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WHILE you were quietly growing, waiting to be born, was someone there beside
you? Tucked up alongside may have been a twin brother or sister, whose ghostly
form disappeared long before your mother even felt you kicking. At least 1 in 20
of us is in fact a twinless twin. Do the maths, and the statistics for these
vanishing twins seem shocking鈥攐f the estimated 133 million people born in
the world last year, at least 7 million should have had a twin. For parents who
learn that one twin of a pair perished early in pregnancy, the news can be
heartbreaking. They need answers. What happened?

Viewed in the cold light of biology, such losses are sadly unsurprising. As
any woman who has suffered an early miscarriage knows, human reproduction is
brutally inefficient. About three quarters of all conceptions never make it to
term, most being lost in the first few weeks of pregnancy. And a twin may appear
on an early ultrasound only to disappear by the next. 鈥淟osing one or both
offspring is too common to be called phenomenal, and occurs for too many
different reasons to qualify as a syndrome,鈥� says Charles Bocklage, a
developmental biologist at East Carolina University in Greenville, North
Carolina. For women who lose a twin, the knowledge that the process is a natural
one may help ease the feelings of guilt they often suffer. But vanishing twins
are more than just a grim example of nature鈥檚 wastefulness. They may also help
us to understand some of the causes of many infant disabilities such as heart
defects and cerebral palsy.

Even if a twin is lost early in the pregnancy, parents who learn of the loss
can suffer from feelings of grief, loss and guilt that are incomprehensible to
relatives who feel they should be celebrating the birth of a healthy surviving
twin. 鈥淭hey can feel the most extraordinary loss. They find it devastating,鈥�
says Elizabeth Bryan, a paediatrician and founder of the Multiple Births
Foundation at Queen Charlotte鈥檚 and Chelsea Hospital in London. Bryan has also
founded a support group, Tamba Bereavement, to help couples who lose one or more
babies in a multiple pregnancy. Surviving twins can be profoundly affected by
their parents鈥� attitude towards them鈥攅specially if they feel somehow
responsible for the loss of their sibling.

Ironically, the chances of loss have increased with the advent of fertility
treatments, which can result in a woman carrying several fetuses. The 鈥渕iracle
mums鈥� who make headlines by delivering five or more healthy babies are in the
minority. 鈥淔or every cute thing or miracle, there is a tragedy,鈥� says Jean
Kollantai, founder of the Center for Loss in Multiple Birth in Anchorage,
Alaska. Couples expecting twins or higher multiples often aren鈥檛 told of the
high risk that some won鈥檛 make it, she says. Many of the couples she has
counselled had already bonded strongly with the fetuses when they learned that
one or more had died. 鈥淚f one of them just vanishes on you, it smacks you right
in the face,鈥� she says.

Clearly, nature is a brutal midwife. But why destroy a presumably normal
fetus just because he or she is a twin? Many scientists think twinning is an
accidental by-product of trying to up the odds of successful conception by
increasing the number of eggs a woman鈥檚 ovary releases. Given the dismal
survival statistics for human conceptions, it makes sense for a woman to
increase her chances of successful pregnancy by releasing more eggs.
Non-identical twins are an accident of this process.

Explanations for vanishing twins are legion, ranging from straightforward
cases of miscarriage to alien abductions. More plausibly, they may be a natural
way of reducing the number of fetuses if more than one implants and starts to
develop. Sometimes parents of quads, quints or more make the agonising decision
to have their surgeon remove some of the fetuses to increase the chance the
remaining babies will survive. 鈥淭he most simple idea is that the human uterus is
not adapted for multiple pregnancy,鈥� says Isaac Blickstein, a twins expert at
the Kaplan Medical Centre in Rehovot, Israel. 鈥淢aybe it鈥檚 nature鈥檚 way of
handling multiples efficiently.鈥� Certainly, vanishing twins affect about a third
of women who have had fertility treatment.

Three months ago, Britain鈥檚 Human Fertilisation and Embryology Authority
announced that it was reducing the maximum number of embryos that could be
transferred in a single IVF treatment from three to two, in a bid to reduce the
number of multiple pregnancies that happen after fertility treatment. It is
unlikely to be the whole answer to the problem, though. Blickstein and his team
have found that even if only single embryos are replaced, they split to form
identical twins at over ten times the rate in unassisted pregnancies. No one yet
knows why this happens.

