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Issue 7 - 2014
Welcome to the 7th issue of Fertility Research Review.
This issue begins with the miracle of 2014 – a live birth after uterus transplantation from a postmenopausal donor. This is the culmination of a 20-year research programme and an extraordinary achievement. Live birth after uterus Other research reviewed this issue includes confirmation that low-dose aspirin should not be recommended to prevent pregnancy loss and a suggestion to continue first-line clomiphene for 12 anovulatory cycles before initiation of expensive second-line gonadotrophins. Though perhaps letrozole is a better option than clomiphene for women Continue clomiphene in anovulatory women Good news for older men – paternal age has no effect on reproductive outcomes of ICSI with younger oocyte donors. Good news for younger women – most men will agree to their partners using their cryopreserved embryos in the Low-dose aspirin does not event of their death.
prevent pregnancy loss We hope you enjoy our selection for this edition and welcome your comments and feedback.
If you have colleagues or friends within New Zealand who would like to receive our publication, send us their contact Letrozole vs clomiphene email and we will send them a copy of the next issue.
for infertility in PCOS Kind regards,
Dr Mary Birdsall
Ectopic pregnancy lower with frozen embryo transfer Embryo selection using time- Livebirth after uterus transplantation
lapse monitoring Authors: Brännström M, et al.
Paternal age no issue for ICSI Summary: The first live birth after uterus transplantation has proven the feasibility of live uterus donation, even from
with young egg donors a postmenopausal donor. A 35-year-old woman with congenital absence of the uterus received a uterus transplant from a living 61-year-old, two-parous donor. Menstruation commenced in the recipient 43 days after transplantation Use of surplus cryopreserved and continued at regular intervals with median 32-day cycles. The recipient and her partner had undergone IVF prior to the transplant resulting in cryopreservation of 11 embryos. Single embryo transfer was performed 1 year after transplantation and resulted in pregnancy. Triple immunosuppression with tacrolimus, azathioprine and corticosteroids was continued throughout pregnancy, during which three episodes of mild rejection were reversed by Ovarian stimulation for fertility corticosteroid treatment. Blood flows of the uterine arteries and umbilical cord were normal throughout pregnancy. Foetal growth parameters were normal and a male baby with a normal birthweight for gestational age (1775  g) was delivered by caesarean section at 31 weeks and 5 days after the patient was admitted with pre-eclampsia. Teenage acne associated Apgar scores were 9, 9 and 10.
Comment: This is an extraordinary achievement and is the culmination of a meticulous 20-year research
programme from this Swedish group. They also have another two pregnancies beyond 32 weeks.
The major issues with uterine transplantation are around the surgical morbidity particularly for the donor. The
Abbreviations used in this issue
surgery to remove the uterus and the adjacent vessels lasts many hours and the British are currently exploring HR = hazard ratio
the use of uteruses from deceased women. This report offers hope to women who are born without a uterus, that ICSI = intracytoplasmic sperm injection
they may experience the wonder of pregnancy and birth, truly the miracle of 2014.
IVF = in vitro fertilization
PCOS = polycystic ovary syndrome
Reference: Lancet. 2014 Oct 6. doi: 10.1016/S0140-6736(14)61728-1. [Epub ahead of print]
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Fertility Research Review
How long should we continue clomiphene citrate in
Preconception low-dose
aspirin and pregnancy
Authors: Weiss NS, et al.
outcomes: results from the
Summary: Continuing treatment with clomiphene for a further 6 cycles was justified in a retrospective study of
EAGeR randomised trial
114 women with anovulation for at least 6 ovulatory cycles without successful conception. Ongoing pregnancy Authors: Schisterman EF, et al.
was achieved in 35  women (31%) resulting in a 54% cumulative incidence rate of ongoing pregnancy after 7–12 clomiphene treatment cycles. The authors questioned guideline recommendations to switch to expensive Summary: Low-dose aspirin is not recommended for
gonadotrophins after failure to conceive with clomiphene within 6  cycles. Randomised comparative trials of the prevention of pregnancy loss based on results of continued clomiphene vs gonadotrophins are needed.
a randomised double-blind trial in 1078  women with one to two previous pregnancy losses. Women were Comment: This study shows that women with anovular PCOS who have not conceived after 6 months of
randomised to receive pre-conception initiated daily clomiphene still have a reasonable chance of a pregnancy if they choose to continue on with clomiphene for low-dose aspirin (81  mg/day) or placebo for up to another 6 cycles. This is useful as options on from clomiphene are much more complex and expensive with 6 menstrual cycles. Treatment continued until 36 weeks' additional risks. It is sometimes difficult to convince couples to stick with a treatment when a pregnancy has gestation in women who conceived. All women also not resulted, so this will be useful information to share with them.
received folic acid. There were no significant differences in live birth rates (58% vs 53%; p=0.098) or pregnancy losses (13% vs 12%; p=0.781) between women who received low-dose aspirin or placebo. Higher live birth rates were seen in women with a single documented loss at less than 20  weeks' gestation during the previous year. Low-dose aspirin was associated with increased vaginal bleeding, but this adverse event was not associated with pregnancy loss.
