This study included all cases (25 HypoPT women, 3 pseudo-HypoPT women) followed in pregnancy by 9 Italian referral centers for endocrine diseases, between 2005 and 2018. Most women of both groups had a natural pregnancy with a full-term birth, however the 24% of women with HypoPT reported a previous history of spontaneous miscarriages, 2 out of 3 women in the group of women with pseudo-HypoPT.
Most women of both groups increased significantly calcium supplementation and calcitriol dosage during the pregnancy compared to the pre-pregnancy period. The average calcium supplement doses were mostly maintained or increased throughout pregnancy, and the average calcitriol doses were mostly maintained at same dosage. During the breastfeeding in HypoPT women, the average dose of calcium supplements and calcitriol decreased significantly compared to the third trimester.
In most of cases the average serum albumin-corrected calcium levels were monitored and maintained in the low/normal reference range in the HypoPT women and in the normal reference range in the pseudo-HypoPT women throughout pregnancy and breastfeeding.
A general improvement in HypoPT-related clinical manifestations, such as cramps, tetany, and paresthesia, was shown during pregnancy compared to the previous six months.
Results in the context of what is known
Until now, only limited case reports or case series of pregnant/lactating hypoparathyroid women have been published (1, 20, 22, 24, 29–33). Among these, the largest case series described 12 cases with HypoPT (20, 33), while for women with pseudo-hypoPT, only case reports are available (34–36, 38). Therefore, this study identified the largest cohort of hypoparathyroid women, mostly with postsurgical HypoPT, which represents the prevalent form (39, 40).
In our study, in most cases pregnancy was natural and full-term. On the other hand, the few cases preterm delivery (3/25 HypoPT women) may be due to inadequately controlled serum calcium concentration (mean serum calcium levels < 8 mg/dl in the third trimester), which increases uterine irritability (11, 24, 41). These 3 women also had maternal complications, such as gestational diabetes (n = 3), pre-eclampsia (n = 2), placenta previa (n = 1) and polyhydramnios (n = 1), that are unlikely to be related to HypoPT. A recent case series study reported four pregnancy (4/17) of HypoPT women (n = 12) complicated by polydramnios (24%), therefore further studies are needed but this potential complication could be considered in such patients (33).
Two patients with a previous history of spontaneous miscarriages reported stopping calcium therapy without consulting their reference physician, and it is well known that an inadequate therapeutic management of HypoPT during pregnancy, with resulting poorly controlled serum calcium, can lead to a high risk of miscarriage (20, 21, 42, 43). Regarding other miscarriages, no specific causes were reported.
Our study confirmed a wide variation in the required doses of calcium and calcitriol during pregnancy in hypoparathyroid mothers, as already described (11, 20, 33, 38, 44–48). This variability may be due to variations in dietary calcium intake (11, 49, 50), which should be carefully monitored. This correlation could not be calculated in total group, due to the lack of data, however in more than half of patients, who increased the calcium supplementation dose, mean dietary intake of calcium during pregnancy was suboptimal. Moreover, these variations could also be due to the fact that the physiological hemodilution in pregnancy lowers the serum total calcium level, a reduction that may be interpreted as hypocalcemia (10, 21, 24, 46, 48, 49, 52).
This study confirmed the downtrend of calcium and calcitriol doses during the breastfeeding in women with HypoPT, as reported in other studies (10, 24, 26, 33, 46, 47, 49, 51, 52). It is probably related to high levels of PTHrP (53) and could also be related to an increase in mean dietary intake of calcium during breastfeeding. Moreover, during the breastfeeding, hypercalcemia and hyperphosphatemia episodes were reported in literature (24, 20, 33), as described respectively in 2 and 5 of our HypoPT women. Therefore, a careful biochemical monitoring is also necessary in this period.
The analysis of biochemical exams showed mostly the maintenance of the average serum albumin-corrected calcium levels in the low/normal reference range throughout pregnancy. Indeed, biochemical monitoring of serum calcium levels was carried out constantly, as currently recommended by the guidelines (11, 22, 25). However, serum/urinary calcium and phosphate oscillations were reported. A general improvement in HypoPT-related clinical manifestations during pregnancy could be attributed to the increase in synthesized calcitriol and PTHrp, as described above (11).
In a large retrospective population analysis, we show that serum calcium levels were strictly monitored during pregnancy and the post-pregnancy period, while other biochemical parameters, such as phosphate, 25-OH vitamin D, magnesium, and creatinine clearance tended to be poorly evaluated. Therefore, in future, also in light of the new guidelines, an accurate and complete biochemical monitoring is needed in pregnant/lactating hypoparathyroid women, in order to further reduce biochemical fluctuations and maternal/fetal complications (11, 22, 25). Moreover, the average dietary calcium intake will have to be monitored more accurately, as it may be responsible for fluctuations in serum calcium. Cholecalciferol supplementation was reported only in about 30% of our women, a rate that the retrospective nature of the study could have underestimated. However, a greater attention in cholecalciferol supplementation should be carried out, as recommended by the guidelines (22).
Prospective investigations in women with HypoPT and pseudo-HypoPT during pregnancy and breastfeeding are necessary in order to increase knowledge about biochemical alterations, maternal and fetal clinical complications, and to improve the quality of care available today.
In particular, further studies are needed to confirm the upward trend of mean urinary calcium levels throughout gestation and then the return to levels similar to pre-pregnancy period during the first postpartum six months, described in our study in a small subgroup of patients with HypoPT as in other studies (11, 54). In addition to the known physiological rise of calcitriol levels during pregnancy, especially in the third trimester, in hypoparathyroid women, the PTH deficiency and the conventional treatment with calcium and calcitriol could contribute to increased renal calcium excretion (11, 54–56), with associated increased risk of renal stones (11). Further studies in hypoparathyroid women should be also conducted on phosphate homeostasis during pregnancy and especially during breastfeeding, period in which it tends to increase. It would be useful to measure the excretion of 24 h urinary phosphate and to study the effect of PTHrp. Regarding 25 OH vitamin D level, a slight decline of the circulating levels of 25-OH vitamin D in the third trimester, as described in our study, is congruent with the well-known increased conversion to calcitriol, in addition to the transfer of 25-OH vitamin D to the fetus (4, 11). However, it has been analyzed in a few cases in our study, therefore further investigations are needed.
Regarding complications, further clinical investigations will be necessary to study maternal complications, such as reported in our study and in previous investigations (11, 24, 33, 41), in order to verify their incidence, relation with these disorders and to verify systematically neonatal complications through the support of colleagues specialized in neonatology.