Of course, there are no indications for oestrogen replacement therapy [synonymous with hormone replacement therapy, HRT] in pregnancy. However, there are certain endocrinopathies which are coincidental to pregnancy, which do require hormone replacement for practically the entire duration of gestation.
In this article, we examine practical aspects of such conditions and highlight the basic principles of management.
The general principles that guide the treatment of endocrine disease in pregnancy are summarised below:
Endocrinopathies and their management in pregnancy: hallmarks
- Multi-disciplinary care, involving Endocrine Physician
- Specific Results flow chart.
- Acute management guide.
- Anaesthetist informed
- Written plan of management for the rest of pregnancy, in labour and post-partum.
- Patient information letter or leaflet.
- Paediatrician informed.
Many endocrinopathies are uncommon. The common ones may have inter-patient factors that may require differences in management strategy. Recommendations for the management of replacement therapies are usually based on experience, reliable guidelines and the occasional clinical review1.
It certainly helps if the patient’s GP or her Endocrinologist is aware of a planned or early ongoing pregnancy, as the necessary information retrieval is easily and smoothly undertaken. Occasionally, it may be wise to repeat hormone profiles, so as to obtain a baseline against which to formulate achievable goals.
Joint management clinics are useful in this regard, since they avoid the duplication of interaction and divergence of core care, and save the patient, repeated visits. Most women will probably require relatively few such visits, as long as the Community Midwife and other hospital practitioners have access to a written plan of care.
The Endocrine Nurse Specialist is invaluable, as they can bridge the gap between patient, GP and community midwife on the one hand; and the hospital, on the other.
Certain endocrinopathies affect the patient’s psyche so much that it may reflect on their sense of self-worth and risk-taking behaviour: these need to be taken into account in understanding their attitude to their condition and recommended treatment(s).
Many patients with endocrine disorders probably know about their condition than the average doctor. The internet, as a source of useful and confusing information must not be ignored when it comes to why a patient challenges a decision, asks disturbingly difficult questions, or seeks a second opinion . Specific information leaflets will do for most patients. However, these must be updated regularly, as new developments occur all the time.
The management of many endocrinopathies will not be clearly detailed in the protocols of many secondary care hospitals. Yet, information on the treatment and steps that could be lifesaving may not be available outside hours, on weekends and when the Endocrine Consultant is not readily reachable.
Ovarian Hormone Therapy
Progesterone promotes gestation. Two instances in the course of pregnancy appear to warrant its supplemental use. Following ovarian stimulation, and the use of agents to inhibit a premature LH surge, the corpus luteum seems unable to produce critical levels of progesterone. Most UK assisted conception centres administer parenteral Progesterone for up to 2 weeks after egg retrieval. This was described by one author2 as ‘progesterone replacement’.
In recent times, progesterone has also been suggested as a potential tocolytic . The ‘progesterone withdrawal theory’ may be recalled, as one explanation for the onset of term labour. Some studies show that it may have a role in the prevention or postponement of preterm labour3,4. The duration of its administration, and whether maternal progesterone levels are influenced will determine whether this is more of a placebo effect. Currently, progesterone is not commonly used for tocolysis in the UK. One Canadian survey5 of prescribing habits found that only 7% of Canadian obstetricians prescribed progesterone for the purpose. It points out the general reluctance to use it, despite published evidence, including randomised controlled trials, citing the bad experience with Diethylstilboestrol (DES).
This remains the commonest HRT in pregnancy. Details of the management of diabetes mellitus in pregnancy have been detailed elsewhere6.
Insulin therapy is the cornerstone of management of Type I Diabetes in pregnancy. The patient’s lifestyle and activity, access and use of educational plans and programmes and dietary optimisation, are equally important. Although the patient’s BMI has no direct relationship with the required dose of insulin, morbid obesity is particularly associated with increased insulin doses. So does smoking, alcohol use and a sedentary lifestyle.
The correct dose of insulin is that which keeps the pre-prandial and post-prandial blood sugars between 4 and 6 mmols. Multiple doses may be required to achieve this, and very occasionally, intensive subcutaneous insulin may be necessary7. Somogyi phenomenon and hypoglycaemia awareness are infrequent in pregnancy, but may affect compliance and psycho-social lifestyle.
