2023-10-22 21:25:30
We have already told an amazing story regarding how, at the beginning of the 20th century, doctors learned to save children who had previously died due to Rh conflict with their mother. How are such pregnancies managed now and why is it still not completely safe? We talked with Doctor of Medical Sciences, obstetrician-gynecologist of the Central Pedagogical Center Alexander Konoplyannikov.
Every day for the last 30 years, at the Center for Family Planning and Reproduction on Sevastopolsky Prospekt in Moscow, Alexander Georgievich Konoplyannikov saves children who simply might not exist without him. He and his colleagues give some young patients five to seven blood transfusions in utero to keep them alive. So doctors have already saved more than 1000 children. This is not just regarding Muscovites: women with Rh-conflict pregnancies come here from all over Russia and even from neighboring countries.
Alexander Konoplyannikov during an intrauterine blood transfusion operation. Photo: personal archive
What is Rh sensitization
The disease, from which thousands of infants around the world died, has always been known. At the beginning of the 20th century in the West it was called “erythroblastosis”, and only at the end of the 40s the cause was established that causes what is now commonly called hemolytic disease of the fetus and hemolytic disease of the newborn – depending on whether it develops in utero or following birth baby into the world. It’s all regarding the incompatibility of Rhesus between mother and fetus.
Alexander Georgievich explains the mechanism of Rh sensitization as follows: “Erythrocytes of a Rh-positive fetus enter the bloodstream of a Rh-negative mother, usually during childbirth, but mixing of blood flows can also occur during pregnancy if there were any pathologies or invasive interventions, be it superimposition stitches on the uterus or something else. Be that as it may, for a Rh-negative mother this fetal blood protein is foreign. And her body quite logically responds to such an invasion with an immune response. First, the primary one is the production of immunoglobulins M, and then the secondary one is the production of immunoglobulins G – antibodies. Since they have a small molecular weight, they freely pass through the placenta and attach to the red blood cells of the Rh-positive fetus. The process of destruction of the child’s blood begins – hence the name of the disease (“hemos” – blood, “lysis” – destruction). The fetus first begins to develop anemia, then the level of toxic bilirubin increases, and then sweating of the vascular wall occurs, an edematous form and death of the fetus.”
If Rh sensitization has occurred, then nothing can be done regarding it. Antibodies will remain in the woman’s blood forever and will begin to increase in the next pregnancy as the fetus develops. It is then that the process of hemolytic disease of the fetus can start in utero. Moreover, in each subsequent pregnancy the degree of its severity will increase.
It is impossible to cure Rh sensitization once and for all. “To do this, you need to completely replace the bone marrow, which is responsible for the production of blood cells, but this is impossible,” explains Konoplyannikov. “Moreover, it is important for women to understand that these antibodies do not pose any danger to themselves. And they do not affect their health and longevity in any way; they may not even be detected in the blood outside of pregnancy. They pose a danger only during pregnancy and only for the fetus.”
Rhesus vaccine
Alexander Georgievich recalls that in the 800-page work “Gynecology according to Williams,” only one page of text was devoted to Rh sensitization and it began with approximately the following words: “Before, in the 20th century, there was such a problem, but we came up with a drug and solved it “
The “drug” is anti-Rhesus gamma globulin, which was invented back in the 60s of the 20th century. If a woman is Rh negative, then the administration of this drug makes the onset of Rh sensitization impossible.
“The drug is administered to a woman with negative Rh during pregnancy at 28 weeks. And this is not a random number. The half-life of the drug – that is, the time it circulates and actively works in a woman’s blood – is 12 weeks. We add twelve to twenty-eight and get a full-term pregnancy at 40 weeks. There is no point in administering the drug earlier. Before this period, the fetus is too small and its circulating blood volume (CBV) is too small, and therefore a negligible amount of fetal red blood cells (fetal red blood cells – editor’s note) enters the mother’s blood. The task of anti-Rhesus gamma globulin is to bind all fetal red blood cells of the fetus in the mother’s blood and destroy them, without giving the immune system a chance to respond with antibodies. That is, in essence, to neutralize them. Therefore, all women with negative Rh have their blood taken for antibodies three times during pregnancy: at registration, at 18 weeks and at 28. If there are no antibodies, we administer anti-Rhesus immunoglobulin,” explains Alexander Georgievich.
