Spring dd Multiple Birth by benbenzhou


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									   Spring 2008

 Unexpectedly high life birth rates in older women
Two related findings deserve special               Considering that these statistics in-       carriage rate in a normal, fertile popu-
notice: In a first analysis, Dr. Barad of          cluded women up to age 47, they are         lation is approximately 15%. A clinical
CHR, demonstrated that, in parallel                nothing but remarkable. Since women         miscarriage rate of only 21.4% in our
with the introduction of DHEA supple-              of such advanced ages experience            extremely adversely selected patient
mentation into CHR’s treatment pro-                very high pregnancy loss rates, the         population has, therefore, to be con-
tocols, the overall program’s life birth           question, however, remained, whether        sidered extremely low and surprising.
rates in older women have steadily                 these exceedingly satisfactory preg-             This finding raises immediate ad-
improved. In 2006, we for the first                nancy rates would also translate into       ditional questions, the first one being,
time used DHEA systematically in, still            equally exciting life birth rates.          why would older women, under treat-
carefully selected women (resulting in                We are now pleased to report that        ment at CHR, have so much lower
only 43% of women receiving DHEA)                  they do! Our life birth rate after IVF in   miscarriage rates than universally re-
and achieved a quite stunning clinical             women above age 40 was 20.8% per            ported in the literature for women of
pregnancy rate of 23.5% per transfer.              embryo transfer. In practical terms this    this age? The answer is that we do not
In double- and triple- checking our                means that only approximately 21.4%         know for sure; it appears that slowly
2006 pregnancy data in preparation for             of women, who conceived ended their         a picture is emerging that can explain
the annual CDC submission, we noted                pregnancy with a miscarriage, less          these findings and makes perfect
that our pregnancy rate had been even              than half the number one would ex-          sense.
higher than we previously had as-                  pect, considering the very advanced
sumed and reported. Our true clinical              age of our patients. The average mis-       (for explanation, see below, “Does DHEA
pregnancy rate in women above age                                                              reduce aneuploidy?”)
40 was 26.4%. Our originally quoted
data had been lower because our em-
bryology staff had been unaware of a
few, mostly out of town, pregnancies.
                                                   Does DHEA reduce aneuploidy?
                                                    We previously reported that women after DHEA supplementation produce statisti-
                                                    cally significantly more chromosomally normal (euploid) embryos. We at that time,
 ANNOUNCEMENT                                       however, cautioned from reaching the conclusion
 We are pleased to announce that fertility          that DHEA reduces chromosomal abnormalities (an-
 preservation pioneer KUTLUK OKTAY,                 euploidy) and noted that our findings could be due to
 MD, has joined CHR as of January 2008              the fact that DHEA appears to increase egg and em-
 in the position of Director of CHR’s newly         bryo numbers, which, of course, would also increase
 formed Fertility Preservation Institiute. Dr.      the number of euploid embryos.
 Oktay’s research interests in premature              At the same time we, however, also pointed out that
 ovarian senescence due to chemo- and
                                                    DHEA, at least theoretically, also could have an affect
 radiation therapies, and his widely recognized
 work in fertility preservation, including the
                                                    on chromosomal abnormality rates (ploidy), since
 first published ovarian transplant in the          we believe that DHEA somehow affects the whole
 world literature, match very well with CHR’s       4.5 months long follicular recruitment process and,
 principal research activities on ovarian aging.    therefore, also could affect ploidy.
 Appointments with Dr. Oktay can be made              As women age, the rate of aneuploidy in their em-
 by calling CHR at 212-994-4400.                    bryos increases. As a consequence of more chromosomally abnormal embryos, their
                                                    miscarriage rates go up with advancing age. This is exactly the reason why the ex-
                                                    pected number of miscarriages in our study group of women above age 40 (until
                                                    age 47) would be expected around 45-50%. The fact that we see less than half the ex-
                                                    pected miscarriage rate strongly hints at a reduced aneuploidy rate in embryos of
                                                    our patients. Together with our earlier data on more euploid embryos after DHEA
                                                    treatment, all of this suggests that DHEA, indeed, may have a direct effect on ploidy
                                                    and may reduce the risk for abnormal embryos. This then, of course, would also, at
                                                    least partially, explain why we overall see so much better pregnancy rates with DHEA
                                                                                                benefit may appear to them.
A Desirable Fertility Outcome?                                                                                     Physicians, who advise
                                                                                                              patients on risk/benefit, are