It is to be remembered that weight gain and hypoglycaemia are the commonest side-effects of insulin therapy, and these may affect compliance.
Metformin may be a useful adjunct to insulin therapy, especially when a patient requires very high total doses of insulin to achieve euglycaemia8. This use is yet to be approved of, in the United Kingdom.
Recombinant insulin however, remains a good option in controlling brittle diabetes, and ensuring better 24-hour control.
Insulin doses are to be adjusted in 1-2 unit steps, weekly.
An unexplained fall in insulin requirements in the last few weeks of pregnancy may be an indication to consider delivery.
The administration of corticosteroids to mothers, towards enhancing fetal pulmonary maturation, or in short regimes for acute prophylactic events, sepsis, rheumatic disorders or allergies are not regarded as replacement therapies.
Congenital Adrenal Hyperplasia[CAH] is a frequent indication for steroid therapy. The premise of this within the concept of ‘HRT in pregnancy’ needs some clarification.
A conceptus is at risk if its parents are known to be heterozygous for the autosomal recessive enzyme defect. They may have had a previously affected child. It is remarkable that the fetal adrenal glands have already commenced hypersecretion of precursor steriods by the 6th to 8th week of pregnancy. Prenatal treatment in this case is aimed at inhibiting androgen production (in the female conceptus), thereby preventing virilisation before 9 weeks elapsed since mother’s last menstrual period, and to prevent the progression of such virilisation thereafter9.
When mother herself has CAH, the administration of corticosteriods is a replacement therapy. In some cases, high maternal serum testosterone levels may suggest an inadequate glucocorticoid suppression of adrenal androgens10.
Up to 75% of women with classic CAH also have a defect in their ability to synthesize Aldosterone.
The need to replace the mineralocorticoid , is what CAH mothers also share with mothers with Addison’s disease.
Addison’s disease is certainly less commonly seen than CAH. In case reports, they were often diagnosed late11, presented with vomiting and collapse in pregnancy12 or after delivery13.
Fludrocortisone therapy is aimed at replacing Aldosterone function. There is a need to reduce the dose of Fludrocortisone if the patient develops pre-eclampsia or unexplained fluid retention.
Apart from clinical symptoms, monitoring of blood pressure, serum electrolytes and plasma renin levels will give an indication of adequacy of its replacement14.
Hydrocortisone is typically prescribed15 as corticosteroid replacement but Prednisolone or Cortisone may be given, as they are metabolised by the placenta.
The dose of Hydrocortisone may need to be increased in the presence of vomiting in early pregnancy, or doubled in the third trimester14.
The consequences of prolonged steroid replacement therapy on both the mother and her fetus need to be carefully discussed. In the fetus, this includes fetal growth restriction, adrenal suppression and probably a long-term effect on neuropsychological development16.
Following delivery, some patients with Addison’s disease may suffer profound hypotension, and feel quite unwell17. It is preventable if ‘stress doses’ of corticosteroids have been prescribed to cover the duration of labour. It is important that the Anaesthetists are informed about a patient in labour, who is on such doses of steroids.
In the classical ‘Addisonian crisis’, the patient presents with extreme weakness, confusion, hypotension, hyperaemia and hypoglycaemia. This is very rare. Treatment includes saline and dextrose resuscitation and administration of intravenous hydrocortisone and fludrocortisone. Their doses are tapered down over 10 days.
A deficiency of thyroxine has both maternal and fetal consequences. Hypothyroidism was one of the endocrine dysfunctions for which the effects of hormone replacement were so easily demonstrated in sub-primate species.
Although hypothyroidism itself is associated with subfertility, the achievement of pregnancy may be complicated miscarriage, preterm delivery and fetal death. In the mother, there is usually a family history and diagnosis typically antedates conception.
There is no other therapy than Thyroid hormone replacement18.
Most clinicians aim to achieve pregnancy-specific reference ranges of TSH and T4 peri-conceptionally, and follow these through with serum level checks and indicated dose adjustments at the beginning of every trimester.
Maternal symptoms alone are not a good indication of adequate hormone replacement, except with significant over-dosing. It is believed in some quarters that iatrogenic overdosage is the commonest cause of subclinical hyperthyroidism in the US. Fetal losses have been documented in association with this19.
Doses need to be reduced postpartum, particularly if there has been an upward adjustment in pregnancy.
