When Nancy Ross, 30, of Potomac was pregnant for the first time, she and her husband did what excited expectant parents usually do. They shopped for baby furniture, planned colors for the nursery, haggled over names. "My husband even went out and bought baby food," she said. "I remember unpacking the groceries and finding the jars, and he grinned and said, 'Just practicing.' "
The couple was devastated when Ross miscarried during her eighth week of pregnancy. During the next 13 months, Ross, then 26, had three more miscarriages.
"People would say to me, 'You're young, you can try again,' " she recalled. "But to my warped way of thinking, I felt that my age just gave me more years to fail."
Pregnancy is such a precarious condition that the mystery is not so much why some women miscarry, but why so many don't. The path from conception to implantation to delivery is fraught with peril; any number of things can go wrong, which is why at least one in every four pregnancies ends in a miscarriage.
The embryo may stop developing normally, usually because it started out with the wrong number or arrangement of chromosomes. The mother's body may reject it, mistakenly seeing the embryo as a foreign invader. The uterus itself may be unable to sustain a pregnancy: It may be anatomically misshapen, for instance, or scarred by fibroid tumors, or full of infectious microorganisms, or hampered by blood clots that clog the pathway that nourishes the fetus.
New research indicates that as many as half of all previously unexplained miscarriages are caused by conditions that until recently were undiagnosed. The two most widely studied are an immunological incompatibility between mother and father and a subtle blood-clotting defect in the mother. But even though some medical centers are reporting success rates for some of these problems that approach 80 percent, the explanation for chronic miscarriage remains, for many women, a frustrating mystery.
As one 35-year-old Northern Virginia woman who miscarried four times in one year put it, "Within nine months, I went from thinking I was normal and was going to have children to thinking I was never going to have natural children. And each miscarriage was just another nail in the coffin."
Exact figures about how often miscarriages occur are hard to come by. Current estimates are that 25 percent of women will be aware of having at least one miscarriage during their childbearing years. Another 10 to 20 percent can expect to have 'silent' miscarriages that occur even before they know they are pregnant. And about one in 300 will become a "chronic miscarrier," defined as a woman who has lost at least three pregnancies.
As women wait longer to start their families, fertility experts say, it is likely that the miscarriage rate will rise. After age 35, the rate of miscarriages increases sharply. According to figures compiled by the Columbia-Presbyterian Medical Center in New York, the miscarriage rate hovers at around 10 percent for women in their teens and twenties, but increases to about 18 percent by the late thirties. For women in their early forties, the miscarriage rate is 34 percent; by age 45, it is 53 percent.
But the good news is this: Of the women who have just one miscarriage, 80 percent have no problems with their next pregnancy. And even among chronic miscarriers who receive no special medical treatment, an estimated 40 to 60 percent will eventually have a healthy baby.
With aggressive therapy, the odds may be even better. Page Faulk, an immunologist at the Center for Reproductive and Transplantation Immunology at the Methodist Hospital of Indianapolis, says he and his colleagues have their best success with chronic miscarriers who have never had a successful pregnancy. These women are believed to have problems different from those who suffer miscarriages after the birth of one or more children. By using immune therapy, Faulk says, international experience with 1,500 women has led to a success rate of at least 80 percent. Identifying the Problem
When a woman miscarries once, her obstetrician is likely to tell her to just try again. Even after the second miscarriage, obstetricians have traditionally waited to see whether a pattern emerged. "Chronic miscarriers" were not labeled as such until after they lost three pregnancies.
But as more women wait until their middle to late thirties to start trying to become pregnant, doctors are being forced to look for an explanation sooner than they once did. "For a woman in her late thirties, I start working her up after she has had two miscarriages," said Paul Gindoff, an infertility expert and assistant professor of obstetrics and gynecology at the George Washington University School of Medicine. "There's no point in wasting time waiting."
Sherry Zuckerman of Silver Spring had her second miscarriage just weeks before her 30th birthday. "Not only was there the awful physical and emotional pain," she said, "but my goal had been to have a family by the age of 30." Instead, Zuckerman spent her thirties undergoing high-technology infertility treatment that included implantation of frozen embryos and in-vitro fertilization.
