News for ASRM 2018: Procuring enough uteri for transplant will be a challenge in coming years

Researchers predict that it will be a great challenge to procure enough organs to meet the increasing need and willingness to undergo uterine transplant (UTx) in near future report the results of a feasibility study presented at the American Society for Reproductive Medicine’s Scientific Congress in Denver, Colorado.

 Uterine transplant is the emerging treatment for thousands of women of childbearing age who suffer from absolute uterine factor infertility. The world recently saw the birth of the world’s 12th and India’s first baby born after a uterine transplant. There is a growing interest among the community about transplant procedure, as evident by the long waiting list of patients at the high-volume transplant centers around the world.

Researchers from Division of Reproductive Endocrinology and Infertility, University of Pennsylvania, Philadelphia, Pennsylvania carried out this study to quantify and characterize candidacy and interest in UTx.

They examined the medical and social histories of all deceased donors from the database of large organ procurement organization (OPO), the Gift of Life Donation Program (GLDP) to see how many women would have been eligible to donate uterus after death. Of the 585 total donors, 186 were females, of whom 94 were of reproductive age.

After applying ‘liberal’ screening criteria, which included no evidence of active Hepatitis B/C, diabetes, and no active intravenous drug use only 31 were found eligible to be a potential donor. If in addition to above criteria more stringent criteria that includes parity, related gynecological conditions that could impact the future pregnancy, age < 45 years, and no smoking were set, only 6 women were left in the list as being eligible for the uterine donor.

The researchers report that only 1-5% of all organ donors from a large OPO could potentially be eligible to qualify as a deceased donor.

Abstract O-86 presented Monday, October 8, 2018. 
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How to evaluate the azoospermic male? ASRM committee recommendations

The Practice Committee of the American Society for Reproductive Medicine (ASRM) in collaboration with the Society for Male Reproduction and Urology recently issued guidelines about the diagnosis and evaluation of the azoospermic male partner. The committee opinion was published recently in journal Fertility and Sterility.

Of all the infertility cases about 30% is because of ‘male-factor’ of whom about 10-15% of men will receive the diagnosis of azoospermia. Recent studies have documented a decline in sperm count globally with a concurrent increase in male factor infertility.

Azoospermia is classified into 3 categories-pre-testicular, testicular, and post-testicular according to the etiology but in clinical practice, azoospermia is commonly classified as obstructive azoospermia (OA) and nonobstructive azoospermia (NOA) which can be of central or testicular origin. 

 

Azoospermic men with normal size testes with normal serum follicle-stimulating hormone (FSH) levels are more likely to have obstructive azoospermia, while men with a significant elevation in FSH have a testicular failure, and thus testicular NOA.

On the other hand, low gonadotropins levels with low to low-normal T points towards a diagnosis of central NOA.

According to the American Society for Reproductive Medicine (ASRM) Practice Committee, the evaluation begins with a standard reproductive history and physical examination, followed by measurement of serum FSH and testosterone(T), luteinizing hormone (LH), free T, estradiol, and prolactin. Most experts state that an FSH >7.6 mIU/mL would be considered abnormal.

Semen volume and FSH levels play an essential part in determining the etiology of azoospermia. If men have low semen volume and normal FSH the lab test should be repeated after 2-3 days of abstinence, with attention to proper collection technique. A post-ejaculate urinalysis is advised to rule out retrograde ejaculation. If there is no retrograde ejaculation and semen pH is < 7.2, a transrectal ultrasound (TRUS) is the next step to identify a possible ejaculatory duct obstruction (EDO).

In men with normal semen volume, determining serum FSH and testicular volume is critical to decide in favor of testicular biopsy for the prognostic purpose. Elevation of serum FSH along with low testicular volume strongly suggests NOA. In case sperm retrieval is planned for ICSI, the testicular biopsy is deferred till the sperm retrieval when a biopsy sample is concurrently sent to the lab.

A normal testicular biopsy indicates an obstruction at some level in the reproductive tract. If the cause of OA is not iatrogenic, then the cause is a bilateral epididymal obstruction. It should be confirmed by surgical exploration. Vasography is only indicated if reconstructive surgery is planned simultaneously.

