The Alan E. Beer Center for Reproductive Immunology & Genetics helps families grow by researching and treating couples who experience recurrent miscarriages, multiple pregnancy losses or repeated in vitro fertilization failures.

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The Importance of Pathological Evaluation of Pregnancies that Terminated in Spontaneous Miscarriage

Introduction Return to Contents

It is important that we evaluate the placental tissue of the babies that our registered patients have lost. This tissue leaves a roadmap of the problems experienced from the beginning, and an evaluation enables us to help our patients end this long journey of disappointment. Solving the immunological problems and treating them appropriately will give our patients a very good chance of becoming a mother. It is important that the proper diagnosis is made and that our patients are treated appropriately; otherwise, there is a great likelihood that they will lose another pregnancy.

When a pregnancy fails, women often have a Dilatation and Curettage (D and C). When pregnancy tissue is obtained, it is sent to a pathologist usually associated with a laboratory or a hospital. Once the tissue is received, it is fixed in a formalin solution and embedded in paraffin (the final product is a paraffin block). The pathologist cuts the block into small slices, stains the tissue in the paraffin and looks at it under the microscope to determine that the tissue is pregnancy tissue and that it is normal and not infected. This is usually all that is done. Once the pathology report is given to you and your doctor the paraffin blocks and the slides are saved forever.

Registered patients may send the paraffin blocks to our office, along with payment (personal checks, Mastercard or Visa are accepted. Please note: specimens will not be forwarded to the lab until payment is received). We recut the tissue, make new slides, stain them with special antibodies that help us find the secureness of the attachment of the baby to the uterus (category 1); blood clots (category 2); inflammation (category 3); inflammation and blood clots (category 4); and the presence of natural killer cells and the damage caused by them (category 5). Once the testing is done by our office, the paraffin blocks are sent back to your hospital, your doctor and the pathologist.

Instructions Return to Contents

Our registered patients must submit the following items before we can conduct any testing:
  1. Pathology Specimen
  2. Payment for Testing Services

Therefore, to submit a pathology specimen for testing, please take the following steps:

  1. Request Tissue from Pathology Department
    Please download and send this letter to the pathology department in the hospital or clinic where the D and C was done or the passed tissue evaluated. This is a different department than that which evaluated the tissue for chromosomal analysis (karyotype). These specimens are usually sent to different laboratories. If there is any doubt, consult with your doctor’s office. They will be able to give you the address and phone number of the pathology department where the tissue was sent. The letter requests that they send the tissue to our office.

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  2. Submit Payment
    The cost of the consultation with physicians at our program is $250 (US). The price for a placental immunopathology test is $400 (US) per each pregnancy loss. Personal checks, Mastercard or Visa are accepted. Please note: specimens will not be forwarded to the lab until payment is received.

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Background Return to Contents

There are five categories of patients with implantation failure or recurrent pregnancy loss. Each category of patient represents a distinct problem that can lead to death of the embryo or the fetus. Each of these immune problems leaves its mark in the placental tissue and helps us to know that the immune abnormalities existed even before the pregnancy was initiated. Each category of problems has two or three features of abnormality in the placental issue and the blood vessels supplying the placenta. These are discussed below. This evaluation helps us to tailor the immune testing and therapy for the next cycle of conception. If some of the terms are unfamiliar, please check the glossary for a definition.

Category 1 Patients Return to Contents

Category 1 patients lack maternal blocking antibodies.

  1. DEPTH OF TROPHOBLAST INVASION. The trophoblast is the cell of the embryo that attaches the embryo to the uterus and begins to invade (root) into the uterine tissue called the decidua. This process is very aggressive in a normal patient who does not experience miscarriage. The trophoblast grows through the three zones of the endometrium (the lining of the uterus). It then travels deeply into and through the decidua and finally ends up in the muscle of the uterus. When this process is very superficial and the placenta attaches very shallowly and incompletely, it is graded as INADEQUATE.
  2. BLOOD VESSEL CONVERSION BY THE TROPHOBLAST. Within a few days of a positive pregnancy test the trophoblast grows into the uterus and is directed by a high oxygen gradient around blood vessels to the arteries that have grown into zone three of the endometrium. These trophoblast "tap into" these vessels and cause the mothers blood to circulate around these cells. Soon a maternal blood supply to the baby is established. During this period women experience some spotting called implantation bleeding. The trophoblast grows inside the blood vessel of the mother and replaces the natural lining of the blood vessel. It then grows into the muscle of the artery and replaces it so that it can not constrict, clamp down and shut off the blood supply to the baby. This process is very easy to see from the pathology specimen. If it has not occurred at the proper time and on the proper day it is judged INADEQUATE. If it has occurred with the proper speed and is well established it will be judged ADEQUATE.
  3. SYNCYTIUM FORMATION. The trophoblast cells that attach the baby to the uterus, invade the blood vessels of the uterus and establish the building blocks of the placenta. They also undergo a change that allows food to be transferred to the baby. This is called syncytium formation. The trophoblast cells join together and fuse to create a membrane that allows food and fuel to pass to the blood of the baby and to pass wastes from the baby to the mother. This membrane (syncytium) is very easy to see and to determine if enough of it has been built.
  4. IMPLANTATION SITE. The site where the pregnancy implanted in the uterus must be found to determine if there is an immune attack against the baby. In order to find this site special antibodies against INTERMEDIATE TROPHOBLAST are applied to the tissue. The intermediate trophoblast are the ones that glue the pregnancy to the uterus and they are the cells that invade the uterus and anchor the placenta. If the implantation site is not present or not found then the above characteristics cannot be accurately evaluated. In the pathology report this will be reported as IMPLANTATION SITE, PRESENT or NOT PRESENT. When this is not present there will be areas of the pathology report that state "cannot be evaluated because implantation site is not present." This does not mean that the baby did not implant it only means that on the tissue available in the pathology department the implantation site was not included in the tissue. Perhaps it passed spontaneously and was not included in the pathology specimen.

