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For most women most of the time, a miscarriage in isolation is sensibly regarded as just bad luck. Generally a miscarriage is more likely to mean that the body's reproductive system is working than that it is not -- that next time, and without specific intervention, a normal healthy pregnancy, and in due course a baby, will result. But a miscarriage that's followed by a second one, and then perhaps a third -- or a miscarriage that occurs after a long period of infertility - or a miscarriage in the middle three months of pregnancy -- is another matter. Rather than reassuring, such a miscarriage is a sign, maybe a reminder, that all is not well and that tests should be done. Here we consider Are You Having a Miscarriage?Return to Top The first experience that a pregnancy is not doing as well as it should be doing usually consists of some bleeding and then cramps. Eventually there can be an uncanny feeling of wellness: the nausea of pregnancy disappears, the nipples lose their soreness. None of these symptoms is an invariable harbinger of doom. But they usually lead to tests -- typically a transvaginal ultrasound, perhaps with a serum hCG (depending on the stage of the pregnancy) -- tests that will decide if all is well or not. Miscarriages differ in the form they take, depending on how far the pregnancy has got. Here we will look at Menstrual MiscarriagesReturn to Section Top A menstrual miscarriage is one that is so early that it does not delay the period. There are no symptoms of pregnancy. It's not possible, without doing a blood pregnancy test late in the luteal phase to distinguish a menstrual miscarriage from a normal period. (Remember that these symptoms -- exaggerations of normal experiences -- are also likely when a period is late and when the lining of the uterus -- the endometrium -- is thicker because of a prolonged follicular phase and a late ovulation.) An ultrasound examination will not reveal a pregnancy sac. Some gynecologists call such a miscarriage a "biochemical pregnancy", because the only hard evidence for pregnancy comes from a biochemical test (the pregnancy test, or level of serum hCG). Subclinical MiscarriageReturn to Section Top A subclinical miscarriage is the miscarriage of an early pregnancy that delays the period a week or two. As well as having a positive pregnancy test, a small gestational sac may develop on transvaginal ultrasound; but when the miscarriage takes place it's like a delayed period, though it can be heavier and longer than is normal for you. No curettage of the cavity of the uterus is necessary. Not all gynecologists consider this to be a separate category of miscarriage, so it too is sometimes called a "biochemical pregnancy", confirmable by pregnancy test or serum hCG. Clinical MiscarriagesReturn to Section Top The best recognized sort of miscarriage can be called a clinical miscarriage, to set it apart from the other miscarriages we've talked about. In this case there's a gestational sac present, and can be seen with a transvaginal ultrasound, and there can be symptoms of pregnancy. A fetal heart can develop and might also be seen on ultrasound, but it can be late in appearing (more than six weeks after the last menstrual period -- or, more accurately, longer than four weeks from conception) and, when the embryo doesn't grow, the fetal heart slows and then it stops. When miscarriage takes place, with bleeding and then pain, it's usual to have a curettage of the uterus to make sure the uterus has emptied and that bleeding or infection do not complicate matters. If a transvaginal ultrasound shows that miscarriage has been complete then curettage is not necessary. Before the days of ultrasound, we used to distinguish a threatened miscarriage (bleeding, generally without pain, and a cervix that remained closed) from an inevitable miscarriage (with painful contractions accompanying bleeding and a dilating cervix). Nowadays a miscarriage will be regarded as inevitable if the gestational sac on ultrasound is smaller than it should be and when the fetal heart is absent or is slow, at a time when it should be visible and when it should be faster than about 120 beats per minute. In cases of doubtful dates -- and of course we usually give a much wanted pregnancy the benefit of such doubt -- a second ultrasound is carried out a week or two later: if the pregnancy has developed normally it's likely to be normal; if growth has slowed further then miscarriage will be inevitable. The symptoms of miscarriage can sometimes be confused with the symptoms of an ectopic pregnancy (discussed on WebPage 14). The ultrasound is useful in making this distinction too. Your doctor will be particularly interested in what parts of the pregnancy form before miscarriage takes place. The earlier the damage to the pregnancy the less developed the embryo or fetus will be, so that with many conceptuses (or "the product of the conception") that have abnormal chromosomes there's no embryo at all, just trophoblast (placenta) and chorion (membranes). If embryonic structures are present, it's the head-end of the embryo and the heart that develop first; the tail can be very deficient. The further the pregnancy has progressed, the more complete the development will have been of the embryo or fetus. It's unusual for a completely normally formed embryo to be lost in the first three months of pregnancy. Just how complete the development of the pregnancy is at the time of miscarriage can also be judged by having a pathologist examine the miscarriage tissue, either after it's been expelled from the uterus spontaneously (the natural process of miscarriage) or after the tissue has been proactively removed from the uterus by vacuum curettage. The most useful test to do on miscarriage tissue (before it has been placed in a fixative solution for the pathologist) is to send some trophoblast tissue for culture to permit a karyotype, or analysis of the chromosomes. If a karyotype is done on incompletely formed miscarriage tissue, then in over 60 percent of cases the chromosome constitution will be abnormal. Vice versa, an abnormal chromosome constitution in the embryo