>>> Posting number 16830, 
                                                dated 26 Jun 1997 21:00:23

.....INTRODUCTION.....
The concept "suboptimality score" refers to a numeric score based upon the number
of prenatal, perinatal, and neonatal factors present in the medical history and/or
the maternally recollected history of a given child; and suboptimality scores have
been used in a number of autism studies, whose findings provide clues to causation
in various autism-spectrum subgroups. 
      Usually, only adverse events (eg, hyperbilirubinemia, maternal bleeding during
pregnancy, gestational- and neonatal-infections, etc) are scored; therefore, a low
score is optimal and means that a minimal number of adverse events occurred.
Conversely, a high score indicates that a larger number of adverse events had
occurred to the autism-spectrum child during his or her neonatal, perinatal, and
in-utero time.
      According to Gillberg and Gillberg, "The concept of reduced optimality... was
introduced by Prechtl (1968), who later showed it (1980) to possess the capacity...
for detecting intercorrelations between nonoptimal factors...[and]... newborn
neurological abnormalities." (1-3)

Prior the use of an optimality "score", the observation of adverse events has been
used to evaluate various factors related to possible neurologic sequelae. For
instance, by 1975, Torrey, Hersh, and McCabe could write, "Since 1960 there have
appeared... at least 12 reports to the effect that autism and/or childhood
schizophrenia are associated with the mother's pregnancy and delivery..." (4). 
      In other words, the association of autism and various pre-, peri-, and
neonatal adverse events has long been known, and this association suggests that in
*some* autism-spectrum children, causation may have been other than genetic.

In more recent years, various studies have used various lists of factors to be
tallied in regard to each individual within a neurologically defined group -- eg,
kids with autism and one or several control groups. In some studies, siblings were
used as a control group, thereby minimizing genetic factors as suboptimality scores
are interpreted.
      For example, a child whose medical history had hyperbilirubinemia, maternal
bleeding during pregnancy, non-clear amniotic fluid, and respiratory distress would
receive a score of 4. (see cite 1)
      Importantly, some of the studies have been remarkably thorough, comparing
autistic children with siblings and/or mentally retarded kids, and/or non-sibling
normal kids, and often the kids are matched (between groups) with regard to age and
gender.

Several optimality/autism studies and their findings shall be discussed in
subsequent posts. A general trend seen in the findings is that autism kids tend to
have a higher suboptimality score (ie, had more adverse events) than do kids with
ADD than do normal kids (eg, 1); and many of the factors identified in the
optimality/autism studies have been mentioned by a number of parents on the autism
list. 

1. Gillberg C, Gillberg IC. Infantile autism: a total population study of reduced
optimality in the pre-, peri-, and neonatal period. J Aut Dev Disorders 13.2.153-166
1983.
2. Prechtl HFR. Neurological findings in newborn infants after pre- and paranatal
complications. In: Jonxis et al editors; Aspects of prematurity and dysmaturity: a
Nutrica symposium; Leiden:Stenfert Kroesse, 1968.
3. Prechtl HFR. The optimality concept. Early Hum Development 4.201-5 1980.
4. Torrey EF et al. Early childhood psychosis and bleeding during pregnancy. J Aut
Childhood Shizophrenia 5.4.287-297 1975.


                                                >>> Posting number 16831, 
                                                dated 26 Jun 1997 21:15:41

In 1988, Susan Bryson and colleagues presented a fine suboptimality/autism article
(1), whose abstract states:

     "Using an optimality scale, the pre-, peri-, and neonatal
     histories of autistic children were compared with those of their
     siblings, [non-autistic] children matched for verbal
     intelligence, and normal controls. Reduced total optimality
     differentiated the autistic children from all control groups, as
     did suboptimal prenatal scores. Neonatal optimality of the
     autistic group was reduced relative to siblings and normal
     children but not relative to IQ-matched controls. The findings
     are accounted for by a subgroup of the cases, consistent with
     the view that autism is not the product of a single etiology."

Some comments and quotes:           Tc = Teresa comments

1. Tc: The study's design is excellent, via three control groups. However, the study
was limited in having a small n = 17 of autistic subjects.
2. Tc: The study used a list of 61 optimality factors that were not
delineated in the article but that can be requested by writing Dr. Bryson.
3. Tc: One of the most striking findings is that "...the total optimality scores of
the autistic children were reduced relative to those of *all* control groups." 
[Original text placed "all" in italics for emphasis.]
4. Importantly, "The present findings of reduced prenatal scores are specific to
autism and cannot simply be accounted for by mental retardation."
5. "In the present study... [keeping in mind its n = 17, the factors that]
differentiated the autistic from all control groups... were delayed first cry,
respiratory distress syndrome..., and anemia in the newborn."

