For years, Chani Gali was unable to conceive. She had been to private doctors, various medical centers, and numerous cycles of in-vitro fertilization treatments, all without success. And no one could tell her what the problem was. "I suffered some crushing disappointments," she says. "And I didn't take breaks between treatments, I did them one after the other, and each failure immediately increased my motivation to keep going. After each failure, a doctor would suggest that I try through egg donation, which to me was foolishness. I knew deep down that I didn't need that, and that the doctors were only offering it as a solution in order to quiet their
conscience."
And then Kaplan Hospital offered her the chance to participate in an experiment. In the late 1990s, Prof. Nava Dekel of the Weizmann Institute, an expert on women?s fertility, was performing a routine experiment on something that interested her: the connexin43 protein, which she has been studying since 1988.
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"It's a protein that's involved in communication between cells," she says. "I'm searching for its expression in the uterus during the ovulatory cycle. We thought that perhaps through its expression, or lack of expression, we would be able to understand the interaction between the embryo and the womb, and in particular, to see whether it affects the implantation of the embryo in the womb. There are two critical stages in fertility treatments: embryo conception from an egg and sperm, where the success rate reaches 100 percent, and embryo transfer to the womb, where the success rate plunges to just 15 percent."
The goal of the experiment was to examine the endometrium in women who had failed time after time to get pregnant, women who had never been able to have an embryo successfully implanted in their womb. Dekel went to the neighboring hospital in Rehovot and asked for volunteers who were being treated in the department of Dr. Amihai Barash, director of the hospital?s in-vitro fertilization ?(IVF) unit. A dozen women agreed to take part in the experiment, which required taking a biopsy sample from their endometrium, using an instrument called a pipelle. Dekel took the samples back to her lab at the Weizmann Institute and began to analyze them.
Before she had finished all of her analyses, Dekel received some surprising news from Kaplan: 11 of the 12 women who had taken part in the experiment had become pregnant and given birth to healthy babies. "We were stunned," says Prof. Dekel. "We didn't understand what had happened. In order to be more certain, we requested permission from the Helsinki Committee (which approves medical experiments in Israel?) and then appealed to all the women who were being treated at Kaplan at that time. Out of a group of 134 women, 45 volunteered, and the other 89 served as a control group."
Gali, 35, a school secretary from Ashdod, was one of the volunteers. An endometrial biopsy was done on each, and the subsequent rate of pregnancies and births was double that of the control group. In 27.7 percent of the women in the trial group, the embryo transfer was successful, while this was the case for just 14.2 percent of the control group. And 48.9 percent of those in the trial group in whom a successful embryo transfer was achieved eventually went home with a baby, compared to just 22.5 percent from the control group. The study?s findings received a scientific seal of approval when they were published in 2003 in the U.S.-based journal Fertility and Sterility.
Gali was among the lucky women who became pregnant immediately during the first experiment. Her eldest daughter Odaya is now six years old. Two years later, Shira was born, by the same method, followed by Rafael, now eight months old.
Trying and crying
Iris Bar-Ze'ev was physically and emotionally exhausted when she first made the trip from her home in Kiryat Haim to Kaplan Hospital in Rehovot. The IVF unit at Kaplan was her last hope. For seven years, Bar-Ze'ev had been trying to get pregnant, and time after time, had been informed over the telephone that "the transfer didn't work." She was married 10 years ago and soon afterward became pregnant, but the pregnancy ended in the eighth month.
"I had a lot of bleeding and the doctor told me there was no point in continuing the pregnancy," she recounts. "He gave me a pill that caused contractions for 24 hours, and then a spontaneous abortion." Since then, all her efforts to become pregnant again had failed. She endured painful invasive procedures and in-vitro fertilization at various
centers in Israel, all to no avail.
"The doctor gave me an ultrasound and said that everything was normal," she recalls, "and we tried again and didn't get anywhere. They gave me an iodine test, which is a very painful exam - I?ve heard of someone who fainted from it. They insert iodine into the womb so they can see if there are any blockages, and with me they found that the oviduct in one ovary was abnormal, but they said it was nothing serious. We kept trying and nothing happened. We went to another doctor, who said that we shouldn't have any problem. I went through more tests and my husband Yaron went through a bunch of tests, too, and in order to improve the odds, we did a sperm enhancement. And for a year and a half nothing happened.
"I started to cry because I was in such despair. My friends had all gotten pregnant and had kids, and I was trying every month and nothing worked. At that point I just sat down in the doctor's office in the clinic and burst into tears. He said that everything would be all right, but nothing was all right. And that was the easy part.?
The hard part was the next stage, the IVF treatments. Bar-Ze?ev tried various fertility experts ("Eilat was about the only place we didn?t get to") and paid each one thousands of shekels out of her own pocket. To this day, she has frozen embryos stored at several centers in the country. Before going to Rehovot, she had been through 13 egg extractions and about 30 implantation attempts, with nothing to show for it.
She went after her goal with great persistence, and with hardly any break between fertility treatments, "aside from one time when I took a break of a few months. People told me, 'Relax, go abroad, maybe it?s psychological,' but that didn?t help either. I knew that it wasn't psychological."