means that, with a few exceptions, the miscarriage will have been inevitable. If the chromosomal constitution is normal, on the other hand, there must have been another explanation for the miscarriage. With repeated miscarriages, therefore, or when a miscarriage looks inevitable after a period of infertility, a karyotype of the miscarriage tissue is an important test to determine the problem. I discuss this in more detail further on, under Chromosomal embryopathy. A second useful test to do on the miscarriage tissue is a pathology test to examine the site of implantation, looking for evidence of inflammation or thrombosis, and if possible judging the extent of spiral artery conversion by extravillous trophoblast (discussed on WebPage 4). Missed Miscarriage, or Missed AbortionReturn to Section Top A pregnancy where there's no embryo growing can persist into the second three months (the second, or middle trimester) of pregnancy, especially if progesterone treatment has been used to try to salvage the pregnancy but has succeeded only in delaying the natural process of miscarriage, for example if there is a chromosome abnormality. A true missed abortion, as this persistent state is known, is not a good thing to have happen, because the tissue of the miscarriage hardens and can be difficult to curette from the cavity of the uterus, risking damage to the endometrium in the form of intrauterine adhesions (discussed on WebPage 17). Midtrimester MiscarriagesReturn to Section Top Should a normally formed fetus miscarry, usually in the middle three months of pregnancy (the second, or mid trimester), then the essential distinction for the cause of the miscarriage you and your doctor will want to make is the one between cervical incompetence and premature labor. The pattern of events is different -- and the treatment of the two conditions is very different -- so careful recall of the order of events is important. With cervical incompetence a normally formed fetus can be lost, after 14 weeks' or more of pregnancy, due to softening, shortening and then opening of the cervix. Such an "incompetent" cervix allows the membranes of the pregnancy to bulge through. Symptoms can be minimal until it's too late, consisting just of backache and an increase in wetness or discharge from the vagina. There might be no symptoms at all before the membranes (the waters) break, a rush of fluid is experienced, and the fetus is expelled into the vagina with minimal bleeding and pain. The placenta will usually follow and bleeding is then common. With premature or immature labor (if the fetus is still well short of viability), in the absence of cervical incompetence the process is like labor -- with the onset of painful, episodic contractions of the uterus and bleeding before the waters break; the fetus and placenta are then expelled. With such a pattern the common causes are an infection (sometimes, ironically, associated with the presence of a stitch in the cervix, or a cervical ligature, used to treat cervical incompetence); and abnormalities of the uterus (discussed on WebPage 18). Sadly, it's still not always possible to find a treatable cause even in repeated cases, and then a variety of antibiotics, medications and hospitalization may be called for in trying to keep the pregnancy in place until the newborn can be expected to be viable. I discuss this treatment further on WebPage 9. How Usual are Miscarriages?Return to Top Table 8.1 shows the average chance of a pregnancy ending in miscarriage according to the age of the woman. (The male partner's age has very little, if any, effect.) There's a steady rise with age from the early twenties (when it's about 12 percent for clinically obvious miscarriages), and a substantial increase in risk after the late thirties (when it's about 20 to 25 percent for clinical miscarriages). After about the age of 42, more than half of all pregnancies achieved will miscarry. It used to be thought that it was the aging uterus that caused miscarriages to become more common in older women, but clinical studies with donated eggs and embryos from younger women to older women show that this is not the case. The aging process affects the eggs, leading to chromosomal or metabolic embryopathy, which I discuss further on (see also the WebPage 7 box, How eggs might get their "use-by'' date: mishaps in the mitochondria). As a result, many women in their forties, and some even in their fifties and sixties, have recently conceived and successfully undergone pregnancy with eggs donated by much younger women. Recurrent MiscarriageReturn to Top Just as getting pregnant is a matter of chance, so is having a miscarriage. It's uncommon for every pregnancy to miscarry -- although in some women it does seem to happen this way. Gynecology textbooks classically claim that repeated miscarriages should be investigated if a woman has had three or more of them in a row, a condition formerly called habitual abortion (nowadays, more gently, recurrent miscarriage). But this is an old-fashioned perspective. It was 1982 before it was generally known that there's an increased chance of miscarrying with just about every cause of subfertility (discussed on WebPage 7) and with most treatments for infertility. If a miscarriage takes place with a background of infertility, it can help -- in getting a total view of the reasons behind the disability -- to investigate even one miscarriage by sampling the miscarriage tissue and performing a karyotype. If the karyotype is normal then the chances are that the miscarriage was caused by whatever is causing the infertility. Whether the karyotype of a miscarriage is normal or not, we can presently find a cause for about two-thirds of couples who have had three or more miscarriages; about half of these couples will have a successful pregnancy as a result of treatment. There's probably no medical condition that produces a longer list of tests than the investigation of recurrent miscarriages calls for -- although the good news is that most of them can be done on the one sample of blood. Your doctor, however, might be selective, and exactly which tests are most likely to be helpful will depend on the