Science Pulse    Recurrent Miscarriage: Mysteries & Facts

Recurrent Miscarriages, also called recurrent pregnancy loss (RPL), is diagnosed after at least 2 or 3, or more, consecutive pregnancy losses in the first or early second trimester (less than 15 weeks gestation). It is one of the most common clinical problems in reproduction, yet a definite cause can be established in only about 50% of the cases, often leaving patients distraught and frustrated. Consequently, some patients will turn to alternative therapies of unproven benefit. Medically known causes and treatments are described in this article.

Egg Quality Factor
The normal biological aging process of the egg causes the egg to function less accurately during the fertilization process at the critical time of chromosomal duplication and pairing. The resulting chromosomally abnormal embryos have a lower chance of implanting in the uterine lining. If implantation does occur, these embryos have a higher chance of leading to a first trimester miscarriage. We test for egg quality by performing a blood test for the FSH and Estradiol hormones on menstrual cycle day 2 or 3. For some patients we may recommend a more extensive test called a Clomid Challenge Test.

Other Hormonal Factors
Other hormonal abnormalities that result in miscarriage must be very subtle because the cycle is normal enough to allow egg development, ovulation, fertilization, and implantation, yet the pregnancy is lost at a later time. The amount of progesterone produced by the follicle after ovulation and the effect of that progesterone on the lining of the uterus may be of importance. A low progesterone level or an inadequate maturation of the uterine lining is called a luteal phase defect.

Abnormalities of other metabolic hormones can cause a luteal phase defect. If the prolactin level is elevated, it is important to evaluate for prolactin-elevating drugs, hypothyroidism (check the TSH), and pituitary tumors. The prolactin level can be lowered to a normal range with medications.

Women who have polycystic ovary syndrome (PCOS) are at higher risk of miscarriages because of an intraovarian hormonal imbalance. If PCOS is suspected, checking for LH, androgens and insulin resistance can be helpful in discussing treatment with insulin-sensitizing agents (metformin).

Anatomical factors
The anatomical factors are a variety of structural abnormalities of the cervix and uterus that are found in about 15% of women with recurrent pregnancy loss. These factors are diagnosed by performing a hysterosalpingogram (HSG), mid-cycle ultrasound or saline hysterogram, with attention directed to the shape or contour of the uterine cavity.

Potential abnormalities that may be found and associated with recurrent miscarriages are polyps, fibroids, and uterine septums. These anatomical abnormalities can lead to an unfavorable uterine environment for the embryo at the time of implantation and early embryo development. These can lead to early pregnancy loss. All of these abnormalities can usually be corrected with minor surgery.

Chromosomal Factor
There are 2 types of chromosomal factors. One is a random event; the other is genetically inherited by the fetus. At least 60% of all miscarriages are chromosomally abnormal embryos that arose from sporadic, random genetic defects in the sperm or the egg. These are defects that would not have been detected by analysis of the couple's chromosomes (karyotype). However, these defects become more common as the woman ages. The miscarriage risk increases from about 15% of pregnancies before age 35, to 35% by age 40 and to 50% by age 45. About 99% of the time a chromosomally abnormal embryo will be miscarried. Because perhaps 1% will continue to develop, amniocentesis or chorionic villus sampling, which determine the genetic makeup of the fetus, is suggested for women over 35. When the genetic makeup of the fertilized egg is very abnormal, no embryo forms. On ultrasound examination an empty sac or a "blighted ovum" is seen in the uterus.

Some patients have chromosomal abnormalities in each cell, including eggs and sperm, which place them at greater risk of making a larger proportion of abnormal embryos. The fetus then genetically inherits this abnormality. Every cell in our body other than eggs and sperm has 46 chromosomes arranged in 23 pairs. It is possible that between the two chromosomes of a designated pair there could be a mix-up in the sequence of genes that make up these chromosomes, but the total number of genes is still normal. This mix-up is called a "balanced translocation" and causes no symptoms, diseases, or abnormalities in the patient or partner. However, if this genetic rearrangement occurs in a sperm or egg, the embryo will be chromosomally abnormal, and a miscarriage will follow. Balanced translocations can be detected by performing a chromosomal analysis. Chromosomal analysis requires a blood sample from both partners. The white blood cells are cultured to produce an analysis, or karyotype, of the chromosome pairs. The karyotype will be abnormal in about 5% of cases of couples that have suffered from three or more miscarriages. It is difficult to say what the risk of repeated miscarriages will be with a balanced translocation, however a normal full term pregnancy is still possible.