Patients like Ben-Ze'ev are in almost daily contact with their fertility center. The woman takes a daily regimen of fertility drugs (usually via injection?) to induce ovulation and increase the number of eggs that will be extracted from the ovaries. When blood tests and an ultrasound show that ovulation is imminent and sufficiently large follicles (containing the eggs?) are observed in the ovaries, then it is time to proceed with the extraction. This procedure is usually done under sedation. Afterward, in the laboratory, the eggs are fertilized with sperm (sometimes by means of a direct injection of a single cell into the egg) and develop there. In two to five days, once the embryos are produced, they are returned directly to the womb. Two weeks later, another blood test is done to confirm that the pregnancy has taken hold. If not, it's back to the starting point.
"There are many breakdown points along the way," says Bar-Ze'ev. "A lot of couples don't make it. Basically, you're turned into a machine. Everything is done according to plan and in accordance with calculations. There?s no pleasure in sex, and you can forget about spontaneity. A lot of couples can?t handle it. I would cry all the time, but I found out that, fortunately, our marriage is very strong."
Iris and her husband began to think about looking for a surrogate. "We were ready to go to the ends of the earth to have a child," she says. "We started the process, and we're talking thousands of dollars here, but at the last minute we thought about it again and asked ourselves if we had really tried everything yet and were ready to give up. And on second thought, we decided to give it a few more tries."
Doing a pipelle
Four years ago, Iris Bar-Ze'ev happened to hear about Dr. Amihai Barash, director of Kaplan's IVF unit. "There were no articles about him in the papers. It was just word of mouth. I heard about him from a friend of my aunt who had tried to get pregnant for 15 years and was never successful until she went to him. He examined my uterus and said that my endometrial lining was too thin and that he wanted to try to thicken it up."
Dr. Barash says that in the field of fertility, the problem of embryo transfer is of foremost concern throughout the world. "Sperm problems are solved with micro-manipulations in the lab. We've come a very long way in fertilizing embryos, in stimulating ovaries, in producing eggs, in inserting sperm into eggs. But we haven't made much progress when it comes to embryo transfer."
This failure has also spawned an ethical dilemma regarding the multiplicity of embryos: In each treatment cycle, a large number of embryos are usually returned to the woman?s womb, in the hope that at least one of them will take hold. In many cases, when four or five embryos do take, the woman is advised to undergo a process to thin them out. Not all women agree to this.
"To my mind, multiple embryos are a therapeutic failure," says Dr. Barash. "In the textbooks, twins and triplets appear in the pathology chapter, in the chapters about illness, in other words - because of premature births, immature fetuses, the hardship for families in raising these children, and health systems that are collapsing because of the huge costs that have grown exponentially since the establishment of IVF units. Keeping a premature baby in a neonatal unit costs around NIS 250,000 a month, and I'm not even talking about the implications of raising damaged children."
Barash was the first in Israel to adopt the biopsy method, which was discovered entirely by chance, as a routine aspect of treatment in his department. The method is known as pipelle, after the instrument used to carry it out. "It's a simple pipette that was originally designed for taking endometrial biopsy samples, and it's practically become a brand name here now. Women come to me and say: 'Do a pipelle on me.'"
Barash found Bar-Ze?ev to be a suitable candidate for treatment. She underwent a biopsy and several fertilized eggs were subsequently extracted from her body. Then two embryos were returned to her womb. The embryo transfer was successful, but something was wrong with the pregnancy.
She had bleeding and miscarried after about three weeks.
"That was the time that Yaron really broke down," says Bar-Ze'ev. "Usually I was the desperate one and this time he got depressed and I still felt optimistic. I told him that it would be okay, that we'd had a successful transfer."
On the second attempt, she got pregnant again. "We laugh about it, because we got the sperm in the orchard among the orange trees near Rehovot," she says. "Yaron didn't want to go to the hospital bathroom to do it, and it would have been too far to bring it all the way from home, so we found this orchard and put the sperm in a special cup we had with us. I'll never forget that moment, when I called to find out the results of the blood test two weeks later. I was shaking all over. Someone who hasn't been through it will never be able to understand what I'm talking about.
Dr. Barash's secretary said: 'Iris, there's a pregnancy and it's normal.'"
That sperm collected in the orchard led to the birth of Shahar, now two and a half. A month and a half after the successful birth, Bar-Ze?ev became pregnant again, this time without any medical intervention. This time she gave birth to her daughter Shaked. "I never dreamed that I could have a totally normal and natural pregnancy," she says. "The pipelle apparently solved my problem."
No one really knows yet just exactly what the pipelle does. Even Dr. Barash and Prof. Dekel are not sure how it helps to promote implantation and pregnancy. Dekel is continuing to research it, and meanwhile has a variety of theories. "It's certainly a breakthrough in terms of offering something practical for treatment, but at this stage we don't yet fully understand the molecular and biochemical background," she says.
This is not the first time that a medical solution has been discovered by chance. Zyban, a drug that helps people quit smoking, was originally developed as an antidepressant, and Viagra was first invented to dilate blood vessels in cardiac patients.