circumstances. I'll approach the relevant tests according to a consideration of the possible causes of miscarriage. I should say straight away that these different categories are not well known outside Sydney IVF: your gynecologist might or might not consider or categorize the causes of miscarriages this way. But it's a sensible approach, explaining miscarriages this way works, and it forms the foundation of the comprehensive miscarriage management program developed at Sydney IVF. Testing for the Causes of MiscarriagesReturn to Top The key biological events that lead to successful pregnancy are fertilization (by a genetically normal sperm of an egg that is both genetically normal and, in its cytoplasm, metabolically capable), cleavage (as the egg becomes a ball of cells, now under the command of both parents' genes), implantation (by a hatched blastocyst into an adequately responsive endometrium), establishment of molecular dialogue between invading trophoblast and well developed decidua (which includes critical elements of the blood coagulation system and the immune system or immunological rejection occurs), and then what could be called the placental building industry, the sound, earthquake-proof construction of chorionic villi to compose a mature placenta and a reliable supply of placental perfusion (see WebPage 4 for an account of the steps involved). So the logistics are hugely important. But so too is the passenger, the developing embryo, which by the time it is a blastocyst is already making at least 1500 mostly indispensable molecules, with much more to come, involving switches on probably every chromosome. Think of chromosomes as racks of genes, so generally the bigger the chromosome the sooner it becomes indispensable, requiring the right genes, without faults, and in the right dose (two copies). We'll consider the causes of miscarriage in the following groups: - chromosomal embryopathy, in which a genetic error at conception dooms the embryo; - embryopathy before implantation, in which the gross genetic make-up of the embryo is normal but there's a harmful event that cripples the embryo before it has a chance to implant properly (it can arise preconceptionally in the egg or sperm, or it can be a postconceptional event affecting the cleaving embryo); - embryopathy after implantation, in which the embryo implants but fails to establish a substantial placenta; - embryopathy after placentation, in which the placenta forms and there is some degree of fetal development, but the pregnancy is then rejected; and - fetal loss, where a normal embryo or fetus is expelled from the uterus late in pregnancy Chromosomal EmbryopathyReturn to Section Top The condition described as chromosomal embryopathy produces miscarriages in which the embryo does not develop properly because of a gross genetic error present from conception. (The embryo is pathological, hence the term embryopathy; in these cases the karyotype of the pregnancy tissue is not normal -- see Plate 8A) If the chromosomes are abnormally endowed at conception then often there'll be little or no chance of the pregnancy coming to term as a baby, especially if there are say 69 chromosomes instead of the normal number of 46 chromosomes (triploidy -- see Plate 8B). Likewise, if there is a chromosome missing then there will sooner or later be a catastrophic shortage of genes, so that development will generally stop very early (resulting in a menstrual miscarriage). Only a missing sex chromosome will permit, in some instances, development to the point of birth and beyond (this karyotype, 45,X, results in Turner syndrome). An extra chromosome is almost as harmful, with many trisomies causing menstrual or subclinical miscarriages, but with trisomy 13, 18 or 21 (Down syndrome, see Plate 8C), as well as trisomies of the sex chromosomes (e.g. 47,XXX; 47,XYY; and 47,XXY, or Klinefelter syndrome), sometimes not causing miscarriage, but instead developing to birth and resulting in a baby with a greater or lesser set of disabilities (generally soon fatal in the case of trisomy 13 and trisomy 18). Such aneuploidies can also arise after fertilization, during cleavage, producing a mixture of normal and abnormal cells, a condition called mosaicism. Abnormalities that would be lethal with all cells affected can be compatible with life if only a proportion of cells have abnormal chromosomes. Finally, a balanced translocation (see Plate 8D) is a well recognized cause of recurrent miscarriage, as bits of chromosome either miss out or are present in the embryo's cells to excess. The more common abnormal karyotypes that cause miscarriages are listed in Table 8.2. Because of the inevitability of miscarriage when the chromosome number is abnormal, knowing whether a pregnancy's karyotype is or was normal or abnormal is fundamental to interpreting a miscarriage and estimating the likelihood it will happen again. How is a karyotype done? Answer: with difficulty and a lot of work (see the box, Karyotyping step by step). We begin by getting some living tissue from the conception -- in the form of chorionic villi in early pregnancy, amniotic fluid cells later in pregnancy, or from either the placenta or the fetus's skin in the case of an immature delivery. In early miscarriages, trophoblast has to be teased free from the mother's decidua under a dissecting microscope, a difficult skill most pathology labs seem to have trouble with. (If decidual cells are inadvertently karyotyped the not-useful result 46,XX is obtained, representing the karyotype of the mother instead of the pregnancy). This tissue then needs to be set up in tissue culture, so that the cells continue to multiply in the laboratory. After this, the chromosomes are photographed through a microscope while the cells are dividing. Even with the help of a computer, one highly trained technician (a cytogeneticist) will be able to do no more than about 10 karyotypes per week. The karyotype is therefore a rather expensive test. Unfortunately, though, by the time a miscarriage is expelled, the trophoblast tissue might have degenerated too much for the cells to survive in tissue culture for karyotyping. If finding a reason for a particular