Infertility Basics. 20 years ago, 15 years ago, 10 years ago, maybe even 5 years ago, Preimplantation Genetic Diagnosis (PGD) would not be considered basic. These days, it most certainly is.
It doesn't mean that it's not highly sophisticated and very technical. It's just that these days, PGD is used so frequently for single gene disorders and genetic screening, that it's considered a basic.
I had the honor and privilege of listening to one of the most gifted and engaging speakers I've ever heard talk about the human genome, chromosomes, single gene disorders, family, Preimplantation Genetic Diagnosis (PGD) and Screening and the human condition.
Dr. Mark Hughes, the Laboratory Founder and Director of Genesis Genetics Institute, gave a lecture to a multi-department Grand Rounds at Norwalk Hospital a few weeks ago. Dr. Spencer Richlin of RMA of Connecticut asked Dr. Hughes to come and present information so that the different departments of the hospital could understand better how and why PGD and Chromosome Screening should be of interest to them, outside of anything to do with infertility.
Thank you to Norwalk Hospital for being forward thinking enough to host and support bringing Dr. Hughes here to speak.
Dr. Hughes is a pioneer in PGD and was involved in the Human Genome project.
Dr. Hughes spoke about what PGD has to offer about preventing life threatening and debilitating diseases. Dr. Hughes' website offers answers to frequently asked questions, especially about mutations on specific diseases and how DNA testing is done.
PGD is unique in what it offers in terms of single gene disorders.
From Dr. Hughes' website:
"The PGD genetic probes we build for our families are custom designed. This is because each person's DNA is unique.
The DNA that two individuals mix together to make a baby is also unique. Genesis Genetics Institute is known globally for our ability to test for some of the rarest genetic conditions, as well as the more common ones. Couples who are at-risk for essentially any serious inherited disease (we will not test for trivial traits) can reduce this risk to their offspring by working with our team."
Next week, we'll talk about Comprehensive Chromosomal Screening (CCS)and what it has to offer in terms of examining the embryo before transfer. Basic yes. But also breakthrough technology that offers reassurances that were only dreamed of even a few years ago.
CCS: Top Fertility Specialist Dr. Leondires Discusses New Fertility Technology
Dr. Mark Leondires
, Medical Director of Reproductive Medicine Associates of CT, recently spoke with reporters from WTNH about the breakthrough and award winning new fertility technique called "Comprehensive Chromosomal Screening". CCS
, as it is also referred to, is an embryo screening technique available in only five fertility centers in the United States.
How CCS Improves Pregnancy Rates
CCS can verify that all 23 pairs of chromosomes are healthy and normal. Techniques used in the past, including PGD
(Preimplatation Genetic Diagnosis) could screen up to 9 chromosomes and focused mainly on single gene disorders.This reduces the miscarriage rate tremendously as the majority of first trimester miscarriages are due to chromosomal abnormalities. This technique also reduces the occurance of multiple births
as one can be more confidant about the viability of the embryos that are replaced into the uterus.
Dr. Leondires takes you step by step through this process in the interview, as well as showing you how CCS looks in the lab itself.
Higher Pregnancy Rates with Preimplantation Genetic Diagnosis
Reproductive Medicine Associates of Connecticut (RMACT) is among a select group of fertility centers throughout the USA offering this new genetic screening resulting in higher pregnancy rates.
Affiliated doctors at Reproductive Medicine Associates of New Jersey and the Robert Wood Johnson Medical School offered IVF patients under the age of 43 who had had less than one failed prior cycle the opportunity to participate in the randomized trial. Twenty-eight patients participated in the trial and all received routine IVF care through embryo culture to day five of embryo development. At that point, patients were randomized with 13 enrolled for PGD with aneuploidy screening (AS) and 15 enrolled as controls. There was no difference in maternal age between the study patients and the controls.
Prospective Randomized Controlled Trial Demonstrates Preimplantation Genetic Diagnosis with Aneuploidy Screening Increases Pregnancy Rates
The AS patients’ embryos underwent four-hour trophectoderm screening for 24 chromosomes so that only chromosomally normal embryos would be transferred, while control patients had embryo transfer without further intervention. Clinical pregnancy rates following transfer were significantly higher for AS patients than for controls (92% vs. 60%) and sustained implantation rates for AS patients were also higher than for controls (75% vs. 56%).
Preliminary results suggest that blastocyst biopsy with 24 chromosome aneuploidy screening and fresh embryo transfer may optimize embryo selection and eventually facilitate single embryo transfer. The researchers are continuing the current study in order to determine whether there are specific groups of patients who may or may not benefit from this technique.
O-05 A Prospective Randomized Controlled Trial Demonstrating Significantly Increased Clinical Pregnancy Rates
Read more in the next week or so to learn what this may mean for you on your path to fertility.
Medical Day!! Consider this a preview for a comprehensive series on Preimplantation Genetic Diagnosis (PGD) that our own Dr. Spencer Richlin is putting together. Dr. Richlin is passionate on the subject and determined to have patients understand the big picture as well as all the intricacies that this very sophisticated technique uses.
