My name is Wafa Tabatabai. I'm a professor of medicine and division of endocrinology at Montefiore Medical Center and Albert Einstein College of Medicine with a secondary appointment in orthopedics. I want to thank Endocrine Society for the opportunity to talk to you about management of hypoparathyroidism in pregnancy. I don't have any relevant disclosures. I would like to start by reviewing basic concepts in diagnosis and management of hypoparathyroidism according to the summary statement and guidelines from the second international workshop published in JBMR in 2022. As we know, hypoparathyroidism is diagnosed based on presence of low ionized serum calcium or albumin-adjusted calcium in the presence of an undetectable, low, or inappropriately normal intact PTH when we utilize either a second or third generation assay on two occasions at least two weeks apart. Additional abnormalities caused by low PTH which support this diagnosis include elevation in serum phosphorus, reductions in active vitamin D, and elevations in 24-hour urinary calcium. Additional hypoparathyroidism is diagnosed if these abnormalities, meaning the low calcium and low PTH, persist for more than 12 months after surgery. Hypoparathyroidism is a rare condition with an estimated prevalence ranging from 6.4 to 37 per 100,000 person-years. Therefore, we do not have a lot of high-quality data such as clinical trials, especially when it comes to management of hypoparathyroidism in pregnancy. Therefore, the recommendations of the second international workshop is mostly based on expert opinion and also from data published in small case series and case reports. In general, management of hypoparathyroidism in non-pregnant patients relies on conventional therapy as first line, which would include calcium supplementation and also active vitamin D with the following goals, maintaining the serum calcium in the lower half or just below the reference range, avoiding symptomatic hypocalcemia, avoiding hypercalceria, which is defined as urinary calcium of 250 milligram per 24 hours for adult women or 300 milligram per 24 hours for adult men, avoiding hyperphosphatemia. And if conventional therapy is inadequate, PTH replacement can be considered. And in this context, we define inadequate therapy if the patient has symptomatic hypocalcemia, hyperphosphatemia, renal insufficiency, hypercalciuria, or poor quality of life despite best therapeutic efforts, individuals with poor compliance or malabsorption, or those who are intolerant of large doses of calcium and active vitamin D, or individuals who require high doses of conventional therapy, which is defined as calcium more than 2 gram per day or active vitamin D of more than 2 microgram per day. It is recommended that non-pregnant patients with hypoparathyroidism have their serum calcium, creatinine, phosphorus, and magnesium checked every 3 to 12 months. Hydroxyvitamin D is to be checked every 6 to 12 months. And 24-hour urinary excretion of calcium and creatinine is to be checked every 6 to 24 months. More frequent testing is recommended in unstable or symptomatic patients. And also serum calcium should be checked a few days after any medication adjustment. Baseline imaging for assessment of prevalent nephrocalcinosis or nephrolithiasis is also recommended. Now, pregnancies associated with changes in calcium regulating hormones and also in calcium homeostasis. These changes may result in altered requirements for calcium and active vitamin D in patients with hypoparathyroidism during pregnancy. During pregnancy, due to normal expansion of the intravascular volume, albumin levels decline, thereby leading to decline in the albumin-bound fraction of calcium, with ionized calcium remaining unchanged. Endogenous also remains unchanged. PTHRP, which is produced by the placenta and breast tissue, begins to rise from the 3rd to the 13th week of gestation and increases by about threefold by term. And as a result, levels of endogenous active vitamin D increase by two to threefold as early as the first trimester, which leads to increased absorption of calcium from the gastrointestinal tract. Estradiol levels also increase by about a hundredfold during pregnancy and stimulates CYP27B1, which further enhances the formation of active vitamin D. In women who have residual parathyroid function, PTH is suppressed during pregnancy and subsequently rises into the mid-normal reference range by third trimester. So in patients who have hypoparathyroidism, due to increased endogenous production of active vitamin D and PTHRP during pregnancy, the requirements for calcium and active vitamin D analogs may decline. However, this decline may be offset by the increased requirements for calcium by the developing fetal skeleton, as well as the increased maternal urinary calcium losses that are due to increased active vitamin D levels. Therefore, it is necessary to closely monitor albumin-adjusted serum calcium during pregnancy as the requirements for calcium and active vitamin D may