DALI: Vitamin D and Lifestyle Intervention for GDM Prevention: dosing study

Gestational Diabetes (GDM) is defined as 'carbohydrate intolerance resulting in
hyperglycaemia of variable severity with onset or first recognition during
pregnancy'. The prevalence of GDM in Europe is reported to vary considerably,
in some populations GDM occurs already in up to 20 % of all pregnancies. There
are few published studies about preventing GDM.

The overall aim of the DALI study is to identify the best available measures to
prevent GDM in an ongoing pregnancy, to provide a cost-benefit calculation of
GDM prevention for health care systems, and to establish a pan-European cohort
of mother-offspring pairs for future analyses with a central biobank and data
base. For this purpose, a randomised controlled trial will be conducted in 10
European countries. In this vitamin D dosing study, the optimum dose of vitamin
D to be supplemented to obese pregnant women in order to reach a target
maternal serum concentration > 50 nmol/l in most women.

Six women will be recruited at each site: 2 randomised to each vitamin D doses,
500, 1000 or 1500 IU/day. Women will be followed up for approximately 7 months,
from 12 weeks to delivery.

The vitamin D supplements (Biovinci) used in this dosing study will be provided
by Pharma-Vinci A/S (Denmark). Three doses are available (500, 1000 and 1500
IU/tablet) that are indistinguishable from each other.
Women will use vitamin D supplements from the start of the intervention until
delivery and will receive their drug packs on a monthly basis. Drug packs will
be returned and adherence measured by counting remaining pills (monthly).
Women will have the vitamin D packs delivered monthly by the research nurse,
who will also collect the remaining tablets from the previous pack. A report on
remaining tablets will be submitted to the trial coordination team.

Risks and burden to the participant:
* Clinical assessments
There are 4 study assessment visits over 6-7 months. The assessments consist
of: urine samples, blood samples (including OGTT), ultrasound, body weight
measurement, and filling out questionnaires. Height will be measured at
baseline.

Most assessments can be performed shortly after a routine appointment to the
obstetrician / midwife, removing the need to have study-specific hospital
visits. The measurements will add approximately 30 minutes to a routine
appointment. The OGTT will take 2.5 hours. Venepuncture has a risk of bruising
and discomfort, but there is no risk of serious harm.

* Interventions
Women will be asked to take one of the doses of vitamin D supplementation,
which will not be a burden for the participants.

Potential risks of Vitamin D supplementation:
Vitamin D supplementation can potentially entail the risk of intoxication which
would be a serious complication that is virtually impossible at the doses
tested. Other potential risks are maternal hypercalciuria/nephrolithiasis and
allergy/asthma in the infant; they also seem unlikely at the doses used. In
addition, hypercalcaemia and hypercalciuria have been included as
exclusion/stop criteria to further minimize the risk.

It is important to highlight that even for women receiving 1500 IU/day, after
adding diet and multivitamin supplementation, the UL of the recommended dietary
intake of 4000 IU/day will not be surpassed.

We also want to highlight that the doses used will be lower than those
currently used in other trials that have not reported adverse consequences so
far:
*
(http://clinicaltrials.gov/ct2/show/NCT00856947?term=vitamin+D+pregnancy&rank=2,
http://clinicaltrials.gov/ct2/show/NCT00610688?term=vitamin+D+pregnancy&rank=4
* http://clinicaltrials.gov/show/NCT00292591
* http://clinicaltrials.gov/ct2/show/NCT00920621

Intoxication
Currently, the upper limit recommended for vitamin D3, termed NOAEL for the *no
observed adverse-effect level,* is set at 4000 IU/day. However, no ill effects
have been observed in people taking high doses of vitamin D3 (31,35), even as
high as 10,000 IU/day during 5 months (17). Similarly, hypercalcaemia
secondary to excess vitamin D only results when serum vitamin D3 concentrations
have consistently been above 375*500 nmol/L (36). Doses and concentrations
associated with intoxication are widely apart of doses and concentrations
considered in this the dosing study. It could conceivably only happen through a
medication error or intentional overdose.

