Under our care
80 % (24/30) of our patients have
had at least one successful pregnancy (Figure 1) as defined by a live birth or an ongoing pregnancy of > 20
weeks (p< .0003). (a low p value such as this shows a very high statistical
Figure 1: Overall pregnancy success at Braverman Reproductive Immunology
All the documented losses were
aneuploid (abnormal) which shows that our therapies are effective in maintaining
No significant difference was determined between the types of infertility
as shown in Figure 2.
- Primary has no history of a successful birth prior to the miscarriages
- Secondary has a history of a full term birth followed by miscarriages
- Tertiary has a history of miscarriages prior to and after a full term birth.
Figure 2: BRI pregnancy success rate based on type of infertility
If we consider only
the first attempt to conceive,
of our patients will get a successful pregnancy with 83.4% of cycles being done with own patient oocytes. There was no
significant difference among the groups as seen in Figure 3.
Figure 3: BRI pregnancy success rate at first attempt based on type of
If we consider, patients requiring donor oocyte,
100% had at least one loss
to our care despite a good quality embryo (donor was less than 35 years old)
But under our care,
80% of them had a successful pregnancy at the first attempt (4/5), while 20% were not after one single attempt (1/5).
By providing our patients adjusted and adequate therapies, these women
are now already or soon to be happy mothers.
The most important aspect in deciding to treat patients with a history
of recurrent miscarriage is to understand their risk of further miscarriages when
no treatment is offered. To this end the literature appears abundantly clear.
- Women with a history of miscarriage and whose pregnancy was proven genetically
normal (by testing of the Products of Conception or by PGS tested embryos)
have a significantly greater risk for further miscarriages.
- Women with documented losses where the Products of Conception were genetically
abnormal do not appear to be at risk for further miscarriages.
- Women with a history of miscarriage which were proven genetically normal
still have an increased risk for further miscarriages, even if they have
another loss that is proven to be genetically abnormal.
- Women who have a miscarriage where the genetics were not able to be tested,
have a high likelihood that the pregnancy was genetically normal and therefore
they are at increased risks for future miscarriages if:
a. There was presence and loss of a fetal heart beat (this becomes more
significant the further along the pregnancy goes).
b. Those with a history of 5 or more miscarriages
c. Those patients that miscarry with donor embryos from a young donor (<
35 years old)
d. Multiple losses in a young women (under age 35 with no history of abnormal
karyotype i.e. the mother or father do not have genetic abnormalities)
Treating any group of patients where there is no clinical history of genetically
normal (euploid) losses should offer no benefit as the losses in this
group of patients would therefore, most likely, be genetically abnormal
(aneuploid) and the literature shows that aneuploid losses are
not predictive of further miscarriages, i.e. most of these patients would succeed
To this end then it also is true that any study looking at the risk of
future miscarriages that includes as its majority a patient population
with mostly aneuploid losses (chemical pregnancies, loss prior to fetal
heart rate, or of course abnormal genetic testing of the products of conception)
will have an artificially high rate of success with subsequent (future)
pregnancies (i.e. if the aneuploid pregnancy does not increase risk for
another loss then these patients have a good chance of pregnancy
At the time much of the literature predicting future success in the recurrent
pregnancy loss population was written, many of these issues were not addressed,
leading to misunderstand and therefore misinterpretation of predicted
success rates in women with recurrent pregnancy loss where no medical
therapy was initiated.
It also holds true that evidence of
treatment success in the group of women at risk for further miscarriages (those with history
of euploid loss) should show:
- a decrease in the number of euploid losses (over the predicted rate without
treatment) once therapy is initiated i.e. most of the losses should be
aneuploid as these would not benefit from treatment
- And of course an increase in the successful pregnancy outcome rate.
With this in mind we begin a review of the literature that attempts to
define the chances of success after a history of recurrent pregnancy loss,
then we will discuss our success rate in a group of well-defined at risk
patients and compare this with the known literature.
1. The Brigham study: the reference to date in establishing outcome of
a subsequent pregnancy in RPL patients
One of the first studies focusing on RPL patients and subsequent pregnancy
losses was published in 1999 in the Journal of
Human Reproduction (1) and remains to date the most quoted study focusing on recurrent miscarriages.
They unknowingly excluded most of the patients that would have “euploid”
losses , leaving them with mostly a population of patients that were having
aneuploid losses, which we now understand do not have an increased risk
of reoccurrence. Calculations of success after any number of miscarriages
in this group of patients would therefore be artificially elevated.