Immunologic factors
The immune system protects our bodies against foreign micro-organisms by recognizing any cells that are different from our own and making antibodies that attack and destroy those cells. Some women with recurrent pregnancy loss have autoantibodies. These are antibodies in their blood vessels that are made to attack their own tissues (e.g., antiphospholipid (anticardiolipin), antinuclear, or antithyroid antibodies). Antiphospholipid antibodies, along with lupus anticoagulant, may interfere with the formation of a normal placenta early in pregnancy and increase the risk of abnormal blood clotting in the placenta later in the pregnancy. This compromised placenta will lead to compromised growth of the fetus and an eventual miscarriage. If one has a positive antibody test, the test should be repeated 6-8 weeks later. If both sets of tests are positive, the recommended treatment may include one "baby" aspirin tablet per day, and sometimes the addition of daily heparin.

Thrombophilia Factors
Various enzymes regulate effective flow and clotting of blood. If there is a deficiency in some of the clotting enzymes, then small blood vessels of the placenta may be at greater risk of forming clots. Clots of the placenta will compromise blood flow to the growing embryo, placing the pregnancy at greater risk of a miscarriage. There are now a number of clotting enzymes that are recommended to be tested for in patients with recurrent miscarriages. If specific combinations of these enzymes are found to be in an abnormal range, then recommended treatment is a "Baby" aspirin per day with the possible addition of heparin.

Most miscarriages are the result of a random genetic defect leading to abnormal chromosomes for that particular fetus. This random event is unlikely to recur. For patients who have had three consecutive first-trimester miscarriages, and normal results after full evaluation, the chance of the next pregnancy leading to the delivery of a child is approximately 65%. Therefore, despite having had three recurrent miscarriages, the odds are still in favor of the next pregnancy being a normal pregnancy. While it can be incredibly frustrating both for patient and physician, to face repetitive failed pregnancies, it is still important to understand that the odds are still in the patient's favor of eventual success. This may require fertility treatment, from low-tech intervention such as Clomid to high tech intervention such as IVF with preimplantation genetic screening (PGS), but in general, success is in our favor. If you are, or know someone who is experiencing recurrent miscarriages, please discuss this with a fertility specialist who may be able to recommend treatment options. - Isabelle Ryan MD

Isabelle Ryan MD is recognized by prestigious medical associations for her pioneering research leading to new insight into the important clinical problem of endometriosis related infertility. She offers patients a combination of clinical expertise and warm personal care. Dr. Ryan is Director of Pacific Fertility Center's Third Party Parenting Program, which includes our in-house egg donor agency.

Ask the Experts    PGD and Embryo Development

A.
I don't have all the information needed to give you a complete answer but I'm going to assume that you are a typical IVF patient (in your late 30's) and were doing PGD to eliminate embryos with chromosomal abnormalities or aneuploidy. During your IVF cycle the eggs that were harvested from your ovaries were inseminated and those that fertilized and continued to develop were analyzed genetically. Depending on your (maternal) age, somewhere around 50% of your eggs would have been genetically abnormal. The genetically abnormal embryos look and behave in the same way as normal embryos.

Most genetic abnormalities cause an embryo to fail at the time of implantation (5 or 6 days old) or cause a pregnancy to fail early (miscarriage). When we look at embryos under the microscope in the days leading up to transfer, there is no way of knowing which are genetically normal or abnormal. Both types of embryos grow and develop similarly. In fact, some embryos that we know are abnormal (e.g. resulting from an egg that is fertilized by 2 sperm) often develop faster and look more beautiful than normally fertilized embryos.