6. "Maternal bleeding [during pregnancy] also occurred with an increased frequency,
consistent with earlier reports..."
7. "Meconium staining..., lower mean gestational age, and decreased 5- minute Apgar
score... were present in both the autistic children and IQ- matched controls."
8. Tc: With larger n, there might have been some shifting of factors in regard to
autism-specific, autism-and-MR specific, etc.

9. Tc: This study's findings are consistent with a number of prior studies wherein
high suboptimality scores are common in the autism group.
10. "One of the striking results in the present study is that obstetrical conditions
were not related to functional level in the autistic children. Finegan and
Quarrington (1979) reported a similar finding." (2) 
      "This study extends their work by demonstrating that a positive relationship
between obstetrical optimality and nonverbal intelligence does exist in the
IQ-matched control group. These data validate the independence of autism and mental
retardation and raise the possibility that the role of obstetrical complications in
the etiology of the two [MR and autism] may be different."

11. Tc: As of today (6.26.97), I do not yet have the F and Q 1979 study, but item
10 is very fascinating.
12. "The authors emphasize... that about one fourth of the autistic cases appear to
account for the findings reported here. This is consistent with the current view
that the autistic syndrome is a manifestation of a number of different etiologies
(e.g., Coleman, 1979, 1987)."
13. Tc: My impression from a number of optimality/autism studies is that
suboptimality scores may be like a "tip of the iceberg". The 1/4th finding described
by Bryson et al (see item 12 above) may, therefore be a safe, responsible,
*underestimation* for the following reasons:
A.    Not included in regard to each child are the effects of adverse events
subsequent to the neonatal period, which have been shown to have a cumulative effect
upon neurologic signs present neonatally (eg, 3).
B.    Optimality scores do not reflect the severity of adverse events. For example,
a neonatal infection might add 1 to the score of a normal kid and autistic kid
(seemingly equal weight), but the autistic child's infection may have been more
severe and yet not so reflected in the optimality score.
C.    Optimality scores may not reflect "low-level factors" like (i) high levels of
dissociated bilirubin in kids with low serum levels, and (ii) non-convulsive
seizures.

14. Bryson et al discuss genetic factors and mention, "Folstein and Rutter (1977)
hypothesize that autism is manifested when adverse obstetrical events are
superimposed on a familial predisposition toward cognitive disability". (4)
15. Tc: Bryson et al's summary of Folstein and Rutter 1977 appears to point toward
a historically significant *speculational* hypothesis of cognitive-genes are the
primary predisposing factor. We note, circa 1997, that "cognitive genes" are very
different from immunodeficiency genes. Furthermore, high suboptimality scores not
related to cognition-genes separated autism from IQ-matched mental retardation.
Also, many high- functioning normal families have one autistic child, a fact
consistent with a model wherein Folstein and Rutter's speculated genes-predisposing-
toward-cognitive-disability is irrelevant.
16. Some of the optimality factors used by Bryson et al include maternal age, prior
abortions, chronic maternal disease, Rh incompatibility, vaginal bleeding,
prescribed mediation, induced labor, ruptured-membranes- birth-delay, meconium
staining, analgesia, anemia, resuscitation, time of first cry, respiratory distress
syndrome, septicemia -- and these from a longer list of 61 items.

17. A crucial ingredient in the Bryson et al and similar findings is that, generally
speaking, any one adverse-event factor is not enough; and studies that look at one
factor may conclude "no link to autism".
      However, when the "occurrence density" and "cumulative effects" are included
in a composite "suboptimality score", then autism begins to separate itself out as
an additive effect derived from having too many of the adverse events in the pre-,
peri, and neonatal life of a child, ie, a child sooner or later to be diagnosed with
autism. 
      These pre-, peri-, and neonatal adverse-events seem quite independent of
Folstein & Rutter's speculational autism-related cognitive-genes (4, as summarized
in 1). 

REFERENCES

1. Bryson SE, Smith IM, Eastwood D. Obstetrical suboptimality in autistic children.
J Am Acad Child Adolesc Psychi 27.4.418-22 1988.
2. Finegan J, Quarrington B. Pre-, peri-, and neonatal factors and infantile autism.
J Child Psychol Psychi 20.119-128 1979.
3. Hadders-Algra M et al. Minor neurological dysfunction and behavioural
development. A report from the Groningen perinatal project. Early Human Development
11.221-9 1985.
4. Folstein S, Rutter M. Infantile autism: a genetic study of 21 twin pairs. J Child
Psychol Psychi 18.297-21 1977.