miscarriage is important enough, your doctor might recommend a curettage or a chorionic villus sampling (CVS) as soon as practicable after a transvaginal ultrasound shows no surviving embryo. Whether miscarriage tissue has been available for karyotyping or not, recurrent miscarriages in the first trimester should mean the couple ought to have their karyotype checked to exclude a balanced translocation (in which as we saw above a piece of one chromosome has been translocated to another position). Such a translocation does no harm to the person concerned, because there's no overall gain or loss of genetic material, but when the chromosome pairs split up and move into eggs or sperm (discussed on WebPage 3), there'll be a shortage of genes for one egg or sperm, and an excess of genes for its sister egg or brother sperm (shown in Plate 8.1D); other eggs and sperm can be normal (the ones that receive the normal member of the pair). For more on balanced translocations of the chromosomes, see the box, Unbalancing translocations. Embryopathy Arising Before ImplantationReturn to Section Top Injuries endowed prior to conception or occurring between the time of conception and implantation that result in miscarriage we call preimplantational embryopathies. They can arise before conception in the egg or in the sperm, or after conception in the early embryo. Egg Cytoplasm ProblemsReturn to Sub-section Top The egg brings many resources to the post-conception partnership, particularly an endowment of proteins and protein-forming instructions (called messenger RNA) arising from the egg's DNA, or genome, well before ovulation and packing the egg's cytoplasm to the brim. One reason eggs are so large compared with sperm is because they are packed with these substances, which will be utilized by the daughter cells of the embryo for days or weeks into the pregnancy before, gradually, the embryo's own genome, with the contribution derived from the sperm, takes over. More than anything else, the quality of the cytoplasm will determine the early embryo's metabolism. Deficiencies of the egg cytoplasm can be in-built, with the egg faulty from the start, or they can be acquired, with an inherently good egg not developing to its potential. Although the details are not clear yet, defects of the egg cytoplasm might include abnormalities of the mitochondria (see the WebPage 7 box, How eggs might get their "use-by'' date: mishaps in the mitochondria). The embryo's mitochondria come entirely from the mother and, indeed, the new embryo will not make any new mitochondria until two weeks of development have occurred. So presumably an embryo that comes from an egg with too few mitochondria will run out of energy before it can implant properly (becoming a "blighted ovum"). Whether due to defective mitochondria or some other deficiency within the cytoplasm, sooner or later the effects of aging eggs will, for any woman continuing to put her reproductive ambitions to the test, result in blighted ovum-type miscarriages; as more time passes there will be sterility. This sequence, this life-transition, we've labeled the oopause. It's described more completely on WebPage 7. Unfortunately we do not have a reliable test yet for the quality of egg cytoplasm, so a diagnosis of oopause is a diagnosis we are left with when no other diagnostic leads look plausible (what doctors call a "diagnosis of exclusion"). At least as common, in programs of in vitro fertilization particularly, but also in many ovulation disorders accompanied by poor development of preovulatory follicles, is when the egg's cytoplasm is spoiled because ovulation occurs without enough exposure to follicle stimulating hormone. Either the amount or the duration of FSH can be suboptimal. The result will be partial follicular atresia and it is usually able to overcome with adequate ovulation induction. Some (probably most) of the miscarriages that we attribute to low levels of serum progesterone in the luteal phase, so-called luteal phase defects, are actually due to spoiling of the follicle, and hence the egg, in the follicular phase. Lastly, partial follicular atresia and poor eggs can result from certain genetic diseases that are important to reveal. Persisting with infertility or recurrent miscarriage treatment in this situation can risk a serious handicap in male offspring, called fragile X syndrome. This is the most common cause of serious mental deficieny in boys in the community. Their mothers, who are carriers of this sex-linked recessive condition, can present with fewer and more poorly responding follicles during IVF treatments. Tests for recurrent miscarriage where there is evidence of poor development of ovarian follicles should include a transvaginal ultrasound on about day 7 of the follicular phase (to look for development of follicles, see WebPage 7) and perhaps a PCR test for fragile X DNA in the woman. Sperm ProblemsReturn to Sub-section Top As well as an abnormal karyotype (see earlier), the sperm can bring at least two further kinds of problem to the post-conception partnership, namely DNA breaks and a defective sperm centriole. For an explanation, see the box, Miscarriage tests men should have .... Embryo ProblemsReturn to Sub-section Top It is nature's way that injuries sustained by an embryo are usually "all or nothing". Either the injury will be mortal, ending in embryonic death or miscarriage days or a week or two later, or it will be shrugged off by the exuberance embryos show in growing. Injuries suffered between the time of conception and implantation can include nutritional deficiencies and transport-timing problems within the fallopian tubes, as can happen with disease of the fallopian tube and, to some extent, fertilization and development in vitro (i.e. IVF). Recurrent miscarriage can occur with a one-sided hydrosalpinx (for more, see the WebPage 20 box, Hydrosalpinx, re-introducing a villain). A noxious external event, such as a high fever or an alcoholic binge (it probably needs to be a real bender) might also injure an embryo sufficiently to cause a later miscarriage. Apart from tubal disease (see WebPages 5 and 13), these causes are generally one-off and no special