The egg is a very large cell and when it is released from the ovary it has already been programmed to develop for 3 or more days after fertilization. Mom pre loads her eggs with the necessary information for this early development. In most cells, including sperm, there are internal checks to make sure that the cell is functioning normally and that it is genetically normal. Cells that are abnormal, commit suicide in a process that we call apoptosis. Eggs however, seem to have a very poor internal surveillance mechanism, and even those that are grossly abnormal (e.g. with a whole extra chromosome) can fertilize and develop even to the point of giving you a live child. Down syndrome is the classic example, although at least 75% of embryos affected with this condition miscarry early in pregnancy.

So, eggs are endowed at ovulation with the necessary information to keep them going and looking normal for days, regardless of their genetic constitution. There is no relationship between their genetic status and how beautiful they look in our petri dish. If there were, we wouldn't need to do PGD. We can keep embryos alive in the laboratory for 5 or 6 days and some of the abnormal embryos might stop developing by that time. However, our experience with PGD over the years tells us that about 50% of the genetically abnormal embryos will still look beautiful on their 5th day of life.

The pattern of development that we see with human embryos, regardless of their genetic status, is extremely variable. As you have witnessed first hand, normal embryos often arrest for reasons that we don't always understand. This is true, regardless of whether the embryos are growing inside of you or in our lab, and this leads to a very inefficient process of reproduction in human females because she only ovulates one egg per month. We do know that the younger a woman is, the better the chance that the embryo will continue to grow. Embryos are more likely to fail in older women. In very young women, over 50% of embryos will implant in the uterus, but in women over age 40 less than 10% will implant. Although we can't fully explain this phenomenon, a major contributing factor is egg age. Since women have all the eggs they will ever have when they are born, a 40-year-old woman is trying to get pregnant with a 40-year-old egg. And 40-year-old eggs just don't perform as well as younger eggs.

Are PGD results consistent from one cycle to the next? The PGD technicians tell me that they get similar results for a patient 2 out of every 3 times.

Any embryo that has not developed in 2 days will not get you pregnant. If an embryo is to be ready for implantation, it must be alive and increasing its cell number every day. We expect a full round of cell division (e.g. from 4 to 8 cells) every 16 hours. Further, an embryo transferred to your uterus on day 4 or day 5, following your PGD analysis, should have enough cells to begin forming a placenta. It sounds like your embryo had arrested (i.e. it was dead).

Human reproduction is a very complex undertaking, and often patients feel like they're left with more questions than answers after their fertility treatment. Don't be afraid to ask your questions, no matter how simple or complicated they might be. Chances are, we've encountered your situation before. - Joe Conaghan, PhD, HCLD

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Conception Health    Sperm Boosters: Fact or Fiction?

Now there are several preparations being marketed to promote fertility. In this article, I chose to review three of the major products being actively marketed for the purposes of improving sperm.

The oldest supplement is ProXeed™. ProXeed™ is a citrus-flavored powder and can be dissolved in juice or other cold beverages. It is recommended by the manufacturer to be taken twice a day. The active ingredients in Proxeed™ are L-carnitine, L-acetyl carnitine and fructose. The cost is approximately $335.00 per 3-month supply.

Fertile One® is a pill that contains L-carnitine, anti-oxidant vitamins (ferulic acid, vitamins C and E, garlic, co-enzyme Q10 and selenium), ginseng root, zinc and B-complex vitamins (B-6, B-12, B-9 and folic acid). Cost is approximately $273.00 per 3-month supply.

FertilityBlend® for Men is a supplement containing L-carnitine, ferulic acid, vitamins E, B6, B12, and the elements selenium and zinc. The cost is only about $80.00 per 3-month supply.