        Tw i n s
Practically every fertility treatment          CHR’s        embryo
                                                                                                              more limited in what they may
                                                                                                             recommend. Since medical
                                                                                                            risks are numerically quanti-
                                                                                                            fiable, it is relatively easy to
increases the risk for multiple births.        transfer policy al-                                         compare risks of alternative
Depending on fertility treatment, mul-         ways was based                                              treatments, as long as benefits
tiples represent anywhere from ap-             on the accep-                                              remain constant. A physician’s
proximately 5-35% of deliveries. The           tance of twins                                             advise is then bound by what
reason is quite simple: in 99% of nat-         and the rejec-                                            such a comparison suggests be-
ural cycles only one egg is released.          tion of triplets                   “An infertile
                                                                               couple delivering
                                                                                                         cause if outcomes are the same,
The natural multiple prevalence is,            or even higher                                           good medical care requires that
                                                                                a twin gestation
therefore, only around one percent,            order births.                  has the immediate         the procedure with lower risk be
with a large majority being twins.                      Everybody               pleasure of two        chosen.
    Since fertility treatments turn single     agrees that singletons              children.”             In applying all of this to twinning
egg into multiple egg cycles, more             represent the lowest risk                              after infertility care, opponents of
than one egg is released, can get fer-         pregnancy and that, with increasing              twin pregnancies have correctly ar-
tilized, and the consequence is then a         order of pregnancy, the risk to babies           gued that twin pregnancies carry high-
multiple birth.                                and mothers increases. CHR always                er perinatal and maternal risks than
      Increasingly successful infertility      felt that the additional risk of twinning        singletons. What they, however, have
treatments have resulted in an epi-            was minor enough to be more than                 forgotten is that the benefits from both
demic of multiple births. Quite rightly,       made up by the benefits a twin preg-             are not the same. A singleton preg-
lay public and medical community               nancy bestows on an infertile couple.            nancy results in the birth of only one
have identified this as a major prob-          Until recently, most of our colleagues           child, while an infertile couple deliver-
lem. Indeed, CHR’s Medical Director,           agreed with us. More recently ini-               ing a twin gestation has the immediate
Dr. Gleicher, was in the vanguard of           tially starting in Europe, but now also          pleasure of two children.
efforts to reduce multiple births, when        in the U.S., an increasing number                    In a mathematical sense this means
he, in a study in the prestigious New          of colleagues have started to argue              that historical outcomes between
England Journal of Medicine in the             that twins represent an unfavorable              singletons and twins can, and really
year 2000, found the risk for high or-         outcome of infertility treatment, to             should not be compared. If it is done
der multiples (triplets or more) with          be practically avoided at all cost. We           anyhow, then the mathematics has to
intrauterine inseminations to be un-           strongly disagree!                               be corrected. Since the woman with
controllable and suggested that pa-               Our disagreement with many of our             a singleton delivery will have to un-
tients be taken earlier into in vitro fer-     colleagues is based on hard statisti-            dergo another, second pregnancy and
tilization (IVF) (Gleicher et al. N Engl       cal facts, and here is a short sum-              singleton delivery to achieve the same
J Med 2000;343:2-7). Amongst all               mary: The sudden antipathy towards               outcome as the twin delivery achieved,
infertility treatments, IVF gives us the       twin delivery stems from the fact that           the risks of a singleton delivery have to
best control over an increased risk for        perinatal (the offsprings’) and ma-              be multiplied by two before they can
multiples because we (that is patient          ternal risks in a twin pregnancy are             be compared. When this is done, –
and physician) decide how many em-             somewhat higher than in a singleton              surprise – surprise -, twin deliveries no
bryos to transfer into the uterus. The         delivery. But so are the benefits, and           longer carry excessive risks for infants
more are transferred, the higher the           this is usually forgotten!                       or mothers.
multiple risk, though the age of the                   Risk/benefit calculations form                 Dr. Gleicher presented this argu-
mother also plays a significant role.          the basis for all decision making in             ment for the first time in November
    As the utilization of IVF in infertility   medicine, since nothing in medicine              2007 at the World Congress for IVF
has increased over the last decade,            is completely risk free. Patients and            in Montreal, Canada. A more detailed
so has our ability to control multiple         physicians, once risks and possible              presentation and mathematical analy-
risks. CHR has always prided itself            benefits of a medical intervention are           sis of published data was submitted for
for achieving high clinical pregnancy          known, then make a decision. What                publication. The obvious conclusion is:
rates, without exposing patients to            level of risk a person is willing to             Twins are a very desirable outcome for
risk for high order multiples. Many pa-        take to achieve a certain benefit, of            most infertile couples undergoing fer-
tients bare witness to CHR’s conser-           course, varies between individuals.              tility treatments. The profession has
vative embryo transfer policy, even            In other words, patients have an ab-             apparently begun to listen because
if, at times, it has taken efforts and         solute right to take more or less risk,          Dr. Gleicher recently received two re-
strong arguments to convince them              based on their own attitudes towards             quests for review articles on the sub-
of the wisdom of such an approach.             risk and how important a specific                ject from European specialty journals.