tests are useful. Note, though, that if an episode such as a fever occurs, and if the pregnancy continues, then the chance of a birth defect is just barely different from the generally expected incidence of birth abnormalities. Most people, in other words, will not choose to have an abortion just because such an event has been experienced. No doubt many genetic conditions can also cause the embryo to fail at this point. The embryo when it is ready to implant has already activated more than 1500 specific genes. If by chance both copies of one of these genes has an error, the deficiency could cause the embryo to fail and miscarriage to follow. This is even more so for the greater number of specific genes that are called to action after implantation. Embryopathy After ImplantationReturn to Section Top The possible reasons for an embryo or fetus to sustain injury after implantation are many. In general the later in fetal life such an injury occurs the more likely it will be to reveal itself as an abnormality at birth instead of as a miscarriage. We will look at this period in three stages. These categories are not completely distinct and causes applicable in one can also apply under the other headings. Nonetheless to bring some order to the field we'll consider the different causes just once, in the most typical stage at which they operate. As the hatched blastocyst successfully attaches to the endometrium, it releases a gas, nitric oxide, that signals the surface endometrium to dissolve under it, and then it squeezes through, embedding into the endometrial stroma. At least three things then need to be correct:
The Maternal Decidual ReactionReturn to Sub-section Top Unless the lining of the uterus is hospital to the penetrating blastocyst, the pregnancy has no hope of becoming established properly. One of the most important tests to do for investigating recurrent miscarriage, therefore, is to establish that there is a normal decidual reaction as seen on a premenstrual endometrial biopsy. We do the test in a month the woman is not trying for pregnancy (because we don't want inadvertently to disrupt an implantation, even if it would be a fluke to hit it). It's carried out with intravenous sedation and local anaesthetic, and takes just a few minutes in the day surgery. This tells us
But if the premenstrual biopsy is normal, and if tests for these molecules (as these tests are developed) are normal, we have little to go on. Maternal Recessive GenesReturn to Sub-section Top There are probably hundreds of maternal genes that are still needed to work correctly before the woman's side of the placenta develops properly. Before I categorize them, let's briefly consider some facts about how you inherit most of them. Production of correct proteins from the great majority of these genes is likely to depend on autosomal recessive inheritance. This means that you need just one normal allele of each gene for it to function properly and code for a correct protein (which is just as well, because there are so many of them that the chances are we all carry a mutation in one or a few of them). For most people most of the time, therefore, a sprinkling of mutations among these genes is just part of being human. Trouble, however, can come about in one of two ways. The first is if there is what could be called inbreeding, such as marrying your cousin. This makes it very much more likely that a bad allele will team up with a bad allele. If this has been going on for centuries you'll be safer, because harmful genes are likely to have been bred out over the generations, but if it's a recent thing in your family or town it dramatically increases the chance of homozygous inheritance of the faulty alleles and, because there's no normal allele, the protein will be abnormal and genetic disease will follow. The second way is more random, and there's nothing you can do about it. Just by chance, even if you and your partner have quite different family and genetic backgrounds, you might inherit a different bad allele from each parent but affecting the same gene. Genetically speaking this is a heterozygous state, but for all intents and purposes the effect will be that of homozygosity for a mutation. We call this compound heterozygosity. If the affected gene is needed for a critical function in the uterus then recurrent miscarriage will be inevitable: every single pregnancy will be affected. We believe this could account for at least some situations of recurrent miscarriage when there are more than five more-or-less similarly timed recurrent miscarriages with no intervening normal pregnancy and the karyotypes for the parents are normal. Until we know what the missing factor is and how we might replace it in the uterus, gestational surrogacy will be the only effective treatment (see WebPage 22 for the issues). Testing for these mutations is still very difficult, even though as a result of the Human Genome Project we know what the correct DNA sequence should be for almost all of them. Why is testing difficult? To begin with, there might be hundreds of proteins that could be the culprit, so we don't even know where to start looking. In many cases we hardly know yet what many of the proteins do. And of course we can't get to take samples where the implantation is going wrong before it's all too late and the pregnancy has been lost. Moreover even when we do think we know which protein it is, and which gene to look at, most genes are huge, way too big for a non-research lab to sequence the DNA and to find the mistake, at least for a realistic amount of money (though sequencing is fast becoming quicker and cheaper). Nonetheless we're making progress. Among faulty proteins that can be corrected with administered replacement proteins are rare errors in the blood coagulation proteins fibrinogen and factor XIII ("factor thirteen"), which are needed to provide the scaffolding for the newly invading trophoblast and therefore for construction of the placenta. At Sydney IVF we are also interested in leukemia inhibitory factor (LIF), interleukin 10 (IL-10), regeneration and tolerance factor (RTF), vascular endothelial growth factor (VEGF), complement, and sticky