Several studies have shown that the amino acid L-carnitine may promote sperm development. In a recent clinical trial¹, 102 men with low sperm motility were treated with L-carnitine and acetyl L-carnitine. There was a significant correlation between higher levels of carnitine in the seminal (sperm) fluid and better sperm concentration, total sperm count, sperm total motility, rapid forward progression, live sperm count, membrane function, nuclear DNA integrity, capacity for cervical mucus penetration, linearity of spermatic movement, and amplitude of lateral sperm head movement after 3 and 6 months of L-carnitine/acetyl L-carnitine treatment. Another high quality study, a randomized, placebo-controlled trial of L-carnitine and acetyl L-carnitine showed that after 6 months of treatment increases were seen in all sperm parameters and the most significant improvement in sperm motility was present in patients who had lower initial absolute values of motile sperm (<4 million forward or <5 million total motile spermatozoa per ejaculate)². There are no published randomized controlled trials looking at pregnancy rates on L-carnitine.

Several studies on the B Vitamins have been published showing anti-oxidant effects and virtually all find some benefit to the addition of this group to a daily vitamin regimen.

Ferulic acid is found in various medicinal herbs, has recently been shown to scavenge oxygen free radicals and increase the intracellular cAMP and cGMP (energy molecules). The only published article on ferulic acid involved adding this substance to previously ejaculated sperm specimens where it was shown to improve sperm motility³. A medline search did not reveal any studies on sperm after ingestion of ferulic acid.

It is interesting that Fertile One® contains garlic; at least one study has reported an inhibitory effect on garlic on sperm motility and survival in human and mouse sperm⁴ and crude extracts of garlic bulbs have been shown to immobilize ram sperm and are being investigated as a potential male contraceptive⁵.

Selenium is a trace mineral that is incorporated into several anti-oxidant proteins. It has been shown to improve human sperm parameters⁶ and fertility improved slightly when selenium-deficient mice were treated with it ⁷. What is not clear is whether most men with a normal diet would be selenium-deficient.

Folic acid supplementation may also be beneficial, especially for men who smoke Cigarettes⁸. Treatment of men with folic acid and 5 mg zinc improved sperm counts by 60% and also improved morphology (shape)⁹. Vitamin E has also been shown to improve sperm parameters and sperm-egg binding¹⁰. Co-enzyme Q10 has been shown in one small uncontrolled study to improve sperm motility in males¹¹ but studies of men with a varicocele (dilated scrotal veins) suggest that high levels of seminal fluid Co-enzyme Q10 are found with men with the lowest sperm motility, suggesting that Co-enzyme Q10 would not be beneficial for men with a varicocele¹².

Considering all these studies, there does seem to be a beneficial role for dietary supplementation for men with low sperm counts and low motility. The supplement marketed as FertilityBlend® for Men has almost all of the most well studied ingredients and is considerably less expensive than the others. Avoidance of garlic extracts and further supplementation with folic acid may also be beneficial. - Carolyn Givens, MD

References:
1. Correlation between seminal carnitine and functional spermatozoal characteristics in men with semen dysfunction of various origins. De Rosa M, Boggia B, Amalfi B, Zarrilli S, Vita A, Colao A, Lombardi G. Drugs R D. 2005;6(1):1-9.

2. A placebo-controlled double-blind randomized trial of the use of combined l-carnitine and l-acetyl-carnitine treatment in men with asthenozoospermia. Lenzi A, Sgro P, Salacone P, Paoli D, Gilio B, Lombardo F, Santulli M, Agarwal A, Gandini L. Fertil Steril. 2004 Jun;81(6):1578-84.

3. Effects of ferulic acid on fertile and asthenozoospermic infertile human sperm motility, viability, lipid peroxidation, and cyclic nucleotides. Zheng RL, Zhang H. Free Radic Biol Med. 1997;22(4):581-6.

4. Spermicidal effect in vitro by the active principle of garlic. Qian YX, Shen PJ, Xu RY, Liu GM, Yang HQ, Lu YS, Sun P, Zhang RW, Qi LM, Lu QH. Contraception. 1986 Sep;34(3):295-302.

5. Sperm immobilization activity of Allium sativum L. and other plant extracts. Chakrabarti K, Pal S, Bhattacharyya AK. Asian J Androl. 2003 Sep;5(3):230.

