Bruce W. Hollis and Carol L. Wagner
Keywords Vitamin D · Cholecalciferol · Pregnancy · Lactation · Health outcomes
Key Points
• The function of vitamin D during pregnancy is diverse, involving genomic alter- ation that is involved in decreasing birth complications and infant asthma development.
• The vitamin D requirement during pregnancy and lactation has been greatly underestimated.
• Women should take 4000 IU/d vitamin D prior and during pregnancy.
• Lactating mothers should consume 6000 IU/d vitamin D to satisfy her require- ment as well as the requirement of her nursing infant.
Introduction
Pregnancy and lactation represent a time of rapid body changes, which include physical proportions, physiology, and responsibility. Arguably, the requirement and metabolism of vitamin D is one of the most important changes during this period, although this would never be surmised from current Institute of Medicine (IOM) recommendations [1]. During these dramatic times of physiologic change, the roles of vitamin D in the pregnant versus lactating woman are quite different. In the preg- nant woman, the primary role of vitamin D appears to be immunomodulatory while also retaining its calcium regulating function. During lactation, maternal vitamin D intake serves the primary role of supplying the nursing newborn infant with
B. W. Hollis (*) · C. L. Wagner
Medical University of South Carolina, Charleston, SC, USA Darby Children’s Research Institute, Charleston, SC, USA e-mail: [email protected]; [email protected]
adequate vitamin D for its skeletal integrity function, but may have immunoregula- tory functions as well in both mother and her breastfeeding infant.
Brannon and Picciano [2] and Abrams [3] provide a historical perspective of vitamin D recommendations during pregnancy and lactation that covers the past 50 years. In this chapter, we will provide new insights into vitamin D requirements and functions during pregnancy and lactation.
Vitamin D Nomenclature and Metabolism
There are two forms of vitamin D: D2 and D3. Vitamin D2, or ergocalciferol, is made by plants, and vitamin D3, or cholecalciferol, is made by animals, including humans, and both are often referred to as the “parent compound.” For the remainder of this review, vitamin D will be used as a reference to both compounds unless otherwise noted.
Vitamin D3 is formed in the skin upon exposure to ultraviolet light exposure [4];
vitamin D3 is also acquired through dietary supplementation, along with vitamin D2, with the recommended amount of this supplementation a source of lingering contro- versy [1, 5–7]. Since we are largely a society that avoids sun exposure, the role of dietary supplementation becomes extremely important. Once in the circulation, vitamin D is converted into 25-hydroxyvitamin D—25(OH)D—the major circulat- ing form of the vitamin. This conversion of vitamin D to 25(OH)D is achieved pri- marily in the liver, but can also be achieved in a variety of tissues in an autocrine/
paracrine fashion [8]. Finally, 25(OH)D is converted into the hormonal form of the vitamin—1,25-dihydroxyvitamin D (1,25(OH)2D)—in the kidney for endocrine function and other tissues for autocrine/paracrine function [8].
Vitamin D Metabolism During Pregnancy When Compared with the Non-Pregnant State Including Lactation
A striking difference exists in vitamin D metabolism during pregnancy and fetal development compared with non-pregnancy and non-fetal states, a point that has been known for at least the past three decades, but which has received little attention until recently [9–13]. The conversion of vitamin D to 25(OH)D appears unchanged during pregnancy, following first-and-zero-order enzyme kinetics [14]. By contrast, the conversion of 25(OH)D to 1,25(OH)2D during pregnancy is unique and unparalleled during life. At no other time during life is 25(OH)D so closely linked with 1,25(OH)2D production. By 12 weeks of gestation, 1,25(OH)2D serum concen- trations are more than twice that of a non-pregnant woman and continue to rise twofold to threefold from the non-pregnant baseline, rising to over 700 pmol/L, attaining levels that would be toxic due to hypercalcemia to the non-pregnant indi- vidual, but which are essential during pregnancy [15]. Similarly, in the fetus, cord
blood levels of circulating 1,25(OH)2D are even more closely tied to fetal levels of 25(OH)D [16, 17]. In neither the pregnant mother nor the fetus does this conversion seem to be controlled by the classic calcium homeostatic mechanisms [15, 18].