The second “Rh vaccine,” as this injection is popularly called, is administered to a woman within 72 hours following the birth of an Rh-positive child. Moreover, Konoplyannikov says that Mark Arkadyevich Kurtser, the former chief physician of the Central Pedagogical Center for Surgery and Rehabilitation, developed a protocol in which it is simply impossible not to give an injection. In the medical and discharge history, not only is a record of the administration of the drug made, but the serial number taken from the drug packaging is also affixed there.
But then a reasonable question arises: if this vaccination is mandatory, why do some pregnant women still experience Rh sensitization, why do they en masse go to Konoplyannikov’s Center for Prenatal Blood Transfusions for intrauterine blood transfusions for children who have already been diagnosed with hemolytic disease of the fetus? Konoplyannikov himself believes that the reason for this is the human factor.
“At conferences, congresses, forums where I have been speaking for the last 30 years, I always say that if a woman with Rh sensitization comes to us, it is always the fault of the doctors, and in all this time no one has been able to prove to me otherwise,” says Konoplyannikov. – After all, in fact, Rh sensitization occurs only following the blood flows of the mother and fetus have mixed, that is, either following childbirth, or following an abortion or miscarriage. And then the question arises: why didn’t the woman get an injection during pregnancy, which can prevent the occurrence of an immune response? Even if a miscarriage or abortion occurred at 6–7 weeks, when Rh is still forming, it is better to get such an injection. We cannot know down to the day when conception occurred or when implantation occurred; we always have a gap of 2 weeks. And it’s better to play it safe in this situation, even if by your standards the period is still short (6-7 weeks) and the risks are small.”
Another risk group is women who do not monitor their pregnancy and give birth at home. Or those who refuse the “vaccination”, fearing interventions during pregnancy.
“Why does the patient go to give birth at home? Probably because we, the doctors, made it so that she did not want to go to the maternity hospital: somewhere we were rude, inattentive, scared. There are also those who simply refuse the injection: they are afraid, because, whatever one may say, it is a blood product. And this is also the doctor’s task – to explain the consequences of refusing to administer anti-Rhesus gamma globulin. And this is fraught with the fact that following a woman has once had Rh sensabilization, antibodies will forever remain in her blood, which will then kill all subsequent children in the womb. We should not intimidate, but show all possible scenarios, including negative ones,” the doctor reflects.
“No need to stimulate the immune system”
Over the past 50 years, doctors have developed different treatments for Rh sensitization. So, back in the 70s of the 20th century there was a protocol that involved the administration of a number of medications to all women with Rh-conflict pregnancies. But this therapy did not give any effect.
Even earlier, a system was developed for implanting a skin flap from the child’s father into a pregnant woman’s shoulder or buttock. “Doctors assumed that this foreign Rh positive tissue would attract antibodies, be rejected, and the fetus would be safe,” Konoplyannikov explains the meaning of the procedure, “but it doesn’t work. A patient came to us in the early 90s with two grafted flaps. Her child had a severe form of hemolytic disease.”
Then, in the 70s, another attempt was made to rid women of antibodies – plasmapheresis, roughly speaking, blood purification. “It was assumed that a certain amount of antibodies were removed from the blood along with the plasma. This is true. But how will the immune system respond to this? She will begin to produce even more of them. And they will get to the fruit faster. So we always say don’t stimulate the immune system.”
The most dangerous operation in the world
So, Rh sensitization must be prevented by all means. But if it does happen, there is no “cure”. However, doctors have learned to save children in the womb.
“Mark Arkadyevich Kurtser often asks students, and doctors, a provocative question: do they know what the most dangerous operation in the world is. Most often, everyone answers that it is open heart surgery. But actually it is not. The most dangerous operation in the world is blood transfusion. Because even if we follow all the rules, we don’t know how this procedure might affect us in 20–30 years, when new viruses, infections, and genes are discovered. But blood transfusion is the only operation that can save the life of a fetus and newborn with hemolytic disease,” explains Konoplyannikov.
Cordocentesis – intrauterine blood transfusion to the fetus – is performed for signs of severe hemolytic disease starting from the 19th–20th week of pregnancy.
Intrauterine blood transfusion surgery. Photo: personal archive of Alexander Konoplyannikov
“Before, we simply might not do this: the risks were too high. There the fruit is only 300-400 grams! Therefore, I try to do cordocentesis no earlier than 22–23 weeks. But right now I am regarding to operate on a patient at 19 weeks, the baby weighs only 374 grams, he already has a severe form of hemolytic disease, but I hope we will save him. Overall this is a very dangerous operation. Imagine, we have to get a needle into a millimeter-thick umbilical cord vessel and give the child in a small volume the maximum amount of hemoglobin and hematocrit – what is popularly called “washed” red blood cells.”