6. Male fertility is linked to the selenoprotein phospholipid hydroperoxide glutathione peroxidase. Foresta C, Flohe L, Garolla A, Roveri A, Ursini F, Maiorino M. Biol Reprod. 2002 Sep;67(3):967-71.

7. Sperm oxidative stress and the effect of an oral vitamin E and selenium supplement on semen quality in infertile men. Keskes-Ammar L, Feki-Chakroun N, Rebai T, Sahnoun Z, Ghozzi H, Hammami S, Zghal K, Fki H, Damak J, Bahloul A. Arch Androl. 2003 Mar-Apr;49(2):83-94.

8. Low seminal plasma folate concentrations are associated with low sperm density and count in male smokers and nonsmokers. Wallock LM, Tamura T, Mayr CA, Johnston KE, Ames BN, Jacob RA. Fertil Steril. 2001 Feb;75(2):252-9.

9. Effects of folic acid and zinc sulfate on male factor subfertility: a double-blind, randomized, placebo-controlled trial. Wong WY, Merkus HM, Thomas CM, Menkveld R, Zielhuis GA, Steegers-Theunissen RP. Fertil Steril. 2002 Mar;77(3):491-8.

10. A double-blind randomized placebo cross-over controlled trial using the antioxidant vitamin E to treat reactive oxygen species associated male infertility. Kessopoulou E, Powers HJ, Sharma KK, Pearson MJ, Russell JM, Cooke ID, Barratt CL. Fertil Steril. 1995 Oct;64(4):825-31.

11. Coenzyme Q(10) supplementation in infertile men with idiopathic asthenozoospermia: an open, uncontrolled pilot study. Balercia G, Mosca F, Mantero F, Boscaro M, Mancini A, Ricciardo-Lamonica G, Littarru G. Fertil Steril. 2004 Jan;81(1):93-8.

12. Coenzyme Q10: another biochemical alteration linked to infertility in varicocele patients? Mancini A, Milardi D, Conte G, Bianchi A, Balercia G, De Marinis L, Littarru GP. Metabolism. 2003 Apr;52(4):402-

Patient Odyssey    My Wildest Dream

At age 30 I started trying to get pregnant. I had endometriosis, I hadn't used birth control for almost ten years and I had never been pregnant. I had also never imagined I would have difficulty conceiving. There was a great deal of irony in the amount of energy I put into trying not to get pregnant before my husband Red and I mutually agreed we were “ready”. After trying for more than a year, we went to see Dr. Carl Herbert and I was diagnosed with unexplained infertility. Thankfully, Dr. Herbert took excellent care of us and at age 34 I conceived my first daughter with the help of Clomiphene and IUI.

Conceiving my second daughter, however, proved more challenging, but was accomplished through IVF three years later. Even though I had tried IUI again and had produced many follicles, my IVF cycle revealed that the quality of my eggs was inferior. Dr. Herbert had the unhappy task of relating this distressing news to us during my embryo transfer, but he did so with tremendous grace and kindness. I have the utmost trust and confidence in Dr. Herbert and I feel blessed that he gave us the opportunity to conceive. Despite the quality of my embryos, we beat the odds and I conceived anyway. Yahoo!

Ultimately my goals were met, but it was the journey through infertility that has brought light and clarity into my life. With the help of my amazing doctor and with nurses like Ann McGovern (to whom I cried countless times), the laborious process of conceiving against the odds was made easier by their warmth and encouragement. I don't know if it ever got "easier" being met with my period after each month's unsuccessful attempt, however. By far the most searing memory, beyond all the shots and ultrasounds, was news, from what seemed like every woman on the planet, of other people's pregnancies. And not only were they pregnant, but, their pregnancies were achieved unaided and on their first try. Of course!

What saved me and my marriage both times was a combination of therapy, friends and family. My husband was amazing through it all and our marriage is stronger and brighter as a result. When all is said and done and both my girls are strapped in their car seats or cuddling with me on the couch, all of the infertility effort seems like a distant memory. I feel so blessed to have conquered my infertility. My wildest two dreams have been realized.
- Jennifer

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-- Best regards from all of us at Pacific Fertility Center.