It鈥檚 one thing to know that twins vanish, though, and quite another to
understand how. The first hard evidence emerged last year from researchers in
Germany who uncovered a gene that seems to influence how twins survive and grow
in the womb.

Andreas Busjahn of biotech company Valigen and his team at the Max
Delbr眉ck Centre for Molecular Medicine in Berlin were studying pairs of
twins in the hope of tracking down genes involved in heart disease. They were
looking at a gene called PPARG, which they thought might influence a person鈥檚
blood cholesterol levels, when they noticed something very odd. When they
compared the area of chromosome 3 that contains PPARGin non-identical
twins, they found that the twins shared the same genetic markers鈥攕tretches
of DNA in or near a gene of interest, which researchers use as labels鈥攆ar
more often than you would expect. Normally, siblings should share these markers
half the time, just by chance. But Busjahn found that on average, 65 per cent of
his non-identical twins shared these markers, including a marker located within
the gene itself. Crucially, the closer a marker was to PPARG, the
higher the chance it had of being shared鈥攁nd the odds of this peak in
sharing being due to chance were less than 1 in 10 million. 鈥淚t鈥檚 quite
extraordinary, and highly significant,鈥� says Busjahn. In other words, it looks
like PPARG may somehow be involved in twinning.

The gene itself gives some hint of how this might work. PPARG codes
for a protein that plays a key role in energy and fat metabolism. What鈥檚 more,
researchers in London and Geneva have recently found that the gene is essential
for the early development of the placenta. If each twin of a pair carries the
same version of the PPARG gene, they will compete on equal terms in the
womb for nutrition from their mother. But if they differ, the twin with the
鈥渂etter鈥� version could outstrip its sibling, who wanes and vanishes, says
Busjahn. This could explain why when both twins survive they are more likely to
share the same variant of PPARG.

Whether a twin vanishes may be at least partly down to a roll of the genetic
dice. It鈥檚 a chance event that could have profound implications for the
surviving sibling, too. Peter Pharoah, Professor Emeritus of Public Health at
the University of Liverpool, thinks that a vanishing twin may explain
many鈥攅ven most鈥攃ases of cerebral palsy and other birth defects. If
he鈥檚 right, it could radically change the way we think about birth defects.

Obstetricians have known for many years that if one member of an identical
twin pair is stillborn, the survivor has a higher than normal risk of developing
birth defects, especially cerebral palsy. Cerebral palsy, or CP, is one of the
leading causes of childhood disability, affecting about 2 in every 1000 babies.
Doctors once thought CP was the result of brain damage caused by a lack of
oxygen during a traumatic birth. But recent studies indicate that birth trauma
accounts for only about 1 in 10 CP cases. 鈥淭hat still leaves a lot of children
where the cause isn鈥檛 known,鈥� says Ann Johnson, a paediatrician at the National
Perinatal Epidemiology Unit in Oxford. Many experts believe CP develops while a
baby is still in the womb.

Trace evidence

To pin down the link with twinning, Pharoah and his colleagues studied the
fates of same-sex twin pairs where one twin had died during pregnancy. They
found that the prevalence of cerebral palsy in the twins was 29 per
1000鈥攖en times as high as normal. 鈥淲hen you think that the normal cerebral
palsy rate is 2 per 1000, it鈥檚 enormous,鈥� says Pharoah. What鈥檚 more, when you
combine this with other forms of brain damage, the overall risk of neurological
disability was a staggering 20 per cent.

Clearly, if a twin dies in the womb, it spells trouble. But Pharoah thinks
that many other children with cerebral palsy may once have had a twin鈥攐ne
that vanished unnoticed in the first few weeks of pregnancy, before 18 weeks.
His evidence comes from the clues that vanished twins can leave behind.

