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Preconception management of endocrine disorders.

Byline: Bharti Kalra, Yashdeep Gupta and Sanjay Kalra

Abstract

Endocrine function is closely interlinked with pregnancy. Maternal and foetal outcomes can be improved if optimal endocrine function is achieved, and maintained prior to conception. This needs a systematic approach which includes rational screening, appropriate management, and pragmatic counseling. This review describes aspects of pre conception management related to various endocrine glands. Pre conception management of diabetes and thyroid will be covered in later articles.

Keywords: Adrenal, congenital adrenal hyperplasia, Hyperprolactinaemia, Metabolic bone disease, Pituitary, Polycystic ovary syndrome.

Executive Summary

All known endocrine disorders must be managed, and endocrine function optimized with appropriate therapy, prior to conception. Definitive (surgical, radioactive, or short term medical) therapy should be planned and completed. Long term medical treatment, including hormone supplementation/replacement, should be stabilized prior to conception.

Screening must be conducted for common subclinical endocrine disorders, which have the potential to adversely impact maternal or foetal outcomes. This can be done by taking a detailed history and conducting a physical examination. Menstrual disturbances, frequent headaches, visual symptoms, galactorrhoea, bone pains, muscle weakness, hirsutism and obesity/ weight gain are pointers of endocrine dysfunction.

Targeted endocrine function testing is indicated in women presenting with subfertility, bad obstetric history, and previous history of endocrine dysfunction.

In every case, the woman should be informed about the expected natural history of her condition, planned investigations for screening, diagnosis and management, course of treatment, financial implications, and anticipated foeto-maternal prognosis. Shared, informed decision making should be practiced at every step, in the spirit of person centered care.

Introduction

Endocrine function is closely interlinked with pregnancy.1 Maternal and foetal outcomes can be improved if optimal endocrine function is maintained. Endocrine dysfunction can usually be managed if detected early. Hence, there is a need to optimize endocrine function during the pre-conception period. This can be done by rational screening, appropriate management, and pragmatic counseling. Endocrine services are thus an integral part of pre conception management. Conventional categorization of drugs with regards to their use in pregnancy is followed in this text, even though the United States Food and Drug Administration (US FDA) has recently discontinued this process.2

Pituitary

Pituitary disorders may be associated with subfertility and adverse outcomes in pregnancy. Certain disorders, such as prolactinoma, may worsen during pregnancy. Hence, it becomes imperative not only to detect and manage them prior to conception, but also to prepare the woman for expected changes in pituitary function during the antenatal period.

Pre Conception Care

Screening for pituitary disorders in the preconception period is indicated only if clinical index of suspicion is high, and is based upon symptoms and signs. Required imaging, including MRI, should be performed prior to conception.

Hypogonadotropic hypogonadism is managed by induction of ovulation. Other hypopituitary states should be managed with appropriate replacement therapy. Patients with central hypothyroidism should aim to achieve a normal free T4 prior to conception. Antenatal monitoring is also done with free T4 values at regular intervals.

Patients on dopamine agonist therapy may have rapid restoration of fertility even before resumption of normal cycles and normalization of prolactin levels. Patients therefore need counseling regarding use of non-hormonal contraception till adequate tumour shrinkage and normal prolactin levels are achieved.

Prolactin levels should be normalized before conceiving. Asymptomatic patients harboring microprolactinomas do not need to be prescribed dopamine agonists.3 Symptomatic prolactin-secreting microadenomas may be treated with bromocriptine or cabergoline before pregnancy, to lower prolactin levels, decrease tumour size, and restore gonadal function. Both these molecules are classified as category B by US FDA. These drugs can be stopped once pregnancy is diagnosed and confirmed. Guidelines recommend using cabergoline in preference to other dopamine agonists because it has higher efficacy in normalizing prolactin levels, as well as a higher frequency of pituitary tumour shrinkage. Pre-conception duration of dopamine agonist therapy is an important prognostic factor, with duration of more than one year improving the chances of uneventful pregnancy.