In men with the congenital bilateral absence of the vasa deferentia (CBAVD or vasal agenesis), unilateral renal agenesis should be ruled out. Most men with vasal agenesis will also have seminal vesicle hypoplasia or agenesis which manifests as low semen volume and pH.

CBAVD is also strongly associated with mutations of the CFTR gene. Hence, before planning a sperm retrieval for ICSI in men with CBAVD or congenital unilateral absence of the vas deferens (CUAVD), genetic testing should be offered to female partner to rule out her carrier status (∼4%) for CFTR gene.

Men with suspected NOA due to an elevated FSH and a normal ejaculate volume have bilateral testicular atrophy.  They should be offered genetic testing to exclude chromosomal abnormalities and Y-chromosome microdeletions (YCMD). A diagnostic testicular biopsy is not usually indicated in such cases. 

Low gonadotropins levels may be because of feedback inhibition secondary to exogenous T or illicit anabolic-androgenic steroid use, a high T level with suppressed gonadotropins will be confirmatory in such instances.

In men with markedly elevated serum FSH levels, the diagnostic testicular biopsy is only indicated when there is uncertainty about the etiology of the azoospermia- obstructive or nonobstructive. In all other cases, a testicular biopsy is done when sperm retrieval is planned for ICSI.

A diagnostic biopsy is also not necessary in patients with expected obstruction and normal FSH levels.

Full-text Practice Committee of the American Society for Reproductive Medicine in collaboration with the Society for Male Reproduction and Urology

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Novel microfluidic device quickly corrals vigorous motile sperms for IVF

Courtesy: Pixabay

Cornell University scientist has created an innovative microfluidic device that effectively separates the motile, highly energetic sperms; thereby increasing the chances of fertilization for couples undergoing IVF.

The current method of separating sperms for IVF is highly tedious, manual and can take hours for completion. Doctors and technicians spend hours to separate the motile, good quality sperms making the process expensive and time-consuming.

“With the new method, it’s 5 minutes instead of hours,” said Alireza Abbaspourrad, a researcher involved in the latest study.

The new device takes advantage of sperm’s ability of positive rheotaxis—natural tendency of the sperms to face against fluid flow after reaching a specific velocity. The researchers devised a microfluidic channel through which the semen sample flows to which the researchers added a “C” shaped corral and a retaining wall.

The structure creates interference to flow of sperms, and the highly motile, stronger sperm enter the corral only to be trapped by the retaining wall. “We could separate the good sperm from the not-so-strong in a reasonably elegant way. We are able to fine-tune our selection process,” said Soon Hon Cheong, another researcher involved in the study.

Meisam Zaferani, a doctoral student at the Cornell, said the device might find broader application beyond its uses in Assisted Reproductive Techniques, especially in dairy and livestock industries. “The unprecedented efficiency of our device in comparison to previous studies and its benign, passive nature makes it favorable for sperm separation,” he said.

The study, “Rheotaxis-Based Separation of Sperm with Progressive Motility Using a Microfluidic Corral System,” published in the Proceedings of the National Academy of Sciences July 30.

Cornell newsletter

Here is the short video of how the technique works

News from ESHRE 2018: Endometrial scratch does not result in more pregnancies

Endometrial scratch is often offered as an adjuvant therapy to improve the IVF success rates, but the results of a large randomized control trial have shown that the “add-on” procedure does not improve the pregnancy or live birth rates. The study results were presented at the European Society of Human Reproduction and Embryology (ESHRE) 34^th annual conference in Barcelona, Spain by Dr. Sarah Lensen, a researcher from the University of Auckland, New Zealand.

The study involved 1300 women who underwent IVF across 13 fertility centers in 5 countries (New Zealand, UK, Belgium, Sweden and Australia).

It is proposed that causing injury to the endometrial lining invokes an inflammatory response that helps create a favorable environment for the implantation of the embryo. A survey conducted in Australia, New Zealand, and the UK by Lensen and colleagues in 2016 revealed that about 83% of physician offer endometrial scratch to patients before IVF cycles, especially those who have recurrent implantation failure.

Lensen said in a statement at the conference, "Results from earlier studies have suggested a benefit from endometrial scratching in IVF, especially in women with previous implantation failure. However, many of these studies had a high risk of bias in their design or conduct and did not provide strong evidence. There was still uncertainty about the validity of a beneficial effect."

