provided based on the pathology requisition. Was there enough clinical information to exclude bias in which placentas were sent to pathology? For example, if all Cesarean sections, or manually removed placentas, or postpartum hemorrhage were sent to pathology, then the prevalence of either the evidence of an acute hemorrhage or of myofibers might be enhanced.  I was surprised that 21% of cases had “significant retroplacental blood and that 21cases (13.5%) had basal plate myofibers (some detected by actin). The authors describe clinical criteria as well as histological features, that suggest using an actin stain, but it was less clear how they had selected the individual cases. While I don’t think these questions (misreadings) of the paper would have any impact on the conclusions, would it not be helpful to be able to communicate directly with the authors and  have questions answered or points clarified. The authors likely have more information than they can impart in the confines of a formal paper.

I would also like the ability to have an open discussion of placenta accreta in general.  In my page on Chorioamnionitis, I organized it around naïve questions, and I think that is a good approach for out of the box discussion. For example, I have assumed that placenta accreta forms over an area without decidua and the chorion plate then attaches firmly to the muscle. As a result the placenta cannot be detached from the uterus (as it also can not be detached from the decidual tissue). What do we know about this gluing? I believe that fetal fibronectin and annexins are critical components. But how strong is this gluing? In classic cases of accreta with hysterectomy, the placenta remains adherent in some areas with the cleavage going through the placental tissue. How much force does it take to remove a placenta with cleavage through the myometrial layer without tearing the placenta?

How many patients with BPMF had risk factors that far exceed those of histological risk, such as placenta over an old C-section scar? What is the mechanism of accreta in those who do not have clinical risk factors?  Perhaps a plausible mechanism is that the implantation in some way destroys the underlying endometrium in some cases. How does this relate to the other histological lesions reported in the paper, which did not reach statistically significant correlations? Finally, with mechanical removal of the placenta in cases with accreta, why does the uterus not contract and stop the maternal hemorrhage?

Most important to me was that the article reminded me of the useful studies that could be accomplished if we worked as a large network of perinatal pathologists. A simple study would be to look at prior placentas from cases that had Cesarean hysterectomy specimens with confirmed placenta accreta. Any such study would want to collect some basic data on gravidity, prior Cesarean sections, and the gravid order of any placental pathology found. We would also want to keep track of the number of sections taken of the placental base. This study would be retrospective, with specific criteria for basal plate myofibers. The controls could be 2 placentas based on gestation and proximity to the index case. Slides could be blindly reviewed by other pathologists in the study, and questionable cases could be reviewed by all using digital images. The group could help navigate the administrative side such as IRBs and HIPPA in the USA. We might be able to find some funding for recuts and mailing, and find statistician help. The authors of the above paper might be the ones to initiate and coordinate it, or someone else who is so inspired.

I am just throwing out ideas.  Are there any others out there who think this might be a good idea? I suspect others might have different goals or structures for the group. I hope to hear from you.

(1) Wyand R., Cramer S. F., Oshri A., Heller D. S. Association of Retroplacental Blood with Basal Plate Myofibers. Pediatr Develop Pathol (2018) 21:371-379.

A Simple Measure: Kick counts (and a plea for measuring the untethered length of the umbilical cord)

8 Sep

The following news article on Kick Counts strikes me as very important:

 https://www.huffingtonpost.com/entry/counting-kicks-prevent-stillbirths_us_5b927693e4b013f66bd56b19

The success of a program to educate mothers about kick counts in reducing stillbirth may still need further confirmation in other states, but it is a very promising start.

The obstetricians seem to accept the cord wrapping as the cause of death. No one is still doing another simple measure, the length of cord from the start of the wrapping to the placenta. Our simple in vitro research suggests that too short of a functional free cord length put the cord for risk of torsion that can collapse umbilical vein blood flow. If obstetricians started recording this length we might learn when the shortness of this distance becomes dangerous.

The article also does not state explicitly, but implicitly shows, that there is time to rescue the infant. The innovative studies of Drs Theonia Boyd, Mana Parast and others have shown that there is time for fetal vascular occlusive lesions to develop in the placenta, which is evidence of hours to days of a continuing or intermittent process, before fetal death. The autopsy of stillborn infants often shows pleural and pericardial effusions, and dilated cardiac chambers, suggestive of less than immediate asphyxia. The pathology evidence suggests that some stillbirths can be detected and prevented. This innovative inexpensive program to just educate mothers is perhaps the most encouraging evidence yet. When I was on the FIMR panel in Louisville, mothers were often aware of some decreased fetal movement, but did not know that this was potentially (certainly not always) a symptom of fetal hypoxia and needed prompt evaluation.

Note: I have not reviewed clinical studies of kick count as an intervention. I have one reference showing a lack of effectiveness. (1) There is an area that I would not ordinarily review as a pathologist. Does anyone have a useful review?

(1) Grant A, Elbourne D, Valentin L, Alexander S: Routine formal fetal movement

counting and risks of antepartum late deaths in nomally formed

singletons. Lancet 1989, 2:345-347.