Low-dose vs high-dose calcium supplementation against preeclampsia

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A recent study revealed that low-dose calcium supplementation is noninferior to high-dose supplementation in preventing preeclampsia, shedding light on considerations for maternal health and pregnancy strategies worldwide.

Low-dose vs high-dose calcium supplementation against preeclampsia | Image Credit: © chompoo - © chompoo - stock.adobe.com.

Low-dose vs high-dose calcium supplementation against preeclampsia | Image Credit: © chompoo - © chompoo - stock.adobe.com.

A recent study revealed that low-dose calcium supplementation is noninferior to high-dose supplementation in preventing preeclampsia, according to a recent study published in the New England Journal of Medicine.

Takeaways

  1. Low-dose calcium supplementation (500 mg per day) is found to be non-inferior to high-dose calcium supplementation (1500 mg per day) in managing the risk of preeclampsia during pregnancy.
  2. Hypertensive disorders affect 2% to 8% of pregnancies, leading to significant maternal deaths and an increased risk of preterm birth. This highlights the importance of strategies to reduce hypertensive disorders during pregnancy.
  3. Since 2011, the World Health Organization (WHO) has recommended calcium supplementation in pregnancy to decrease preeclampsia risk. High-dose calcium supplementation (1000 mg per day) has shown a reduction of over 50% in preeclampsia risk and 24% in preterm birth risk.
  4. The study conducted 2 randomized, noninferiority trials with participants aged 18 or older, nulliparous pregnancy, and under 20 weeks' gestation. Participants were randomized to receive either 500 mg or 1500 mg oral calcium supplementation per day, with additional vitamin D3.
  5. The incidence of preeclampsia and preterm birth did not significantly differ between the 500 mg and 1500 mg groups, indicating noninferiority for preeclampsia risk. However, additional data is needed to determine the impact of both doses on preterm birth.

Two percent to 8% of pregnancies are impacted by hypertensive disorders of pregnancy, leading to approximately 45,000 maternal deaths per year and an increased risk of preterm birth. This makes it vital for countries to implement strategies for reducing hypertensive disorders of pregnancy.

Since 2011, the World Health Organization (WHO) has recommended calcium supplementation in pregnancy to decrease preeclampsia risk. Data has indicated a reduced preeclampsia risk by over 50% and preterm birth risk by 24% from high-dose calcium supplementation of 1000 mg per day.

Currently, data about the efficacy of low-dose calcium supplementation is lacking, with previous trials containing small sample sizes. To evaluate the impact of low-dose calcium supplementation on preeclampsia and preterm birth risks, investigators conducted 2 randomized, noninferiority trials.

The trials were independently powered, but had similar interventions, methods, and outcome definitions. Participants included women aged 18 years or older with nulliparous pregnancy at under 20 weeks’ gestation planning to remain enrolled until 6 weeks postpartum. 

Exclusion criteria included nephrolithiasis history, signs, or symptoms, parathyroid disorder history, previous thyroidectomy, and disease treated with digoxin, phenytoin, or tetracycline therapy. Participants were randomized to receive either 500 mg or 1500 mg oral calcium supplementation per day.

In the 500 mg group, supplementation was taken as a single 500 mg tablet per day, vs 3 500 mg tablets per day in the 1500 mg group. Two groups in the trial also received 250 IU of vitamin D3 per day. Thirty-five days of supplementation was provided to participants at each trial visit, with pill counts used to determine adherence.

Follow-up visits occurred each month during pregnancy, at delivery, and at 6 weeks postpartum. An open-ended 24-hour diet recall was used to determine the baseline dietary intake of participants, while hemoglobin concentrations were measured from a finger-prick blood sample collected at randomization and at 32 weeks’ gestation.

Preeclampsia and preterm birth were the primary outcomes of the analysis. Preeclampsia was defined by gestational hypertension and proteinuria or by gestational proteinuria and chronic hypertension. 

Preterm birth included live births before 37 weeks’ gestation.Secondary outcomes included preeclampsia with severe features, gestational hypertension, pregnancy-related death, small for gestational age, low birth weight, fetal death, stillbirth, and infant death before aged 42 days.

There were 33,449 women included in the first trial and 45,186 in the second. These trials had median adherence rates of 97.7% and 92.3%, respectively. Baseline characteristics were similar between both trials, with most participants aged 18 to 24 years and having normal blood pressure. Rates of daily dietary calcium intake under 800 mg were 87% and 67%, respectively.

In the first trial, preeclampsia was reported in 3% of patients receiving 500 mg and 3.6% of those receiving 1500 mg. In the second trial, these rates were 3% and 2.7%, respectively. This indicates noninferiority from the 500 mg dosage compared to the 1500 mg dosage in managing preeclampsia risk.

The incidence of early-onset preeclampsia also did not differ between both groups. Additionally, preterm birth was observed in 11.4% of the 500 mg group and 12.8% of the 1500 mg group in the first trial, and 10.4% and 9.7%, respectively, in the second trial. There was also no evidence indicating improved secondary outcomes among the 1500 mg group vs the 500 mg group.

These results indicated low-dose calcium supplementation is not inferior to high-dose supplementation for preventing preeclampsia. However, additional data on the impact of both doses on preterm birth is necessary.

Reference

Dwarkanath P, Muhihi A, Sudfeld CR, et al.Two randomized trials of low-dose calcium supplementation in pregnancy. N Engl J Med. 2024;390:143-53. doi:10.1056/NEJMoa2307212

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