The women in the study group (690) received an endometrial scratch performed by Pipelle cannula between day 3 of the preceding cycle and day 3 of the IVF/embryo transfer cycle, while the control group (674) didn’t receive any such treatment.

In this intent to treat analysis, the clinical pregnancy rate in the endometrial scratch group was 31.4% and in the control group 31.2%; live birth rates were 26.1% in the former and 26.1% in the latter. No difference was seen in rates of biochemical pregnancy, ectopic pregnancy, or multiple pregnancies among both the groups.

The researchers also looked at other side effects of endometrial scratch and found that the median pain score for the procedure was 3.5. Women also suffered from vasovagal attack, excessive pain, and excessive bleeding. 

“Our results contradict those of many studies published previously,” said Lensen, “and, although our trial was the largest and most robust study undertaken so far, it can be difficult for one trial to change practice. However, there are other trials underway at the moment, including two large studies from the Netherlands and UK. Nevertheless, even based just on our results, I think clinics should now reconsider offering endometrial scratch as an adjuvant treatment.”

ESHRE Press Release

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The International Glossary on Infertility and Fertility care updated

The International Committee for Monitoring Assisted Reproductive Technology(ICMART) along with 20 more organization notably ASRM, ESHRE, IFFS, MOD, AFS, GIERAF, ASPIRE, MEFS, REDLARA and FIGO has released a new evidence and consensus based updated document that includes the current definitions of 283 terms that are used in infertility and fertility care. 

The updated document was simultaneously published in Fertility and Sterility and Human Reproduction.

Earlier, the list contained 87 terms in 2009 and was developed to facilitate better communications between infertility professionals and researchers around the world.

Twenty-five Infertility professionals around the world grouped into 5 groups to work on adding more words and terms to the existing list, particularly in areas of male fertility, epidemiology and public health. The final list was reviewed by independent experts around the globe in particular category.

The definition of infertility was revised in the new glossary - “A disease characterized by the failure to establish a clinical pregnancy after 12 months of regular, unprotected sexual intercourse or due to an impairment of a person's capacity to reproduce either as an individual or with his/her partner. […] Infertility is a disease, which generates disability as an impairment of function.”

According to the new edition ‘subfertility’ and ‘infertility’ could be used interchangeably.

Richard J. Paulson, MD, ASRM President, said in a press release, “The new glossary is a great tool that will help us improve patient care as well as collaborative research.  Agreeing on standardized definitions and meanings that go beyond culture and context is essential for medical and scientific advancements. Everyone in the field of reproductive medicine and science will benefit from using the new glossary.” 

Here is the link to download the complete glossary in PDF format: Zegers-Hochschild et al, The International Glossary on Infertility and Fertility Care, 2017, Fertility and Sterility, in press.

Source: ASRM Bulletein.

China likely to lead the world ART scene with 800,000 annual cycle: ESHRE NEWS

Courtesy: http://www.nhs.uk/

The world’s total IVF babies have reached 7 million says a Preliminary Global Data report presented at Geneva by David Adamson on behalf of International Committee Monitoring Assisted Reproductive Technologies (ICMART).

Some interesting statistics as reported in September issue of Focus on Reproduction by European Society of Human Reproduction and Embryology (ESHRE).

The growth of ART is very explosive, with more than 1.5 million cycles reported as per 2013 data.

Japan still dominates the world with 368,627 cycles recorded for 2013, but China is soon predicted to take over with an estimated 800,000 cycles annually.

About ¾ of world total assisted reproductive activity takes place in ten countries from Europe, America and Australia. Statistics from Asian, Middle eastern and African countries is scarce and patchy.

ICSI is a huge favorite among physicians from Europe and far exceeds the number of IVF cycles (607,000 cycles over 275,000 cycles).

ICSI also remains the preferred procedure in the Middle East, Latin America, and North America.

The global delivery rate remains at 20%, with a slightly higher rate of 22% in the freeze-thaw cycles. The number of ‘freeze-thaw’ cycles are steadily increasing over ‘fresh’ cycles.

