Children born to women who took fertility drugs to get pregnant are more than twice as likely to develop leukaemia, according to new research from France.
Scientists from the Centre for Research in Epidemiology and Population Health (INSERM) based in Villejuif, Paris, looked at nearly 2500 children, 764 of whom had acute leukaemia, and quizzed their mothers on their fertility history. They discovered that women who used fertility drugs, which work by stimulating the ovaries, had a 2.6-fold greater risk of having a child diagnosed with acute lymphoblastic leukaemia (ALL)-the most common form of childhood leukaemia. They also had a 2.3-fold higher risk of having a child diagnosed with the rarer acute myeloid leukaemia (AML).
These findings, presented at the Childhood Cancer 2012 conference in London, are the first to show a specific connection between the use of fertility drugs and childhood leukaemia.
"Previous studies have suggested a link between infertility treatments and acute childhood leukaemia, but there haven't been many studies, most of them have been small, and they focused either on IVF [in-vitro fertilization] or hormonal treatment," reported lead researcher Dr Jeremie Rudant. "Our study was much larger and it's the first time that a specific increased risk linked to fertility drugs has been found."
Strangely, however, the study found no increased risk of leukaemia in the children born to mothers who had undergone IVF-even though almost all of these women would also have received ovary-stimulating drugs-and those who had been artificially inseminated.
The study also revealed that the children of parents who struggled to conceive naturally -taking at least a year to do so-were 50-percent more likely to develop ALL than the children of fertile couples. This suggests that infertility itself, or its underlying causes, might have a role to play in the development of childhood leukaemia.
Although the results are far from conclusive-and have yet to be published-they add to the growing concerns surround-ing the use of assisted repro-ductive technology (ART), the term that describes the various artificial methods now available to help with conception, such as IVF. Now that the technology has been in use for more than 30 years, with over four million babies born as a result, the long-term risks-both for mother and child-are becoming more apparent.
Childhood cancer is just one of the associated risks; others include breast and womb cancer in the mother, birth defects, multiple births and cerebral palsy.
The cancer connection
Fertility drugs, often used in conjunction with IVF, have not only been linked to cancer in children, but in the women who take the drugs, too. The drugs, which work by increasing levels of certain hormones in the body, may also be boosting the risk of hormone-related cancers such as breast and uterine (womb) cancer, according to several studies.
Clomiphene (Clomid), in particular, has been associated with certain hormonal cancers in women. In one study by the National Cancer Institute (NCI) of more than 12,000 women, clomiphene was linked to a significantly higher risk of invasive breast cancer (Hum Reprod, 2004; 19: 2005-13). Another NCI study, involving around 8000 women, revealed that clomiphene users were more likely to develop cancer of the uterus. Indeed, those taking the highest doses had the highest risk of the disease (Am J Epidemiol, 2005; 161: 607-15).
Earlier studies had suggested that the use of ovulation-stimulating drugs might raise the risk of ovarian cancer. But now, it appears that most of the data does not support a causal link (Curr Drug Saf, 2011; 6: 250-8). According to one review, the risk of invasive ovarian cancer was restricted to those women who remained childless despite infertility treatment (Curr Opin Obstet Gynecol, 2008; 20: 313-9), which again suggests that infertility itself could be a factor in the development of ovarian cancer.
Still, no one knows for sure and there's a lot of conflicting evidence. There's also a lingering question as to whether fertility drugs lead to the development of borderline ovarian tumours-tumours considered unlikely to spread, but which are still usually treated with surgery (Semin Reprod Med, 2012; 30: 131-45).
Other ART-ful risks
Besides cancer, the other big concern with infertility treatment is the risk of birth defects in the children born as a result. According to a 2009 report by the US Centers for Disease Control and Prevention (CDC), babies conceived through ART are two to four times more likely to have birth defects compared with babies born naturally. Of the pregnancies resulting in a single birth, ART was associated with twice the risk of heart defects and more than twice the risk of a cleft lip, with or without a cleft palate, and more than four times the risk of oesophageal and anorectal defects (Hum Reprod, 2009; 24: 360-6).
