Achieving a Pregnancy with
Congenital Adrenal Hyperplasia
An Information sheet
Many women with CAH are able to conceive without adjustment to their routine treatment. Sometimes, however, the adrenal treatment has to be precisely adjusted in order for pregnancy to occur. There are several components in the process of achieving normal function of the ovary and of the uterus simultaneously and activity coming from the adrenal gland can cause problems at each stage.
In general, higher doses of steroid treatment are more effective at suppressing the adrenal gland and improve fertility. The timing of steroid treatment throughout the day also has to be considered as even a few hours of "adrenal escape" can have an adverse affect on fertility at particular times in the menstrual cycle. Therefore, a balance has to be achieved between the side-effects of higher dose steroid treatment such as weight gain and the beneficial effects of treatment on fertility.
An excess of testosterone coming from the adrenal gland can prevent the ovary from releasing an egg and if this happens periods become irregular in their timing or may stop altogether. Progesterone coming from the adrenal gland can prevent the lining of the womb from becoming receptive to the embryo which can therefore fail to implant. The effect of progesterone is often overlooked and can be the most difficult to correct.
The bottom line – these are the simplified rules:
• Prednisolone 2.5 mg every 8 hours will suppress testosterone, and, more importantly, progesterone in most people with CAH. Do not miss a dose but varying by an hour or two is OK. Most women will get pregnant on this regimen but some may need to take it 4 times per day (about every 6 hours).
• The concentration of progesterone should be below 2.0 nmol/L (0.63 ng/mL) on day 7 of the cycle (7 days after the first day of the period). The progesterone measurement can only be used once 17 hydroxy-progesterone is down (ie completely suppressed) as the two compounds cross react in most systems.
• Plasma renin activity should be completely suppressed as progesterone also comes from the aldosterone pathway. The dose of fludrocortisone may need to be increased, or added if it is not routinely taken, in order to achieve this.
Achieving regular periods
By taking regular steroid treatment, usually hydrocortisone or prednisolone, over activity from the adrenal gland can be controlled. On blood testing this is shown by having normal or low levels of testosterone, androstenedione and 17 hydroxy-progesterone on the routine blood test. Once this is achieved then regular periods should start to happen although there can be a delay of many weeks or even months before the regular cycle is reliable depending on how good the past control has been.
Most women with CAH have more than 12 follicles visible within each ovary thus meeting the criteria for the label "polycystic ovaries". This is not the same as polycystic ovary syndrome. Once the adrenal treatment has been adjusted correctly then polycystic ovaries are rarely a problem and they usually behave in the normal fashion delivering an egg - ovulating - reliably. In other words – polycystic ovaries on ultrasound are not usually a problem for women with CAH.
It is possible to have periods without ovulating, particularly in a transition phase when changing from a time with no periods at all. That is, periods can return before ovulation is reliable and by keeping consistent adrenal treatment, ovulation usually follows. There are several ways to check for ovulation.
• Ultrasound: The best is to use ultrasound of the ovary on several occasions throughout the cycle to watch the follicles grow to a size when the eggs should be released, followed by the appearance of a corpus luteum that is formed after ovulation. This is called ovulation tracking.
• Home testing kits: Home ovulation kits can be found in chemists and this works well for women with CAH.
• Blood progesterone: The test commonly requested by doctors is the measurement of progesterone on a blood test and this does not work well for women with CAH as it can give a false impression that ovulation has occurred. This is because the test can pick up interference from progesterone or 17hydroxy-progesterone made by the adrenal gland.
Achieving a receptive endometrium
The lining of the womb, or endometrium, thickens in the first two weeks of the fertility cycle to become receptive for the embryo which should implant about one week after ovulation. If progesterone is in the circulation during the first two weeks of the cycle then the lining does not develop properly. On an ultrasound scan the endometrium appears too thin – less than 7 mm instead of over 10 mm. This effect of progesterone is how the progesterone only – or minipill – works as a contraceptive.