Preimplantation Genetic Diagnosis (PGD)
Preimplantation genetic diagnosis (PGD) is an advanced laboratory procedure in which embryos are screened for genetic diseases or chromosomal problems prior to placing them in the uterus. Introduced in the 1990s, its initial purpose was to help patients avoid passing genetic diseases, such as cystic fibrosis or Tay-Sachs, to their child. It has been shown to be very effective for this purpose, and more recently, its indications have expanded. For example, it has also become a screening test for aneuploidy, which is an error in cell division resulting in an embryo with an incorrect number of chromosomes, either too many or too little.
Chromosomal abnormalities are the most common cause for miscarriage in the human population and are often a reflection of reproductive aging (otherwise known as the female "biological clock"). Couples utilizing preimplantation genetic diagnosis would have their embryos evaluated prior to embryo transfer and only the most genetically normal embryo(s) would be selected. It is a relatively complex procedure that involves manipulation of the embryo, so it is offered judiciously to patients in situations where the benefits outweigh the risks.
Patients who believe they are candidates for PGD should schedule a consultation with a physician separate from their new patient consultation. At that consultation, detailed information (including risks and benefits) will be reviewed and their treatment strategy will be individualized based on their situation. Considering this procedure involves an embryo biopsy, which is equivalent to surgery on the embryo on a microscopic level, there is approximately 1-3% chance that the embryo will be harmed. Having an experienced embryologist perform the biopsy minimizes this risk.
PGD has also been recently used as a tool to prescreen embryos in patients over 35 for chromosomal abnormalities in order to help the embryologist and physician choose the best embryo(s) to place into the uterus. Utilizing PGD in this context is somewhat arguable and should only be performed after extensive counseling.
So,coming soon, all the different pieces of PGD; how it's used, what it can tell us, how it's performed and when. Dr. Richlin is working on it, he wants you to understand all the different pieces.
Infertility is not always about not being able to get pregnant. Sometimes it's also about not being able to maintain the pregnancy long enough to deliver a baby. Miscarriages are devestating when you are trying to create your family. When more than one miscarriage occurs, we refer to that as "recurrent pregnancy loss". Please read below for further information. Tomorrow's blog will focus on the other, less medical aspects of recurrent pregnancy loss, including the specific ways that you can manage this type of infertility.
Recurrent Pregnancy Loss
In all women, 15-25% of all clinically-diagnosed pregnancies end in spontaneous miscarriage and recurrent pregnancy loss (RPL) affects 2-4% of reproductive-aged women. The definitions for the diagnosis of RPL are:
- Two consecutive first trimester or early second trimester miscarriages with fetal heartbeats
- One or more second or third trimester miscarriages that are not explained by an obvious correctable source
Recurrent pregnancy loss causes anxiety and fear in couples seeking to build their families after several miscarriages. It is important to note that successful outcomes will occur for more than two-thirds of all couples with RPL, regardless of their reproductive histories.
RPL has many possible causes, but in up to 50% of cases no specific medical cause can be detected. This is termed idiopathic or unexplained RPL. Your physician at RMACT will thoroughly investigate all possible etiologies, including genetic, hormonal, anatomic, immunologic, microbiologic and thrombophillic (blood clotting disorders) causes. These will be explained below.
Unexplained RPL can lead to intense emotions such as frustration, anger, guilt and depression. Often patients blame themselves inappropriately. It is important to keep in mind that these feelings are normal, and there are many resources available in our office to support you personally and emotionally. Patients should be reassured that exercise, sexual intercourse or eating unhealthy foods do not cause miscarriages.
Treatment plans vary by the diagnosis made. Any correctable conditions should be aggressively treated. In those cases where no specific diagnosis can be made, studies have shown that weekly monitoring and support of early pregnancy supplementation of progesterone and estrogen if indicated, can improve the miscarriage rate and empower patients.
Causes of Recurrent Pregnancy Loss
- Parental genetic causes: In the general population, approximately 1% of people have stable structural abnormalities of their chromosomes. This group of conditions likely does not impact the health of that individual but can lead to the production of abnormal sperm and eggs. These types of abnormalities typically involve having a piece of one chromosome break off and reattach itself to the wrong chromosome and are called translocations.
Studies on couples with translocations have shown a high number of miscarriages. Treatment options for RPL include genetic counseling, early amniocentesis or chrorionic villi sampling (CVS) or the use of donor sperm or eggs. Recent studies have shown that patients with recurrent loss due to genetic factors may benefit from an advanced treatment option called pre-implantation genetic diagnosis (PGD), which involves the biopsy of an embryo derived from IVF (using your own sperm and eggs) to study the chromosomes of that embryo and find the chromosmally normal one. Using this technique, we can select the normal embryos for transfer and increase the implantation rates while decreasing the miscarriage rate.
- Embryo genetic causes: This is the mostly likely reason for pregnancy loss which is secondary to improper development of the early embryo. This occurs when the normal complement of 46 chromosomes is not present and therefore a healthy child cannot develop. For couples with RPL, chromosomal analysis of the miscarriage itself can provide useful information.