                                          >>> Posting number 17057, 
                                          dated 1 Jul 1997 16:18:31

.....RAMIFICATIONS FOR FUNDING & RESEARCH.....
Many of us opine that the NIH's primary autism-research focus is searching for genes
(i) that can cause autism, or to a limited extent, (ii) that are (non-immune-
related) susceptibility factors.  However, the NIH's exuberance for finding
autism-related cognition-genes is a strategy that ignores or belittles numerous and
often repeated autism-parents' anecdotes regarding (i) infections, prolonged
antibiotics protocols, and vaccinations, and (ii) anecdotal and published data (eg,
1- 3) pointing towards adverse-events during an autistic child's prenatal,
perinatal, and/or neonatal time periods.
      My posts on this topic have repeatedly stated not that all genetics/autism
research is inappropriate, but that *ignorning* the anecdotal information and
published data regarding environmental factors during the prenatal, perinatal,
neonatal, infant and toddler periods is not sound methodology, not even for
researchers funded for gene-search quests.

Research strategies and funding guidelines that are too highly focused upon
gene-search strategies and therefore that ignore or, at best, pay mere lip service
to the anecdotal and published data have at least two important ramifications:
     (i) Various kinds of causes, treatments, and preventions are
     likely to be overlooked, as exemplified by autism cases wherein
     significant improvements are induced via diet, and/or treatments
     for underlying infections; and
     (ii) The gene-search strategies themselves will be impaired by
     the presence of adverse-events confounds among family-history
     data.

Why is the NIH autism-research strategy so focused upon searching for autism genes,
particularly via a model that includes speculation of autisms caused by rare
combinations of primary, secondary, tertiary, and background genes?
A.    One answer might be "herd mentality". Genome research is a hot item,
well-funded. In this climate, certainly important are questions such as "What do
genes do? Where are they? How do their mutations or allelic variations subserve
specific phenotypic traits and/or illnesses?". However, aside from a few notable
single-gene causes of autism (eg, tuberous sclerosis, fragile X), several decades
of autism-gene-searches have been relatively non-productive. Nonetheless, in a
decade of the genome, giving funding to gene-search projects for autism is
consistent with a prevailing mind-set regarding how to conceive and research medical
problems, a process that is not necessarily prudent, given the anecdotes and data
concerning *known* dietary and environmental factors...
B.    Another answer might be "medico-legal implications". Numerous parental
anecdotes and a goodly number of studies indicate that if too many adverse-events
occur during the pre-, peri-, and neonatal time periods, then serious neurological
problems including autism may occur (eg, 1-3 and cites therein). 
      The tally of adverse-events is often called a suboptimality score, and the
debate about the significance of high adverse-events scores continues (eg, 3-5).
However, a clue regarding why research ought focus upon gene-search strategies and,
thereby, look away from pre-, peri-, and neonatal and subsequent adverse-events
factors has been provided by Robert Goodman (4), who cautions against placing too
much faith in non-gene models of autism causation:

     "These conclusions [re: likelihood of non-gene causations in
     many cases of autism] deserve careful scrutiny since a proven
     aetiological role for perinatal problems would have important
     scientific and medico-legal implications. If perinatal problems
     are a major aetiological factor in autism, then obstetric [ie,
     prenatal and perinatal] and neonatal practices that reduce the
     rate of perinatal problems should prevent some cases of autism.
     Conversely, suboptimal obstetric and neonatal care could
     arguably cause or precipitate autism -- a possibility that is
     bound to worry obstetricians, paediatricians, and their defence
     organizations."   p809

I do not want to here state that the NIH's autism-research strategy is necessarily
formed by deliberate avoidance of (i) numerous parental anecdotes and (ii)
adverse-events findings in suboptimality/autism studies; but, as Dr. Goodman makes
clear, the possibility of financial incentives to "look the other way" by focusing
entirely upon gene-search strategies ought be considered -- as we wonder why so many
parental anecdotes and adverse-events findings (eg, 1-3) are virtually ignored.

REFERENCES

1. Gillberg C, Gillberg IC. Infantile autism: a total population study of reduced
optimality in the pre-, peri-, and neonatal period. J Autism Develomental Disoders
13.2.153-66 1983.
2. Bryson SE, Smith IM, Eastwood D. Obstetrical suboptimality in autistic children.
J Am Acad Child Adolesc Psychi 27.4.418-22 1988.
     Tc: This study used three age-matched control groups: siblings,
     IQ-matched non-autistics, and normal children. Suboptimality
     scores among autistics differentatiated against all three groups
     used for comparisons.
3. Piven J, Simon J, Chase GA, Wzorek M, Landa R, Gyle J, Folstein S. The etiology
of autism: pre-, peri-, and neonatal factors. J Am Acad Child Adolesc Psychi
32.6.1256-63 1993.
     [This study reports strong adverse-events findings regarding
     autism, and then (by a mathematical maneuver whose validity I
     strongly question) declares those findings irrelevant if a
     birth-order adjustment is made.]
4. Goodman R. Technical note: are perinatal complications causes or consequences of
autism? J Child Psychol Psychi 31.5.809-12 1990.
     [Cites 4 and 5 contain a summary and discussion of three models
     having a role for suboptimality factors and for genes.]
5. Gillberg C, Gillberg IC, Steffenburg S. Reduced optimality in the pre-, peri-,
and neonatal periods is not equivalent to severe peri- or neonatal risk: a rejoinder
to Goodman's technical note. J Child Psychol Psychi 31.5.813-5 1990.