"I'm the youngest of five children, and my mission in life has been to have a family," she said. "I always wanted at least three or four children." Zuckerman, a federal employee, estimates she spent about $50,000 on high-technology infertility treatments, most of it covered by her husband's insurance.
What troubled her was not the cost but the enormous frustration of losing the pregnancy time after time. "After a while," she said, "having a family became my ultimate goal."
Last August, by the time she turned 37, she had suffered a total of six miscarriages, all before the third month of pregnancy. "The physical pain of a miscarriage is as bad as what people tell me labor is like," she said. "That's like adding insult to injury."
Women like Zuckerman and Ross often receive no explanation for their heartache. A thorough miscarriage workup, which can cost $1,000 or more, turns up a definitive answer only about 50 percent of the time.
But that uncertainty is not a deterrent for many women. "Women really don't seem to care how many tests you do," said Jonathan Scher, assistant clinical professor of obstetrics and gynecology at Mt. Sinai Medical Center in New York. "They just want to know that it's not something bizarre and irreparable causing the miscarriages."
When a cause for repeated early miscarriages, defined as those between the second and third months of pregnancy, can be found, it usually falls into one of the following categories:
Infection. An infection early in the pregnancy can be transmitted to the embryo and stop it from developing. In addition, a chronic pelvic infection -- caused by organisms such as chlamydia, a sexually transmitted disease that public health officials say has reached epidemic proportions, may be present without symptoms, making miscarriage more likely because of scarring in the fallopian tubes.
The organisms responsible for chronic uterine infection usually respond well to antibiotics. They can be detected through a culture of the cervix, a simple procedure that costs about $100.
Hormonal imbalance. Subtle aberrations in the delicate hormonal mix of pregnancy can cause as many as 25 to 30 percent of miscarriages in women over 35, a time when the ovaries are producing less estrogen and less of the pregnancy hormone progesterone. The most common hormonal problem diagnosed after miscarriage is luteal phase defect, a deficiency of progesterone late in the menstrual cycle that prevents a fertilized egg from implanting properly. Among the others: hyperprolactinemia, the production of too much of the female hormone prolactin, and an underactive or overactive thyroid.
To detect a hormonal problem, the first step is a blood test. In addition, many women require an endometrial biopsy, a microscopic inspection of the uterine lining late in the menstrual cycle. Cost of the biopsy: about $250.
If a problem is detected, the next step is to replace what's missing or remove what's in excess. This may involve taking thyroid hormone for hypothyroidism, an underactive thyroid; bromocriptine, a drug that inhibits the secretion of the pituitary hormone prolactin for hyperprolactinemia, or Clomid, a common fertility drug, plus progesterone suppositories for luteal phase defect.
Some doctors even prescribe progesterone suppositories in the absence of a detectable deficiency, just in case. "It causes no harm and can be satisfying to the patient, almost a placebo effect," said Gindoff. "It can be tough to have a few miscarriages and be told there's nothing wrong with you."
General medical disorders. Very rarely, chronic miscarriage is the first symptom of a disease elsewhere in the body, such as diabetes or lupus, an autoimmune disorder in which the body attacks its own connective tissue. Lupus can be diagnosed through a battery of sophisticated -- and expensive -- tests currently available only at large medical centers. Cost: more than $300.
Structural defects. Some miscarriages can be traced to an abnormality in the shape or structure of the uterus. A structural defect can be seen on a hysterosalpingogram, an X-ray of the uterus, or a hysteroscope, a look into the uterus through a flexible fiber-optic tube. Both tests cost about $250.
The most common structural flaw is fibroids, benign growths on the uterine wall that can prevent the embryo from implanting. Occasionally, the woman's uterus is split in two by a wall-like growth called a septum. Either of these can be repaired surgically. Other anatomical abnormalities of the uterus, though, cannot be corrected, such as many of those seen in women whose mothers took the drug diethylstilbestrol (DES) when they were pregnant.
