A window on the fetus

Researchers are now able to tell a great deal about the health of a baby and its mother by studying the placenta.

fetus 88 (photo credit: )
fetus 88
(photo credit: )
The placenta - or afterbirth - has long been regarded by obstetricians and midwives as an afterthought. The dark reddish-blue or maroon gob about 22 centimeters in diameter and weighing about half a kilo connects the developing embryo/fetus to the wall of the uterus and provides it with nutrients from its mother while removing fetal waste to be eliminated by the mother's kidneys. Tiny blood vessels branch out over its surface and form a network covered by a thin layer of epidermal cells, thus forming finger-shaped structures called chorionic villi. This amazing structure, without which human babies and other mammals could not thrive in the womb, is nevertheless cast away or buried (even though today, the umbilical cord that connects the fetus to the placenta is usually saved for its embryonic stem cells, that could be used for bone marrow transplants). But the placenta is the focus of research by a handful of scientists who believe it can provide a great deal of information about the mother, the fetus and the baby. One of them, Prof. Harvey Kliman of the Yale University School of Medicine in Connecticut, says: "Behind every healthy baby is a healthy placenta." He has even done research (which must first be corroborated in larger studies) indicating that an examination of the placenta can predict with impressive exactitude whether the baby who was connected to it will show symptoms of autism some two years after birth. Kliman recently lectured at the Jerusalem conference called "Across the Endometrium and Into the Promised Land of the Placenta" and chaired by Hadassah University Medical Center fetal ultrasound expert Prof. Simcha Yagel at the Inbal Hotel. Kliman, who was born in Buffalo, grew up on Long Island, New York. Born to young parents (including an engineer father) who did not tie him to their apron strings, Harvey decided in 1970, at the age of 17, that he wanted to drive a motorcycle the length of Israel. When he came, the ride didn't work out, but he did participate in the International Summer Science Institute at the Weizmann Institute in Rehovot and ended up at Kibbutz Sde Boker in the Negev. "I recall an old man who told me stories there; only later did I learn this was [Israel's first prime minister] David Ben-Gurion." Kliman has visited Israel frequently since then, especially for professional reasons. Kliman returned to the US and earned his BA at Syracuse University and his MD from the University of Chicago, which also awarded him his doctorate in biochemistry. He was a resident in pathology at the University of Pennsylvania. He delivered about 30 babies as a medical student, but as he liked to sleep through the night, he decided not to specialize in bringing babies into the world, even though he now treats patients with infertility and other problems. Studying pathology, he researched the placenta and devised a way to purify the stem cells inside. Today his method is used around the world. "I took a full-term placenta - which is a big, bloody thing - cut it up into pieces, then minced the 'meat' and used enzymes to digest it," he said in an interview with The Jerusalem Post during the conference. "Then I peeled away what looked like little peas. The ends of fetal circulation have a skin cover and an inside layer where stem cells are. I learned how to extract them." PLACENTAS, HE continued, "say a tremendous amount, but you have to be educated about them. The most important thing to know is the gestational age [how much time has passed since conception]. I remember one young pathologist who didn't bother to go up from the lab to the labor floor to see the patient and find out the gestational age of her placenta." He said he is one of A few - and probably the only - pathologist to be an obstetrician/gynecologist who prefers not to deliver babies. "There are some ob/gyns who left to become pathologists, but I don't know of a pathologist who sees patients today." The placenta "totally supports the fetus's life. You can have a pregnancy with a placenta and not a fetus, but not the opposite. Today, medicine still focuses almost completely on the fetus rather than on the placenta. We put women through pregnancy without a gasoline gauge. The tank that provides the fuel is the placenta, and we can't tell how much gas is left by the last part of the gestation," he said. "When a woman is not pregnant, only .5% of her blood goes through these blood vessels in the uterus, but when she is pregnant, it reaches up to 25%. The vessels open up, and this characteristic makes humans different from apes," he explained. But the skin-covered villi, which together look like a hand in a bucket of water, do not allow the woman's blood to leak out into the water. There is no direct connection between the mother's and fetus' blood." "The placenta is part of the fetus," he explained. "They are made of the same material. When you look at a placenta, it's like a window on the baby. We look for symmetry in the placenta. It's difficult to create symmetry.We can tell off the bat if something is put together perfectly. When genes are abnormal, however, you get abnormal growth patterns and folding in the placenta. Basically a funny-looking placenta." THE HUMAN brain is also a complex folded tissue. "Whatever is abnormal in the placenta in these cases of genetic defects is likely what's abnormal in the brain. Something is wrong with the way the brain is folded - and we may see the same thing in both the placenta and the brain," he continued. Normally, the villus produces the needed hormones for pregnancy. "I thought I could look at the villi in a placenta to know what problems were in a fetus," he continued. "Irregularities in the fetus are three to four times more likely when there is abnormal folding in the placenta." He conducted studies on the stored placentas of women whose children were diagnosed with autism - the development disorder causing impaired social interaction and repetitive behavior. His aim was to find a marker that would show up in the afterbirth, so that diagnosis would not have to wait for two or three years. He believes he has found a possible connection between this abnormal folding and autism. "It isn't the irregular folds themselves that cause problems, but a marker, as the fetus and placenta are connected to the same genetic material," Kliman stressed. "The earlier the intervention for autism, even just after