The rise in circulating 1,25(OH)2D concentrations in the mother/fetus is a remark- able observation. Early on, it was thought that this increase was to ensure adequate delivery of calcium to the maternal skeleton preservation and fetal skeletal develop- ment. Calcium homeostasis, however, is not linked with this increase in 1,25(OH)2D because at 12 weeks’ gestation there is no increase in calcium demand by either the mother or fetus. In contrast, this increased concentration of 1,25(OH)2D sustained during pregnancy is not sustained during lactation, when maternal calcium demand is at least as high as during pregnancy [19]. Thus, in the mother and fetus during pregnancy, the rise in 1,25(OH)2D is dependent on substrate availability—in this case 25(OH)D— and is largely independent of calcium homeostasis [15].
Why is calcium metabolism uncoupled from 1,25(OH)2D generation during pregnancy and not lactation? One of the leading theories is that 1,25(OH)2D is an important immune modulator involved in maternal tolerance to the foreign fetus whose DNA is only half that of the mother’s. Based on early epidemiological stud- ies involving pregnant women with preeclampsia, a clinical picture of inflammation and vasculitis, vitamin D deficiency has been implicated [20, 21]. Experimental animal models also have strongly suggested vitamin D deficiency as a potential mechanism of placental dysfunction [22, 23].
Obstetrical “Paranoia” with Regard to Vitamin D Administration During Pregnancy
We refer to this type of thinking as “medical lore”; however, in this particular case because it carries forth into current medical care, we view it with serious concern. It happens when medical students are taught something that is based on outdated data that have been carried through to the present. This is absolutely the case with the use of vitamin D during pregnancy. Why is this?
Because of the British experience with idiopathic infantile hypercalcemia attrib- uted to hypervitaminosis D, a terrible inaccurate association occurred that had a profound effect on the potential of vitamin D supplementation, not only during infancy but also during pregnancy. In 1963, Black and Bonham-Carter [24] recog- nized that elfin facies observed in patients with severe idiopathic infantile hypercal- cemia resembled the peculiar facies observed in patients with supravalvular aortic stenosis (SAS) syndrome. Shortly thereafter, Garcia et al. [25] documented the occurrence of idiopathic hypercalcemia in an infant with SAS who also had periph- eral pulmonary stenosis, mental retardation, elfin facies, and an elevated blood concentration of vitamin D. This is an interesting observation because in 1964, when the article was published, there were no quantitative means of assessing circu- lating concentrations of vitamin D. In fact, at that time, it was not even proven that vitamin D was further metabolized within the body. By 1967, vitamin D was viewed
by the medical community as the cause of SAS syndrome [26, 27]. As a result of the theory that maternal vitamin D supplementation during pregnancy caused SAS syn- drome [28], animal models were developed to show that toxic excesses of vitamin D during pregnancy would result in SAS [29, 30]. In these earlier cases (22), vita- min D had nothing to do with the etiology of SAS. What was described as vitamin D-induced SAS syndrome is now known as Williams Syndrome [31, 32].
Unfortunately, vitamin D intake during pregnancy is still associated with SAS.
Williams Syndrome is a severe genetic affliction related to elastin gene disrup- tion [31] that is caused by deletion of elastin and contiguous genes on chromosome 7 g 11.23. This syndrome is characterized by multiorgan involvement (including SAS), dysmorphic facial features, and a distinctive cognitive profile [32]. Such patients often exhibit abnormal vitamin D metabolism, which makes them suscep- tible to bouts of idiopathic hypercalcemia [33]. This relationship was suspected as early as 1976 [34]. Subsequently, it was shown that children with Williams Syndrome exhibit an exaggerated response of circulating 25(OH)D to orally admin- istered vitamin D [35]. Thus, the fear of vitamin D-induced SAS is based on studies that are no longer valid yet continue to be cited and feared, and thus impact treatment.