After cordocentesis, the woman spends at least a day in the maternity ward under the supervision of doctors and under the control of CTG. “Cordocentesis can provoke premature birth, so all women are given ginipral following it, and the fetus experiences a huge load on the heart, and we make sure that it does not have bradycardia.”
Of course, intrauterine blood transfusions are not indicated for everyone. Each woman with Rh sensitization is monitored individually during pregnancy. “It’s not that with such and such a titer we prescribe something for everyone. In no case. We always look at everything together: the antibody titer and fetal ultrasound data, assess the size of the liver and the speed of blood flow in the median artery of the brain. And only following analyzing all this, we make certain decisions regarding intrauterine transfusion and prolongation of pregnancy to a certain date,” says the doctor.
Caesarean is the only option
“Can a woman with Rh sensitization give birth to a child on her own? Of course it can. At any time. But we are interested in the outcome of these births. We are fighting for the life of a fetus, a child. What is the point of performing 2, 3, 5 cordocentesis if he dies during natural childbirth? After all, these children are sick: they have anemia, weak blood vessels, and our task is to help them be born as quickly as possible and without physical exertion. Caesarean section solves this problem,” explains Alexander Georgievich.
After birth, children with hemolytic disease of the newborn are given a transfusion of red blood cells or an exchange blood transfusion according to indications – this is when part of the child’s blood is taken and replaced with another. Plus, these children undergo phototherapy. All other treatment depends on the period at which the child was born. After all, this can be either premature birth or a full-term pregnancy of 37–38 weeks.
“They always ask whether these children will be healthy. It all depends on how early the baby was born. If we were able to ensure that a woman was able to carry her pregnancy to term, when resuscitators and neonatologists can already help the child, deliver him and eliminate the hemolytic disease, then everything will be fine with him. And if the child was nevertheless born much prematurely, then he may have certain health problems associated specifically with prematurity.”
There is a possibility to give birth to a healthy child
Even 20 years ago, Konoplyannikov and Kurtser developed a protocol for a procedure that allows a woman with Rh sensitization to carry and give birth to an absolutely healthy child. And 17 such patients were carried out at the Center for Psychology and Rehabilitation as part of the study.
“This is called PGD diagnostics (preimplantation diagnostics. – Ed.), its meaning is that we take eggs from a woman, and sperm from a man, and carry out fertilization. And then we select embryos that are Rh negative. We implant them in a woman as part of an IVF protocol, and she calmly bears a healthy child. What is the difficulty? In order for this to work, the man must be heterozygous, that is, his cells must carry both positive and negative Rh factors. But in our study, the percentage of heterozygous men was significantly lower than homozygous ones,” says Alexander Georgievich.
When this protocol was developed, the entire procedure was completely free of charge as part of the study. Now it is not included in the compulsory medical insurance. And the patient who decides on this type of IVF will need to pay not only for the IVF itself (since she clearly does not have a diagnosis of “infertility”, which means she is not entitled to a quota), but also for the very selection of embryos. Only a few can afford this. But Konoplyannikov hopes that it will be possible to introduce PGD diagnostics into compulsory medical insurance.
There is another solution to the problem.
“In fact, of course, it would be possible to protect the fetus from antibodies, but this is not our task, this should be done by geneticists, bioengineers, and biophysicists. It is necessary to develop a protein that would increase the molecular weight of antibodies and prevent them from crossing the placental barrier. Then a woman might calmly and with antibodies in her blood bear a healthy child. But no one in any country in the world will do this, because this requires money, time, scientists, development, experiments on animals, clinical studies. Why all this if there is a Rhesus vaccine? And it showed its effectiveness.”
Over the past 30 years, the number of Rh sensitizations has indeed been rapidly decreasing – both in Moscow and in Russia as a whole. So why doesn’t the problem go away completely? It can be assumed that part of the blame lies with private clinics. But it is not possible to verify this.
“We can monitor all situations within the compulsory medical insurance and monitor the administration of anti-Rhesus gamma globulin. But if this is a private clinic and a woman goes for an abortion or curettage due to a miscarriage or missed abortion, we cannot track whether she received this injection there. The drug costs money, and it is logical that it will increase the cost of the procedure. It is clear that a woman who is not informed regarding the risks is likely to choose the cheaper option. And as part of a cheap procedure, immunoglobulin may not be administered. But I hope that now that the entire medical system is being digitalized, we will be able to solve this problem too.”
Cover photo: SViktoria / Shutterstock / Fotodom
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