Category 2 Patients Return to Contents

Category 2 patients have developed antiphospholipid antibodies that cause the blood of the mother and the baby to clot too quickly during placental formation. These antibodies also inactivate the phospholipid glue, so that the placenta cannot attach itself firmly to the uterus. This problem leaves its mark in the placenta and it can be evaluated easily.

  1. VASCULITIS OF DECIDUAL VESSELS. Vasculitis is inflammation of the blood vessels that feed the placenta. This process does not cause inflammation of the blood vessel unless antiphospholipid antibodies are present. The pathology report will state whether this VASCULITIS is PRESENT OR ABSENT.
  2. THROMBOSIS OF DECIDUAL VESSELS. Once there is inflammation in the placental blood vessels blood has a tendency to clot to fast. A clot (thrombus) then forms in the blood vessels. This process is called thrombosis. The pathology report will grade this as EXTENSIVE, MODERATE OR MILD. Any amount of thrombosis it too much. This is caused by the antiphospholipid antibodies.

Category 3 Patients Return to Contents

Category 3 patients have developed antibodies to the babies and the placental DNA. This antibody to DNA or the breakdown products of DNA (polynucleotides and histones) turns the ANA test positive and this antibody causes inflammation in the placenta.

  1. VILLITIS. Villitis is inflammation of the tissue of the villi (the entire root system of the placenta) On the outside of the villi is the syncytium (the dialysis membrane that feeds the baby and exchanges its waste). The inside of the villi or villus contains the blood vessels of the placenta that join with the umbilical cord. On the outside of the villi or villus the mother’s blood circulates. Antibodies to DNA cause inflammation of the entire villus as is seen in a tonsil that is inflamed from infection. This is graded as SEVERE, MODERATE OR MILD.
  2. INTERVILLOSITIS. When the inflammation is severe it spreads from one villus root to another and there is inflammation between them. This is graded as SEVERE, MODERATE OR MILD.
  3. DECIDUAL INFLAMMATION. The inflammation can also spread into the soil (decidua) that the placenta has attached to. This is graded as SEVERE, MODERATE OR MILD.

Category 4 Patients Return to Contents

Category 4 immune problems of antibodies to sperm are not amenable to placental analysis.

Category 5 Patients Return to Contents

Category 5 patients have elevated and aggressive Natural Killer Cells (CD 56+ and or CD 19+5+). These cells are identified by treating the tissue with a special antibody to CD 56 marker on CD 56+ cells. They can be counted and evaluated. The CD 19+5+ cells produce antibodies that inactivate the hormones produced by the trophoblast (Estrogens, Progesterone and HCG). They also inactivate the hormones that are important in providing the "links" that enable the uterine muscle to grow and the decidua tissue to remain firmly attached together. These latter hormones are Serotonin, Endorphins and Enkaphlins.

  1. DECIDUAL NECROSIS. Necrosis refers to death of a cell or tissue. Decidual necrosis simply means that the "soil" which is attaching and nourishing the developing placenta falls apart. This process is graded as SEVERE, MODERATE OR MILD. In addition at the end of the pathology report the numbers of Natural Killer Cells in the placenta.
  2. DECIDUAL INFLAMMATION. When this type of tissue and placental injury is occurring the decidua becomes filled with cells that cause inflammation (just like Category III patients). These cells are of different types. They are called Monocytes, Lymphocytes, Plasma Cells, Granulocytes. Their numbers are evaluated as SEVERE, MODERATE OR MILD.
  3. FIBRIN DEPOSITION AND FIBRINOID FORMATION. Following decidual necrosis and decidual inflammation the placenta tries to heal itself just like a cut on your skin heals with scar formation. It attempts to form a scar where the injury has occurred. This scar formation begins with fibrin being deposited in the placenta and then the fibrin ages and forms fibrinoid. This is easily quantitated in the decidua and placenta and is reported as SEVERE, MODERATE, MILD OR ABSENT. This finding means that the injury to the placenta began very early in pregnancy and was more than two or three weeks old.
  4. TROPHOBLAST MORPHOLOGY. Just like the roots of a plant, the placenta (the root of the baby) has many different cells and many different structures. There are 7 or 8 different types of cells or roots and the morphology (health or disease) of these is easy to see under the microscope. The morphology will be reported as NORMAL OR ABNORMAL. Abnormal morphology can be caused by the immune attack against it. It can also be abnormal if the baby has a genetic abnormality that is incompatible with life. This finding confirms the immune attack against the placenta. If the morphology is abnormal and the immune attack is not present then it is likely that the baby had a genetic abnormality that was incompatible with life. This is not always an either or situation. Babies with genetic abnormalities can also be destroyed by an immune attack. Not all genetically abnormal babies miscarry. Some are born alive. If there is high suspicion that there is a genetic abnormality a special stain can be done of the tissue called the FISH procedure.

The information contained in this article is not intended to be a medical diagnosis, treatment or medical advice in any way, as it is general information and cannot be relied on without consultation with your physician. It is not intended nor is it implied to be a substitute for profession medical advice. As medical information can change rapidly, we strongly encourage you to discuss all health matters and concerns with your physician before embarking on new diagnostic or treatment strategies.

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Alan E. Beer Center for Reproductive Immunology & Genetics
15151 National Ave. #2; Los Gatos, CA 95032; Phone: (408) 356-9500; Fax: (408) 356-9509; E-mail: info@repro-med.net.
Date: 7-24-08, Time: 9:52 am.

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