More recently, an Australian study from the University of Adelaide-the most comprehensive study of its kind in the world-compared the risks of having major birth defects with each of the reproductive therapies commonly available inter-nationally, including IVF and ICSI (intracytoplasmic sperm injection), where a single sperm is injected directly into an egg. Overall, the risk of any birth defect in pregnancies using ART was 8.3 per cent, compared with 5.8 per cent for pregnancies without ART. However, there were significant differences in risk among the various types of treatments.
The risk of birth defects for IVF was 7.2 per cent while the rate for ICSI was 9.9 per cent. Yet, interestingly, when the researchers took into consideration certain parental factors that could have affected the results, the IVF-birth defect link was no longer significant, whereas the link was still significant for ICSI, suggesting that the treatment itself could be causing serious abnormalities.
What's more, the researchers found that women who used the fertility drug clomiphene outside of a closely supervised clinical setting had triple the risk of a child with a birth defect (N Engl J Med, 2012; 366: 1803-13).
The single biggest risk for ART, however, is for multiple births, which increases the chances of stillbirth, neonatal death and disability in the children born. The UK's Human Fertilisation and Embryology Authority (see www. hfea.gov.uk) says that, on average, one in four IVF pregnancies is a multi-ple pregnancy compared with one in 80 among women who conceive naturally.
Babies are also more likely to be born prematurely and, so, are underweight at birth (Eur J Obstet Gynecol Reprod Biol, 2009; 146: 138-48). This can lead to various health problems, such as visual impairment and cerebral palsy. Indeed, children born through IVF are around twice as likely to have cerebral palsy (Arch Pediatr Adolesc Med, 2009; 163: 72-83).
There are also risks to the mother other than cancer, such as ectopic pregnancy and ovarian hyperstimulation syn-drome (OHSS), a potentially dangerous overreaction to fertility drugs. It's thought that up to one in 10 women taking such drugs will develop OHSS.
Of course, for anyone desperate to have a child, the proven and possible risks associated with infertility treatment may seem well worth it. However, these risks should be weighed against the chances of success, which are only about 25 per cent for either IVF or ICSI, and even less than that for other types of ART (see www.hfea.gov.uk).
Moreover, ART is not the only option for couples struggling to have a child. There are a number of natural ways to boost fertility and, with it, the chances of becoming pregnant, many of which are supported by good evidence (see box above and on page 19).
Indeed, the British charity Foresight, the Association for the Promotion of Preconceptual Care, has put together a thoroughly researched natural fertility programme that boasts a success rate of over 75 per cent (visit their website at www. foresight-preconception.org.uk for more information, or call 01275-878-953).
Finally, don't forget that there's always the option of adoption or fostering, as there's no shortage of domestic and foreign-born babies and children in need of loving homes.
Factfile: Natural ways to boost fertility
- Eat well. To raise levels of fertility hormones, follow a varied wholefood diet with high-quality proteins, and plenty of fresh vegetables and fruits. Drink only filtered or glass-bottled water.
- Maintain a healthy weight. Being either too overweight or too underweight can contribute to infertility (Fertil Steril, 1988; 50: 721-6).
- Stop smoking. A UK study of more than 17,000 women found that the more cigarettes a woman smokes per day, the less likely she is to conceive (Br Med J [Clin Res Ed], 1985; 290: 1697-700). Smoking has a negative impact on male fertility, too (Acta Med Port, 2009; 22: 753-8).
- Avoid alcohol. Even moderate alcohol consumption (five or fewer drinks per week) can contribute to infertility in women (BMJ, 1998; 317: 505-10). Also, the risk of endometriosis, a common cause of infertility, is around 50-per-cent higher in women with any amount of alcohol intake compared with teetotallers (Am J Public Health, 1994; 84: 1429-32). In men, alcohol consumption negatively affects sperm concentration and motility-the ability of sperm to propel themselves towards an egg (Fertil Steril, 2012; 97: 53-9).