Women with macroprolactinomas who do not respond to, or do not tolerate dopamine agonist therapy, should be offered surgical resection before attempting pregnancy. Patients with macroprolactinoma, who are on bromocriptine or cabergoline, should continue their medication during pregnancy. Especially if they did not have prior surgical or radiation therapy, the tumour is invasive or is abutting the optic chiasma.

Monitoring during pregnancy is done using symptoms (headache) and visual field charting. Serum prolactin is not recommended as a monitoring marker during pregnancy. Routine pituitary MRI should not be advised during pregnancy in patients with microadenomas or intrasellar macroadenomas unless there is clinical evidence for tumour growth such as visual field compromise.

Growth hormone secreting macroadenomas should be treated surgically, and replacement therapy optimized prior to conception.

Parathyroid/Metabolic Bone Disease

Metabolic bone disease (MBD) directly affects musculoskeletal health, 4 and may impair the ability of the body to withstand the physiologic stresses of pregnancy and labour. Pregnancy-induced osteopenia/porosis may be precipitated by pre-existing bone metabolic impairment.

Pre Conception Care

A detailed history of symptoms suggestive of MBD must be taken as part of preconception counseling. Past history should probe for history of pregnancy-induced osteoporosis, and cumulative length of breast feeding in multigravida. The nutritional history should evaluate calcium and vitamin D sufficiency, while lifestyle history should enquire about exposure to sunlight.

MBD, including osteomalacia /vitamin D deficiency, hyperparathyroidism and hypoparathyroidism must be managed appropriately prior to conception. Vitamin D and calcium supplements should be discontinued in women who are actively planning pregnancy, except in those with documented hypoparathyroidism. Hypoparathyroid women should continue calcium and Vitamin D supplements (both category N drugs) before and after conception, to ensure maintenance of serum calcium in the lower range of normal.5 Serum parathromone (PTH) may vary during pregnancy, and may not be a reliable marker. Urinary calcium to creatinine ratios are also difficult to interpret during pregnancy.6

Adrenals

Disorders of the adrenal cortex and medulla present a heterogeneous group of conditions. While some impair fertility, e.g., Addison's disease, Cushing's syndrome and congenital adrenal hyperplasia (CAH), others may flare up during pregnancy and cause unwanted consequences, e.g., pheochromocytoma. Certain preparations used for adrenal hormone replacement may have untoward effects on the foetus if administered for prolonged periods during pregnancy.

Pre Conception Care

Adrenal disorders, including pheochromocytoma, Cushing's syndrome, Addison's syndrome and CAH must be managed prior to conception. The risk of obstetric complications such as GDM and pregnancy- induced hypertension increases with adrenal disorders or adrenal replacement. Patients and their family/caretaker(s) must be educated about their disease, treatment options, and what to expect after remission.7 Patients with CAH must be offered genetic counselling as part of pre conception care. The Endocrine Society recommends against routine prenatal dexamethasone therapy to prevent CAH in pregnancy, and does not recommend any specific treatment protocols.

Addisonian patients needing glucocorticosteroid replacement during pre-conception or pregnancy should use hydrocortisone instead of prednisolone or dexamethasone. However, prednisolone preparations may be used if hydrocortisone is unavailable. While all three drugs fall in category C as described by the US FDA, glucocorticoids that traverse the placenta, such as dexamethasone, should be avoided as treatment of pregnant patients with CAH.8 Patients needing mineralocorticoid replacement may use fludrocortisone, also a category C drug, during preconception or pregnancy. Though it is difficult to draw definitive conclusions about the need for glucocorticoid therapy in all non-classic CAH (NCCAH) women, pre conception treatment may benefit those with infertility or with a history of abortions.