Barash believes that the method stimulates the endometrial tissue and thickens it, thereby solving part of the problem in women whose endometrial lining is too thin. Dr. Irit Granot, who worked with Dekel at the Weizmann Institute and is now director of the IVF laboratory at Kaplan Hospital, found reports in the medical literature indicating that as early as 1907, experiments were carried out on mice that produced similar results: "They scratched the mouse's uterus and it responded as if ready to receive an embryo. We think that it works the same way in women: As soon as the womb is injured by the biopsy, it 'learns' to respond and to produce conditions for the reception of the embryo."
Since 2002, approximately 1,300 women have undergone in-vitro fertilization at Kaplan, about a third of them with the pipelle and the rest with regular treatment. Forty-eight percent of those treated with the pipelle became pregnant, compared to 31 percent of the women who received only the regular treatment. The percentage of live births from all these pregnancies mirrored that of the general population (the average miscarriage rate in the world is 13 percent).
Last week, the Israeli Association for Fertility Research held its annual conference. At the conference, a new study was presented that is currently being conducted by Dr. Yulia Gnainsky from Dekel's department at the Weizmann Institute. "We're trying to find out what the genetic mechanism is that operates in response to the mechanically-induced injury to the uterus," says Dekel. "In the first stage, we took samples from women receiving IVF treatment and women not receiving treatment and looked at all the genes in the two tissues of the uterus. We analyzed about 20,000 genes for each sample. Afterward, in a process of elimination, we were able to isolate two genes that stood out among the women receiving treatment, one whose expression increased and one whose expression decreased. In parallel, we produced a rat model, since the rat has two uterine horns, and we scratched one horn, and the conditions for embryo reception were generated there. In the rat, too, in the scratched horn, we found one gene whose expression increased and one that decreased, in exactly the same pattern as in the women. Now we're focusing on these two genes and examining whether the increase in one or the decrease in the other or some combination between the two is the cause of what happened."
A new door opens
It must be borne in mind that the pipelle procedure does not help everyone, and certainly not on the first attempt. Rishon Letzion elementary school teacher Gita Haim-Nissim, 46, had been through 24 years of infertility treatments. "There was a stage when I completely gave up," she says. "I said, whatever will be will be. I went to university, got my teaching certificate and gradually came to terms with it. I told myself that it was apparently not meant to be."
Three years ago she gave birth to her only daughter, following treatment with the pipelle method − but only on the sixth attempt. "I went through 18 treatment cycles," she says. "Lihi was born after the 19th cycle. I started at age 37, and before that I had done all kinds of other treatments, not IVF, and had been from one doctor to another, from one medical center to another, until finally I came to Dr. Barash. A friend told me about him; she had been his patient."
Idit Shavit, 40, of Moshav Kidron, tried for 10 years to get pregnant. She saw the top specialists, was treated at various IVF centers ("I went through 16 or 17 treatment cycles − I stopped counting at some point"), invested thousands of dollars in the effort and never managed to give birth. Eventually, she and her husband adopted a daughter.
"Dr. Barash is our neighbor on the moshav and that's how I heard about the pipelle," she says. "It was like a sudden ray of light, after I had totally given up on having a child. Suddenly a new door was opened after I thought they had all been closed. After we adopted we decided to try just one more time. He did the pipelle procedure on me and I became pregnant right away, in that one cycle, with one embryo. I had a girl. Today she's two years and four months old."
Despite the success, Shavit, a dance and movement teacher, is now a strong advocate of adoption and not of IVF treatment. "Relatively speaking, I didn't suffer a lot of physical hardship," she says. "Because I dance, and I'm very strong, but it makes you gain weight and disrupts your natural cycle. I felt disconnected from my body. And it can be very damaging to one's femininity and sex life and marriage. It really undermined my confidence. At SuperPharm, I wouldn't dare to pass through the baby products' aisle because I felt like an impostor and a fraud who still wasn't accepted in this society, and that I mustn't set foot in these places. To this day, even after I've given birth, conversations about children don't feel natural to me.
"In general, I feel that it's the reason why I never got very far in any area. I did earn a master's degree and I taught in a teachers? college, but never full-time, because most of my energy always went to treatments. I never pushed hard in my career, I acted like my bags were always packed, because I'd think: 'It doesn't pay to really start anything because I could be getting pregnant any time now.' What pulled me out of that was psychotherapy and the decision to adopt. It helped me to decide that I was going to stop suffering and stop using that as an excuse for my failings."
Miram Ben-Shimol, 35, from Ashdod, gave birth to her daughter Liam, now 16 months old, after treatment with the pipelle procedure. Previously, she had experienced many failed treatments. "At the birth, I made everyone crazy. I pushed and pushed and the midwives told me to relax and I couldn't. I just wanted it to be over and to see that
everything was okay."
Were all the treatments and suffering worth it?
"If I had known beforehand what I was missing in life, I would have lost my mind, it would have been awful. The lucky thing is that anyone who doesn?t have kids does not realize what this hunger for children really is. Of course it was worth it. Everything else is dwarfed by comparison. Nothing else in life can compare. On the contrary, now I realize what emptiness there was in my life before.
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