Mhm.

A.

United States Army Medical Department continuing 

education program,

The 24th annual Armed Forces seminar on 

obstetrics and gynecology,

genetics of spontaneous abortion 

and heritable aspects of common 

gynecological disorders 

with Jolie Simpson,

MD.

Associate professor O.

B.

G.

Y.

N.

Department,

Northwestern University Medical School,

Chicago Illinois.

In a nutshell,

as we all know,

the extent of spontaneous abortion is really 

quite large.

Uh We could draw some fancy graphs and 

show you that only a small portion of all 

concept asses ever make it to the to the live born 

nursery.

Uh And let's just consider this.

We can divide this really into about three major 

groups.

First of all,

the pregnancies are 

embryos that have reached.

So shall we say the pre clinical stages,

that is embryos that are less than 

about four weeks of embryonic age,

less than six weeks or even four weeks from the 

last menstrual periods.

In other words,

conditions uh 

Pregnancies in which we have not recognized in by our 

conventional techniques,

secondly clinically recognisable 

pregnancies.

Those uh first trimesters if you will,

in which spontaneous abortion occurs.

And finally uh those 

2nd and 3rd trimester 

abortions or stillbirths if you will.

So here are three major groups that we can focus on.

There's really been only one attempt uh to my 

knowledge to assess the incidence 

of embryonic abnormalities that occur 

prior to the time of clinically recognized pregnancy.

And this was done in the in the 50s.

But I heard he can rock and they did a very interesting 

series of I guess we could call it 

experiments.

I'm not sure we would get this past the human 

ethics committee these days but such 

as progress.

At any rate,

they took a series of women at the boston lying in 

hospital who were uh going to 

undergo a hysterectomy for one reason or the other,

usually from my Omagh's.

And they requested that they take their basal body 

temperature and then at various 

periods of time thereafter,

depending upon when they had undergone,

were scheduled to undergo their operation.

Um They entered the hospital so that 

uh these investigators in new the time 

in which the biphasic curve rose and 

presumably which ovulation took place.

And then they then took the 

specimens that clamp both fallopian 

tubes as well as blocked the cervix and 

first flushed out sequentially the 

tubes and the uh endometrial area 

to try to find any free line blastocyst.

Now,

you recall,

it takes about three days from the time of 

population.

Uh The album,

using the term loosely as it's used in medicine,

is in the fallopian tubes for about three 

days and then it's free lining the endometrium 

cavity for another three days prior to its time of 

implantation.

So,

by flushing out,

First of all,

they could obtain any embryos that were 

less than about six days of,

of age.

And in doing so,

they noted that four of the eight that they 

detected were so abnormal in terms of 

morphology than it was practically 

inconceivable in their words,

that continued pregnancy could have occurred.

And therefore,

since we're talking about the period of time prior 

to the expected men sees,

it was most likely that this individual never would have known that 

she was pregnant.

To begin with the 

second piece of the uh their 

investigation was that they then look at the 

implant it Blastocyst.

Now the ages arranging from somewhere around 

seven to about 21 days 

past the date of ovulation or in other words,

had two more to that if you want to get the minstrel age as we 

usually tail in clinical 

obstetrics.

And in doing so,

I think you can show the first slide the next set.

And in doing so,

they noted that eight of the 26 

implanted blastocyst less than about 

2 to 3 weeks of embryonic age were grossly 

abnormal,

so that the incidence of fetal 

wastage in this pre clinical group,

if you will,

is really quite high.

Now,

it's important to remember,

as we discuss in more detail the genetics of 

spontaneous abortion,

that what we're talking about here are embryos that are 

morphological e abnormal,

and the ones that are left might still 

have a gross change in the chromosome number of their 

structure.

Uh,

they might well have a mutant gene that which 

which would have conferred lethality later on.

Or they could have had apologetic mechanism that would 

have produced a malformation.

So if you will,

we start with the fact that this is the incidence of 

fetal wastage.

And then we go to some more specific areas that are more 

amenable to clinical diagnosis.

Now it's known 

um,

to most of us,

uh,

hopefully all of us That the incidence of 

spontaneous abortion in the first trimester is 

around 12-15%.

This is a fairly common figure.

It tends to hold up from country to country from 

center to center and seems to be 

about,

it seems to be a fairly reliable figure that we can remember.

There's been a lot of controversy over the years about the 

ideology of spontaneous abortion.

And if this were the late 50s 

and I were up here,

we would have to play homage to the theory of poor 

steroid of genesis in the placenta.