                                          >>> Posting number 17423, 
                                          dated 7 Jul 1997 18:51:43

.....BLEEDING DURING PREGNANCY.....
Background:  The phrase "suboptimality score" refers a tally of adverse events,
usually considered in regard to the pre-, peri, and neonatal periods (1-2). For any
given infant, a high suboptimality score indicates that a number of adverse events
were present, and high suboptimality scores are often followed by neurological
sequelae (eg, 3). Furthermore, these studies have revealed a trend wherein a higher
number of adverse events (ie, a higher "suboptimality score") is associated with
gradations of neurologic impairment, and this appears to be true across a gradient
from ADHD to autism to cerebral palsy. (eg, 3 @#@).
      Lists of adverse-events vary from study to study, but many similar categories
are included in most studies -- eg, the presence of maternal bleeding during
pregnancy, meconium staining, hyperbilirubinemia, respiratory distress, anemia, etc
(eg, 4-6); and when comprehensive adverse-events criteria are utilized, the studies
tend to differentiate children with cerebral palsy, mental retardation, siblings,
and normal controls (eg, 4-6), a very powerful finding indeed! In fact,
suboptimality findings may be pointing towards autism etiologies in a goodly
percentage of cases.

.....Autism & bleeding during pregnancy..... 
Bleeding during pregnancy occurs during the in-utero time of many non- autistic
children (7), yet a strong association between autism and bleeding during pregnancy
has been reported by several research groups when the bleeding is placed among
suboptimality scores (4-6) or when the rate of bleeding among autistics is compared
to average rates among normals or IQ-matched controls (8).
      As data, although mother's memories of bleeding during pregnancy are not as
reliable as other adverse-events factors (discussed in 5), an early autism study
used prospective sampling (n = 30,000) and thorough medical records, among whom (by
age 7), 14 autistic children and 4 Asperger-like children were found (8). The
medical records of these patients' mothers showed double the rates of
pregnancy-bleeding than occurred among mothers of IQ-matched controls or of normal
controls. Unfortunately, although Torrey and colleagues looked at additional
adverse-events factors, a suboptimality score was not tabulated (8).
     Nonetheless, the study used medical records obtained *prospectively*, and its
findings are remarkably similar to autism/bleeding findings dervied from maternal
recollections and/or medical records (4-6), thereby adding weight to the validity
of the several autism/suboptimality studies wherein higher rates of maternal
bleeding were reported (4-6).
     Furthermore, Torrey et al observed several other tendencies that may be
important: (i) In the autism group (and not the IQ-matched or normal controls), most
bleeding occurred in the first and second trimesters, and (ii) "Mothers in the
autistic... group were minimally symptomatic with no abdominal pain or cramping."
-- which is different from the matched low-IQ controls, among whom  "...four of the
five mothers of children in the low- IQ control group were symptomatic enough [re:
bleeding] to require medical attention at the time."

.....Suboptimality Findings Are Underestimations..... 
In suboptimality studies, adverse-events common to autistic subjects are instructive
regarding etiological pathways in many cases of autism; and, among studied groups
of autistics, the relative frequencies and types of adverse-events have significance
to (a) immunodeficiencies and other immunological findings as well as to (b)
research strategies for finding additional (if any) autism-genes.

Importantly, adverse-events scores in suboptimality/autism studies (eg, 4- 6) may
*under-represent* the number of adverse-events that occurred during pregnancies. For
instance, consider two traditional adverse-events factors: hyperbilirubinemia and
bleeding:
A.   Bilirubin neurotoxicity as severe as kernicterus can occur during periods of
low serum levels of bilirubin (9-10); yet having no prolonged incident of
hyperbilirubinemia would not add to an infant's suboptimality score, even though (in
some infants) bilirubin neurotoxicity may have occurred in some brain areas.
B.   Similarly, vaginal bleeding during pregnancy is an adverse-events factor
included in most suboptimality/autism studies (eg, 3-5, 8).
     1.   Chorioamnionitis is one of the primary causes of vaginal
     bleeding; often occurs in response to an infection; and often is
     occurring even when no vaginal bleeding is present (11).
     2.   Intrauterine bleeding may affect placental function and
     fetal development even though vaginal bleeding does not always
     occur (12).
C.   Thus, when Bryson et al reported that "...about one fourth of the autistic
cases appear to account for the [suboptimality] findings reported here" (5), their
"one fourth" figure is likely to be an under-estimation, especially since maternal
bleeding and hyperbilirubinemia were among the factors they studied.