Comment: Pregnancy loss is associated with
considerable grief and many couples are keen to try anything that may increase their chances of having a healthy baby in a subsequent pregnancy. Most miscarriages however, are due to chromosomal abnormalities meaning that no medications are going to be helpful.
For many years, aspirin has been suggested as being useful in the miscarriage setting by possibly improving the blood supply to the implanting embryo. Whilst aspirin may do no harm, it is very useful to have another trial confirming that low-dose aspirin does not improve the chances of a live birth following a pregnancy loss. More than that, low-dose aspirin also increases the risk of bleeding during pregnancy, with the associated angst around a threatened miscarriage.
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Letrozole versus clomiphene for infertility in
Clinical validation of embryo culture and
the polycystic ovary syndrome
selection by morphokinetic analysis:
Authors: Legro RS, et al.
a randomized, controlled trial of the
Summary: Letrozole was associated with higher live-birth rates and ovulation
rates compared with clomiphene in a double-blind study of 750  women with PCOS. Women were randomly assigned to receive letrozole or clomiphene for up Authors: Rubio I, et al.
to 5  treatment cycles. The cumulative live-birth rate was significantly higher with Summary: Embryo selection using EmbryoScope, an incubation integrated time-
letrozole vs clomiphene (27.5% vs 19.4%; p=0.007) with a rate ratio for live birth of lapse monitoring system, improved reproductive outcomes compared with standard 1.44 (95% CI 1.10-1.87). There were no significant differences in overall congenital incubation and morphology evaluation in a prospective randomised, double-blind anomalies, but there were four major congenital anomalies in the letrozole group vs study in 843 infertile couples undergoing ICSI. There was no difference in pregnancy one in the clomiphene group. The cumulative ovulation rate was significantly higher rates per cycle (61.6% vs 56.3%) or pregnancy rates per transfer (65.2% vs 61.1%) with letrozole vs clomiphene (61.7% vs 48.3%; p<0.001). Pregnancy losses (31.8% between the time-lapse system and standard incubation. Ongoing pregnancy rates vs 29.1%) and rates of twin pregnancy (3.4% vs 7.4%) were similar for letrozole were significantly increased using the time-lapse system (51.4% vs 41.7% per vs clomiphene. Adverse events were similar in both groups with the exception of a cycle and 54.5% vs 45.3% per transfer). Implantation rates were also significantly higher incidence of hot flushes with clomiphene and higher incidences of fatigue and increased using the time-lapse system (44.9% vs 37.1%) and early pregnancy loss dizziness with letrozole. was significantly decreased (16.6% vs 25.8%).
Comment: This is a trial that should change clinical practice. The investigators
Comment: Time lapse is where embryos are photographed every few minutes
had a group of young obese women with PCOS and randomised them to as opposed to being checked daily by the embryologist. This is the trial we have clomiphene versus letrozole and found significantly more pregnancies in the been waiting for to give us some idea if the newest toy in the IVF Lab has any letrozole arm of the study. There have been concerns as to whether letrozole may merit. This group randomised patients to time lapse versus routine culture and be associated with a higher rate of foetal abnormalities however these worries reported an improvement in ongoing pregnancy rates of 10%. In the world of IVF have not been confirmed so letrozole should now be considered to be the first-line this is a big improvement.
agent for ovulation induction in obese women with PCOS.
The big debate now around time lapse, is what is the important part? Is it choosing the right embryo from a bunch of embryos by knowing exactly when an Reference: N Engl J Med. 2014;371(2):119-29.
embryo reaches certain milestones or is it not disturbing the embryos throughout their culture period. Hard to know, but this new toy looks useful.
Is frozen embryo transfer cycle associated
with a significantly lower incidence of ectopic
pregnancy? An analysis of more than
Paternal age and assisted reproductive
outcomes in ICSI donor oocytes: is there an
Authors: Huang B, et al.
effect of older fathers?
Summary: The incidence of ectopic pregnancy was significantly lower after frozen-
Authors: Beguería R, et al.
thawed embryo transfer compared with fresh embryo transfer in a retrospective study of 31,925 women undergoing IVF. Clinical pregnancy was achieved in 45.4% Summary: The effect of paternal age on semen quality and reproductive outcomes
of women using frozen embryos and 42.7% of women using fresh embryos. Ectopic was investigated in a retrospective study of ICSI in 4887  oocyte donation cycles. implants were evident in 1.01% and 1.97% of these pregnancies, respectively, Semen quality was found to diminish with age: for every 5 years of age, sperm volume giving an ectopic pregnancy rate of 2.22% vs 4.62%. Blastocyst frozen-thawed decreased by 0.22  ml (p<0.001), sperm concentration increased by 3.1  million embryo transfer had the lowest risk of ectopic pregnancy; fresh embryo transfer sperm/ml (p=0.003) and percentage of motile spermatozoa decreased by 1.2% had the highest risk, followed by day-3 embryo frozen-thawed transfer. The authors (p<0.001). Paternal age had no effect on reproductive outcomes such as pregnancy, commented that these findings are consistent with ovarian stimulation being miscarriage and live birth when the oocyte donor age was <36 years. The authors associated with an increased risk of ectopic pregnancy.
suggested that this indicates ICSI and oocyte quality can jointly overcome the lower reproductive potential of older semen.