Uh,

but by and large,

I think this probably has fewer advocates that it might 

have uh,

in the past,

hopefully no endocrine spies in the audience 

when chromosomes became readily 

available for to the uh to to 

be applied to spontaneous aborts is it 

became apparent that a very large percent 

of spontaneous aborts,

his head chromosomal abnormalities.

And the next slide uh reminds us the 

next slide,

subtle hints do wonders.

The next slide reminds us that about 40 

to 50% of all spontaneous 

aborts is are chromosomally abnormal.

Uh Now I put the other categories,

mutant genes and apologetic disorders,

to remind us that we really don't know anything at all 

about the role of mutant genes or apologetic 

mechanisms in causing spontaneous abortions.

However,

if on the other side,

for example,

if we were to extend this slide and to ask 

ourselves what is the extent of the incidences 

of such abnormalities in the newborn population?

We'd find that the figures from top to bottom would be about 

0.5%,

and 1%.

That is only chromosomal abnormalities,

makeup.

Oh,

perhaps 1/4 of all of the congenital 

abnormalities that one would prospectively detect in the 

newborn nursery.

That's a that's a minimum figure of the 2%.

So that uh this is only one 

of several genetic mechanisms among equals,

if you will in causing malformations and yet it 

happens to be the only one that we can look at in the 

spontaneous abortion population.

And I would armchairs and submit that 

uh looking at such data and 

extrapolating to the newborn population,

it's logical to deduce that the vast majority of 

first trimester,

spontaneous aborts is probably results 

from a genetic mechanism.

We know that about half a chromosomally abnormal.

Uh It's certainly logical that others could result from 

gene mutations of the type we mentioned simple 

mandolin inheritance and from polytechnic types 

of mechanisms.

Now,

if we look at the chromosomal abnormalities,

next slide,

we notice,

try to focus,

we notice that the incidents 

the I can't tell whether it's 

focused,

but it doesn't seem to be a little better.

Thank you.

Uh It's interesting that the spectrum of 

these anomalies is vastly different from what one 

would see in the newborn nursery.

For example,

on the right side of the column,

you can look at the prevalence of abnormal 

chromosomal abnormalities in all 

conceptions and on the left,

you can see the prevalence is and spontaneous abortions 

as dr Goebbels has eluded the vast majority 

of of uh of our 

chromosomal abnormalities that occur in the live born 

population that tend to be auto 

soma trisomy or more expressly,

in fact making up the largest portion sex chromosome.

Apollo sex chromosome a.

Policy.

So me X xy males,

xy Y males and X.

X.

Females.

It's really relatively rare to 

find prospectively of 45 X female.

In fact,

the prevalence is only about one in every 3000 

females.

Uh It's likewise extraordinary rare to 

find a trip Lloyd or Tetra employed as Dr Goebbels has 

mentioned.

Yet if we look in the spontaneous abortion 

population,

we find that these abnormalities make up 

a relatively large proportion.

For example,

7% of all chromosomally 

abnormal spontaneous abortions turned out to have a 

45 X compliment.

Um,

No,

I'm sorry,

7% of all spontaneous abortions have a 45 

x compliment.

About 20% of the chromosomally 

abnormal.

A vortices have such a compliment.

Likewise,

we can see that auto some will try.

Somebody represents a relatively high 

proportion.

And in fact if we wanted to clear up the slide,

we could break that down and prove to you 

that it's trisomy,

not simply for 13,

18 and 21 is one detecting the live 

born population,

but rather for practically any autism in the 

compliment.

Likewise,

Trip Lloyd constitutes about 8% of 

spontaneous abortions.

Tetra ploiesti about 2% of spontaneous 

abortions,

so that we're really dealing with fairly high prevalence is 

that these disorders.

Yet many of these are extraordinarily 

rare,

are not detected at all in the,

in the live born population.

This is yet another indication of some of the mechanisms 

that take place in biology,

uh,

to select against embryos that have not 

developed normally up until that period of time.

Now,

unfortunately,

we're rarely going to have the availability of 

spontaneous abortion.

Certainly we can't pull the hospital charge from 

Uh,

20 years ago or 10 years ago or three 

months ago for most hospitals and know what the 

compliment is of of a spontaneous 

abortion.

So I think in terms of counseling and giving you some 

practical advice to tell to patients,

we should start with first of all,

a series of patients who have had spontaneous 

abortion and asked what's the recurrence risk?

And the next slide,

I hope starts us off on that.

And indeed it does.

If you could focus it.

Uh this these data are collected 

by Warburton and fraser and uh 

The early 1960s at McGill.

And they have held up in many other places.

And they simply remind us of the risk 

of recurrence of spontaneous abortion 

following X numbers of previous 

abortion.

