Registration Dossier

Administrative data

Endpoint:
health surveillance data
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented study conducted to good scientific principles.

Data source

Reference
Reference Type:
publication
Title:
Long Term Effect of Calcium Supplementation during Pregnancy on the Blood Pressure of Offspring: Follow up of a Randomised Controlled Trial
Author:
Belizan JM, Villar J, Bergel E, del Pino A, Di Fulvio S, Galliano SV & Kattan C
Year:
1997
Bibliographic source:
British Medical Journal, 315, Issue August 2: 281-285

Materials and methods

Study type:
medical monitoring
Endpoint addressed:
developmental toxicity / teratogenicity
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The objective of the study was to examine the long term effect of calcium supplementation during pregnancy on the offspring's blood pressure during childhood using the population of a large, multicentre, randomised, placebo controlled trial.
The trial examined the effectiveness of 2g of elemental calcium supplementation per day (four tablets of calcium carbonate 500 mg) for the prevention of hypertensive disorders of pregnancy. Women were eligible for the study if they were multiparous, had singleton pregnancies and had blood pressure values below 140/90 mmHg at the time of randomisation. Supplementation was started at 20 weeks' gestation and continued until delivery. In all, 1194 pregnant women were enrolled in three public hospitals (580 women) and one private hospital (614 women).
GLP compliance:
no

Test material

Constituent 1
Reference substance name:
Calcium carbonate tablets
IUPAC Name:
Calcium carbonate tablets
Details on test material:
The trial used medication tablets as the source of the test material.

Method

Type of population:
general
Ethical approval:
confirmed and informed consent free of coercion received
Details on study design:
In the main study, dosing started at 20 weeks gestation and continued until delivery. Four tablets of calcium carbonate were taken per day for approximately 20 weeks (2000 mg/day ingested). In total, 1194 pregnant women took part in the test. The control group was treated with a placebo.

The follow-up study was restricted to 614 children born between August 1987 and November 1990 at the private hospital and their mothers. From January 1993 to March 1996 the mothers and their children from the index pregnancy were located. If the mothers agreed, blood pressure measures, an anthropometric evaluation and a short health questionnaire were performed on themselves and their child. The mothers continued to be blinded to whether they had received placebo or calcium in the main study.

Systolic and diastolic blood pressures were measured in the children (mean age 7.1 years, age range 5 years to 9 years and 10 months) and in the mothers. The height and weight of the children were also measured.

At the end of the whole examination, a general health questionnaire was given to the mother which asked about any major illnesses, hospital admissions or episodes of urinary stones or gall stones. When a mother reported that she or her child had a diagnosis or symptoms of one of these diseases, a detailed history was taken, including information on the diagnostic method.

Results and discussion

Results:
Complications and outcomes in pregnancy:
The reports of women with anaemia, premature rupture of membranes, diabetes mellitus, third trimester haemorrhage, and receiving medical treatment, and the numbers of hospital admissions, inductions of labour, and caesarean sections were closely similar in the calcium and placebo groups. The rate of urinary tract infection was higher in the calcium group (12/257) than in the control group (7/261) (P=0.23). The incidence of gestational hypertension was lower in the calcium group (15/257) than in the placebo group (22/261). One woman in the calcium group and two in the placebo group had pre-eclampsia.
At birth the weight, length, gestational age, and the rate of preterm delivery were closely similar between the two groups. A higher proportion of the newborn infants in the calcium group had an Apgar score <7 at the first minute (20/248 vs 10/251), and more newborns were admitted to the neonatal intensive care unit (38/248 vs 29/251) (not significant).

Mothers' and children's characteristics 5 to 9 years after delivery:
The mean maternal systolic blood pressure was similar in both groups but the mean diastolic blood pressure was lower in the calcium group. Women in the calcium group had a lower risk of high diastolic blood pressure (>= 90 mmHg) than those in the placebo group.
The mean systolic blood pressure for children was lower in the calcium group than in the placebo group.
The proportion of children with high systolic blood pressure was lower in the calcium group (11.4%) than in the placebo group (19.3%). The proportion of children with high diastolic blood pressure was also lower in the calcium group )10.2%) than in the placebo group (12.7%).

Side effects:
The incidence of symptomatic kidney stones in the mothers was 2.3% and 2.7% for the calcium and placebo groups respectively (not significantly different). Gall stones were reported by 3.1% of mothers in the calcium group and by 2.3 % in the placebo group (not significantly different).
None of the children had symptoms of kidney or gall stones. Children whose mothers had received calcium supplements were admitted (at least once) to hospitals at a similar rate to those whose mothers had not (26.7% vs 27.4%).

Applicant's summary and conclusion

Conclusions:
The authors conclude that calcium supplementation during pregnancy is associated with lower systolic blood pressure in the offspring, particularly among overweight children.