Chromosomal abnormalities. Sometimes a fertilized egg ends up with one chromosome more or less than the normal human complement of 46; sometimes the chromosomes are in the wrong spot on the gene. Either problem can stem from simple bad luck, or it can be attributed to advanced maternal age or to a genetic flaw in either parent.
The most familiar chromosomal defects -- such as Down syndrome, which causes mental retardation -- are those that allow an embryo to develop physically. But other defects are less familiar because they are, as the scientists put it, "incompatible with life." They may account for a large proportion of miscarriages, many of them so early that they occur even before a woman has missed a menstrual period.
For a chronic miscarrier, a chromosomal analysis or karotype test of her, her husband and the miscarried embyro can be used as guidance in planning subsequent pregnancies. Scher usually delays administering a karyotype test until all other causes have been eliminated, because it can be expensive -- as much as $800 altogether -- and because it turns up a problem less than 5 percent of the time. When There's No Explanation
What about the other 50 percent of chronic miscarriers, for whom no treatable cause is found? One emerging school of thought is that the bulk of them are in fact the result of an immunological mismatch between mother and father that causes the mother's body to reject the fetus. Another is that many are caused by a subtle blood-clotting problem in the mother that chokes off the embryo's source of nourishment. Treatments for both conditions are now being investigated, and some early reports of success rates approach 80 percent.
In addition, there is the great unknown in miscarriage: the effect of the environment. Scientists are trying, with limited success, to pinpoint which of the particular toxins now under suspicion -- among them cigarette smoke, pesticides, cleaning solvents, radiation from video-display terminals, even electric blankets -- can be shown conclusively to endanger a pregnancy.
The immunological theory. "Human pregnancy is a type of transplant," says Faulk of Indianapolis's Methodist Hospital. Ordinarily, the mother's immune system recognizes the pre-embryo -- still just a tiny sac of cells called a blastocyst -- because the antigens, or proteins, surrounding it read "foreign." The mother then mounts a protective immune response in the form of "suppressor" immune cells and "blocking" antibodies to keep the body from rejecting the baby.
But, for chronic miscarriers, some doctors theorize, the mother's and father's antigens are so similar that the blastocyst is surrounded by antigens that do not register as "foreign." In this case, the embryo is not protected by the suppressor cells. Instead, it becomes a mere irritant in the uterus, which expels it.
"Without the blocking and suppressor cells protecting the blastocyst, the 'killer' immune cells just move it right out," says Faulk. "If you put a piece of charcoal in the uterus, they'd do the same thing."
Immunologists have managed to trick the mother's immune system into activating its protective response by giving her injections -- before pregnancy and at intervals throughout -- with foreign white blood cells, taken from the father or from a pool of donated blood. Faulk and his colleague Carolyn Coulam are now experimenting with capsules containing plasma from donated semen, inserted into the mother's vagina, as a less expensive alternative to shots.
In addition, the Indiana scientists are experimenting with intravenous gamma globlin, a blood component, in five women, in an attempt to boost production of an immune system compound known as anti-idiotypic antibody. Women who produce this antibody are less likely to reject their fetuses.
The blood clot theory. Another significant proportion of chronic miscarriages are now thought to arise from a blood-clotting disorder in the mother. Scher of Mt. Sinai says this condition may account for as many as half of all previously unexplained miscarriages.
Clotting problems are diagnosed by blood tests for certain antibodies associated with blood-clotting components. These can clog blood-vessel walls, including the walls of the uterine artery, and cut off nourishment to the developing placenta.
Scher and his colleague Susan Cowchock at the Jefferson Medical College in Philadelphia have experimented with two drugs to treat this disorder: baby aspirin, which thins the blood, and either prednisone, a steroid, or heparin, an anti-clotting medication. According to Scher, preliminary results indicate that aspirin plus heparin appears to have a high success rate in the approximately 65 women treated so far.