You can see the uh population 

risk uh if mother had undergone no 

spontaneous abortions was around 

12%,

in some other figures.

And to the right or the risk figures after 

123 and even four spontaneous 

abortions have taken place.

There are relatively few in the 

Uh,

four category and that may explain the 

slight drop in incidences.

But by and large,

we're talking about a 25% 

risk and this is a ballpark figure that I use 

if someone asked me,

what's the risk of recurrence after one or two 

figures,

25% are buying is by and large.

The figures that we look at.

Uh,

this doesn't seem to vary a great 

deal depending upon maternal age or,

or depending upon several other factors that we might 

take place.

I remind you that we're talking about first trimester 

abortions,

second trimester abortions.

I don't need to tell this group or ideologically 

distinct,

such things as as,

as uterine anomalies and the likes of this and they 

tend to fall into different category and 

correspondingly have a slightly higher risk.

Uh,

I might point out here that,

uh,

in case there's anyone who has been asleep for the last 20 

years,

that,

uh,

the previous figures were that after three 

spontaneous abortions,

the risk for any subsequent abortion was about 

80-90%.

And this is really the origin of the term 

of habitual abortion.

I suspect now that there's probably,

uh,

no biological justification for using such a 

term.

Uh,

it might be in a convenient administrative tool 

to determine when one might determine one 

might,

uh,

study such couples,

but it doesn't really have any biological meet.

Uh,

it's interesting,

uh,

that genetically along these lines,

That about five of 

couples who have had three or more 

spontaneous abortions will turn out to have a 

balanced translocation in one of the other 

parent.

And this might then this offers an explanation in 

these families as to why spontaneous 

abortion occurred in such families.

It's very often wise to take a good 

pedigree in several generations,

particularly the maternal side of the family.

And see whether or not there are other individuals in 

whom spontaneous abortions or malformations have 

occurred.

This would increase your risk although uh 

still uh if the data were negative,

not necessarily be a reason for not performing the study.

Now,

what happens next slide?

Uh If we did have the availability of 

chromosomal studies prior to counseling 

such families,

these data are are scanning and they're from 

the boueiz in paris.

And uh um 

at least based upon present indication,

would suggest that the recurrence risk really doesn't vary a 

great deal depending upon whether or not the 

first to Boris's chromosomally abnormal,

chromosomally normal,

those data or not statistically significant.

Uh interesting enough.

However,

next slide and tying in with some 

of dr Goldberg's comments that uh there 

does seem to be non random distribution of annual 

clarity.

Chromosomal abnormalities in the population.

Are these data and this are the boueiz,

suggesting that if the first two borders was chromosomally 

normal,

the second was also likely to be 

chromosomally normal and likewise that the 

first were abnormal,

The second was more likely to be abnormal.

The interesting point about this factor is that 

uh this suggests not only that the couple 

might have chromosomally abnormal aboard us,

but it might also incidentally this one 

numerical abnormalities and not trance locations.

Uh It also suggests that this couple might be at a 

relatively high risk for having a nonlethal 

chromosomal abnormalities.

So that for example,

if we could identify this group out from the 

largest pool of individuals who spontaneous 

aborts is well then this might be a 

couple than whom we might offer antenatal diagnosis 

even had they had no previously.

Uh even if they do not 

confirm to one of the other indications that 

dr Goldberg's mentioned translocation previous.

Try somebody or increased maternal age.

Uh Next slide please.

Now One would logically deduce that if 

the incidents of chromosomal abnormalities in the first 

trimester borders population is 

50% and therefore 

uh there's a selection occurring that 

if we move further along the line in 

particular to the stillborn population,

we might find also in incidents that's 

higher than in the newborn population.

You recall once again that about one in every 200 

live-born births has a chromosomal abnormality.

Well,

if we look at the stillbirth population,

it was done in the study quoted from The Lancet,

you can see how long the top line 

Uh that about 9% of ante 

partum macerated stillbirth.

Stillborn infants have a chromosomal abnormality.

The hitch here is that they were only able to successfully culture about 

20% of these.

If you look at the intra partum uh stillbirths 

with a correspondingly increased success rate in the 

cultures,

they still got about a 4% incidents and 

likewise the early neonatal death,

this shouldn't surprise anyone.

Likewise was high.

The next slide shows us that if we break this 

down further into the type of 

abnormality and in particular 

exclude the central nervous system anomalies 

and essentially spina bifida,

which can be diagnosed by alfa alfa 

feta protein.

Wind finds really a quite high incidence of chromosomal 

abnormalities in this stillborn population.

So this is yet another indication.