Observational Studies Suggesting the Function of Vitamin D Extended Beyond Calcium Homeostasis During Pregnancy
The role of vitamin D and skeletal function during pregnancy and lactation has been previously discussed [1, 2, 3]. Beyond skeletal functions, what are other functions with respect to vitamin D in pregnancy and lactation? To discover what these might be, we rely on associative or observational studies, and in the past 15 years or so many of these studies have been performed.
Of high interest is the association of dietary vitamin D3 intakes in pregnant women and preeclampsia. Olsen and Secher [36] point out that in the early 1940s, studies were performed giving pregnant women halibut liver oil, which is rich in vitamin D3, and decreases in preterm birth and preeclampsia were observed, which was attributed to marine n-3 fatty acids [36]. Through the ensuing decades, it became clear that vitamin D’s actions in the human body could exist well beyond skeletal events and, thus, people started looking at the link between vitamin D and other disease states and conditions [20, 21, 37–40, 41–47]. Early observational studies uncovered strong relationships between maternal circulating concentrations of 25(OH)D and preeclampsia [20, 21, 37, 38], altered placental vascular pathology [39], cesarean section [40], glucose tolerance [41], adverse birth outcomes due to race [42], infection rates [43], brain function [44–46], and respiratory function [47].
While public policy cannot be set for supplementation practices based on obser- vational studies, this information is invaluable at pointing research in the direction that could yield public policy changes in vitamin D consumption. These next steps are interventional studies and randomized clinical trials (RCTs). One has to exhibit
caution, however, even with RCTs, as results can be problematic when analyzed on an intent-to-treat basis. There also may be high nonadherence to protocol, thereby diluting the potential good or harm of a given treatment at higher doses. A bio- marker of a drug or, in this case, “vitamin” or preprohormone is better served. For these reasons, analysis of effect of vitamin D therapies using 25(OH)D concentra- tion is a far better indicator of true “effect.”
Randomized Controlled Trials Investigating Vitamin D Supplementation During Pregnancy
Vitamin D supplementation trials involving pregnant women have been performed since 1980 [48]. Those early studies were small, did not look at meaningful end- points, and did not supplement with enough vitamin D [48]. As a result, no mean- ingful information or public policy changes occurred based on these studies. In 2001, our group conceived a large RCT investigating the supplementation of vita- min D to a population of pregnant women. Our study was radical in design in that we proposed supplementing pregnant women who were less than 16 weeks of gesta- tion with up to 4000 IU/d vitamin D3 until delivery in a double-blind fashion. The goal of the study was to see how much vitamin D was required to raise circulating maternal 25(OH)D concentrations to at least 32 ng/mL by the end of gestation.
Using mathematical calculations from previous studies, we calculated how much vitamin D3 we would need to provide [49, 50]. We selected the 32 ng/mL concentra- tion of circulating 25(OH)D based on the suppression of secondary hyperparathy- roidism [51]. We obtained funding from the National Institute of Child Health and Development (NICHD) in 2002; however, because of safety concerns about the use of a 4000 IU/d dose of vitamin D3, we had to obtain an investigational drug applica- tion approval from the Food and Drug Administration (FDA; #66,346). This approval was obtained in 2003 and the study began in early 2004. Along with this NICHD-sponsored study, we also received funding from the Thrasher Fund to per- form a parallel study involving vitamin D supplementation of pregnant women in a community-based format. At the initiation of these RCTs, our endpoints were safety of the dosing, attained circulating level of maternal 25(OH)D, growth parameters of the infant, and bone-mineral-density of the mother and infant. As for the other factors mentioned in the previous section on vitamin D relationships based on observational studies, those associations had not been made at study initiation, and as a result we had no idea to even look for them, let alone propose them as end- points. As such, these endpoints were analyzed as post hoc analyses.
