Cleveland Clinics performs first Uterine Transplant from deceased donor in U.S.

The surgeons at Cleveland clinic performed first uterine transplant in U.S. this week.

Earlier in November 2015, Cleveland clinic announced a clinical trial that involved performing 10 uterine transplants in women with Uterine Factor Infertility (UFI).

About 1 in 4,500 women in the United States is born without a uterus - a condition known as Mayer-Rokitansky-Küster-Hauser syndrome, according to the NIH.

UFI is an irreversible condition affecting 3-5% of pregnancies worldwide. "Women who are coping with UFI have few existing options," Tommaso Falcone, chairman of the Department of Obstetrics-Gynecology at Cleveland Clinic, said when the clinical trial was announced. "Although adoption and surrogacy provide opportunities for parenthood, both pose logistical challenges and may not be acceptable due to personal, cultural or legal reasons."

The first two International attempts on Uterine Transplant were unsuccessful due to organ rejection. Finally a team of Doctors in Sweden were able to treat the mild organ rejection. The University of  Gothenburg team  led by Dr. Mats Brännström   achieved its first birth in September 2014. To date, the Swedish group has performed nine uterus transplants, achieving five pregnancies and four live births.

In the Brännström case report, the woman who became pregnant following uterus transplantation took tacrolimus and azathioprine to prevent organ rejection both before and during her pregnancy.

Uterine Transplant is a complex process involving multiple steps. Each Candidate selected for the transplant undergo a extensive medical evaluation and psychological counseling, and her candidature has to be approved unanimously by the team of experts in the field.

According to the team at Baylor hospital, Dallas:

 

 

The selection criteria for the recipient are :

· Women with uterine infertility
· Ages 20-35, with working ovaries
· Body mass index of less than 30
· Cancer-free for at least five years
· No history of diabetes
· Non-smoker

The criteria to be a donor are:

  Ages 65 and younger
· At least one full-term delivery
· Body mass index of less than 30
· Cancer-free for at least five years
· Test negative for HIV, herpes and hepatitis B and C

According to the Cleveland clinic, once a woman is selected for the transplant she has to follow the following protocols:

• Her ovaries are stimulated to produce multiple eggs, starting the in vitro fertilization (IVF) process.
• Her eggs are retrieved, fertilized with sperms in a laboratory, and 6-8 embryos are frozen.
• Lifebanc, an organ procurement agency, begins the search for a donor between 18-40 years of age.
• The donor’s next-of-kin signs an informed consent for uterus donation.
• The donor uterus is removed along with the uterine arteries and   transplanted within six to eight hours into the patient’s pelvis.
• Over 12 months, the transplanted uterus fully heals.
• Women who receive the uterus transplants will not be able to become pregnant without ARTs, because the transplanted uterus will not be connected to their fallopian tubes, where normal fertilization takes place.
• One year after transplant, the frozen embryos are then thawed and implanted, one at a time, into the patient until she becomes pregnant.
• During her pregnancy, she takes immunosuppressant drugs.
• She is monitored by a high-risk obstetrics team throughout pregnancy and delivery.
• She has a monthly cervical biopsy to check for organ rejection.
• The baby is delivered by cesarean section.
• After one to two babies, she has a hysterectomy to remove the transplanted uterus.
• Her anti-rejection drugs are stopped after hysterectomy to reduce long-term exposure to transplant medications.

Andreas Tzakis, MD, the transplant surgeon at the Cleveland clinic says “It is critical that the risks for uterus transplant, which is not lifesaving, are no greater than the risks for other transplants. Like transplants of the face and extremities, uterus transplant is considered life-enhancing rather than lifesaving.”

He further adds “Unlike any other transplants, they are ‘ephemeral,” he says. “They are not intended to last for the duration of the recipient’s life, but will be maintained for only as long as is necessary to produce one or two children.”

References:

http://www.livescience.com/52799-uterus-transplants-cleveland-clinic.html

http://www.dallasnews.com/lifestyles/health-and-fitness/health/20160129-baylor-dallas-to-become-one-of-first-u.s.-hospitals-to-offer-uterine-transplants.ece

http://www.reuters.com/article/us-ohio-transplant-idUSKCN0VZ0O7

Induction of labor in older mothers does not hike the Caesarean section rate! The 35/39 Trial.

Since last 30 years, we have seen a trend of increasing number of women delaying childbirth till later in life, especially in industrialized nation . In a span of 10 years, births to women 35 years and older increased from 12% to 20% in UK.