.....Conclusion..... 
Suboptimality/autism studies have identified pre-, peri-, and neonatal factors that,
if in sufficient co-occurrence, may be causally related to pathogenesis of autism
in some cases, perhaps well in excess of 25% of all cases.
      While the various researchers assign differing interpretations to the
suboptimality/neurologic findings, that the suboptimality/autism findings have been
replicated by several research groups indicates that these findings and their clues
to neurotoxicity ought not be ignored by gene- search strategies now prevalent in
autism research. 
      Importantly, when the gene-search researchers tally *some* adverse-events,
those tallies need be interpreted in the context of the better suboptimality
studies, wherein large numbers of items were utilized (eg, 4-6).

In a subsequent post, literature about vaginal bleeding during pregnancy will be
examined for clues regarding pathogenic etiologies in a large subgroup within
autism. By focusing upon maternal bleeding during the prenatal period, the following
discussion will tend to focus upon kids whose autism-causation got a complete or
significant start in utero and/or perinatally and/or neonatally. 
      However, as list-participant Bob Jensen has pointed out and as I too believe,
the concept of Suboptimality ought be extended beyond the neonatal period, because
studies have shown that mild neurological atypicality present during the neonatal
or early infant periods tends to become worse in children experiencing additional
adverse-events capable of affecting the CNS (eg, 3).
     Among these later occurring adverse-events, I would include (i) excessively
repeated ear-infections and antibiotics-treatments, especially if the antibiotics
are of a kind known to bind albumin and thereby displace bilirubin, such as
amoxycillin and ampicillin  --  which also crosses the placenta from mother to fetus
(13-16), and (ii) vaccinations, because of their ability to modify cytokines
patterns (reviewed in 17-18) and to induce febrile seizures (19). 
      In other words, adverse-events prior and subsequent to a child's peri- and
neo-natal periods ought be considered in determining the cumulative sum of
adverse-events that may reveal clues to etiology in his or her specific case of
autism.



                                          >>> Posting number 17426, 
                                          dated 7 Jul 1997 19:02:43

.....Autism & Maternal Bleeding During Pregnancy.....
Several suboptimality/autism studies have identified bleeding during pregnancy as
a factor seen in specific autism medical histories having a high number of adverse
events (4-6, 8). Thus, questions arise: What are the causes of bleeding during
pregnancy (BDP)? How might the various BDP causes induce neurological damage? And,
how do BDP and its causes interact with other adverse-events factors identified in
pregnancies that resulted in a child later diagosed as autistic.
      That "Vaginal bleeding is common during pregnancy..." (7) and that most
incidents do not result in an autistic child means we shall have to interpret BDP
in conjunction with other factors, as we look to etiologies of autism; yet "Previous
studies have provided compelling evidence... that vaginal bleeding (not immediately
followed by spontaneous abortion) is a predictor of subsequent adverse fetal
outcomes..." (7).
      Among the primary causes of BDP are "...placental complications, including
pracenta previa, abruptio placentae, vasa previa, circumvallate placenta, and
rupture of the marginal sinus." (7) Furthermore, "It has been suggested that
gestational bleeding with little or no other symptomatology is almost always the
consequence of marginal separation of the placenta..." (7, citing 20).

Since BDP is known to have occurred in conjunction with other adverse- events in
subsets of autistics' medical histories (4-6,8), BDP points towards possible
mechanisms. For instance, "Clinical observations on fetal blood suggest that
gestational bleeding not associated with placenta previa involves permanent
deciduo-placental damage, possibly leading to impairment of oxygen transfer and
fetal nutrition in general..." (7, citing 21).
      Furthermore and also consistent with the suboptimality/autism findings are the
following: "Early-pregnancy bleeding was found to be associated with more preterm
deliveries and lower birth weight. The frequency of congenital anomalies... was
unaffected. Neonatal death and low Apgar scores were seen more often... These data
suggest that vaginal bleeding in early pregnancy is a useful indicator of risk for
suboptimal outcome." (22).

.....Some Factors Associated with Bleeding During Pregnancy.....

I.    Abruptio Placentae: "Abruptio placentae is the separation of the placenta from
its normal site of implantation before the delivery of the fetus... Major sequelae
are... menacing, with 15% of infants developing significant neurologic defects
within the first year of life..." (23).

