Primary hyperparathyroidism (pHPT) does not decrease fertility but is detrimental to the health of mother and fetus. It is therefore an unfortunate truism that the optimal timing for parathyroid surgery in pregnancy would be before the pregnancy had occurred.
All women with pHPT of reproductive age (defined by WHO as 15–49 years) meet the National Institute for Health Research/International Consensus criteria for parathyroidectomy and are therefore usually referred for surgery. Those with known multiple endocrine neoplasia type 1 are managed more conservatively, being advised to undertake family planning and undergo surgery when their biochemistry, symptoms or end-organ damage necessitate.
Pregnant women with pHPT present a clinical dilemma, due to the need to balance the risks of untreated pHPT to the fetus and mother against the risks of the treatment.
HOW OFTEN DOES THIS OCCUR?
It is hard to get an accurate estimate of the scale of this problem. First, the diagnosis of pHPT is most commonly incidental; calcium is not routinely measured in healthy young women, during pregnancy, or even in recurrent miscarriage. Secondly, the symptoms of hypercalcaemia (i.e. nausea and vomiting, fatigue and other non-specific malaise) overlap with those of a ‘normal’ pregnancy, causing the diagnosis to be easily missed. However, the best estimate is that pHPT occurs in 1 in 2000 (0.05%) women of reproductive age.1
Surgical series have shown that 8–10.5% of all parathyroidectomies are undertaken in women of reproductive age (equating to around one quarter of all parathyroidectomies in women) and 1–1.25% during pregnancy.2,3 Given that the number of women having their first pregnancy after 35 years of age increased ninefold between 1970 and 2012,4 it is probable that pHPT in pregnancy will be encountered more in the future.
RISKS OF DISEASE VERSUS SURGERY
As well as pre-eclampsia and miscarriage, pHPT has been linked to intrauterine growth retardation, polyhydramnios and stillbirth. Neonatal hypoparathyroidism and hypocalcaemia may result and, if unrecognised, present with tetany or seizures. The risk of these complications is dependent upon the biochemical severity of the pregnant woman’s pHPT, as demonstrated in at least one large surgical series.2
Safe, non-surgical control of hypercalcaemia is restricted to oral or intravenous hydration. The effects of calcitonin are short-lived, bisphosphonates are known to cross the placenta and be detrimental to fetal skeletal development, and the safety of cinacalcet is unknown and worrisome, given the presence of its target – the calcium-sensing receptor – in many tissues including the kidney, bone, brain and breast.
Surgery is the only definitive cure for pHPT. Standard pre-operative imaging using ionising radiation (SestaMIBI scanning, 4DCT, etc.) is ill-advised in pregnancy and, even with high quality ultrasound by an experienced sonographer, most pregnant women will have unlocalised disease.3 Thankfully, cure may still be achieved in 97% of patients with a bilateral neck exploration when undertaken by a high-volume parathyroid surgeon. Parathyroidectomy under local anaesthesia and sedation is feasible, but usually confined to localised disease. Thankfully, modern general anaesthetic agents are non-teratogenic, and so the pregnancy-specific risks from general anaesthesia are restricted to miscarriage or preterm delivery.
The overall background risk of miscarriage in pregnancy is approximately 15%, but is highest early in the first trimester, decreasing to below 5% in the second.5,6 The risk attributable to anaesthesia in neck surgery has been reported as a number needed to harm of 356 to precipitate one stillbirth and 63 for one preterm delivery.7
Given the greater background miscarriage rate in the first trimester, the second trimester is universally accepted as the most favourable time to intervene, with the greatest benefit to the woman and fetus. However, there is no absolute cut-off, with a gradual decline in the background rate of miscarriage through the first and into the second trimester. Surgery in the third trimester can be performed, but with an increase in the risk of premature labour.
THE BEST TIME TO OPERATE IN PREGNANCY
All pregnant women with pHPT need to be managed by a team including an endocrinologist, an obstetric physician, an obstetric anaesthetist and a parathyroid surgeon experienced in complex parathyroid disease. The best available evidence suggests that asymptomatic women with an apparently uncomplicated pregnancy and mild hypercalcaemia (i.e. up to 0.25mmol/l above the upper limit of normal) may be managed with conservative outpatient measures alone. The women who remain stable and asymptomatic may optimally undergo parathyroidectomy post-partum, ideally before a subsequent pregnancy!
Women with significant hypercalcaemia (serum calcium 0.25mmol above the upper limit of normal), symptoms or pregnancy complications related to pHPT should undergo surgery. The decision to offer parathyroid surgery should be made with the informed involvement of the patient and her family. The safest time to undertake surgery is the second trimester and the exact timing is dependent on the severity of hypercalcaemia and/ or symptoms. Severe uncontrollable hypercalcaemia and symptomatology prompt urgent intervention, whereas stable disease may be treated with less urgency, but also ideally within the second trimester. Surgery requires a parathyroid surgeon comfortable with the management of unlocalised disease, an anaesthetist experienced in both neck endocrine surgery and obstetric anaesthesia, and a member of the obstetric team to perform fetal monitoring before and after general anaesthesia.
WHAT FURTHER CARE IS NEEDED?
Post-operatively, calcium monitoring and prevention of hypocalcaemia are essential, as this can also be detrimental to the pregnancy. Prophylactic oral calcium may be required in patients with severe hypercalcaemia preoperatively. The harmful effects of pHPT to the pregnancy, particularly pre-eclampsia, are not immediately reversed by curing the pHPT, and so the pregnancy should continue to be followed in an obstetric clinic. Post-partum, the mother should be referred for genetic testing, if her pHPT was present at 30 years of age or younger.
The optimal timing of parathyroidectomy in pregnancy could therefore be summarised as ideally before conception, and in moderate–severe disease at some point during the second trimester, with exact timing depending on its severity. If neither of those apply, it should be performed post-partum.
Aimee Di Marco and Fausto Palazzo, Department of Thyroid and Endocrine Surgery, Hammersmith Hospital & Imperial College, London
REFERENCES
- Hirsch D et al. 2015 Journal of Clinical Endocrinology & Metabolism 100 2115–2122.
- Norman J et al. 2009 Clinical Endocrinology 71 104–109.
- Di Marco AN et al. 2019 Journal of the Endocrine Society 3 1009–1021.
- Saloojee H & Coovadia H 2015 Lancet Global Health 3 e342–e343.
- Rai R & Regan L 2006 Lancet 368 601–611.
- McNair T & Altman K 2012 In The John Hopkins Manual of Gynaecology and Obstetrics, pp. 438–439. Philadelphia, USA: Wolters Kluwer.
- Balinskaite V et al. 2017 Annals of Surgery 266 260–266.