The environmental theory. The clearest connection between miscarriage and an environmental agent is with cigarette smoking. Smokers run about twice the risk of miscarriage as nonsmokers, says Donald R. Mattison, professor of obstetrics/gynecology and interdisciplinary toxicology at the University of Arkansas Medical School in Little Rock. One possible explanation: smokers produce less-than-normal amounts of progesterone, the hormone required to maintain pregnancy in its early stages.
Among the environmental toxins with a suspected impact on miscarriage are ethylene oxide, a sterilizing agent used in hospitals; benzene, a dry-cleaning solvent; electromagnetic fields from power lines, and exposure to the low-level radiation emitted by video-display terminals. But it has been hard to show a clear connection with any of them. "Clusters" of miscarriages have been investigated among rural residents exposed to certain herbicides, for instance, or in the semiconductor industry or in offices that use VDT's, including the USA Today newsroom in Arlington. But, as Mattison noted, "In just about every case in which investigators have gone in, it's been difficult to identify any relationship. You need to ask what is the likelihood that this cluster represents more than a chance ocurrence of a not uncommon biological event."
For clusters in which a biological explanation can at least be theorized, some observers are worried even in the absence of solid epidemiological evidence. In the early 1980s, for instance, one report found higher miscarriage rates for fetuses conceived under electric blankets or on heated waterbeds.
"Our findings were very preliminary," said Nancy Wertheimer, the Boulder, Colo., epidemiologist who conducted the electric-blanket study. "But if a woman is worried about her fertility, she might want to use the appliance only to pre-heat the bed, and then unplug it before she gets in."
Despite all the theories and promising research, chronic miscarriage remains a stubborn and uniquely frustrating problem, for obstetricians as well as the women they treat. It is a variant of infertility that may well be harder to bear than inability to conceive -- because with each new conception, there is another heartache and an overwhelming sense of failure.
The 35-year-old Northern Virginia woman recalls the panic that gripped her after her third miscarriage, when she was told her problem would be defined as chronic. "Two weeks after it happened, I just broke down one afternoon and couldn't stop crying," she said. "It was not just the loss of that particular baby. By the third time, it's like the loss of the potential ever to have children." Recently divorced, she said her stomach knots when she thinks about trying to have a baby. "If I got married again and got pregnant, I just know I would be a basket case," she said.
Most women with successive miscarriages seem to dread the news that they are pregnant, because it seems a harbinger of another miscarriage, not a birth. But for Zuckerman, pregnancy was always a victory. "I guess my whole approach has been distorted because of going through six years of infertility treatment," she said. "You don't even think about the end product. Just getting pregnant is a success."
Zuckerman adopted a baby girl last year. Six years of infertility treatment was her emotional limit, she said; she and her husband had promised themselves that the fourth in-vitro fertilization treatment would be their last. But one week after her daughter arrived, Zuckerman had her sixth miscarriage. She hadn't even known she was pregnant.
"We do want another child," she said, "but we've decided to hold off on extraordinary measures like IVF for a year or so. I don't look forward to getting involved again in high-tech treatment, but time has a way of making the edges fuzzy."
Nancy Ross had a different experience. When she got pregnant for the fifth time, she took a leave from her job as an optometrist and stayed in bed for the entire first trimester. Doing so was her idea, but her fertility specialist didn't disagree. This enabled her to get past the magic eight-week point -- by which time her four previous miscarriages had occurred -- but still she was tense.
"I wouldn't let myself have fun being pregnant, wouldn't go into a maternity shop, wouldn't let anyone give me a baby shower," she said. "I was just too scared that something terrible would happen."
Nothing did. Sixteen months ago, Ross gave birth to a healthy baby girl. "My husband and I call her our miracle baby," Ross said. "She doesn't take the place of the other babies I lost. But we worked so hard for her that, in our eyes, she can do no wrong." Resources
MIS (Miscarriage, Infant Death, and Stillbirth), a support group for parents who have experienced a pregnancy or neonatal loss. Meetings are held throughout the Washington area; call 460-6222 for more information.