II.   Alpha-Fetoprotein: "Elevated maternal serum alpha-fetoprotein (MSAFP) levels
have been associated with an increased incidence of... pregnancy complications...
[which often include] fetal growth retardation, preterm delivery, late vaginal
bleeding (at or after the 20th week of gestation)... Women with elevated MSAFP had
an increased incidence of... positive maternal Kleihauer-Betke stains,
first-trimester vaginal bleeding, late vaginal bleeding, preterm delivery, fetal
growth retardation..." (24).
     "Alpha-fetoprotein is produced by the fetus, and escapes into the amniotic
fluid via fetal urine and also through any surface defect of the fetus." (25).
Placental separation and chronic inflammation of placental villi are also known to
increase MSAFP (25 & cites therein).

III.  Hyperbilirubinemia: In "data from 12,023 singleton deliveries", Linn et al
found "There was a statistically significant positive relationship between
hyperbilirubinemia and low birth weight, Oriental race, premature rupture of
membranes... neonatal infection, use of the 'pill' at the time of conception,
instrumental delivery, and history of first trimester bleeding."


.....Comments.....
The association between autism and vaginal bleeding during pregnancy is well
established (4-6,8). Though BDP is not specific to autism, the findings in
suboptimality/autism studies suggest that 'BDP in conjunction with other
adverse-events' points to etiological pathways in many cases of autism. Additional
factors related to vaginal bleeding include hypoxia, fetal acidosis, and respiratory
distress syndrome (12, 27-31).
     The suboptimality/autism findings suggest that any one adverse-event is usually
not enough to have induced a child's autism; instead, combinations of adverse-events
factors are required (4-6); and even epidural anesthesia can be an adverse-event
(29). However, although most children whose mothers received an epidural will not
become autistic, the suboptimality findings indicate that in a pregnancy with a high
score of adverse events, to have had an epidural augments or reflects conditions
that can induce neurologic sequelae in the newborn.

Let us review: vaginal bleeding is present in the prenatal history of many autistic
kids and was, in those children, accompanied by other adverse- event factors (4-6).
These various factors are themselves associated with neurological sequelae in the
newborn; and a trait shared by a subgroup of autistics is that their pre-, peri-,
and neo-natal times contained a high number of inter-related adverse events.
     The concept "bleeding during pregnancy" is complex because BDP has many causes
and many studies about each kind of cause (eg, abruptio placentae). Yet, while
reading about these various causes, again I could not help but notice the potential
of so many of the causes to induce neurologic damage in the fetus. Thus, the fact
that several independent (of one another) research groups have found a strong link
between autism and BDP (when in a context of a high-number of adverse events) is not
surprising.

.....In closing..... 
This mini-paper is but a preliminary sketch of how the suboptimality findings (4-6)
can be utilized for understanding pathogenesis in many cases of autism.
Significantly, the adverse-events factors identified in the several thorough
suboptimality studies (4-6) are capable of inducing CNS damage regardless of the
person's genetics. In other words, the factors identified in those studies and the
additional further delineated here are independent of "cognition genes", even as the
adverse-events factors (when combined with one another) affect cognition, emotional
expression, and behaviors.

The adverse events studied as "suboptimality" have ramifications for IgA, 
as delineated in a monograph originally posted within the Suboptimality series (32).

                            Teresa C Binstock
         Researcher in Developmental and Behavioral Neuroanatomy
                           Denver Colorado USA
                                  1997

                                          >>> Posting number 17432, 
                                          dated 7 Jul 1997 19:15:57