In DALI, even though hypercalcaemia associated with the intervention seems
unlikely, we will register hypercalcaemia both as exclusion and stop criteria.
As with other laboratory parameters, specific reference ranges should be used
during pregnancy. Reports on ionized calcium during pregnancy describe reduced
or unmodified values (37, 38), apparently due to an analytical interference of
low albumin concentrations (39). When total calcium and albumin concentrations
are longitudinally measured during pregnancy, both of them decrease, but
decrements are not parallel, so that albumin-adjusted concentration of calcium
increases during pregnancy (39). To ensure prompt availability of the results,
calcium will be measured locally and plain measurements of total calcium seem
appropriate. Albumin will also be measured to have data on albumin-adjusted
calcium but cut-offs on total calcium provided in a review on reference
laboratory values during pregnancy will be used (40):
* 1st trimester: > 10.6 mg/dl | 2.65 mmol/l
* 2nd trimester: > 9.0 mg/dl | 2.25 mmol/l
* 3rd trimester: > 9.7 mg/dl | 2.43 mmol/l

Hypercalciuria
Pregnancy is characterized by an increase in calcium urinary excretion to
figures up to twofold those outside pregnancy (41) with maximal values reached
in the third trimester (42). Nevertheless, despite urinary calcium reaching
values even higher than in women with renal stones, pregnancy is not a
stone-forming state (43).

However, as vitamin D supplementation can facilitate hypercalciuria, we have
decided to use hypercalciuria as an exclusion criterion. Classically,
hypercalciuria is defined after 24h calcium excretion, but as calcium in spot
urine in the morning is adequately representative of 24h calcium excretion to
diagnose hypercalciuria (44), we will use the calcium:creatinine ratio. The
cutoff of this ratio during pregnancy has not been defined: taking into account
the physiologic gestational hypercalciuria, we have therefore set the exclusion
criterion at the screening visit at a figure of 0.6 mmol/mmol creatinine (this
equals the diagnosis of hypercalciuria in healthy adults (45)) and an arbitrary
limit of 150% this value (0.9 mmol/mmol creatinine) to stop the intervention at
any subsequent measurements.

A symptomatic stone during pregnancy is a rare event, occurring in about one in
every 1500 to 3000 pregnancies (46, 47). The diagnosis of a symptomatic stone
under usual clinical care will be accepted as a nephrolithiasis event. As about
80 percent of kidney stones are calcium stones (48), the lithiasis will be
assumed to be composed of calcium unless established otherwise. If a
hyperechoic image in the kidneys or urinary tract is identified during regular
ultrasound exams in a woman without related symptoms, a diagnosis of an
asymptomatic kidney stone will be performed.

Allergy
Vitamin D status and Ig E have recently been reported to display a U-shaped
association with cut-offs being <25 and >135 nmol/l (28). The same association
appears to be present when related clinical outcomes are considered: a positive
association with asthma has been described in a longitudinal study of vitamin D
supplementation in infancy using doses as high as 2000 IU/day (for an infant!)
(49). In contrast, in two longitudinal studies in the US, where the median
vitamin D intake during pregnancy was respectively 548 and 131 IU/day, a
*higher* maternal intake of vitamin D during pregnancy was associated with a
decreased risk of recurrent wheeze in early childhood (05, 51). In a single
study, maternal serum vitamin D concentrations >75 nmol/l were associated with
an increased risk of infant eczema on examination at 9 months and 9 years
compared to children whose mothers had a concentration of <30 nmol/l. (52).

It is worth noting that two trials are currently under way to prevent childhood
asthma using vitamin D doses in the intervention arm of 2400 and 4000 IU/day in
addition to usual prenatal vitamins (53, 54). In the latter trial, an intake of
vitamin D supplements containing more than 2000 IU/day is considered an
exclusion criterion, implying that women fulfilling inclusion criteria may be
receiving close to 6000 IU/day of vitamin D in addition to dietary content.

Birth weight
Vitamin D intake from diet (55) or diet plus supplements (56) has been related
with birth weight; women with lower intakes have offspring with lower birth
weights. An increase in birth weight has also been reported in some
supplementation studies (57, 58) but not on all of them (59, 60). A
dose-response relationship between vitamin D and birth weight has been
described (56, 57). Parathyroid hormone has been suggested to be a mediator of
this effect (61). This effect of vitamin D can be viewed as a beneficial or
untoward effect depending on the setting. Should macrosomia be observable in
the DALI study, which is among obese women at greater risk of higher birth
weights, it should probably be considered an untoward effect.