Comment: Pregnancies following frozen embryo transfers are associated with
better perinatal outcomes such as birth weight and gestational age. Now this Comment: There is now clear evidence that men age from a reproductive
study also reports a reduced risk of ectopic pregnancy. Vitrification of embryos perspective but nowhere near as much as women. However, when older men has enabled thaw survival rates to be more than 95% and frozen embryo are combined with very young eggs (in this study the average egg donor was 26) pregnancy rates are at least as good as fresh pregnancy rates and often superior. then paternal age makes no difference. This is also an enormous database of The time is definitely coming when there will be a complete separation between nearly 5000 donor egg cycles. Therefore, when choosing a reproductive partner, ovarian stimulation and embryo culture and then at a later date replacement of one should always focus on younger is better, but with a young egg donor any frozen embryos.
aged man is OK.
What this study does not report is the health of the offspring, and whether there is still the increased risk of autism, schizophrenia and dwarfism associated with advancing paternal age.
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Fertility Research Review
Posthumous reproduction
Comparison of starting ovarian stimulation on day 2 versus
with surplus in vitro
day 15 of the menstrual cycle in the same oocyte donor and
fertilization embryos: a study
pregnancy rates among the corresponding recipients of
exploring users' choices
Authors: Côté S, et al.
Authors: Martínez F, et al.
Summary: Choices regarding the potential use of
Summary: A small prospective study comparing initiation of ovarian stimulation on day  2 vs day  15 of the
surplus cryopreserved embryos were examined in an menstrual cycle showed no differences in clinical pregnancy rates or number of mature oocytes obtained. Ovarian analysis of signed consent forms from 498 individuals stimulation was performed in nine donors and a mean of 14.0 mature oocytes were obtained after day 2 initiation using this service. Use of surplus embryos for vs 16.89 mature oocytes after day 15 initiation. To date, 20 recipients have received vitrified oocytes and there embryologist training and improvement of assisted have been no differences between recipients of day 2 oocytes (n=8) and day 15 oocytes (n=12) in fertilisation reproductive techniques was consented to by 68% of rate (77.3% vs. 76.5%) or number of embryos transferred (1.50 vs. 1.67). Twelve clinical pregnancies have been individuals and 56% consented to the use of surplus achieved and there have been no differences between recipients of day 2 oocytes and day 15 oocytes in pregnancy embryos in a research project. Consent to use of rates (62.5% vs. 58.3%) or implantation rates (41.67% vs. 45%). These results are useful for fertility preservation surplus embryos for posthumous assisted reproduction in patients with cancer.
differed between men and women: 73.5% of men and 61.8% of women agreed to leave their cryopreserved Comment: This is one of those small but very useful studies comparing a day 2 start of IVF stimulation to a
embryos to their partners for reproductive use in day 15 start in an egg donation programme. They showed that both strategies were equally effective in terms the event of their death. The authors discussed of pregnancy rates and the numbers of eggs obtained. The usefulness of this study is for women with cancer the complex psychological aspects of posthumous who have a very narrow timeframe for IVF with egg or embryo cryopreservation prior to commencing cancer assisted reproduction and the importance of ensuring consent is well informed. Comment: This study shows that many couples
are comfortable with the option of donating their surplus embryos for embryologist training or for research. In New Zealand human embryo research Severe teenage acne and risk of endometriosis
is not permitted, so any advances in this area occur offshore and then we benefit but do not contribute. Authors: Xie J, et al.
The other interesting aspect of this paper is the Summary: Severe teenage acne was associated with an increased risk of endometriosis in a prospective study
difference between men and women concerning of 88,623  female nurses taking part in the Nurses' Health Study  II. A total of 4382  laparoscopically confirmed their willingness to leave their embryos to their endometriosis cases were documented during 1,132,272  woman-years of follow-up. Women who had severe partners in the event of their death. Men seem teenage acne had a 20% increased risk of endometriosis compared with women without a history of severe teenage much more comfortable about their partners acne (HR 1.20; 95% CI 1.08-1.32). Adjusting for use of tetracycline or isotretinoin had no effect on the association. using their embryos, but women seem much less The authors commented that as a visible and non-invasive clinical indicator, severe teenage acne may be useful for convinced about another woman caring for their early detection of endometriosis.
Comment: The Nurses' Health Study continues to produce some interesting data. These researchers have
shown an association between laparoscopically confirmed endometriosis and severe teenage acne. We usually link bad acne with polycystic ovaries and raised testosterone levels so it seems odd that this association is now reported. The average time to diagnosis of endometriosis is 7 years so this observational data may possibly mean that the diagnosis may be made sooner. Next time we see a young woman with bad acne and pelvic pain, maybe we should consider endometriosis.
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BHB MB ChB Auckland; FRANZCOG MSc (Oxon)Mary is the Medical Director of Fertility Associates' Auckland clinic and combines this with a private gynaecology practice. She has a special interest in fertility preservation and the lifestyle Privacy Policy: Research Review will record your
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