REFERENCES
1. Prechtl HFR. Neurological findings in newborn infants after pre- and paranatal
complications. In: Aspects of prematurity and dysmaturity; Nutricia Symposium,
p303-312. Eds: Jonxis JHP et al; Stenfert-Kroese, Leiden; 1968.
2. Prechtl HFR. The optimality concept. Early Human Development 4.3.201-5 1980.
3. Touwen BCL et al. Obstetrical condition and neonatal neurological morbidity. An
analysis with the help of the optimality concept. Early Human Development 4.3.207-28
1980.
     "...obstetrical conditions such as acidemia, preterm birth and
     intrauterine growth retardation have a stronger relationship to
     neurological morbidity when the accompanying obstetrical
     optimality is lower [ie, when the infant has a high
     suboptimality score]."
4. Gillberg C, Gillberg IC. Infantile autism: a total population study of reduced
optimality in the pre-, peri-, and neonatal period. J Autism Develomental Disoders
13.2.153-66 1983.
5. Bryson SE, Smith IM, Eastwood D. Obstetrical suboptimality in autistic children.
J Am Acad Child Adolesc Psychi 27.4.418-22 1988.
     Tc: This study used three age-matched control groups: siblings,
     IQ-matched non-autistics, and normal children. Suboptimality
     scores among autistics differentatiated against all three groups
     used for comparisons.
6. Piven J, Simon J, Chase GA, Wzorek M, Landa R, Gyle J, Folstein S. The etiology
of autism: pre-, peri-, and neonatal factors. J Am Acad Child Adolesc Psychi
32.6.1256-63 1993.
     "Several factors (parity, vaginal bleeding, severe infections in
     pregnancy, use of prescription medications, and
     hyperbilirubinemia) appear to occur at higher rates (i.e., at
     least twofold greater) in autistic subjects compared with
     sibling controls."
7. Williams MA, Mittendorf R, Lieverman E, Monson RR. Adverse infant outcomes
associated with first-trimester vaginal bleeding. Obstet Gynecol
78.14-18 1991.
8. Torrey EF, Hersh SP, McCabe KD. Early childhood psychosis and bleeding during
pregnancy. J Autism Childhood Schizophrenia 5.4.287-97 1975.
9. Gartner LM et al. Kernicterus: high incidence in premature infants with low serum
bilirubin concentrations. Pediatrics 45.906-917 1970.
     [This study is an example demonstrating that bilirubin
     neurotoxicity can occur even during times of low serum bilirubin
     levels. Other factors can be important, and dissociation of
     bilirubin from albumin is a primary mechanism.]
10. Harris RC et al. Kernicterus in premature infants associated with low
concentrations of bilirubin in plasma. Pediatrics 21.875- 1958.

11. Darby MJ, Caritis SN, Shen-Schwarz S. Placental abruption in the preterm
gestation: an association with chroioamnionitis. Obstet Gynecol 74.88-92 1989.
     -- "Histologic chorioamnionitis and funisitis were present
     significantly more often in patients with [placental] abruption
     than in control patients (41 versus 4%; P < .0001)."
     -- "No patient in either group had clinical evidence of
     chorioanmionitis."
     -- "In reviewing our experience with preterm placental abruption,
     we noticed an unexpectedly high incidence of histologic
     chorioamnionitis that was silent clinically."
12. Salafia CM et al. Histologic evidence of old intrauterine bleeding is more
frequent in prematurity. Am J Obstet Gynecol 173.1065-70 1995.
13.Bratlid D, Bergan T. Displacement of albumin-bound antimicrobial agents by
bilirubin. Pharmacology 14.5.464-72 1976.
14. Brodersen R, Ebbesen F. Bilirubin-displacing effect of ampicillin, indomethacin,
chlorpromazine, gentamicin, and parabens in vitro and in newborn infants. J
Pharmaceutical Sciences 72.3.248-53 1983.
15. Davies BE. Br J Clin Pharmacology 20.4.345-8 1985.
16. Adamkin DH et al. The placental transfer of ampicillin. Am J Perinatology
1.4.310-311 1984.
17. Binstock T. Hypothesis: Infection, antibiotics, vaccination-induced
neuropathies: mechanisms of pathogenesis in some cases of autism, ADHD, Tourette's,
OCD, and other neurological disorders. Bit.listserv.autism Jan.3.1997.
18. Binstock T. Hypothesis: Febrile seizures and the amygdala: a causal mechanism
in autism and related disorders. Bit.listserv.autism Jan.31.1997.
19. Chen RT et al. Vaccine Safety Datalink project: a new tool for improving vaccine
safety monitoring in the United States. Pediatrics 99.765-73 1997.
20. Pritchard JA, MacDonald PC, Gant NF. Williams Obstetrics. 18th ed. Norwalk:
Appleton-Century-Crofts p695-6 1985.
21. Turnbull EPN, Walker J. The outcome of pregnancy complicated by threatened
abortion. J Obstet Gynaecol Br Emp 63.553-9 1956.
22. Batzofin JH, Fielding WL, Friedman EA. Effect of vaginal bleeding in early
pregnancy on outcome. Obstet Gynecol 63.515-518 1984.
23. Turner LM. Vaginal bleeding during pregnancy. Emerg Med Clin NA 12.1.45-54 1994.
24. Bernstein IM, Barth RA, Miller R, Capeless EL. Elevated maternal serum
alpha-fetoproetin: association with placental sonolucencies, fetomaternal
hemorrhage, vaginal bleeding, and pregnancy outcome in the absence of fetal
anomalies. Obstet Gynecol 79.71-4 1992.
25. Robinson L, Grau P, Crandall BF. Pregnancy outcomes after increasing maternal
serum alpha-fetoprotein levels. Obstet Gynecol 74.17-20 1989.
     "Renal anomalies... and any obstruction to the [fetal]
     gastrointestinal tract, may also increase amniotic fluid AFP
     levevls... The fetal skin is only partially keratinized between
     14-20 weeks, so that changes in this tissue, including edema
     [important factor!], may also increase amniotic fluid AFP
     levels. Because AFP passes across the fetal membranes into
     maternal serum, an elevated amniotic fluid AFP level tends to
     increase the level in the maternal compartment... Changes in the
     placento-maternal barrier, including increased vascularity such
     as ...placental lakes, placental separation, and...; chronic
     villitis may result in inceased MSAFP levels..."
26. Linn S et al. Epidemiology of neonatal hyperbilirubinemia. Pediatrics
75.4.770-4 1985.
27. Salafia CM et al. Relationship between placental histologic features and
umbilical cord blood gases in preterm gestations. Am J Obstet Gynecol
173.4.1058-64 1995.
28. Perlman JM, Risser R. Can asphyxiated infants at risk for neonatal seizures be
rapidly identified by current high-risk markers? Pediatrics
97.4.456-62 1996.
     [links hypoxia to abruptio placentae and thereby to increase
     risks of subsequent infant seizures and adverse neurologic
     sequelae]
29. Antoine C, Young BK. Fetal lactic acidosis with epidural anesthesia. Am J Obstet
Gynecol 142.55-59 1982.
     -- "Twenty per cent of mothers suffered at least a 20% fall in
     blood pressure following administration of epidural anesthesia.
     An additional 24% required ephedrine, a vasopressor... Thus, 44%
     of these patients suffered significant hypotension..."
     -- "Maternal hypotension may lead to fetal bradycardia and other
     abnormal patterns, fetal hypoxia, acidosis, and neonatal
     depression..."
     -- "Hypotension, through a decreased perfusion of the [placenta's]
     intervillous space, is believed to lead to different degrees of
     fetal deterioration. Fetal asphyxia, acidosis, bradycardia, low
     Apgar scores... are all consequences which may follow prolonged,
     severe hypotension."
     -- "[Fetal] Lactic acidosis was significant in both arterial and
     venous cord blood of the severe hypotension group."
30. Suidan JS, Wasserman JF, Young BK. Placental contribution to lactate production
by the human fetoplacental unit. Am J Perinatology 1.4.306-9 1984.