increase, remain stable, or decline. Due to these alterations in calcium homeostasis during pregnancy and the fact that patients with hypoparathyroidism are at greater risk of adverse outcomes for themselves and their babies, pregnant patients need to be monitored more closely. We know that maternal hypocalcemia can lead to uterine contractions, increased risk of preterm labor or miscarriage, and stimulation of the fetal parathyroid gland, which can lead to secondary hyperparathyroidism in the fetus and demineralization of the fetal skeleton and even fractures in utero. In addition to development of hypercalcemia after birth due to elevated PTH activity, and maternal hypercalcemia can suppress the development of fetal parathyroid glands and lead to transient hypocalcemia in the neonate. Therefore, instead of monitoring serum calcium every 3 to 12 months in non-pregnant patients, during pregnancy and lactation, serum calcium is monitored every 3 to 4 weeks and even more frequently in months before and after childbirth or with symptoms of hypo- or hypercalcemia. Serum calcium goal is also different. We aim for serum ionized calcium or albumin-adjusted calcium to be in mid to lower half of reference range as opposed to lower half or just below reference range in non-pregnant patients. And we aim to keep the serum phosphorus, magnesium, and hydroxyvitamin D within the normal limits like non-pregnant individuals. In addition, it is important to coordinate with pediatrics team to monitor the baby for transient postnatal hypo- or hypercalcemia. An added challenge here is that use of thiazides and PTH or PTH analogs are to be avoided in pregnant patients. As mentioned, most of the available data from management of hypoparathyroidism in pregnancy is from small case series and case reports. This is a recent retrospective chart review from 12 pregnant patients with hypoparathyroidism who completed 17 pregnancies. Nine patients had post-surgical hypoparathyroidism and three had autosomal dominant hypocalcemia. As for their treatment regimen, four patients were treated with calcitriol and the rest were treated with alpha-calcidol. Except one, all were treated with calcium carbonate. Data were extracted on plasma levels of ionized calcium, doses of active vitamin D and calcium supplements during pregnancy in 14 patients, and during breastfeeding in 10 patients. Data on pregnancy complications were available from our 17 pregnancies. In this graph, we see the average dose of alpha-calcidol per week prior to pregnancy and in each trimester from 14 pregnancies. The outliers up here, which are shown in circles, are all patients with autosomal dominant hypocalcemia. As we can see, the average dose of active vitamin D remained unchanged throughout the pregnancy. However, most patients required some dose adjustment, either increase or decrease in the dose of their supplements. So here we can see the proportion of pregnancies during which the average dose of active vitamin D was decreased by 20% or more in color purple, increased by 20% or more in blue, or remained unchanged in gray. As you can see, a large portion of patients required some medication adjustment, notably from second to third trimester, doses were either increased or decreased by 20% or more in half of the pregnancies. The authors also reported on pregnancy complications, which included polyhydromnias, maternal hypertension, perinatal hypoxia, and lack of progress in labor. Overall, 10 of the 17 pregnancies, or 59%, required cesarean delivery, with 4 of them, or 24%, being performed as an emergency procedure. Fortunately, all of the 17 children born to these 12 women with hypoparathyroidism were healthy with no severe fetal complications. What about during lactation? As we know, lactating breast produces PTHRP, which leads to a rise in bone resorption and renal calcium reabsorption, and therefore could lead to lower requirement of calcium and vitamin D analogs. The figure here shows average doses of active vitamin D during pregnancy and lactation for the 10 pregnancies which were followed into the breastfeeding period. The median required dose of active vitamin D decreased with the start of breastfeeding and then subsequently increased with cessation of breastfeeding to doses that were similar to pre-pregnancy. Similar changes also happened in calcium supplementation requirements. In conclusion, pregnancies associated with alterations in calcium homeostasis require more frequent monitoring. Calcium and active vitamin D requirements may remain unchanged, increase, or decrease. PTHRP-involved use of calcium supplements and active vitamin D analogs, use of thiazides and PTH or PTH analogs are currently not recommended. During to increased PTHRP production in lactating breast tissue, calcium and vitamin D requirements declined during breastfeeding and rise after weaning, often to pre-pregnancy levels. Thank you for your attention.

hypoparathyroidism

pregnancy

calcium supplementation

vitamin D

maternal health