Women 35 years and  older are at increased risk of antepartum, intrapartum and postnatal complications  like hypertensive disease, gestational diabetes mellitus, placenta previa, and placental abruption and perinatal deaths. They are also at risk of delivering macrosomic or low birth weight infants.

The rate of obstetrical intervention and caesearean deliveries also rises with maternal age, being 38% in nulliparous women over 35 and nearly 50% in those over 40 years of age.

According to Smith GCS et al the gestational week of delivery associated with the lowest cumulative risk of perinatal death was 38 weeks' gestation and the risk of death increased more sharply among primigravid women after 38 weeks' gestation because of a greater risk of antepartum stillbirth.

Currently, in the absence of maternal and fetal complication, routine induction is available to all women in U.K at 41-42 weeks when the risk of still birth is 2-3/1000 live births. However, based on many observational studies, it is a general consensus among obstetrician that induction leads to increased rate of caesarean deliveries and increased perinatal complications.

Trials of induction of labour at term are mostly in women with complications like hypertension, prelabor rupture of membranes, fetal growth restriction, diabetes, or fetal macrosomia. Only few trials involving women with no complications are found in literature, but lack power and are in 1970s. Trials of induction of labour due to advanced maternal age are lacking 

This 35/39 trial was designed to test the hypothesis that induction of labour at 39 weeks in older nulliparous women reduces the risk of operative delivery. The results of the trial was published in March 3, 2016 issue of New England Journal of medicine.

The investigators performed a multicenter, randomized, controlled trial to compare the rate of cesarean section between  women who were induced at 39 weeks and 0 days – 39 weeks and 6 days ( n= 304) with  those who were managed expectantly(n=314). Inclusion criteria were nulliparity, age 35 years or older and carrying a single fetus in cephalic presentation.

The primary outcome was cesarean section and the secondary outcome being other form of vaginal deliveries, onset of labour, augmentation of labour , intrapartum , postpartum and neonatal complications.

The induction of labour was done according to the protocols of the units, but most used prostaglandin ripening followed, if necessary, by amniotomy and oxytocin infusion.

It was seen that there was no significant difference in the rate of cesarean sections between the induction group (98 of 304 women [32%]) vs. (103 of 314 women [33%]) in the expectant group. Also a total of 115 of 304 women (38%) in the induction group delivered vaginally as compared with 104 of 314 women (33%) in the expectant-management group.

The results were also comparable across different maternal age group according to a sub group analysis.

The authors acknowledge the limitations of the trials "the results may not be generalizable to older multiparous women and may not apply to all nulliparous pregnant women who are 35 years of age or older."

The authors further say that “Our trial did not address whether induction of labor at 39 weeks of gestation can prevent stillbirths. It does, however, provide support for the safety of performing a larger trial to test the effects of induction on stillbirth and uncommon adverse neonatal outcomes in women 35 years of age or older, although such a trial would need to be extremely large.”

The journal article was also accompanied by an editorial by William A. Grobman, M.D, from the Northwestern University Feinberg School of Medicine in Chicago, Illinois,  he emphasized that “it would be premature to alter recommendations regarding the timing of delivery in uncomplicated pregnancies. Although the study did not show evidence of harm from induction at 39 weeks of gestation, it also did not show evidence of benefit, and one could argue that medical interventions in general, and intervention in the natural progress of gestation specifically, should be performed only when benefit has been shown.”

He also stressed that the study lacked sufficient power to analyze differences in perinatal outcomes, whether labor induction at 39 weeks of gestation affects these outcomes remains unknown!

He further added “The trial makes an important contribution to medical knowledge. It is the largest trial of its type to be completed, and it suggests that a belief that guides decisions about the timing of delivery — namely, that induction of labor at term increases the risk of cesarean delivery — may not be true after all.”

In summary,the authors concluded “ in women of advanced maternal age, induction of labor at 39 weeks of gestation, as compared with expectant management, had no significant effect on the rate of cesarean section and was not associated with adverse short-term effects on maternal or neonatal outcomes.”

Currently Dr. Groban is the principal investigator for a larger trial to test the effects of induction on stillbirth and uncommon adverse neonatal outcomes. The trial is currently under way within the Maternal–Fetal Medicine Units Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. This trial, which has a targeted enrollment of 6000 women, is designed to identify differences in perinatal outcomes among nulliparous women with uncomplicated singleton pregnancies who are randomly assigned to induction between 39 weeks 0 days and 39 weeks 4 days of gestation or to expectant management.