adhesion molecules called integrins (though the list is ever changing). Fetal GenesReturn to Sub-section Top If the number of molecules that must work normally for the embryo, as a blastocyst, to hatch, attach and penetrate into the endometrium is large, then the number needed to build a normal maternal-fetal interface ... the number needed to form the placenta ... is even bigger. Like the maternal molecules that need to be normal, many of these are also a inherited with autosomal recessive inheritance. But unlike the maternal molecules, the fetus will get one from each parent, and even if each parent is a (heterozygous) carrier, the way the dice will fall means that only one fetus in every four conceived will be homozygous recessive or compound heterozygous. Only one in four fetuses will miscarry because of the recessive inheritance of a bad protein. So while this might explain quite a number of isolated miscarriages, it will not cause long strings of recurrent miscarriage. More important, therefore, are the fetal genes that are not recessive ... genes that are dominant or partially so, capable of causing at least some mischief when just one faulty allele is inherited. Because then three out of four embryos a couple produces could have a tendency to miscarry. Many of these alleles are rather common in the population, so common that they can scarcely be called abnormal. We refer to them as polymorphisms. Examples include variations in the tissue-typing molecules HLA-G (for more, see the WebPage 4 box, ... shaking hands with HLA-G); a protein called TBP; the enzyme nitric oxide synthetase, which produces nitric oxide, a messenger molecule; and a molecule that blocks the action of immune cells, known as interleukin 1 receptor antagonist, as well as the genes that cause the thrombophilias, discussed in the next section. To work out what the risk is that the embryo or fetus inherits the polymorphism, in single or in double dosage, the prospective father should be tested as well as the prospective mother (see the box, Miscarriage tests men should have ... ). When we learn more about these genes we will be able to help avoid miscarriages by using IVF with preimplantation genetic diagnosis (a theme we explore on WebPage 9). Embryopathy After PlacentationReturn to Section Top The developing pregnancy needs the development of a quickly expanding blood supply through the wall of the uterus to the placenta. As explained on WebPage 4, much needs to go right, in what's sometimes a finely balanced state. We look here at tests probing the potential problems with - anatomical
constraints Anatomical ConstraintsReturn to Sub-section Top The blood flow to the fetus can become insufficient early in pregnancy if implantation is: (1) on a uterine septum (a wall partly dividing the uterus in two -- see WebPage 18); (2) over a uterine fibroid (see WebPage 17); (3) constrained by intrauterine adhesions or endometrial atrophy (also on WebPage 17). These causes are best looked for with a hysterosalpingogram, a transvaginal ultrasound of the uterus and/or a hysteroscopy (investigations described on WebPage 5). We will look at anatomical (uterine) constraints more later in pregnancy, below. Medical ConstraintsReturn to Sub-section Top An overactive thyroid gland (thyrotoxicosis) can cause miscarriages, perhaps because it increases the rate of metabolism in the body generally and progesterone, needed for maintaining pregnancy, is got rid of too quickly. This is looked for with thyroid function tests, which comprise assays in blood of thyroxine and thyroid stimulating hormone (TSH). (The miscarriage shown in Figure 8.1c resulted from an overactive thyroid gland: the embryo is almost normal for its stage of development.) Textbooks list diabetes as a cause of miscarriage, and women with recurrent miscarriages have in the past undergone formal tests to exclude it. This is unnecessary. Diabetes causes miscarriages only when it needs insulin for treatment and it's in poor control. The diagnosis, for these people, will have been made already. If in doubt, it's simple to test for sugar in the blood, with a plasma glucose level. Any severe upset to the mother's health or metabolism can affect the fetus. But these upsets will generally be very obvious already. Failure of the kidneys, causing uremia, is one example, and is checked with a serum urea and creatinine. One of the more subtle, though rare, metabolic causes of miscarriage is Wilson's disease, in which there are high levels of copper in the serum (measured as serum copper), though usually in association with abnormal tests of liver function (and with a yellow ring visible within the iris of the eye). Immune Tolerance or RejectionReturn to Sub-section Top Remember that, from an immune perspective, the fetus is a foreigner. The mother's immune system must learn to tolerate the fetus. If her immune system is too reactive, the mother can reject the fetus -- first by making antibodies and immune cells to it and then through miscarriage. A lot is known about these events, though more is still to be learned. We saw, on WebPage 4, that the endometrium needs NK cells to recognize the implanting pregnancy ... NK cells that are part of the "innate" immune system. The NK cells normally resident in the uterus are characterized as CD56-BRIGHT, in contrast with NK cells circulating in the blood (characterized as CD56-DIM, but also as being CD16-positive and CD57-positive). These NK cells are more likely to turn n the fetus. They have been thought to circulate in higher numbers in women who later turn out to miscarry. These circulating or "peripheral" NK cells should not be present to any great extent in the endometrium of normal women, but they are found there in some women who go on to miscarry. At Sydney IVF we test for these CD57-positive cells, as well as for various T cells, in the blood and in the premenstrual endometrial biopsy. There is one blood-group antibody (agglutinin) that causes recurrent miscarriages in families that have it -- the rare anti-TjA antibody. Other agglutinins are looked for with a blood group and antibody screen. Patients with the disorder known as systemic lupus erythematosus (SLE) form antibodies against their own tissues. People without this disease can also have antibodies against some of their own tissues detectable in the blood, often with no indication of disease. The antibody, or the group of antibodies, most likely to cause miscarriages is known in several different guises as the lupus anticoagulant or lupus inhibitor (it slightly inhibits blood coagulation), and as antiphospholipid antibody or anticardiolipin antibody. Studies have suggested that these antibodies