In 80% of cycles in North America, Europe, Asia number of embryo transferred were 1 or 2 and 100% in Australia/New Zealand.

An estimated 2.4 million cycles were performed in the year 2013, up to 530,000 babies born with an overall cumulative delivery rate of 27.4%.

More than 25% of women were 40 years and more in 2013 and mean number of transferred embryos was 1.81.

Freeze all protocols accounted for 6% of all reported cycles.

Focus on Reproduction Full Text

News from American Society for Reproductive Medicine (ASRM) 2016 Scientific Congress—Pesticides residue in fruits and vegetables linked to lower probability of Live Birth.

Clinical Pearls:

• Higher preconception consumption of Fruits and Vegetable, that have high pesticide residue results in lower probability of livebirth after ART.

American Society for Reproductive Medicine (ASRM) 2016 Scientific Congress is currently ongoing at (October 15 – 19) Salt Lake City, Utah. Some selected abstract and news from the conference.

A prospective cohort study by Chiu Y et al. examined the association between preconception intake of Fruits and Vegetables(FV) that has high pesticides residue and outcome of pregnancies conceived by assisted reproductive techniques. [1]

The study subjects included 300 women who underwent 493 ART cycles at an academic center between 2007-2015.  Food intake was systematically documented by filling a food questionnaire.

Surveillance data from US Department of Agriculture was used to classify food into high and low-to-moderate (L-M) pesticide residues.

Medical records of the academy were used to provide information on implantation, live birth and clinical pregnancy. Pregnancy loss was defined as loss after a positive pregnancy test. Linear regression was used to analyze the result after adjusting for age, BMI, race, smoking, physical activity, total energy intake, alcohol intake, dietary patterns, infertility diagnosis and stimulation protocol.

Out of 493 ART cycles,287 women (58%) had a positive β-hCG with 202 (41%) giving birth to live born infants.

The high pesticide intake was divided into quartiles based on daily consumption of the Fruits and Vegetables. The highest probability of live birth per ART was seen in quartile 1-2 (46-47%) whereas the lowest probability was seen in the 4^th quartile (30%). The association was explained because of higher consumption (≥1.6 servings/d) of FV by women in 4^th quartile as compared to women in the first quartile who only consumed <0.7 servings/day. (P,trend=0.01).

Consumption of FV with Low to moderate pesticide residue did not affect the outcome of ART. 

  

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[1] http://www.fertstert.org/article/S0015-0282(16)61491-7/fulltext

News from American Society for Reproductive Medicine (ASRM) 2016 Scientific Congress— Laparoscopic surgery or ART directly---What comes first in patients with Unexplained Infertility.

Clinical Pearls:

• Both the procedure resulted in pregnancy rate at par with each other, but the researchers advocate doing diagnostic and therapeutic laparoscopy first in patients with unexplained infertility.  

American Society for Reproductive Medicine (ASRM) 2016 Scientific Congress is currently ongoing at (October 15 – 19) Salt Lake City, Utah. Some selected abstract and news from the conference.

It is always an obstetrician dilemma whether to perform laparoscopy first or go for ART in patient diagnosed with unexplained infertility.

 A randomized prospective clinical trial results by Algergawy  A.et al. presented on October 18, 2016 evaluated the outcome of these two approaches.[1]

The study involved a cohort of 423 patients who were diagnosed with unexplained infertility based on normal HSG findings, regular ovulation, normal hormonal profile and normal male partner. These women were randomized into two groups. Women who underwent COH followed by IUI for 3 cycles and then ICSI constituted group 1 (205). The second group (218) consists of women who underwent laparoscopy (Diagnostic and therapeutic).

86 women (41.95%) in the first group conceived within 1 year, 26 cases (12.6%) by IUI. and 60 cases (29.26%) by ICSI.

In the second group, diagnostic laparoscopy revealed multiple pathology like mild to moderate endometriosis, severe endometriosis and hypoplastic fallopian tube. Adhesiolysis, ablation and excision of endometriotic implant was performed. The overall pregnancy rate in group 2 was 84 cases (38.53%). 

Although the pregnancy rate in both group is at par, laparoscopy resulted in better diagnosis of causes of unexplained infertility resulting in better management of cases. It also enabled spontaneous pregnancy in significant number of patients thus avoiding psychological, emotional and physical trauma of ART. It also avoids the many complications of ART like OHSS and multiple pregnancy.