Thyroxine replacement therapy may also be indicated in women with hypofunction secondary to anterior pituitary dysfunction e.g. Sheehan’s syndrome [see below].
Hypothalamic/Pituitary Hormone Therapies
Hypofunction of the hypothalamic and pituitary-derived hormones may present with a range of clinical features, including amenorrhea, infertility and hypothyroidism. Satisfactory management of these may be followed by pregnancy.
Rarely does any significant disorder in this category present for the first time in pregnancy20, 21.
Deficiency in Adrenocorticotropic hormone (ACTH), Thyroid Stimulating Hormone (TSH), Growth hormone (GH) and Antidiuretic hormone (ADH) may occur each in isolation, or jointly. A review in the Lancet22 draws attention to the under-estimates of hypothalamic-pituitary dysfunction consequent upon traumatic brain injury, neurosurgery and cranial irradiation among others.
The three important dysfunctions of note include Diabetes insipidus, Sheehan’s syndrome, and Lymphocytic hypophysitis. Sheehans’ syndrome is becoming increasingly rare because of good management of peripartum bleeding and hypotension, while the Lymphocytic hypophysitis is more frequently diagnosed because of greater awareness of autoimmune disorders and better imaging techniques.
The need to replace the specific deficient hormones should be based upon clinical experience, endocrine testing results cognisant of diurnal variation and the presence of other disorders. Most patients require glucocorticoids and thyroxine replacement17.
In women, who have been on GH replacement therapy before pregnancy, there is no alternative source for endogenous GH only in the first half of pregnancy. Although it is thought that GH replacement therapy is probably not essential during pregnancy23, two successful consecutive pregnancies in a woman who was on Growth hormone replacement24, has been reported.
For now, the best choice is not clear.
Diabetes insipidus [DI] is the main differential to Diabetes mellitus in terms of symptomatology, but has its aetio-pathogenesis in the absolute or relative absence of Vasopressin from the neurons from the hypothalamus.
DI is characterised by polydipsia, polyuria and decreased urinary osmolality25.
The condition appears to worsen in pregnancy because of placental vasopressinase activity. Reporting on two women from Japan, Iwasaki et al26 found that one of them had a subnormal urinary response to Vasopressin, but normal response to Desmopressin. In the same vein, a previously un-diagnosed DI, may manifest for the first time in pregnancy.
Recurrent DI in pregnancy is not unknown27, and may be complicated by severe oligohydramnios despite replacement therapy with Desmopressin.
Although adjuvant therapies do help, the definitive treatment is with nasally or sublingually administered Desmopressin (DDAVP). This may be administered as a nasal spray, and requires some attention to blood pressure and fluid-electrolyte balance.
Principles Of Care
Because of the large molecular weight of hormones, and the theoretical unlikelihood of transplacental passage, it is tempting to assume that indicated HRT in pregnancy is safe. Fetal consequences would be expected to mirror maternal endocrine homeostasis.
This however, is an assumption to be made with caution.
Monitoring of fetal growth in the third trimester is important. It is also a good clinical practice to always question the relationship between certain fetal findings (fetal tachycardia, reduced fetal activity, hydramnios) and the underlying endocrinopathy, and its replacement therapy. Access to, and advice from a fetal medicine service is always useful.
Hormone replacement in pregnancy is a complex subject, but a few fundamental requisites are relevant (Table 1).
The replacement of specific hormones in the pregnant patient is an interesting aspect of antenatal care, which requires a clear understanding of the clinical problem1,28 and the limitations of our knowledge.
Table 1: Requisites in HRT in pregnancy
- Predictable and (in)directly measurable bio-availability of the administered hormone
- Negligible transplacental transport or diffusion
- Easily reversible effects of mistaken overdose
- No significant collateral physiological effects
- Maternal dose of specific HRT is independent of BMI
- Howlett TA. Hypopituitarism: replacement of adrenal, thyroid, and gonadal axes. In: Oxford Textbook of Endocrinology and Diabetes. (eds: JAH Wass and SM Shalet). Oxford University Press pp 145-151.
- Lavery S. Drugs used in reproductive medicine. Current Obstetrics & Gynaecology 13: 355-361.
- da Fonseca EB, Bittar RE, Carvalho MHB. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk : A randomised placebo-controlled double blind study. American Journal of Obstetrics and Gynecology  188: 419-424.