References:

Walker KF, Bugg GJ, Macpherson M, et al. Randomized trial of labor induction in women 35 years of age or older. N Engl J Med 2016;374:813-822

Smith GCS. Life-table analysis of the risk of perinatal death at term and post term in singleton pregnancies. Am J Obstet Gynecol 2001;184:489-496

A new review hype the controversy associated with the ‘pink pill’ commonly dubbed as ‘Female Viagra’.

 

Image Courtesy: L.A. Times

The little pink pill or Flibanserin (Addyi, Sprout Pharmaceuticals)  also dubbed  as the "Female Viagra" was approved by the US Food and Drug Administration (FDA) for the treatment of  hypoactive sexual desire disorder (HSDD) in premenopausal women,  in August 2015, despite  being unsure  about suboptimal risk-benefit trade-offs.

Image Courtesy:  Chicago Tribune

Flibanserin, a 5-HT1A agonist, a 5-HT2A antagonist, and a very weak partial agonist on dopamine D4 receptors, increases levels of dopamine and norepinephrine and decreases serotonin in animal brain areas. Therefore, since dopamine and norepinephrine are thought to promote and serotonin is thought to inhibit sexual desire and arousal, it was suggested that flibanserin enhances sexual desire in HSDD,

A recent systematic review and meta-analysis of randomized clinical trials was published on line on February, 2016 in Journal of American Medical Association (JAMA10.1001/jamainternmed.2015.8565) which assessed efficacy and safety of flibanserin for the treatment of HSDD in women.

The approval of Flibanserin by FDA (a failed antidepressant) has always been shrouded in mystery. It was rejected by FDA twice before it was approved by FDA in August 2015; its clinical review team which voted against it advocating that the benefit-harm balance was unfavorable was overruled by the Clinical Pharmacology and Clinical Division Director. He acknowledged ‘the limited efficacy and worrisome harms, but emphasized the unmet need in women for whom other treatments failed.’

In the recent review by Jaspers L et al from the Erasmus University Medical Center, Rotterdam, the Netherlands, Included five published and 3 unpublished studies constituting a total of   5914 women. The Primary efficacy outcomes were number of satisfying sexual events (SSEs), eDiary sexual desire, and Female Sexual Function Index (FSFI) desire. Safety outcomes were 4 common adverse events (AEs): dizziness, somnolence, nausea, and fatigue and many others. The inclusion of studies focusing on postmenopausal women took into account the potential off-label use.

The study found minimal benefit by the use of Addyi, specifically the pooled mean difference for a Sexually Satisfying Event (SSE) between 100 mg of Flibanserin and placebo was .49%, 1.63 for ediary desire and .27% for Female Sexual Function Index (FSFI) desire domain.

This means that the drug only added .5 additional satisfying sexual experiences per month, while the incidence of adverse effects increased four fold said the study coauthor Ellen T. M. Laan, PhD, from the Department of Sexology and Psychosomatic Obstetrics and Gynecology, Academic Medical Center, University of Amsterdam, the Netherlands, said in a recorded interview with JAMA Internal Medicine.

The risk ratio for study discontinuation due to adverse events was 2.19. The most bothersome was syncope and hypotension that occurred with concurrent alcohol use or CYP3A4 inhibitors, including oral contraceptives and fluconazole.

Meanwhile, many physicians have questioned the results of the study and have reported favorable results with many of the patients using it. They also believe that  the women should be allowed to make an informed decision to choose the ‘pink pill’ as the men are allowed to make an informed decision about ‘Viagra’.

On the basis of the study findings the authors concluded that “The findings of this review suggest that the benefits of flibanserin treatment are marginal, particularly when taking into account the concurrent occurrence of AEs.”

More robust evidence on its safety profile and efficacy is needed before a recommendation can be made in guidelines and clinical practice regarding its use, as majority of American physician indicated that they would prefer an approved HSDD pharmacological product over available non-pharmacological treatments. Further, it is known that an integrative approach involving psychological interventions play a crucial role in treatment of HSDD.

The authors acknowledge the limitation of the study and recommend that future studies should include women from more diverse ethnicity, with a history of somatic and psychological co-morbidities, medication use, and surgical menopause.

References:

http://www.jsm.jsexmed.org/article/S1743-6095%2815%2931530-7/abstract

http://link.springer.com/article/10.1007%2Fs10508-012-0062-0

http://www.cnn.com/2016/02/29/health/female-viagra-gets-mixed-reviews/index.html

http://archinte.jamanetwork.com/article.aspx?articleid=2497781#ioi150116r17

http://archinte.jamanetwork.com/article.aspx?articleid=2497781

http://www.jsm.jsexmed.org/article/S1743-6095%2815%2932579-0/pdf