If the patient of unexplained infertility does not conceive after laparoscopy, then ART can always be performed when needed and previous diagnostic laparoscopy facilitates the results of ART.

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[1] http://www.fertstert.org/article/S0015-0282(16)61545-5/fulltext

Rekovelle (Follitropin delta) granted marketing authorization by European Medicines Agency.

Follitropin delta (Rekovelle, Ferring Pharmaceuticals A/S) is a novel human recombinant follicle-stimulating hormone (rhFSH) indicated for use in controlled ovarian stimulation (COS) in women undergoing assisted reproductive technology (ART) therapy such as in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI).

Follitropin delta is available as solution for injection (12 µg/0.36 ml, 36 µg/1.08 ml and 72 µg/2.16 ml) It is a recombinant human follicle-stimulating hormone (FSH) belonging to the pharmacotherapeutic class of gonadotropins (ATC code: G03GA10). The amino acid sequences of the two FSH subunits in follitropin delta are identical to the endogenous human FSH sequences.[1]

It can be administered as tailored regimen to each individual patient based on the measurement of the woman’s serum anti-Müllerian hormone (AMH) and Body Mass Index (BMI).

Personalized treatment is a novel approach to the management of patients undergoing Assisted Reproductive Techniques (ARTs), with the ultimate goal of helping couples to conceive in an efficient and safe manner.

The approval comes in wake of results of Phase III (Evidence-based Stimulation Trial with Human rFSH in Europe and Rest of World) (ESTHER) trials of follitropin delta for pregnancy-related complexities which was presented at the 32^nd Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE) in Helsinki, Finland.[2]

ESTHER-1 is a multicentric, randomized, assessor-blind, controlled trial conducted in Europe and other centers in the world. The study involved 1,326 patients from 37 fertility clinics in 11 countries between ages 18 to 40 undergoing their first cycle of in-vitro fertilization (IVF) or intracytoplasmic injection (ICSI).[3]

Patients were administered with an individualized dosing regimen of follitropin delta which was fixed throughout stimulation compared with daily follitropin alfa dose of 150 IU (11 µg) for the first five days, (conventional dosing regimen) which was open to dose adjustments after five days.

The number of oocytes retrieved and blastocysts obtained were similar for both the arms of the trial (10.0 and 10.4).

More patients using the individualized regimen of Folliotropin delta obtained the target oocytes number of 8-14 as compared to using conventional regimen. (p<0.05). The study arm also has less incidences of OHSS (p<0.05).

The ongoing pregnancy as well as well as ongoing implantation rates were also similar in both the groups.

Data from the ESTHER-2 trial in which a subset of women underwent additional assessor-blind stimulation cycles (a total of 513 in cycle 2, and 188 in cycle showed no increased immunogenicity risk.[4]

The most common side effects are ovarian hyperstimulation syndrome (OHSS), headache, nausea, fatigue pelvic discomfort and pelvic or adnexal pain,

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[1] http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/003994/WC500214216.pdf

[2] Nyboe Andersen A and Arce JC on behalf of the ESTHER-1 trial group. Efficacy and safety of follitropin delta in an individualised dosing regimen: A randomised, assessor-blind, controlled phase 3 trial in IVF/ICSI patients (ESTHER-1). Poster presented at 32nd Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE) in Helsinki, 3–6 July 2016. 

[3] ESTHER-1 trial. www.clintrials.gov Available at: https://clinicaltrials.gov/ct2/show/NCT01956110. Last accessed: October 2016

[4] ESTHER-2 trial. www.clintrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT01956123. Last accessed: October 2016

Induction of labor does not hike the risk for Autism Spectrum disorders.

Clinical Pearls:

• Contrary to the findings of earlier study, Induction of labor does not increase the risk for development of Autism Spectrum disorders(ASD).

Autism Spectrum disorders(ASD) is a group of complex developmental disability that affects a person ability to interact and communicate socially. It includes several conditions that were earlier diagnosed separately and include autistic disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), and Asperger syndrome.

