You should spend about 20 minutes on Questions 1–13, which are based on Reading Passage 1 below.
The Discovery of the Rhesus Factor
Before the twentieth century, a blood transfusion was a gamble. Some patients recovered, but others suffered a violent reaction, and no one could explain why. The picture became clearer in 1901, when the Austrian physician Karl Landsteiner showed that human blood falls into different groups, later named A, B, AB and O. Mixing incompatible groups caused red cells to clump together, or agglutinate, and could be fatal. Doctors could now match donor and patient, yet a puzzling number of carefully matched transfusions still ended badly. Something else in the blood was clearly involved, and finding out what it was would take another four decades.
The first clue came from an experiment with monkeys. In the late 1930s Landsteiner, by then working in New York, and his colleague Alexander Wiener injected rabbits with red blood cells taken from rhesus monkeys. The rabbits produced antibodies against the monkey cells, and when the resulting serum was mixed with human blood it agglutinated the cells of most people tested — around 85 per cent of a New York sample — while leaving the rest unaffected. Landsteiner and Wiener reported the finding in 1940 and named the substance responsible the Rhesus, or Rh, factor, after the animals that had made the experiment possible.
Unknown to them, a similar discovery had already been made at a bedside. In 1939 Philip Levine and Rufus Stetson described a woman who had delivered a stillborn infant and who suffered a severe reaction after receiving blood from her husband. Her serum clumped her husband's red cells. The most economical explanation was that the fetus had inherited a blood factor from the father which the mother lacked, that she had been immunised against it during pregnancy, and that her antibodies were now attacking any blood carrying it. The two lines of work soon converged.
The condition they were uncovering is now called haemolytic disease of the newborn. It arises when an Rh-negative mother carries an Rh-positive fetus. During pregnancy the two circulations are separated by the placenta, but at delivery, or sometimes earlier, a small quantity of the baby's blood may leak into the mother's bloodstream. Her immune system recognises the foreign red cells as an invader and manufactures antibodies against them. A first pregnancy is therefore usually harmless; the danger falls on later ones, when those antibodies, now present in advance, cross the placenta and begin destroying the red cells of an Rh-positive fetus.
Before prevention existed, the consequences could be devastating. The fetus becomes anaemic and the liver and spleen enlarge; after birth the breakdown of red cells produces intense jaundice, which in severe cases damages the brain and causes deafness, cerebral palsy or death. In countries with large families, the disease killed or disabled thousands of babies every year, and it was among the most feared complications in obstetrics.
Medicine could offer only partial answers. Where the disease was detected in time, labour might be induced early so that the baby could be cared for outside the womb; after birth, an exchange transfusion replaced the infant's damaged blood with donor blood, sometimes more than once. To judge how severely a fetus was affected, doctors inserted a needle into the uterus and withdrew a sample of the fluid surrounding it, measuring the pigment released by broken-down red cells. Each of these techniques was difficult, and none of them prevented the disease.
Prevention came from an idea that inverts the logic of vaccination. Instead of teaching the mother's immune system to respond, clinicians set out to stop it responding at all. If antibodies against Rh-positive cells were injected into an Rh-negative mother shortly after delivery, they would destroy any fetal cells in her circulation before her own immune system had time to notice them. The injected antibodies themselves would soon disappear. The approach was pursued in the 1960s by Cyril Clarke and Ronald Finn in Liverpool and, independently, by Vincent Freda and colleagues in New York, using antibodies purified from the blood of donors.
Trials confirmed that the method worked, and by the late 1960s a preparation known as anti-D immunoglobulin was being introduced in a number of countries. It is now offered to Rh-negative women after delivery, after miscarriage or abortion and during pregnancy itself, and also after any accident in which Rh-positive blood may have entered the circulation. Where the programme is established, deaths from Rh disease have become rare. The fall was one of the clearest successes of preventive medicine in the second half of the twentieth century.
The Rh factor matters outside pregnancy as well. Blood for transfusion is routinely typed for the D antigen, because an Rh-negative patient who receives Rh-positive blood may produce antibodies that make any later transfusion difficult. The same antibodies can also attack an Rh-positive fetus in a subsequent pregnancy, so the rule that donor and patient must be matched for Rh as well as for ABO is one of the foundations of modern blood banking.
The story has an interesting postscript. The name Rh survives in everyday use, although the antigen that matters most in the disease is formally known as D, and the monkey serum used in the original experiments plays no part in modern testing. For a generation of patients and parents, however, the older name stuck, a reminder that in medicine a label can outlive the reasoning that produced it.