- They excluded all of the below patients: all high risk for “euploid” losses.
- Anti-Phospholipid antibodies (this would therefore eliminate many with
autoimmune diseases and silent endometriosis)
- Oligomenorrhoea , light or infrequent cycle, (this would eliminate many
with PCOS, and those with rising FSH levels, another indicator for silent
- Endocrine abnormalities
- Known Endometriosis
- Patients with a history of second trimester loss (euploid loss)
They failed to document the time of first positive βhCG with their
next pregnancies (patients came to the clinic when they wanted, so many
of the biochemical pregnancies in the study population were likely missed).
Many patients who were pregnant but had a “late” bleed most
likely never came in and these losses were not recorded.
This would artificially lower the number of miscarriages in the study
and therefore artificially elevate the successful pregnancy rates.
- There is no timeline in women’s enrollment into the study, they presented
spontaneously (when they wanted to) and 10% of patients presented after
8 weeks, at a time when miscarriages are less likely to happen.
As a result, the study is biased, as seen by the
majority of aneuploid losses (89%) while only 11% of fetal losses occurred with a fetal heartbeat detected
at the time of loss so most likely euploid.
If this was a group at high risk for repetitive losses, most of the losses
in this untreated group would have been euploid.
Therefore, this population group is not at increased risk for a subsequent
pregnancy and are more likely to have a future pregnancy success with
2. Recurrent pregnancy loss patients have a higher risk of future euploid losses
a- Literature Review
Ogasawara and collaborators (2) showed that the likelihood of a loss being
normal (euploid) was higher in recurrent miscarriage patients (48.7%)
compared to the control population of those having a miscarriage for the
first time (23.7%).
Only 35% of RPL patients in this study managed to have a successful pregnancy,
with treatment (compared to 80% for our patients here at Braverman Reproductive
Immunology with treatment).
Interestingly, the frequency of an aneuploid (abnormal) loss significantly
decreased with the number of previous miscarriages, while that of a normal
loss (euploid) significantly increased (showing that those with high number
of miscarriages were most likely losing euploid pregnancies and that these
types of losses tend to reoccur without treatment).
These results were confirmed by another team led by Morikawa (3) showing
that RPL patients are more prone to have another euploid loss. In this
study, euploid losses were shown to be significantly higher in RPL patients
(66.7%) vs. controls (45.7%) while aneuploid losses remain the same between
the two groups. Again showing that it is the euploid losses that most
likely need treatment.
In this study, 49% of patients had a successful pregnancy with treatment,
compared to 80% on our patients here at Braverman IVF & Reproductive
Another study by Carp and collaborators (4) focused on genetic testing
on products of conception in patients with 3 or more miscarriages.
They found that the incidence of aneuploid losses among these miscarriages
was 29% while 71% of losses were euploid. They also estimated that after
an aneuploid loss, 68% will have a live birth while only 41% will have
a live birth after euploid losses.
Altogether these studies showed that:
- RPL patients are more prone to have a another miscarriage that is documented
as a euploid loss
- this risk increases with the number of miscarriages(showing that higher
number of miscarriages is more likely to be associated with euploid losses)
b- Success treating RPL patients with history of euploid losses:
the Ogasawara study
In their study, Ogasawara and collaborators included a large set of patients
with RPL (n=1309) who had between 2 and 20 consecutive first trimester
losses before a subsequent pregnancy (2).
Unlike Brigham’s work, his study design
- Autoimmune disease: Anti-phospholipid syndrome, diabetes, hyper thyroidism
- Oligomenorrhoea (light or infrequent cycle)
- Endocrine abnormalities: PCOS
- Known Endometriosis cases
- All patients with a history of at least 2 losses regardless of the time
of the loss (first or second trimester) were also included
They also included
all the patients whose first beta HCG was drawn 2 weeks after conception
(i.e. 4 weeks of pregnancy) so the
biochemical pregnancies are
Immune therapy was administrated to patients with at least 3 prior pregnancy losses.
In this study, they reported on patients with 5 or more previous miscarriages, and their success rate was
35% despite immune therapy
(compared to 80% in our patients).
The authors acknowledged the fact that the treatments provided are somehow
not really adapted and/or inefficient as:
- The pregnancy success rate should have been higher if the therapy was appropriate
There should have been fewer euploid losses (70% in their study).