According to CDC about 1% of world population have ASD. It is the fastest growing developmental disability in US and the current prevalence is 1 in 64 births and has increased 119.4 percent from 2000 (1 in 150) to 2010 (1 in 68).[1] An article published in JAMA Pediatric 2014 by Buescher et al. estimated that about 3.5 million people in US live with ASD.[2]

Numerous pregnancy related risk factors have been attributed in putting the children at high risk for ASD like children that were born to older parents,  were preterm or low birth weight, born with other chromosomal disorders like  Down syndrome, fragile X syndrome, tuberous sclerosis and  those delivered by cesarean section.

A study published in Annals of Epidemiology attributed three perinatal risk factors like being born too early, too small, and/or by Cesarean delivery to be responsible for 12-13% of ASD in children.[3]

Many other studies have examined the mother’s use of  serotonin uptake  inhibitors (SSRIs) and increasing use of ART as a causative factor for  sudden increase in prevalence of ASD.

Another large population based study published in JAMA pediatrics in October,2013 concluded that “Compared with children born to mothers who received neither labor induction nor augmentation, children born to mothers who were induced and augmented, induced only, or augmented only experienced increased odds of autism after controlling for potential confounders related to socioeconomic status, maternal health, pregnancy-related events and conditions, and birth year. The observed associations between labor induction/augmentation were particularly pronounced in male children.”[4]

This study sparked a widespread debate between physicians and researchers and the lead author of the study Dr. Gregory proposed the culprit to be oxytocin in induced or augmented labors, putting these children at high risk for ASD. After this controversy ACOG put out a committee opinion (597) in 2014 stating that “Current evidence does not support a conclusion that labor induction or augmentation causes autism spectrum disorder (ASD) in newborns, available evidence is inconsistent and does not demonstrate causation.”[5]

A recent study conducted by researchers at Harvard T.H. Chan School of public health in Boston and published in JAMA pediatrics online first on July 25, 2016 found no association between induction of labor and ASD. This large nationwide study performed in Sweden, followed up a cohort of 1,362,950 children born between 1992-2005. Out of which 1.6% (22077) children were diagnosed with ASD by ages 8 years through 21 years.  

In 11% of the mothers’ labor induction was done due to preeclampsia, gestational diabetes and chronic hypertension. After the statistical analysis, the study found an association between labor induction and ASD but when the analysis was performed between siblings and close relatives the association was not documented.

Siblings share many genetic, socioeconomic and maternal characteristics that may increase the risk for development of ASD, so if association is not documented when comparing with them, the association probably does not exist.

The finding of this large study suggests that if clinically indicated, decision to induce labor should not be withheld in fear of baby developing ASD. Not to induce the labor when indicated may have adverse neonatal consequences.

Dr. Bateman concludes "Overall, these findings should provide reassurance to women who are about to give birth, that having their labor induced will not increase their child's risk of developing autism spectrum disorders."

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[1] https://www.cdc.gov/ncbddd/autism/facts.html

[2] http://www.ncbi.nlm.nih.gov/pubmed/24911948

[3] Schieve LA, Tian LH, Baio J, Rankin K, Rosenberg D, Wiggins L, Maenner MJ, Yeargin-Allsopp M, Durkin M, Rice C, King L, Kirby RS, Wingate MS, Devine O. Annals of Epidemiology. January 2014. [epub ahead of print]

[4] Gregory SG, Anthopolos R, Osgood CE, Grotegut CA, Miranda M. Association of Autism With Induced or Augmented Childbirth in North Carolina Birth Record (1990-1998) and Education Research (1997-2007) Databases. JAMA Pediatr.2013;167(10):959-966. doi:10.1001/jamapediatrics.2013.2904.

[5] http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Obstetric-Practice/Labor-Induction-or-Augmentation-and-Autism

Predicting spontaneous preterm birth in twin pregnancies utilizing cervical length and gestational age: Individual patient data meta-analysis.

Multiple births are steadily climbing all around the world. Developed countries making a significantly higher contribution to this rising rate because of women delaying childbirth, elderly mothers and increased use of ARTs.

US twinning rate rose by 101% from 1980 – 2006. About 68,339 twins were born in 1980 that doubled to 137,085 in 2006. The US current twin birth rate is 33.9 per 1,000 live births.