Pre-pregnancy doses of glucocorticoids and fludrocortisone should be continued once pregnancy is diagnosed, and doses adjusted only if symptoms and signs of insufficiency occur. Stress doses of glucocorticoids should be used during intercurrent physical illness, but not with episodes of emotional stress or exercise.9 Dehydroepiandrosterone (DHEA) is not indicated in preconception or antenatal phase, unless DHEA-S deficiency is documented and confirmed. Patients on anti-androgen therapy such as spironolactone should discontinue the drug at least three months prior to conception. Adequate contraceptive measures must be followed in patients on anti-androgen therapy.

Pheochromocytoma and Cushing's syndrome should be treated surgically, and medical therapy stabilized, prior to conception.

Gonads

Polycystic ovary syndrome (PCOS) is a frequently encountered condition in women presenting for preconception care. Women with PCOS are at an increased risk of subfertility, and at a higher risk of pregnancy complications including gestational diabetes, preterm delivery, and pre-eclampsia.10

Pre Conception Care

Preconception assessment of body mass index, blood pressure, and oral glucose tolerance is recommended. Routine screening for nonalcoholic fatty liver diseases (NAFLD) and nonalcoholic steatohepatitis (NASH) is not recommended.

PCOS is a syndrome of hyperandrogenism, and testosterone levels should be normalized prior to conception. Women with PCOS should be counseled to continue life style therapy, i.e., diet and exercise, to achieve weight loss. Every effort should be made to reduce pre pregnancy body mass index (BMI) to as near as normal, prior to conception. Lifestyle modification and physical activity, can be continued in the pre conception phase. Orlistat (category X) and liraglutide 3.0 mg (category C), which are approved for use as anti-obesity drugs in non-pregnant individuals, should be discontinued prior to conception.

Hormonal contraceptives should be discontinued at least 3 months prior to planned conception. Metformin (FDA pregnancy category B) is not recommended as first line treatment of cutaneous manifestations, for prevention of pregnancy complications, or for the treatment of obesity. If, however, it has already been prescribed, it may be continued during pre-conception in women with PCOS who exhibit symptoms and signs suggestive of metabolic syndrome (dysglycaemia, high blood pressure, dyslipidaemia, central obesity). Oral contraceptive therapy (category X), spironolactone (category C), finasteride (category X) and flutamide (category D), if prescribed should be discontinued prior to conception.

Local therapy such as laser and epilatory treatment can be continued during the pre-conception phase. Eflornithine cream is an FDA category C drug for use in pregnancy. An informed and shared decision should be made regarding its use in pre conception, based upon individual risk benefit assessment.

Summary

Rational endocrine screening is an integral aspect of pre conception care. Optimization of endocrine function helps ensure better outcomes in pregnancy.

References

1. Smith ML, Schust DJ. Endocrinology and recurrent early pregnancy loss. Semin Reprod Med 2011;29:482-90.

2. Pregnancy and Lactation Labeling (Drugs) Final Rule. Available at: http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/labeling/ucm093307.html. cited on March 7, 2016.

3. Melmed S, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VM, Schlechte JA, Wass JA, Endocrine Society. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011; 96:273-88.

4. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM, Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:1911-30

5. Hatswell BL, Allan CA, Teng J, Wong P, Ebeling PR, Wallace EM et.al, Management of hypoparathyroidism in pregnancy and lactation-A report of 10 cases. Bone Reports. 2015;3:15-9.

6. McCullough K, Martin N, Palazzo F, Williamson C, Meeran K. Management of primary hyperparathyroidism during pregnancy: a case series of the lessons learnt. Available at: http://www.endocrine-abstracts.org/ea/0031/eposters/ea0031p69_eposter.pdf. Cited on March 7, 2016.

7. Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A. Treatment of Cushing's syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100:2807-31.

8. Speiser PW. Congenital adrenal hyperplasia. F1000 Research. 2015; 4(F1000 Faculty Rev).

9. Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP et.al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010; 95:4133-60.

10. Legro RS, Arslanian SA, Ehrmann DA, Hoeger KM, Murad MH, Pasquali R et.al. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013;98:4565-92.
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Publication:Journal of Pakistan Medical Association
Date:Nov 30, 2016
Words:2123
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