When a fetus disappears from the ultrasound scans, it seldom vanishes
completely. Often, a baby that perishes 12 to 18 weeks into pregnancy gets
partially reabsorbed and forms a 鈥渇etus papyraceus鈥濃�攁 dry, paper-like mass
attached to the placenta. The baby鈥檚 body is fully formed by this stage, right
down to its fingernails, and the tiny skeleton is often visible on an X-ray of
the placenta, or when the midwife or doctor inspects it after birth. Even if a
twin is lost earlier, it may leave a small cyst or thickening on the placenta.
Often these fetuses are not recorded in national statistics. Sometimes doctors
and midwives miss the signs. Other times they decide not to tell the mother and
mar the celebration of one normal birth. Worse, if a mother knows she has
delivered the remains of a vanished twin, she is legally obliged to name the
child and register it as a stillbirth鈥攅ven if it died as a tiny fetus.
Often, the doctors opt to say nothing. 鈥淚 fully appreciate why midwives and
doctors do it,鈥� says Pharoah.

But it could be important for parents to know about a fetus papyraceus.
Pharoah has learned from birth statistics that if a child has a twin fetus
papyraceus, his or her chance of having cerebral palsy leaps to 1 in 10. But of
18 cases recorded in the obstetric records for the Mersey region, a third were
registered with the Office of National Statistics as singleton births. Clearly,
consistent reporting of the fetus papyraceus is crucial, both for medical
research and monitoring of the other twin. 鈥淚t might be very important for the
surviving infant,鈥� says Pharoah. Although the jury is out on whether early
diagnosis and therapy for CP actually improves children鈥檚 motor skills, it is
invaluable for helping parents to cope, says Johnson. The earlier they know, the
sooner they can seek support. 鈥淭hat can make a huge difference to the whole way
in which a family functions,鈥� she says.

Pharoah is now studying the epidemiology of vanishing twins by following up
women whose ultrasound scans reveal twin pregnancy. However, most women who
conceive naturally only have their first scan done between 11 and 12 weeks into
pregnancy. 鈥淚 might be missing the cases where the twin is lost early,鈥� he
admits.

Cerebral palsy isn鈥檛 the only health problem that may be linked to a lost
twin. Although Pharoah has yet to collect evidence to back up his hunch, he
speculates that a wide range of birth defects, from absent kidneys to heart
malformations, may be due to damage caused by the death of a twin. The key to
the connection lies in the placenta and the chorion, the outer protective
membrane that encloses the developing baby in its fluid-filled amniotic sac.
Identical twins come from a single fertilised egg that splits to give two
embryos. Often, the twins share a chorion and a placenta. Sometimes they even
cuddle together in the same amniotic sac.

The shared placenta of such twins makes them vulnerable to problems, as the
placental blood vessels from one twin fuse with those of the other. 鈥淭here is
absolutely sure to be blood communication between them,鈥� says Blickstein.
Sometimes, this results in one twin getting far more blood than the other, the
so-called twin-to-twin transfusion syndrome: one twin grows far bigger than the
other, and both can die from complications.

Even non-identical twins can share a blood supply, Blickstein found.
Sometimes in singleton pregnancies, cells from a vanished, non-identical twin
turn up in tissue samples taken from the placenta by chorionic villus
sampling鈥攁 test used to detect Down鈥檚 syndrome and other chromosomal
abnormalities. This suggests that the twins once shared the placenta.

Whenever twins share a blood supply, Pharoah thinks that blood can shunt to
and fro, resulting in the death of one twin and starving the other of oxygen,
causing brain damage. 鈥淵ou are getting a whole gamut of damage,鈥� he says. 鈥淚
think that a lot of mental retardation is due to the same thing.鈥� If the damage
happens early in development, when organs such as the heart or kidney are
forming, similar shunting could damage these organs as well, he thinks.

Blickstein now has a worldwide team of sonographers hunting down the
placental connections between very young twins鈥� a challenge that is
pushing at the boundaries of technology because the fetuses are so small. 鈥淭he
problem is that we do not have enough sonographic power, even with the most
modern equipment,鈥� laments Blickstein.

Far from floating together in harmony in their watery Eden, it seems that
twins in the womb live a life fraught with dangers and sometimes conflict. And
far from being simply an evolutionary curiosity, vanishing twins are becoming an
important medical issue for parents and children alike. But even as we try to
peer inside the hidden world of the early twinship and understand its secrets,
our increasing reliance on artificial means to assist in creating our children
means that more and more of them are going to go missing.