I think that nature is selecting 

against abnormal offspring at 

a number of places in the 

preimplantation stage,

in the early implantation of blastocyst 

stage.

Uh And in addition in the 

clinically recognized pregnancies,

and finally immediately prior to birth.

Uh really a very nice,

very nice picture in terms of its steely ology.

Let's turn on,

turn the slide off please.

Now we're really late for time and I 

don't want to hold us up too much.

But I like to point out uh I'm closing this 

morning.

About three or four major areas in which common 

heritable heritable factors exist 

in,

if you will very common disorders and 

obstetrics and gynecology that we attend to 

see on a day to day basis.

And we could really divide this into a number 

of different disorders.

The first of all are the apologetic mechanisms and the next 

slide shows you 

if you could focus that.

Thank you today to that I alluded to before.

And I suspect that if we looked at a lot of different 

common guo and variables a conjugal diagonal 

for you any,

anything you want to,

the prevalence of my illness,

for example,

we would find data such as this.

The point of fact is that very few people have looked 

at them and uh therefore we tend to 

think that they don't exist.

But for example,

look at the age the mean differences in the ages 

of monarchy between these different 

relatives.

If you're identical twins,

a series of 51 patients,

uh,

the mean difference in their age of monarchy is 2.8 

months,

not identical twins,

12 months subs 12.9 

months.

The fact that this and this were almost 

identical to suggest that the genetic components 

are fairly play a relatively large role 

in determining the age of monarchy.

Likewise mother,

daughter and other combination so that I 

suspect that we can take the age of monarchy as a general 

indication.

And for example,

I've used this also uh to 

determine the ages of menopause.

And very often I'm confronted with a situation in 

which the age of many of the age of 

expected menopause might change the way we 

might manage a patient.

And it's uh at least find it 

comforting to ask what the age of menopausal might 

be.

For example,

if we're contemplating uh particular 

operation safe from my Omagh's on a patient 

who's 46 demonstrating the fact 

that she had other maternal relatives and 

sibs who underwent their menopause at 47 

might uh tend to make me a little 

hesitant in doing the procedure.

Whereas if everyone else told me that they underwent their 

menopause and their family at age 59 or age 

60 that suggests that we might be a 

little less likely to ride out the situation 

now in the area of infertility.

Next slide.

you know,

just turn that one off.

Could you back thank you.

In the age of in in the area of infertility genetics 

plays a very large role in lots of situations.

And we're going to allude to these tomorrow morning with DR.

Goebbels discusses gunbattles,

genesis and I cover uh some forms of 

genital ambiguity.

There are three areas that that in which heritable 

factors have definitely been identified.

And at least at least like to mention them because I think 

that they're worth.

You're asking in terms of general histories.

The first of these are military infusion anomalies,

uh incomplete fusion defects by Cornthwaite 

uterus.

The likes of this.

Uh If I cared to,

I could cite at least a dozen cases in which 

multiple sibs or females and 

more than one generation appeared to have 

such abnormalities.

Uh the most likely mechanism for these 

situations is that we're looking at apologetic or 

multifactorial inheritance and the 

recurrence risk.

Then if we were asked to uh Pro for 

that might be in the range of 5%.

Now that's getting pretty shaky and I would prefer not to give a 

recurrence risk for such a thing.

But you've pressed the wall.

That's probably what I'd say,

not only because it is an abnormality of a 

single organ system,

but because there are heritable tendencies that have been 

demonstrated second area uh 

disorder that we often come across for 

which proven probably apologetic 

conditions can can be demonstrated as 

endometriosis.

Again,

we could quote five or six cases in which four or 

more Sibs have been affected.

A number of instances in which a 

mother and her multiple affected Sibs had been 

affected.

The third areas Leventhal syndrome,

there's at least one excellent article from Memphis 

group in The Great Journal about three or four years ago.

That suggests that Stein Leventhal syndrome may indeed be an 

excellent dominant disorder.

I don't think there's any question but that there are inheritable 

tendencies uh for Stein Leventhal syndrome,

but the exact mode of transmission is 

still,

I think,

open to question the final group that 

I might mention our next slide,

some of the heritable factors in G.

Y.

N.

Cancers.

Uh I hasten to add that 

uh I wouldn't recognize left notify 

tripped across it on the stage on the way out,

but it's important to recognize that many of these 

cancers are indeed heritable in 

particular.

Three for three,

there seemed to be relatively few 

indications of any type of heritability.

There's not much known about vulvar and and and 

and vaginal cancer in terms of their genetics,

but there have been substantial studies and cervical 

cancers and really,

almost no indication of a heritable tendency.

This to me would strengthen the hypothesis that 

herpes virus was an ideological 

factor.