The tests we order to see if such antibodies can be implicated are the lupus anticoagulant and the serum anticardiolipin antibody ; these tests are important tests to do, because treatment is available with aspirin, heparin and corticosteroid drugs. Blood levels of antinuclear antibody (ANA) are often increased in women with recurrent miscarriages and in patients with SLE, but unless there are other antibodies there in very high levels it will be unclear whether ANA is the cause or the result of the miscarriages, or whether the ANA is completely unrelated. One of the most tantalizing hints about occasional primarily immunological causes for recurrent miscarriages has come from the discovery that a proportion of women can be treated by being immunized to their partner's (or to a stranger's) white blood cells (the details are on Webpage 9). The ThrombophiliasReturn to Sub-section Top Just as the normal immune system, particularly the "innate" immune system, is poised between tolerance and rejection, so also is the next cog in the rejection process, the blood coagulation system. A number of polymorphisms cause the blood to clot more readily, a phenomenon called thrombophilia. This can be an advantage if you're having a baby in the bush, out in the wild, a long way from a blood transfusion service, but in the trigger-happy state of imminent miscarriage it can be the final straw that puts a blood clot between the trophoblast away from the decidua. The clotting factor alleles that can be behind an excessive tendency to miscarry, and for which DNA PCR tests are available, are Factor V Leiden (the G1691A allele), prothrombin G20210A, and the MTHFR C677T. Factor V Leiden is present in about 3% of Caucasians; it is almost never found in blacks and Asians. It is mainly implicated in late miscarriage and stillbirth, but a double dose of the gene in the fetus (which can happen if both parents are carriers) might cause circulation failure in the placenta in earlier pregnancy. MTHFR (which stands for methylene tetrahydrofolate reductase) is responsible for turning folic acid into metabolites that have several critical roles in the developing fetus and in the mother. The C677T allele is a very common variant, present in more than 40% of Hispanics and Italians, about 35% of other Caucasians, and less than 10% of blacks. In the mother the C677T MTHFR allele predisposes the fetus to neural tube defects as well as to miscarriage. This is the major reason why folic acid supplements are so important for pregnant women. If you have the allele, the dose of folic acid you should take is a minimum of 5 mg per day (which is 10-times the previously recommended dose for pregnant women). The C677T allele in the father predisposes both to oligospermia (see WebPage 10) and to an increased risk of heart disease and stroke (which is why in surveys the gene becomes less common among older groups of men!). Men with the allele also benefit from high dose supplements of folic acid. Food IntoleranceReturn to Sub-section Top Another way the immune system can be tweaked to reject the fetus, it seems, is as collateral damage when an immune reaction is induced by certain foods, particular a sensitivity to gluten, found in celiac disease. Difficulties getting pregnant or miscarrying repeatedly can be the first symptoms of celiac disease, a disturbance of food absorption caused by an immune-based flattening of the surface folds within the intestine, and often occurring before symptoms of gastrointestinal disturbance. The diagnosis can be screened for using blood tests (serum antigliadin antibodies and serum tissue transglutaminase antibodies). If these are positive it is customary to confirm the presence of celiac disease by performing a biopsy of the lining of the small intestine. Fetal LossReturn to Section Top In practice, a distinction between embryopathy arising after implantation and the loss of a completely normal fetus is not always clear. But it helps to understand the things that can go wrong to an otherwise normally developing fetus and what tests can be done. The categories are cervical incompetence, uterine growth restraints and premature delivery from intrauterine infection. Cervical Incompetence The most common structural failure of the uterus in containing the pregnancy is a prematurely opening (or dilating) cervix, called cervical incompetence. It requires careful and repeated vaginal examinations during pregnancy to exclude it as an imminent cause of miscarriage. Sometimes a shortened, possibly incompetent cervix is seen on transvaginal ultrasound of a pregnancy. Treatment of an incompetent cervix involves placing a ligature or suture in the cervix (a cervical ligature, discussed further on WebPage 9), usually at about 12 weeks' gestation so that the suture won't get in the way of an unrelated early miscarriage, for example from a chromosomal cause. If left untreated, miscarriages due to cervical incompetence tend to occur earlier and earlier (though never before about 14 weeks). Cervical incompetence might be more common among infertility patients because of the number of procedures they've had done through the cervix that could have weakened it. Most gynecologists will be on the lookout for cervical incompetence in patients who have spent years trying to get pregnant. Even if the chance (or risk) is low, the penalty for missing the diagnosis while it's still treatable (the hazard) is severe. Placing a suture or ligature in the cervix for an incompetent cervix is usually not a difficult operation, but if the earlier miscarriages were more of the immature labor variety than true cervical incompetence, there's a risk that the irritating