The results of these RCTs have been presented and published over the last few years as displayed in Table 1 [15, 52–59]. The main finding of these studies was that a 4000 IU/d dose of vitamin D3 safely elevates circulating 25(OH)D to a level that, regardless of race, fully normalizes vitamin D metabolism and calcium homeostasis in pregnant women. Further, this dose was safe, with not a single adverse event attributable to vitamin D supplementation (Table 1).
Table 1Recently completed randomized controlled trials providing vitamin D during pregnancy StudyCountrySubjectsTrial typeIntervention Baseline 25(OH)D (ng/mL)
Endpoint 25(OH)D (ng/mL)FindingsAdverse events Hollis et al. (2011, 2013) [15, 52]
USA350RCT400, 2000, or 4000 IU/d vitamin D3 from 14 weeks’ gestation until delivery 400 IU/d: 24.6 2000 IU/d: 23.3 4000 IU/d: 23.2 400 IU/d: 31.6 2000 IU/d: 39.3 4000 IU/d: 44.4 Vitamin D decreased cesarean section and comorbidities of pregnancy
None Wagner et al. (2013, 2016) [53, 54]
USA2013: 160 2016: 504
2013: RCT 2016: post-hoc combined RCT 2013: 2000 or 4000 IU/d vitamin D3 from 14 weeks gestation 2016: 400, 2000 or 4000 IU/d vitamin D3 from 14 weeks’ gestation 400 IU/d: 24.6 2000 IU/d: 23.2 4000 IU/d: 22.8 400 IU/d: 30.7 2000 IU/d: 37.1 4000 IU/d: 41.9 Vitamin D decreased preterm births and complications of pregnancy
None Goldring et al. (2013) [55]
UK180RCT0 or 800 IU/d from ___ weeks onward, or 200,000 IU/bolus given at 27 weeks’ gestation 800 IU/d: 10.0 200,000 IU/ bolus: 10.0 800 IU/d: 17.0 200,000 IU/ bolus: 14.0 Vitamin D tended to decrease infant wheezing but effect was minor
None Sablok et al. (2015) [56]
India165RCT0 IU vitamin D3; 60,000 IU/bolus vitamin D3 at 20 weeks’ gestation; 120,000 IU/bolus vitamin D3 at 20 and 24 weeks’ gestation or 120,000 IU/bolus vitamin D3 at 20, 24, 28 and 32 weeks’ gestation All patients <10.00 IU: <10.0 120,000 IU/ bolus: 15.2 120,000 IU/4 doses: 26.0 Vitamin D greatly decreased complications of pregnancy
None Mojibian et al. (2015) [57]
Iran500RCT400 IU/d vitamin D3 or 50,000 IU/ bolus every 2 weeks vitamin D3 starting at 14 weeks’ gestation 400 IU/d: 15.3 50,000 IU/ bolus every 2 weeks: 14.5 400 IU/d: 27.2 50,000 IU/bolus every 2 weeks: 37.9 Vitamin D significantly decreased incidence of gestational diabetes
None
Chawes et al. (2016) [58]
Denmark623RCT800 or 2800 IU/d vitamin D3 from 24 weeks’ gestation800 IU/d: 13.0 2800 IU/d: 31.0 800 IU/d: 29.0 2800 IU/d: 43.0Vitamin D tended to decrease infant wheezing but was not statistically significant
None Litonjua et al. (2016) [59]
USA881RCT400 or 4400 IU/d vitamin D3 from 16 weeks’ gestation400 IU/d: 23.0 4400 IU/d: 23.0 400 IU/d: 27.0 4400 IU/d: 39.0Vitamin D significantly (p < 0.051) decreased asthma and wheezing in infants up to 3 years follow-up
None
When our studies were completed in 2009, we were aware of the observational data suggesting favorable effects of vitamin D on pregnancy outcomes beyond cal- cium homeostasis. When analyzed on an intent-to-treat basis, the data clearly dem- onstrated increased vitamin D supplementation, decreased complications of pregnancy, and C-section births [15, 52]. Further, RCT data and analysis by our group and others have clearly demonstrated that higher doses of vitamin D during pregnancy improve birth outcomes [52, 54]. RCT studies beyond our own have recently demonstrated vitamin D to greatly decrease complications of birth and ges- tational diabetes [56, 57].