31. Young BK. Placental regulation of fetal oxygenation and acid-base balance.
Chapter 11, p171-177 in: Assessment and Care of the Fetus: Physiological, Clinical,
and Medicolegal Principles. Eden RD et al editors. Appleton & Lange; Norwalk; 1990.
     [An excellent review!]
     [Has a table of factors affecting oxygenation and acid-base
     balance. Items on the table include a number of pregnancy
     adverse-events factors that contribute to suboptimality scores
     in the various autism/suboptimality studies.]

32. IgA & Suboptimality, series of postings to bit.listserv.autism
            >>> Posting number 17059, dated 1 Jul 1997 17:13:27
            5a Suboptimality: IgA & otitis, celiac, gastrointestinal
            >>> Posting number 17060, dated 1 Jul 1997 17:21:14
            5b Suboptimality: IgA & (celiac and/or gastrointestinal)
            >>> Posting number 17061, dated 1 Jul 1997 17:26:23
            5b2 Suboptimality: IgA & (celiac and/or gastrointestinal)
            >>> Posting number 17063, dated 1 Jul 1997 17:30:08
            5c Suboptimality: IgA & recurrent otitis
            >>> Posting number 17312, dated 5 Jul 1997 16:06:40
            5d1 Suboptimality: IgA & Dilantin
            >>> Posting number 17313, dated 5 Jul 1997 16:11:25
            5d2 Suboptimality: IgA & Dilantin
POSTING HISTORY

>>> Posting number 16830, dated 26 Jun 1997 21:00:23
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock
Subject:      1 Suboptimality Scores & Autism

>>> Posting number 16831, dated 26 Jun 1997 21:15:41
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock
Subject:      2 Optimality: Bryson et al 1988

>>> Posting number 17057, dated 1 Jul 1997 16:18:31
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock
Subject:      3a Suboptimality findings & autism-genetics gene-search strategies

>>> Posting number 17423, dated 7 Jul 1997 18:51:43
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock
Subject:      4a Suboptimality: bleeding during pregnancy, iceberg's tip

>>> Posting number 17426, dated 7 Jul 1997 19:02:43
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock
Subject:      4b Suboptimality: bleeding during pregnancy: causes

>>> Posting number 17432, dated 7 Jul 1997 19:15:57
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock
Subject:      4c Suboptimality: bleeding during pregnancy: references