- Hormonal or systemic causes: Approximately 10% of RPL patients will have a hormonal disorder associated with their losses. This includes untreated hypothyroidism (and possibly hyperthyroidism). Patients with known thyroid disease will need to have their TSH levels followed closely and will likely need to have their doses adjusted during pregnancy. Unrecognized or poorly controlled diabetes, and even pre-diabetes, increases the miscarriage rate. This rate is reduced to a normal level once sugar and insulin control is normalized. Lastly, deficiencies of progesterone, the hormone that supports early pregnancies, can lead to miscarriages. This is sometimes termed luteal phase deficiency. Treatment involves supplementing with progesterone during the first trimester.
- Anatomic causes: Developmental anomalies of the uterus are called mullerian anomalies. The most common abnormality associated with RPL is the septate uterus, where a fibrous ridge of tissue protrudes into the endometrial cavity, or womb. Removal of this uterine septum by minimally invasive surgery called hysteroscopy has been shown to improve delivery rates. Other mullerian anomalies, such as bicornuate and unicornuate uterus, are associated more with later-trimester losses or preterm birth and are much less amenable to surgical repair.
- Auto-immune causes: Anti-phospholipid syndrome is a very specific diagnosis with strict diagnostic criteria. It involves your immune system attacking the placenta or placental blood vessels that can lead to miscarriages and poor pregnancy outcomes. Treatment includes blood-thinning injections and low doses of aspirin. Historical treatments with steroids or with infusions of immunoglobulins to treat a suspected or theoretical immune system problem do not have any benefit and have been shown to worsen maternal and fetal outcomes in pregnancy.
- Infectious causes: There have been some studies in the past that have implicated asymptomatic infections of the uterus with RPL. These may include mycoplasma, ureaplasma, Chlamydia and others, but current data does not support these associations to be a strong cause of RPL.
- Thrombophillic causes: This class of blood-clotting disorders is called thrombophillias, meaning "love of clotting" in Latin. It is associated with RPL by causing small clots to form in placental blood vessels that impair the full implantation and function of the placenta. Thrombophillias can also cause blood clots anywhere in your body and may have serious health consequences. Blood tests will help your physician diagnose these conditions and formulate a treatment plan.
- Lifestyle causes: Tobacco use has a detrimental effect on pregnancy outcomes and increases the rate of miscarriage. Smoking greater than 15 cigarettes per day increases the miscarriage rate approximately 1.5 times. Alcohol consumption beyond 10 drinks per week may increase the miscarriage rate by a factor of 2 compared to non-drinkers. Smoking and drinking to excess may worsen the effects of each alone. In addition Obesity has been associated with markedly higher miscarriage rates and poor pregnancy outcomes.
An article in the Wall Street Journal
yesterday discussing male infertility
looked at probable links to genetic defects. The research that this article focuses on by Dr. Dolores Lamb, from Baylor College of Medicine in Houston, reports that between 25-50% of male infertility cases are related to genetic defects. Up until the last few years, hormonal problems were thought to be the main cause of male factor infertility. In fact, now it's been shown that hormonal problems are only diagnosed in about 1% of the cases that are treated.
Below is a quote from the article, giving the definition and breakdown of infertility. While most fertility treatment is focused on the female partner, when there is a male factor problem, there are treatments available, specifically on sperm retrieval and increasing sperm production.
"About 15% of U.S. couples are infertile, defined as unable to conceive within one year of trying, according to the American Society for Reproductive Medicine. About one-third of those cases are due to male factors, and another third to female ones. The remaining cases are a result of problems from both partners, the Society says."
The article goes on to discuss the most common cause of male infertility, namely, varicose (enlarged) veins in the scrotum of the male. Varicose veins in the scrotum accounts for about %42 of the cases that are diagnosed. This condition can be reversed and usually leads to an increase in sperm production. The article briefly mentions other causes of male infertility, but mainly is looking to see what is causing the symptoms of male infertility, for example a low sperm count.
ICSI is also discussed in the Wall Street Journal article. ICSI is a procedure that enables a physician to use (by retrieval) only one sperm, helping men who have extremely low sperm counts who would otherwise not be able to have children. Dr. Peter Schlegel, (chairman of urology at Weill Cornell Medical College in New York) has this to say: "Men who have severe defects in sperm production will very often have an abnormality that you can see in certain genes".
The CFTR gene is also being looked at carefully as there are approximately 1,300 possible mutations in this gene, which helps regulate the production of mucus. One of the results of a mutation in this gene is the person being a carrier for cystic fibrosis. This is not a gene that is normally tested when using prepregnancy genetic analysis (PGD). If both the male partner and the female has this mutated gene and therefore is a carrier, the result could be a child who has cystic fibrosis. There are ways to predict that the male partner may be carrying this mutated gene which would indicate further genetic testing to avoid passing the possibility of passing on this debilitating disease to a child.
The article raises important questions and offers up the most recent research available, bringing attention through the mainstream media to the piece that male infertility plays in creating a viable pregnancy. There is a chart at the end of the article, giving a good overview of what to consider when you are trying to conceive and there is no pregnancy to show for it.
As always, we are here to answer questions that you may have after reading this article. Please feel free to post the questions here and one of our board certified reproductive endocrinologists will answer you.