presence of the suture in the cervix, perhaps inevitably with some bacterial organisms, will make the situation worse instead of better. This is why a rather definite diagnosis of cervical incompetence should be made before a decision to place a suture is reached. At the end of the day it's a matter of judgement and, in hindsight, it would be unfair to expect your obstetrician always to have been correct. Uterine Growth ConstraintsReturn to Sub-section Top Abnormal constraint on the growing gestation can lead to miscarriage. Miscarriages can thus result from abnormalities of the shape of the uterus, abnormalities that can either result from disease of the uterus (see WebPage 17) or have been present from birth (see WebPage 18). Miscarriages due to a wall dividing the cavity of the uterus into two (a uterine septum) and miscarriages due to a fibroid, or benign tumor of the uterus, encroaching into the cavity (a submucous fibroid) typically happen in the first three months -- perhaps, but not always, after a fetal heart has been detected (and they are therefore of the postimplantational embryopathy kind). Miscarriages that are due to other birth abnormalities of the uterus, such as a bicornuate uterus or a unicornuate uterus (see WebPage 18), are typically of the premature labor and "fetal loss" variety. Sometimes the run of miscarriages with these sort of abnormal uteruses gets later and later into the pregnancy each time, the uterus adapting more and more to accommodate the pregnancy, and a viable pregnancy can be expected without special treatment being necessary. These abnormalities are looked for before pregnancy with a hysterosalpingogram or by hysteroscopy. Treatment can be directed at the underlying abnormality (see WebPages 17 and 18) or at inhibiting contractions of the uterus that would expel the fetus (see WebPage 9). Constraint on the growing pregnancy can also come about if the gestation happens to implant in the outer angle of the uterine cavity, very close to where the fallopian tube enters it, namely an angular pregnancy. If they do not miscarry early, angular pregnancies often settle into the cavity proper of the uterus as they grow and cause comparatively little further trouble (except perhaps for an increase in the likelihood of experiencing retention of the placenta after the baby is born). I discuss the diagnosis of angular pregnancy in relation to ectopic pregnancy in WebPage 14. Like an ectopic tubal interstitial pregnancy, an angular pregnancy can sometimes rupture the uterus, placing the mother in great danger. Intrauterine InfectionReturn to Sub-section Top An infection of the fetus leading to very early labor can happen in three ways: (1) the infection can have been there from the start, within the endometrial cavity, in the form of endometritis; (2) it can ascend through the cervix when the pregnancy is being established; (3) it can get to the fetus by way of the blood stream, through the placenta; or (4) it can get there by way of a cervical ligature (posing a dilemma if the diagnosis of cervical incompetence is less than certain). The most obviously infective or inflammatory cause of miscarriage is when pregnancy occurs despite the use of an intrauterine contraceptive device, or IUD. Miscarriage is more common if the IUD is left in place than if it's removed as soon as pregnancy is confirmed and before the IUD's tail disappears into the uterus. If the IUD is left in place, not all pregnancies miscarry (a majority won't), but those that do can do so at any stage of gestation. Endometritis of other infective cause before conception can cause miscarriages in the same way, irritating the fetal membranes and causing premature contractions of the uterus. Once the pregnancy membranes have sealed off the uterine cavity from outside, in the middle three months (or midtrimester) it's much less common for infective organisms to gain entry. But organisms that got in earlier can gain hold, and the more they proliferate, and the more the immune system of the fetus matures, inflammation sooner or later starts, precipitating contractions and (very) premature delivery of the fetus. This is the mechanism behind the majority of "labor-like" miscarriages. The bacteria involved tend to be the same as those that are often found in the vagina between and during pregnancy, especially if they have been overwhelming the vagina's normal acidity. The most prominent organisms that regularly reach a fetus by the bloodstream through the placenta include certain viruses (rubella -- the German measles virus; the attenuated rubella virus used for immunization; cytomegalovirus; herpes zoster -- the chicken pox virus; herpes simplex; and, although not considered to be a cause of miscarriages, HIV, which causes congenital AIDS). Certain bacteria (tuberculosis; syphilis; brucellosis) and certain parasites (malaria; toxoplasmosis) also cross the placenta to infect the fetus. Because blood-borne infections are typically followed by immunity, it's rare for these infections to cause miscarriages repeatedly. Syphilis is an exception. Latent syphilis causes no symptoms but is nonetheless chronic and active, so a serological test for syphilis is a traditional and still standard blood test done in pregnancy and should especially be done for recurrent miscarriages that take place in the second trimester. Some of these infections do cause birth defects (rubella and syphilis being among the best known). If the infections are suspected clinically then prior exposure (and probable immunity) can be determined by measuring IgG antibodies in the blood, whereas a recent infection causes a distinguishable transient rise of IgM antibodies. How you should act on the information of a recent infection during early pregnancy depends on a number of things: the stage of the pregnancy; the likely involvement of the fetus; the circumstances of the conception; and the risk, not just of transmission of the organism to the fetus, but also of the likely severity of fetal damage. We take the treatment of these
conditions further on WebPage 9.
Copyright © Robert Jansen, W.H.Freeman and Scientific American Books (New York) and Allen & Unwin (Sydney) |