You should spend about 20 minutes on Questions 14–26, which are based on Reading Passage 2 below.
How Pregnancy Changes the Mother's Body
Pregnancy is sometimes described as a nine-month wait, but the body is not waiting. Within weeks of conception, and long before there is any visible sign, the mother's organs begin to adapt: the heart pumps harder, the kidneys filter faster and the lungs move more air. These changes are usually called adaptations, because most of them serve the growing fetus, yet they also explain many of the discomforts that women report. Understanding them helps to separate the ordinary from the worrying.
The most striking alterations are in the circulation. By the third trimester the volume of blood has risen by roughly 40 to 50 per cent, an increase achieved mainly by adding plasma rather than red cells. Because plasma is added faster than red cells, the blood becomes more dilute and the concentration of haemoglobin falls; this haemodilution is often called physiological anaemia. To move the extra volume, the heart beats faster — typically by ten to twenty beats a minute — and pumps more with each beat, so that cardiac output rises by something like 30 to 50 per cent. The uterus, meanwhile, grows large enough to press on the vessels behind the abdomen, which is why some women feel faint when they lie on their backs.
Blood pressure behaves in a way that surprises many people. It usually falls in the first half of pregnancy, because the vessels relax and widen, and returns to its earlier level, or a little above it, towards the end. A rise late in pregnancy therefore deserves attention, since it may be a sign of pre-eclampsia, a condition that remains one of the leading causes of maternal death worldwide. A single high reading is usually repeated rather than acted on at once.
The kidneys enlarge slightly and filter considerably more blood. The glomerular filtration rate, a measure of how quickly the kidneys clear waste, rises by up to half within the first trimester and stays high until delivery. The purpose is probably to clear the extra waste produced by the fetus as well as by the mother. One consequence is that small amounts of glucose and protein may appear in the urine of a healthy pregnant woman, which is why a trace of either is not automatically treated as disease.
Breathing changes too, and the breathlessness that many women notice is usually not a sign that anything is wrong. The hormone progesterone stimulates the respiratory centre in the brain, so that each breath takes in more air: the volume drawn in with every breath — the tidal volume — increases by perhaps 40 per cent, while the rate of breathing changes little. Oxygen consumption rises by about a fifth. As the uterus enlarges, the diaphragm is pushed upwards and the lungs have less room at the bottom, which is why the chest seems to expand sideways.
The digestive system slows down. Progesterone relaxes smooth muscle throughout the body, including the wall of the intestine, and the resulting sluggish transit allows more time for nutrients to be absorbed but also encourages constipation. The valve at the top of the stomach relaxes as well, so that acid can travel upwards and cause heartburn. Nausea, which affects a majority of women in early pregnancy, is the exception to this pattern of explanation: the causes are still not properly understood, although hormonal changes have been proposed.
Weight gain is the most visible change, and it is not simply fat. In a pregnancy with a single baby, the additional weight at term is commonly between eleven and sixteen kilograms, made up of the fetus, the placenta, the amniotic fluid, the enlarged uterus and breasts, the extra blood and fluid, and a store of fat laid down for breastfeeding. Metabolism shifts as well: in the second half of pregnancy the body becomes progressively less sensitive to insulin, probably because hormones from the placenta interfere with its action, and this insulin resistance gives the fetus a steadier supply of glucose. In a few women blood sugar then rises too far.
Skin and joints show changes that are harmless but often unwelcome. Increased blood flow gives many women a flushed appearance, while melanin production rises, darkening the skin around the eyes and on the abdomen. Stretch marks appear where the skin is stretched fastest. The hormone relaxin softens the ligaments of the pelvis, allowing the joints to widen slightly in preparation for birth, but the same looseness, combined with a shift in the centre of gravity as the abdomen grows, contributes to back pain, among the most common complaints of late pregnancy.
The mother's mind has attracted increasing attention. Many women report forgetfulness and difficulty concentrating, an experience so widely shared that it has acquired the name 'pregnancy brain'. Studies comparing pregnant and non-pregnant women have produced mixed results: some find small differences in memory tasks, others none, and it is hard to separate hormonal effects from the disrupted sleep of late pregnancy. The immune system, too, is altered in ways that are still being mapped, adjusting to tolerate a fetus that is half foreign while retaining the ability to fight infection.