 According to WHO the rate of singleton preterm birth ranges between 5% to 18% for singleton pregnancy worldwide, the average being 11%, while almost 60% of twins are delivered preterm. About 13% of twins are born before 34 weeks and 7% before 32 weeks.

A multitude of prophylactic therapies have been in use like to gain valuable gestational weeks by supplementing progesterone, vaginal pessaries and strict bed rest without substantially significant results.

The next step was to develop essential biomarkers that can predict the chances of preterm births. Cervical length(CL) has long   been used as a predictive indicator of preterm birth. An earlier review has shown that a CL < or=20 mm at 20-24 weeks' gestation was the most accurate in predicting preterm birth at <32 and <34 weeks respectively. Many other studies have combined fetal fibronectin with CL. 

Studies in singleton pregnancies have also shown that the relationship between CL and spontaneous preterm birth (sPTB) is dependent on the Gestational age (GA) at which the USG is done, a shorter CL early in pregnancy has greater significance than the same measurement at a later GA.

Such studies in twins are few with small sample size and are not comparable. Previous meta-analysis has shown a relationship between CL and sPTB in twins, but did not correlate the GA at screening with prediction of sPTB.

This recent study published in the May, 2016 issue of BJOG is a meta-analysis of independent patient data(IPD), and provides a new estimate in which CL and GA are treated as continuous variables to predict weeks at delivery.

Specific data collected for each patient from the original authors of the study included the exact GA at CL screening, the CL measurement in millimeters and the exact GA at birth in weeks and days.

23 studies met the inclusion criteria, resulting in a total of 6188 transvaginal scans, performed on 4409 twin pregnancies. 

In the first analysis, univariate regression was performed to see what other confounders like maternal age, ethnicity, smoking, BMI, chorionicity, parity and study location affects the GA at birth. 

As second analysis multinomial logistic regression model was derived predicting the probabilities of very early preterm, early preterm, late preterm, and term birth using GA at USG and CL as continuous variables.

Important study results were:

• BMI was the only other variable that correlated significantly with GA at birth in the univariate analysis, but when it was incorporated into multinomial logistic regression model with CL and GA at ultrasound, prediction of GA at birth did not improve.
• A short CL measured at ≤20⁺⁰ weeks by USG indicates a probability of birth significantly earlier than if the same CL was taken at a later GA.
• When screening before 18⁺⁰ weeks, any cervical length <30 mm has a higher risk of sPTB at ≤28⁺⁰ weeks in twins than in singletons.Whereas the best prediction of birth between 28⁺¹ and 36⁺⁰ weeks was provided by screening at ≥24⁺⁰ weeks.
• A 100% probability of preterm birth not occurring before 28 weeks is achieved by CL of 65 mm and 43 mm at ultrasound GA at ≤18⁺⁰ weeks and at 22⁺¹ to 24⁺⁰ weeks, respectively.

In the third analysis, the accuracy of the model to correctly predict term delivery as compared to preterm was assessed. The model has a 68.2% true negative rate, classifying correctly those who were predicted to deliver at ≥36⁺¹ weeks, compared with 26.2, 13.3 and 36.2% correctly predicted to deliver at ≤28⁺⁰, 28⁺¹ to 32⁺⁰ and 32⁺¹ to 36⁺⁰ weeks, respectively (true positive rate).

Although effective intervention for sPTB in twins are limited, the study provides risks of very early, early and late preterm birth, so a personalized cost effective delivery plan, optimal timing of corticosteroids and referring to neonatal unit can be managed. It also justifies serial CL measurements, so that early and late sPTB could be predicted.

To conclude the authors, recommend to start the screening at ≤18⁺⁰ weeks with repeat screening at >22⁺⁰ weeks; this best identifies the patients that may deliver very early at ≤28⁺⁰ weeks as well as the more common later group of sPTB between 28⁺⁰ to 36⁺⁰ weeks. 

References:

http://www.cdc.gov/nchs/fastats/multiple.htm

http://www.who.int/mediacentre/factsheets/fs363/en/

http://www.ncbi.nlm.nih.gov/pubmed/24360590

http://onlinelibrary.wiley.com/doi/10.1111/1471-0528.13575/full

http://onlinelibrary.wiley.com/doi/10.1111/1471-0528.13710/full

Assisted Reproductive Technology is associated with higher risk of Birth Defects!