                                                                                                        DHEA UPDATE

                                                           CHR to begin new prospectively
                                                             randomized study in 2008
                                                                                          not really believe in here at CHR);
                                                                                          (ii) were proven to have open fal-
                                                                                          lopian tubes; and (iii) have a male
                                                                                          partner with normal semen. Such
                                                                                          qualified women will then undergo
                                                                                          cost-free ovarian function testing
                                                                                          at CHR. If their FSH or AMH levels
                                                                                          are abnormal, suggesting that they
                                                                                          may suffer from premature ovarian
                                                                                          aging (POA), we will offer them,
                                                                                          once again free of charge, random-
                                                                                          ization to DHEA and placebo for up
                                                                                          to 8 months. Since they will have no
                                                                                          other obvious causes of infertility,
                                                                                          there will be no further intervention
                                                                                          and we will simply follow their spon-
                                                                                          taneous pregnancy rates, while
  Now that our European colleagues           a study has been performed, and              either on DHEA or placebo.
  have run into the same recruitment         confirms the utility of DHEA supple-            The study will be formally regis-
  problems in attempting to randomize        mentation.                                   tered in early January and adver-
  older women to DHEA and placebo,             We are pleased to report that              tisements, to recruit patients, will
  as we experienced here in New York         our IRB recently approved such a             start running shortly thereafter. If
  City, we have to find another way to       study. Starting in early 2008, we will       you feel that you may qualify for
  test DHEA in a prospectively ran-          prospectively randomize younger              this study, and are interested in
  domized study. Since prospectively         women (below age 38) to DHEA and             participating, please call 212-994-
  randomized studies are considered          placebo if they (i) were diagnosed           4400 and tell our staff that you
  the gold standard, DHEA will not           with so-called unexplained infertility       are calling for the “BELOW 38
  find universal acceptance until such       (as you will recall, a diagnosis we do       DHEA STUDY.”

Abnormal autoimmune function and female infertility
             More weight given to the link between the two
Our FMR1 work demonstrates that POA has two principal                  misdiagnosed, it should not surprise that abnormal au-
causes: (i) a genetic form, characterized by increased triple          toimmune function is so frequently found in women with
CGG numbers (though often still within a generally consid-             infertility. The medical literature on the unusual preva-
ered normal range); and (ii) an autoimmune form, charac-               lence of abnormal autoimmune function in infertile women
terized by abnormal autoimmune laboratory tests, but usu-              has become extensive, though this association was first
ally normal triple CGG repeat numbers (below 31). A small              pointed out by CHR’s Medical Director, Dr. Gleicher, al-
number of women may have a combination of both abnor-                  most 20 years ago (Gleicher et al., Am J Obstet Gynecol
malities.                                                              1989;160:1376-80). Abnormal autoimmune function,
   Both forms also differ in clinical presentation, with the ge-       as a cause of female infertility, therefore, needs to be
netic form of POA usually demonstrating much higher FSH,               taken much more seriously by the profession than it
and lower AMH levels, which means that the genetic form                currently is.
seems to be associated with more severe ovarian dysfunc-                  Maybe this genotypical and phenotypical separation of
tion.                                                                  POA into two distinct sub-types will allow us to develop
    These findings have major potential significance: First,           specific treatments for either type of POA, which will im-
they demonstrate that abnormal autoimmune function,                    prove our ability to successfully treat affected patients.
on its own, is associated with POA, and, therefore, fe-                Studies are underway at CHR to determine whether treat-
male infertility. Since POA is frequently missed and/or                ment responses differ between these two patient groups.

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Chicago, IL 60661

 Editors: Tom Weidner- tweidner@thechr.com
          Alexis Scarpinato- ascarpinato@thechr.com

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Some photos from Japan
  International Ovarian Conference, November 2-3 2007, Hakone, Japan

                                                                       (1) Norbert Gleicher, MD, Medical
                                                                           Director, CHR.

                                                                       (2) Prof. Bunpei Ishizuka, Chairman,
                                                                           International Ovarian Conference
                                                                           2007, Hakone, Japan (left) and Norbert
                                                                           Gleicher, MD, Medical Director, CHR

                                                                       (3) Prof. Hefeng Huang, MD, Associate
                                                          (3)              Dean and Professor of Ob/Gyn,
                                                                           Zhejiang University School of Medicine,
                                                                           Hangzhou, China (left) and Norbert
        (1)                                                                Gleicher, MD, Medical Director, CHR
                                (2)                                        (right) at the Faculty Dinner.

  If you’d like to share your experiences or success
 stories, please contact us by phone, fax or e-mail at:

                  Tel. 312-876-1506
                   Fax 312-876-1804

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