None of this is entirely predictable. The timing and size of these changes vary widely between individuals and between pregnancies, and the range of what counts as normal is broad. What is consistent is the direction: almost every system adjusts, and most of the adjustments reverse within weeks of delivery.
You should spend about 20 minutes on Questions 27–40, which are based on Reading Passage 3 below.
A Little of What You Fancy?
Do the long lists of foods that pregnant women are told to avoid help them, or simply make them anxious?
A woman who becomes pregnant in Britain today may be handed a leaflet, or directed to a website, containing a long list of foods to avoid. Soft cheeses, unpasteurised milk, raw eggs, liver, shark and swordfish, more than two cups of coffee a day: the items differ from country to country, but the direction of travel has been the same for decades. Guidance has grown longer and more detailed, and it has done so largely without public argument. The question is whether this accumulation of warnings makes women healthier or merely more anxious.
Some of the warnings rest on solid ground. Listeria, a bacterium found in soft cheeses, unpasteurised dairy produce and some chilled ready-to-eat foods, is unusual in crossing the placenta; infection during pregnancy can cause miscarriage, stillbirth or severe illness in the newborn, even though the mother may feel only mildly unwell. Toxoplasma, carried in undercooked meat and in soil on unwashed vegetables, can damage the fetus's brain and eyes. No one who has watched a family cope with the consequences would call such warnings excessive.
Alcohol belongs in the same category, though for different reasons. Its effects are common rather than rare, and they are dose-related: heavy drinking in pregnancy can cause a range of lifelong physical and behavioural difficulties grouped under the term fetal alcohol spectrum disorder. Because no one has been able to establish a threshold below which drinking is certainly safe, official advice in many countries has moved towards recommending abstinence. This is precautionary reasoning, but of a kind that most clinicians regard as justified.
Much of the rest of the list is a different matter. Critics point out that items have been added over the years in response to individual reports, theoretical concerns or the decisions of regulators in other countries, and that there is no orderly procedure for withdrawing a warning once it has been issued. Removing one is harder than adding it, because no official wishes to be blamed for the case that follows. The result is a document that grows by accretion, in which a measured judgment about mercury sits beside a vague caution about spices.
The cost of a long list is not only anxiety. Nutrition specialists argue that a woman who eliminates a great many foods may end up eating a narrower and poorer diet, and that the items most worth avoiding displace the items most worth eating. Fish is the clearest example: women who give up fish altogether in order to avoid mercury lose an important source of iodine and of omega-3 fatty acids, which are thought to matter for the development of the fetal brain.
There is also a problem of attention. Research on how people respond to risk messages suggests that the more items a list contains, the less each one is remembered, and that warnings repeated without explanation come to be treated as background noise. Behavioural researchers who study this effect describe a kind of saturation: advice that is not prioritised is advice that will not be followed. On this view, adding a warning is not a neutral act; it may make the other warnings less effective.
The evidence behind the items varies enormously, and the variation is seldom made clear. A minority of recommendations rest on substantial and consistent research; others rest on a single outbreak, on animal studies, or on the simple absence of proof that a food is harmless, which is the classic form of the precautionary principle. The history of the advice about peanuts is instructive. British guidance once asked women with a family history of allergy to avoid peanuts during pregnancy; when reviews found no evidence that avoidance prevented allergy, the advice was withdrawn. That episode shows a system capable of correcting itself, but also one that had given a generation of women a rule with nothing behind it.
Clinicians are caught in the middle. They occasionally see the harm that the warnings are designed to prevent, and they know that many women want to be told exactly what to do. Faced with a woman who asks whether she may eat a particular cheese, a doctor or midwife has little incentive to say that the risk is negligible, because if something goes wrong the advice will be remembered. Defensive practice, rather than evidence, explains part of the length of the list.
None of this is an argument for saying less. It is an argument for saying things in order. A short list of measures — avoiding alcohol, taking folic acid before conception, avoiding listeria and toxoplasma, limiting caffeine, choosing fish low in mercury — would cover most of the avoidable harm. It would be better still if the reasoning were attached: this matters a great deal, this matters a little, this is unknown. Women are not fragile. They are capable of understanding that evidence differs in strength, and they are better served by a short list they can act on than by a long one they cannot.
The question, then, has an answer that is not a number. The right amount of advice is the amount that can be understood, remembered and justified — which is to say, rather less than is currently offered, and rather better organised.
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