Since 1981, ART has been used in the United States. Today approximately 1.6% of all infants born in the United States every year are conceived using ART.  According to 2014 data by CDC, 208,786 ART cycles were performed, resulting in 57,332 live births (deliveries of one or more living infants) and 70,352 live born infants.

As the number of infants conceived by ART continues to increase, it was observed that those conceived after Assisted Reproductive Technology (ART) was born with several Birth defects, especially nonchromosomal birth defects as compared to those conceived the natural way! In fact according to CDC, the risk of certain birth defects was 2 to 4 fold as compared to those conceived naturally.

The largest study of its kind was published in April issue of JAMA pediatrics. The researchers linked ART surveillance, birth certificates, and birth defects registry data for 3 states (Florida, Massachusetts, and Michigan) during a period of 10 years from 2000-2010. The exposure studied was ART and certain techniques among ART births. The main outcome measures were prevalence of selected chromosomal and nonchromosomal birth defects that are usually diagnosed at or immediately after birth.

Of the total 4,618,076 live births, 64,861 or (1.4%) were conceived using ART. According to the lead investigator Sheree L. Boulet, DrPH, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia higher prevalence of  nonchromosomal birth defects (59.57 per 10,000) in ART infants compared with non-ART infants (48.40 per 10,000, P<0.001) was reported. Even after adjustment of all the confounders (maternal age), there was 28% higher risk of non chromosomal anomolies with ART.

Infants born after ART were also more likely to be born prematurely, have lower birth weights and mothers who underwent ART were higher educated, nulliparous, career oriented, elderly (>30 Years) and non-Hispanic white. They were also more likely to have Diabetes and Hypertension.

The birth defects most commonly observed were reduction deformity of the lower limbs (P=0.007), rectal and large intestinal atresia/stenosis (P<0.001), and tracheoesophageal fistula/esophageal atresia (P=0.001) compared with those conceived spontaneously. No statistically significant difference in birth defects was seen among fresh vs frozen embryos.

Other systemic reviews, metaanalysis and registry based studies have also concluded that birth defects are more common in infants conceived after ART, and stress upon need of further research according to various sub-groups of ART.

It was also seen that maternal age is inversely related to risk for chromosomal defects in ART, including trisomy 13, trisomy 21 (Down syndrome), and trisomy 18, probably because older mother undergo Preimplantation Genetic Diagnosis (PGD) as compared to younger woman, primarily for aneuploidy.

"It is possible that younger women with an ART-conceived pregnancy were less willing to undergo chorionic villue sampling or amniocentesis because of heightened concerns about risks to the fetus," wrote Boulet and colleagues. "Another potential explanation is that young women undergoing ART have more serious underlying health issues than older women and thus have poorer-quality embryos."

Other studies have found increased incidence of cancer, heart defects, genitourinary malformations and malformations of the eye later in life.

The current study has several limitations; it lacked data on pregnancies that did not end up in live births, so the prevalence of birth defects may be underestimated. Also infants born with ART are closely followed than those born naturally, so the detection of birth defects may be higher!

The study implies that patients should have a good discussion with their physicians about the ART procedure, including detail information on all the birth defects resulting due to the ART. They should also understand that the actual risk for individual family is very small, but the odds are increased. A careful evaluation of long term effects and defects later in life is also necessary by designing studies for long term follow up of such infants.

References:

http://www.cdc.gov/media/pressrel/2008/r081117.htm

http://www.medpagetoday.com/OBGYN/Pregnancy/57161

http://www.ncbi.nlm.nih.gov/pubmed/23449641

http://archpedi.jamanetwork.com/article.aspx?articleid=2506140

http://www.newsmax.com/Health/Health-News/IVF-reproductive-technology-birth/2016/02/04/id/712683/

http://www.reuters.com/article/us-health-ivf-birth-defects-idUSKCN0X122D

http://www.medscape.com/viewarticle/861447

Kelley-Quon L, et al "Congenital malformations associated with assisted reproductive technology: a California statewide analysis" AAP 2012.