And it was uh,

hitting in a,

in a more or less random fashion in the general population 

with no group,

particular pre predisposed,

except no group predisposed prior to whatever 

socioeconomic factors put them in the high 

risk category.

It's interesting that that vulvar 

cancers and occasionally vaginal 

cancers have also been uh,

a relation has been suggested with herpes in 

this group here for a number of the other 

disorders.

There are clearly heritable tendencies that I think are worth 

remembering about and are worth asking questions 

about uh,

endometrial carcinoma.

Uh,

sometimes in association with adenocarcinoma 

of other systems in particular,

the colon Have been reported to be heritable.

In the number of instances there could be two reasons.

# one,

it may be that we're looking at the indirect 

uh fact that patients who 

develop endometrial carcinoma are more likely to be 

obese have hypertension and diabetes and the 

latter to certainly have heritable tendencies.

So this could be indirect.

On the other hand,

there may be a given subset of patients with 

endometrial carcinoma who have 

a demonstrable genetic basis 

in the ovarian epithelial cancers serious 

mutinous.

Uh at least those are the only two for which good 

data are available.

Uh,

There are unequivocally good half dozen 

families in which multiple 

Individuals in multiple generations,

four or five generations,

sometimes as many as 20 and 25 affected 

individuals.

And the kindred will have ovarian epithelial 

varying the alert carcinomas.

Uh,

one would predict incidentally from other 

models and cancer that heritable cancers 

tend to more likely be bilateral 

and more likely to appear at a relatively young 

age.

I've just recently reviewed these days an attempt 

to come up with such heterogeneity and really haven't 

haven't confirmed that here.

But I think that's something we can look for in the future.

Terror thomas.

But I insisted terry thomas,

turmoil cyst one first of all might 

expect a heritable tendency based upon the 

relatively high prevalence of bilateral itty.

This is something that have been detected for 

other heritable tumors like retinoblastoma and 

Wilms tumor,

which pediatric tumors for example,

we know we all know that Durham boys tend to be 

bilateral in varying percentage depending 

upon what textbook and what month you read.

But any rate certainly heritable tendencies,

interestingly it's now been shown that 

uh terra toma is in the ovary 

probably were result from parthenogenesis 

because using the same G six Pd 

principles,

if one takes uh looks at the G.

C.

G six pd types off terry 

thomas and mothers who are hetero zygotes.

You find that it's all of one type of the other which 

indicates that it's probably occurring at a 

very early age and probably resulting 

from poorly formed over this 

quote unquote.

And let's not get into that any further arena 

blast omagh's or certainly lighting cell tumors.

Again enough 

examples of familial tumors that it's probably worth 

considering granule also cell tumors.

In general,

one does not find any heritable tendencies.

However,

the pukes Jaeger syndrome,

which is autism dominant syndrome in which one 

gets oral melanocytes along the 

lips as well as colonic polyp Asus 

has associated with it fully.

About a 25% prevalence rates for granular 

cell cell tumors.

So that these in general I think are some 

conditions that we might think about in 

G.

Y.

N.

Disorders and uh in many cases 

particularly the territo hmas.

Uh they're worth some prospective analysis and other 

relatives particular uh in multiple affected 

sibs uh We could talk about some other 

disorders like this but I think you get the picture 

uh And in general I close by saying the reason 

there are two good reasons why we haven't come 

up with more common G.

Y.

N.

Disorders that are heritable.

The first of these is that we're looking at an internal organ 

system.

It's a lot easier to detect heritability in 

skin and eyes and nails and 

hands and the likes of that where we can call in all the 

relatives and send them around a big table 

uh and look at them and come up with a pedigree in 

the in a matter of minutes.

Whereas it's obviously much more difficult when we're 

asking questions about endometriosis of the likes of 

that.

And the second is that we're dealing with a sex limited 

system.

Uh Let's say that we have for 

example,

terra thomas are indeed although somewhat 

recessive,

they don't think they are.

Please don't quote me that way.

But let's just say that they are.

If we went about trying to find some familiar 

aggregates at random,

the probability that the any subsequent progeny 

after a pro ban would be affected is really 

not one in four.

It's one in four if both males and females were 

affected.

But since the probability is only one into that,

we have a female coming out of that and the 

probability is only one in eight.

So in other words,

one in eight for every female chances are only one and 

two that we're dealing with the female so that we're going 

to see fewer examples of familial aggregates even 

if a condition is inherited in a in a 

genetic fashion.

This program was produced through the mobile 

facilities of the television branch,

health Sciences Media Division,

Academy of Health Sciences,

United States Army for SAM Houston 

texas.