The number one no-no during IVF
It's common for three or more rounds of IVF (in-vitro fertilisation) treatment to be unsuccessful, that is, to not to result in a pregnancy. The frustration leads many women to seek explanations and investigate alternative options. These may include complementary medicine and other unproven and unsafe medications.
One contentious option - sometimes offered by IVF clinics in Australia and overseas after unsuccessful IVF cycles or unexplained miscarriages - is the use of corticosteroids.
These are steroid hormones that can either be made in the body or in a lab. Synthetic corticosteroids, such as prednisolone, have a potent effect on suppressing the immune response and dampening inflammation.
Corticosteroids are often used to treat life-threatening autoimmune diseases such as lupus, severe allergies and to prevent rejection of organ transplants. But they can also have serious side effects including infections, insomnia, heart problems, mood changes, weight gain and headache.
Demand by people with fertility problems for corticosteroids, and other immune suppressants sometimes offered at IVF clinics, is driven in large part by medical and consumer misunderstanding of how the immune response works.
The immune system in pregnancy
Many doctors hold an outdated view that immunity is naturally reduced in pregnancy. So they infer it's acceptable to suppress the immune system by medication.
The argument for immune suppression in pregnancy ignores clear evidence that a controlled immune response is an essential part of normal embryo implantation, required for healthy fetal growth. Although the uterus often appears unable or unwilling to allow embryo implantation, turning off the immune system with drugs doesn't solve the problem.
The immune system is important because it defends the body against infections and cancer. In pregnancy, immune cells help the uterus tolerate and nurture the embryo despite it carrying foreign genes from the father. Immune cells also encourage blood vessel changes that stimulate development of the placenta.
Most infertile women don't have identified immune dysfunction. Therefore, immune suppression at conception contravenes normal biology, and acts against natural processes that promote healthy fetal development.
The outdated theory holds that natural killer (NK) cells, which are like the soldiers of the immune system and can be found in the uterus, are "embryo killer" cells that must be removed or disarmed. Corticosteroids may be given for up to 12 weeks after conception in an effort to reduce these cells.
There are several problems with this. Results from diagnostic tests for NK cells are unreliable and of questionable value. Extensive studies confirm measuring NK cells either in blood or in the uterus is not useful in predicting infertility or miscarriage. These cells vary enormously within and between different women, all within a normal range.
It is possible that for some women without a high NK cell count, corticosteroids could reduce numbers below threshold levels required to support adequate placental development.
Without enough NK cells and other immune cells at conception, the placenta may not grow correctly and can become overworked as fetal demands increase. This compromises nutritional support for the fetus as gestation progresses, affecting fetal growth and timing of birth.
Not so safe or effective
The false perception corticosteroid drugs are effective and safe is encouraged by records from IVF pregnancies in women taking corticosteroids for autoimmune disorders. The overall, relatively low chance of adverse effects in this rare patient group has prompted broader use of corticosteroids when there is no immune disorder.
But although their pregnancies usually progress normally, there is a higher chance of pregnancy problems and an elevated rate of fetal malformations for women taking corticosteroid drugs. Prescribing doctors judge the potential benefit is worth the minor risk, but this is arguable for women without autoimmune disorders.
A key problem is there is no convincing evidence for any benefit on fertility. A recent meta-analysis drawing together data from 13 studies showed only a borderline effect of using a certain type of corticosteroid in a subgroup of 650 women undergoing IVF, and no effect in a larger group of 1,759 women. Importantly, there was no overall benefit for delivery of a live infant after IVF.
Few studies follow up the health outcomes of the infant after corticosteroid use in IVF. When birth outcomes have been tracked, data suggest adverse effects similar to those in women taking corticosteroids for autoimmunity. One study of 311 women who used corticosteroid drugs beyond the first trimester showed a 64% increase in miscarriage and around a two-fold increase in preterm births.
A larger study showed corticosteroid use during early pregnancy is linked with cleft lip and palate in infants. Fetal organ structures develop most rapidly in the first trimester. Given the pivotal role of immune cells in fetal growth, these effects are hardly surprising. It is unreasonable to claim that using low doses, or limiting drug use to the first 12 weeks, removes the risk.
Proven therapies for infertility associated with implantation failure and unexplained miscarriage are urgently needed, but corticosteroids are not the answer. While in the specific circumstance of autoimmunity some women benefit from these drugs, in most women, suppressing the immune response is likely to cause more harm than good.
Professor and Director, Robinson Research Institute, University of Adelaide
Sarah Robertson receives funding from the National Health and Medical Research Council.