- Dodd JM, Flenady V, Cincotta R et al. Prenatal administration of progesterone for preventing preterm birth. Cochrane Database of Systematic Reviews  1. CD 004947.
- Hui D, Liu G, Kavuma E et al. Preterm labour and birth: a survey of clinical practice regarding use of tocolytics, antenatal corticosteroids, and progesterone. Journal Of Obstetrics and Gynaecology of Canada  29 (2) 117-130
- Black RS, Gillmer MDG. Diabetes in pregnancy. The Obstetrician & Gynaecologist . 5: 143-148.
- American Diabetes Association. Continuous subcutaneous insulin infusion. Diabetes Care 27: S10
- Glueck CJ, Goldenberg N, Wang P et al. Metformin during pregnancy reduces insulin, insulin resistance, insulin secretion, weight, testosterone and development of gestational diabetes: a prospective longitudinal assessment of women with polycystic ovary syndrome from preconception throughout pregnancy. Human Reproduction  19(3) 510-521.
- American Academy of Paediatrics. Technical Report: Congenital Adrenal Hyperplasia. Pediatrics  106(6) 1511-1518.
- Lo JC, Schwitzgebel VM, Tyrell JB et al. Normal female infants born of mothers with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Journal of Clinical Endocrinology and Metabolism  84:930-936.
- Scrimin F, Panerari F, Guaschino S. Addison’s disease and hypothyroidism untreated until twenty-four weeks of pregnancy. Acta Obstetrica et Gynecologia Scandinavica  84(2) 198- 199.
- George LD, Selvaraju R, Reddy K et al. Vomiting and hypothyroidism in pregnancy. British Journal of Obstetrics and Gynaecology  107 (6) 808-809.
- Glazier M, Waldron WM. An unusual cause of postpartum vomiting. Archives of Family Medicine  9 (3) 284-286.
- Arlt W. What’s new in adrenal insufficiency and what’s stress? Education Resource from the Society of Endocrinology. www.endocrinology.org/education/resources/summer school/2004/ss04/ss04_arl.
- Lova K, Husebye ES. Addison’s disease. Eponym. The Lancet  365: 2058-2061.
- Seckl JR, Miller WL. How safe is long-term prenatal glucocorticoid treatment? Journal of the American Medical Association 277(13) 1077-1079.
- Nelson-Piercy, C. Handbook of Obstetric Medicine. 3rd Edition. Informa Healthcare, Abingdon.  pp 125-143.
- Lazarus JH. Current aspects of thyroid disease. Current Medicine. Proceedings of the Royal College of Physicians of Edinburgh 31: 180-185.
- Anselmo J, Cao D, Karrison T et al. Fetal loss associated with excess thyroid hormone exposure. Journal of the American Medical Association  292: 691-695.
- Hime MC, Richardson JA. Diabetes insipidus and pregnancy: case report, incidence and review of the literature. Obstetric and Gynecological Survey 33: 375-381.
- Grimes HG, Brooks MH. Pregnancy in Sheehan’s syndrome: report of a case and review. Obstetric and Gynecological Survey  35: 481-486.
- Schneider HJ, Aimaretti G, Kreischmann-Andermahr I et al. Hypopituitarism. Seminar. The Lancet  369:1461-1470.
- Curran AJ, Peacey SR and Shalet SM. Is maternal growth hormone essential for a normal pregnancy? European Journal Of Endocrinology 139:54-58.
- Brackenbridge AL; Breen L and Russell-Jones D. Growth hormone deficiency and pregnancy. British Endocrine Societies Joint Meeting. Glasgow, UK. 24th March 2003-26th March, 2003. Endocrine Abstracts 5: P55.
- Ball S. Diabetes insipidus. Medicine: the continuously updated review of clinical medicine  33(11) 18-19.
- Iwasaki Y, Oiso Y, Kondo K et al. Aggravation of subclinical diabetes insipidus during pregnancy. New England Journal of Medicine  324(8) 522-526.
- Kumar A, Thirumalavan VS and Kumari V. Diabetes insipidus in pregnancy. Case report. Hospital Physician  47-49.
- Shehata H, Ahmed K. Other endocrine disorders in pregnancy. Current Obstetrics & Gynaecology  14: 387-394.