birth, the more likely we can see improvements." If confirmed by further studies, it could lead to new medications, he added. He is not currently recommending that all placentas be checked for autism after birth. "We're doing a prospective multicenter study for five years using women at high risk for having an autistic child. Of those with one such child, 10% will have another." The placenta has also been used to develop a test during an early stage of pregnancy to determine whether a woman will develop preeclampsia later. A sensitive biomarker called placental protein 13 (PP13) is the first in the world believed to predict preeclampsia, a condition that involves high blood pressure and can lead to complications in the kidneys, liver, blood and brain, as well as to premature delivery. It was developed at Diagnostic Technologies Ltd. (DTL) in Yokneam, Israel based on the work of an "incubator" project at the Technion-Israel Institute of Technology. Used so far on some pregnant Israeli women, the PP13 diagnostic test will now be tried further in Austria by Prof. Berthold Huppertz, a German-born cell biology expert at the University of Graz who attended the Jerusalem conference and will receive the 2009 award of the International Federation of Placenta Associations (IFPA). PREECLAMPSIA complicates five to seven percent of all pregnancies and is responsible for 18% of all maternal deaths during pregnancy, as well as for a third of all premature births. It remains a mysterious disease, even though it was mentioned in Egyptian and Chinese texts going back 3,000 years. While there is no cure, treating women with bed rest, low-dose aspirin or other substances and monitoring their condition can reduce the risk of preeclampsia. The earlier such intervention is undertaken, the better. Preeclampsia is diagnosed when a pregnant woman develops consistent blood pressure readings of 140/90 or more and 300 mg. of protein (proteinuria) in a 24-hour urine sample. Edema (swelling), especially in the face and hands, used to be thought a key sign of preeclampsia, but today only hypertension and proteinuria are needed for a diagnosis. But if a pregnant woman has swelling in her ankles, hands or face and pressing a finger into them leaves a mark, it may be a sign of preeclampsia and should be reported to her doctor. A major problem is that none of the symptoms of preeclampsia are specific only to that condition. "A healthy baby at term is the product of three important factors - a healthy mother, normal genes and good placental implantation and growth," said Kliman. "Placental thickness and volume have been used to predict chromosomal abnormalities and diseases such as preeclampsia." THREE-DIMENSIONAL ultrasound has been used to measure these factors, but it's expensive and requires training. Kliman developed a two-dimensional technique and a mathematical equation that, he suggests, is just as accurate and can help rule out, early in pregnancy, the presence of a placenta that's small for gestational age, thus pointing to possible problems. His father, the engineer with 20 patents, helped Kliman calculate the placenta's volume as if it were a rounded skullcap. "After delivery, we weighed the placenta and found that our estimate was accurate. Thanks to this, knowing that the placenta volume was very small in one of my patients, we saved the baby's life. We put the mother in the hospital for two weeks, giving her liquids and rest. Her placenta swelled up like a sponge during that time, and she was able to have a healthy baby." Kliman, who loves to use metaphors to describe complex biological phenomena, depicts the placenta as a battlefield between two armies. The father, his sperm and his genes naturally want to produce "the biggest baby" so it will survive. To do this the father sends soldiers into the mother to open up the blood vessels supplying the placenta. But a too-large baby might get stuck and could kill her. Therefore the mother tries to fight off the father's soldiers to keep the blood flow to the uterus low. Neither side gets exactly what it "wants," so each has to compromise and a normal baby is born. Preeclampsia is believed to be launched when cells invading the uterus (the father's 'soldiers') fail to transform the uterine arteries into open tubes, leading to decreased maternal blood flow. Kliman noted that he found PP13 "far away from the arteries in the placenta. When I looked close, I saw a zone of necrosis that looked like mass destruction, with hundreds of thousands of dead soldiers hit by napalm on the battlefield." It looks as if the PP13 is one way the father tricks the mother into not destroying the father's soldiers that are trying to open up the mother's uterine blood vessels. Kliman aroused quite a bit of controversy about seven years ago when he and colleagues wrote an article in an ob/gyn journal about endometriosis - a condition in fertile women in which endometrial cells migrate outside the uterine cavity and are affected by hormones, causing pain and possibly infertility. The authors maintained that use of tampons or having an orgasm during menstruation can reduce the risk of endometriosis. Feminist and environmental groups didn't like the conclusion, as they worried about the chemical dioxin (a natural substance used for bleaching some tampons in those days). In addition, Orthodox rabbis certainly didn't like it, as sex during menstruation and the week after is strictly barred by Jewish law (although health is not given as the reason). "The female body was never designed to have 400 menstrual periods during a lifetime. For millennia, females started getting pregnant in early adolescence and then kept getting pregnant, but they died young so they had few periods," Kliman explained. But his retrospective research, he said, proved that tampons serve as a wick to remove menstrual blood from the uterus instead of allowing it to seep into the pelvic area. Orgasms during menstruation, he said, produce wave-like movement that accentuates the release of menstrual blood, which he described as "debris" that should not remain in the body. "I received threats over it from an endometriosis association. I was accused of academic fraud, but my university backed me up, and since then my opponents have given up their stand. I feel very comfortable about that research," Kliman asserted. Whether all his colleagues agree with him or not, Kliman's shifting of the focus away from the fetus and closer to the placenta is welcome, and should make it easier to find some answers to the many remaining puzzles about fetal disease.