At Braverman Reproductive Immunology , none of the tested Products of
Conception were euploid, all were aneuploid showing a significant success
in maintaining euploid pregnancies with treatment.
3- Pregnancy success with Braverman Reproductive Immunology (BRI)
a- What are my chances with Braverman Reproductive Immunology?
the number of miscarriages directly impacts pregnancy success, we have chosen to focus on women with 5 or more losses (N=30 cases) who
lower chances of having a successful pregnancy.
The average age of RPL women was 33.5 years (25-40 years) with first documented
loss, with an average of 6 pregnancy losses (from 5 to 10 losses).
Unlike the Brigham study, we included
patients regardless of their medical history (PCOS, endometriosis, autoimmune diseases etc…) as well as biochemical
pregnancies preventing us from underestimating our pregnancy loss rate.
Prior to conception, all RPL women had been subjected to examination by
ultrasonography and hysterosalpingography to detect anatomical abnormalities
of the genital tract or cervical incompetency.
All of our patients underwent
our unique extensive genetic and immunologic panel screening including:
- Genetic testing: full HLA profile to determine the compatibility between
couple and define predisposition for immune diseases that could explain
- Cellular testing that looks at cell numbers and their propensity to make
certain cytokines which allow us to determine how the immune system is
pointing (Th1 or Th2 dominant state)
- Serum cytokines and antibodies quantification to determine the level of
activity of the immune system
Patients received appropriate therapy before conception (natural conception
or IVF cycle) and the treatment was maintained at least throughout the
first trimester of pregnancy.
Prior to our care, up to
90% of our patients had
at least one euploid loss compared to 11% in the Brigham study.
The high level of euploid losses suggest that immune defects could be responsible
for those pregnancy losses.
Under our care,
80% of our patients had a successful pregnancy.
b- Where do we stand in comparison with other studies?
increased risk of pregnancy losses due to the higher number of previous miscarriages and the different pathologies
affecting our population group (autoimmune diseases, PCOS, endometriosis)
compared to the other studies, we did get
the highest rate of pregnancy success (60%) at the first attempt (subsequent to the serie of miscarriages occuring before our care) and
we had the overall highest pregnancy success rate with an
outstanding 80% success.
In the Birgham study, the pregnancy success rate was 52.15% but largely
overestimated due to the possible missed embryonnic losses as patients
presented to the clinic by 8 weeks and not right after a positive βhCG
test. Furthermore, as seen by the high percentage of aneuploid losses
(89%), they selected a population that was shown to have a lower risk
for further miscarriages.
Ogasawara study is very reliable and comparable to our work in term of
inclusion/exclusion criteria but failed to get a higher rate of pregnancy
success despite the use of immune therapy (35% success).
As stated by the authors, this showed that “therapeutic approaches
are not sufficiently efficacious”
Besides our outstanding pregnancy success rate at first attempt (60%) and
even greater rate (80%) after adjusting our therapy regimen (during the
subsequent attempt), it is important to underline that
none of the documented losses were euploid.
Although not every sample was able to be tested, the fact that none of
the tested samples showed a euploid loss is very significant and shows that
our immune therapies are highly effective in retaining euploid pregnancies.
at Braverman IVF & Reproductive Immunology, keep working in optimizing our pregnancy success rate by developing new
tests to detect immune parameters potentially affecting the establishment
and maintenance of pregnancy.
custom-designed strategies to conteract the detrimental effects of certain factors, we hope to exponentially
help women to become mothers.
- Brigham SA, Conlon C, Farquharson RG. A longitudinal study of pregnancy
outcome following idiopathic recurrent miscarriage. Hum Reprod. 1999 Nov;
14(11):2868-71 Stirrat GM. Recurrent miscarriage. Lancet 1990; 336:673–5.
- Ogasawara M, Aoki K, Okada S, Suzumori K. Embryonic karyotype of abortuses
in relation to the number of previous miscarriages. Fertil Steril. 2000
Feb; 73(2):300-4. PubMed PMID: 10685533.
- Morikawa M, Yamada H, Kato EH, Shimada S, Yamada T, Minakami H. Embryo
loss pattern is predominant in miscarriages with normal chromosome karyotype
among women with repeated miscarriage. Hum Reprod. 2004 Nov; 19(11):2644-7.
- Carp H, Toder V, Aviram A, Daniely M, Mashiach S, Barkai G. Karyotype of
theabortus in recurrent miscarriage. Fertil Steril. 2001 Apr; 75(4):678-82.