- Limit caffeine. In 104 healthy women trying for a baby, those who drank a cup of coffee or more a day were half as likely to become pregnant, per cycle, as women who drank less than that (Lancet, 1988; 2: 1453-6). Indeed, the more caffeine-from any source (tea, cola drinks, chocolate bars)-the poorer the chances of pregnancy (Reprod Toxicol, 1998; 12: 289-95).
- Investigate allergies. Food allergies such as coeliac disease may also play a role in infertility (J Reprod Med, 2010; 55: 3-8). One woman with infertility and coeliac disease conceived eight months after going on a gluten-free diet. The researchers concluded that "coeliac disease should be checked in infertile patients of unexplainable aetiology with anaemia, as just changing their diet can solve their fertility problem" (Fertil Steril, 2010; 94: 2771).
- Consider nutritional deficiencies. A study by Dr Stephen Davies, of the Biolab Medical Unit in London, showed that magnesium deficiency is associated with female infertility, increased miscarriage rates, and increased incidences of premature and low-birth-weight babies. When magnesium supplements were given to six magnesium-deficient women with unexplained infertility for four months, all six conceived within the following eight months and had normal healthy babies. Six other women with unexplained infertility, whose magnesium levels did not normalize after four months of treatment, did so after a further two months of magnesium plus selenium supplementation. These women also conceived within the following eight months, and all gave birth to normal healthy babies (Magnes Res, 1994; 7: 49-57). In men, low levels of zinc have been linked to poor sperm quality and infertility (Nutr Res, 2009; 29: 82-8).
- Get tested for infections. Genital infection is a major cause of infertility worldwide (Enferm Infecc Microbiol Clin, 2001; 19: 261-6). Chlamydia trachomatis infections are the most common, and their incidence has increased over the past 10 years. When left untreated, Chlamydia infection becomes responsible for a large proportion of cases of salpingitis (inflammation of the fallopian tubes), ectopic pregnancy and infertility (Clin Microbiol Infect, 2009; 15: 4-10).
- Manage stress. Infertile couples tend to be more stressed out than fertile couples, which suggests that stress may have adverse effects on reproductive health (Int J Fertil, 1986; 31: 153-9). This may explain why relaxation techniques, such as meditation and yoga, have proved beneficial (Fertil Steril, 2003; 80 Suppl 4: 46-51).
- Limit exposure to toxic chemicals. Growing evidence suggests that infertility may be caused by common chemicals in the environment, such as pesticides and plastics chemicals. Although it's impossible to avoid all such dangerous chemicals, our Special Report in WDDTY vol 20 no 8 outlines the key risks as well as ways to minimize exposure.
Factfile: Pills with promise
- Propolis. In a study of women with infertility and mild endometriosis, supplementation with bee propolis (500 mg twice a day for nine months) was associated with a pregnancy rate of 60 per cent compared with only 20 per cent in those taking a placebo (Fertil Steril, 2003; 80 suppl 3: 32).
- Vitamin C may be helpful in women with luteal phase defect (LPD), a hormonal abnormality that commonly leads to infertility. In infertile women with LPD, 750 mg/day of vitamin C taken for up to six months led to a pregnancy rate of 25 per cent compared with 11 per cent in the untreated controls (Fertil Steril, 2003; 80: 459-61).
- Multivitamins. Taking just a simple multivitamin was found to increase female fertility in one trial. Compared with the placebo group, those taking a multivitamin supplement took 5-per-cent less time to conceive (Int J Vitam Nutr Res, 1996; 66: 55-8).
- l-Arginine (16 g/day) can improve fertilization rates in women with a history of failed IVF (Hum Reprod, 1999; 14: 1690-7). The amino acid can also improve sperm counts and sperm motility in men, as can carnitine, zinc, selenium and vitamin B12 (Altern Med Rev,2000; 5: 28-38).
- Agnus castus. In one trial, more infertile women became pregnant after taking a product containing this herb (30 drops twice a day for three months) than did those taking a placebo (Forsch Komplement"armed, 1998; 5: 272-8).