In CAH, progesterone from the adrenal gland can act as a contraceptive on the endometrium. It may be that only a few hours of exposure to progesterone would be enough to have its effect. Therefore, for the first two weeks of each cycle the timing of taking tablets of prednisolone is critical. Missing one will allow the adrenal gland to make progesterone. For most women, taking Prednisolone 2.5 every 8 hours is sufficient to keep the progesterone level down. A blood test should confirm this when timed for about the 7th day of the menstrual cycle counting the first day of the period as day 1. The aim is to achieve a serum progesterone concentration below 2 nmol/L. There is about a 10% cross reactively of 17 hydroxy-progesterone (17OHP) in the laboratory measurement of progesterone so the 17OHP needs to be completely suppressed before progesterone can be accurately assessed. Some women with CAH persistently make progesterone even when 17OHP is under control and this can be difficult to treat effectively.
It is important to note that progesterone is part of the pathway to aldosterone which is a hormone lacking in salt losing CAH. Plasma renin activity (PRA) is used to estimate if there is a lack of aldosterone. When PRA is raised so the drive to make progesterone from the aldosterone pathway is increased. Therefore, PRA should also be measured on the day 7 blood test and the dose of fludrocortisone can be increased to suppress this source of progesterone if necessary.
In order to achieve a pregnancy the overall aim is to suppress blood concentrations of testosterone, androstenedione, progesterone, 17 hydroxy progesterone and plasma renin activity simultaneously with particular care over the first two weeks of the menstrual cycle. The higher dose of steroid treatment required to achieve this can cause side-effects, particularly with weight gain and sometimes depression or disturbed sleeping pattern. It is therefore important to maximise the chance of pregnancy with each cycle by monitoring ovulation and timing intercourse. Before starting this treatment program it is also important to make sure that there are no other fertility problems. For instance, a partner’s sperm count should be completed before adjusting CAH treatment.
Management in pregnancy
Pregnancy usually proceeds without particular problems for women with CAH. The doses of steroid treatment should be reduced to the normal maintenance levels before any changes are made in order to conceive. The dose of hydrocortisone and prednisolone does not usually have to be adjusted in pregnancy apart from the usual "sick day" rules. Dexamethasone should not be used in pregnancy as it crosses the placenta.
All of the routine blood tests used to monitor women with CAH are not helpful when pregnant. Testosterone, progesterone, 17 hydroxy-progesterone and plasma renin activity normally rise in pregnancy and so suppressing them with higher dose steroid treatment should not be attempted. In any case, the baby is completely protected from the mother’s adrenal hormones which are inactivated by the placenta. Fludrocortisone may need to be adjusted if low blood pressure becomes a problem in the last trimester of pregnancy.
Childbirth for women with CAH
A plan for childbirth should be made well ahead of time. In particular, a careful assessment of any scarring from surgery around the vagina should be made, preferably by a gynaecologist who is familiar with the type of operations that may have been performed earlier in life. If there is any doubt about whether scar tissue could be a problem with vaginal delivery then a Caesarean section may be indicated.
At the onset of labour, or at the beginning of a Caesarean section, hydrocortisone 50 - 100 mg by intramuscular injection should be given and this can be repeated every eight hours until normal tablet treatment can start again. No supplement to fludrocortisone is required. The endocrinology team should be informed as soon as a woman with CAH is admitted so that the adrenal treatment can be reviewed.
Background of this information sheet
This information sheet has been prepared by Professor Gerard Conway, Consultant Endocrinologist University College London Hospitals, London, UK. The information provided is based on experience gained over 20 years in an adult CAH clinic and is not intended to be a comprehensive reference. Other specialist centres may hold different views and as this is an area where there is very little scientific evidence it must be accepted that much of the information is personal opinion. The information sheet is offered in the spirit of informal information and the accuracy cannot be guaranteed as new research may make some of the conclusions out of date.
23rd September 2013