Supplementing Vitamin D during Pregnancy to Prevent Childhood Asthma
In 2006, Dr. Hollis was contacted by Scott Weiss, MD of the Harvard Medical School with an idea to conduct a RCT using vitamin D supplementation during pregnancy to prevent the development of childhood asthma. Dr. Weiss was aware of our ongoing RCT and had excellent observational data suggesting vitamin D sup- plementation during pregnancy could reduce childhood asthma rates [60, 61].
Subsequently, we obtained funding for this project from the National Institute of Heart, Lung and Blood (NHLBI) and the Vitamin D Antenatal Asthma Reduction Trial (VDAART) was born. It was a collaboration between Boston University, Brigham and Women’s Hospital, Harvard Medical School, Kaiser Permanente South California Region, Medical University of South Carolina, and Washington University in St. Louis, and NHLBI. This was a double-blind RCT performed at three clinical centers: Boston, St. Louis, and San Diego, and involved giving supple- mental vitamin D3 (400 or 4400 IU/d) to pregnant women across the three major racial/ethnic groups in the USA from 16 weeks of gestation until delivery. The pri- mary endpoint was prevention of asthma/wheeze in the infant/child at 1, 2, and 3 years post-birth. Nearly 900 high-risk subjects were enrolled and completed the study, which was recently published [59]. The results of this study are quite clear:
vitamin D supplementation during pregnancy will decrease asthma or recurrent wheezing rates in children (Fig. 1).
A nearly identical RCT study performed in Denmark has also been published [58]. The journal in which these articles appeared, JAMA, has attempted to mini- mize the results and impact of these studies with an editorial [62]. In response to this negativity, the authors of these two RCTs performed a meta-analysis [63]. Keep in mind that a meta-analysis of RCTs is the highest form of validation for Therapy/
Prevention/Etiology/Harm as defined by The Centre for Evidence-Based Medicine
at Oxford University [64]. The results from these RCTs and meta-analysis studies are quite clear: vitamin D3 given to a pregnant woman will prevent asthma/wheeze in her child [58, 59, 63]. The mechanisms by which this occurs remain unknown, but it is proposed that epigenetic in utero changes triggered by the vitamin D admin- istered to the pregnant women impart functional change in the fetus.
What is clear from these recent RCTs is that a 4000 IU/d vitamin D3 supplement is beneficial to both mother and child, and these benefits are not via the classic role of vitamin D in calcium homeostasis. What is not resolved is the dose and time of administration to achieve optimum results. We propose that a target concentration of 40 ng/mL circulating 25(OH)D be achieved in pregnancy as early as possible.
Because of biochemical heterogeneity in attaining a given concentration of 25(OH) D, we further propose that all women should consume at least 4000 IU/d vitamin D3
prior to conception [50]. Also in question is whether vitamin D administration dur- ing pregnancy can impact autoimmune disease and neuropsychological develop- ment. More rigorous vitamin D trials are needed to answer this question, but observational and RCT data suggest it to be promising [44–46].
Asthma/Wheeze Free Proportion by Treatment
98 (24.3%) in 4,400 IU arm 120 (30.4) in 400 IU
arm Rate difference of
6.1%
Reduction of 18.3%
p = 0.051
4400 IU Vitamin D
Proportion Free of Asthma/Recurrent Wheeze
400 IU Vitamin D
0.0 0.5 1.0
1.00.90.80.70.6
1.5 Age in Years
2.0 2.5 3.0
16% in 4,400 IU arm 24.9% in 400 IU
arm Rate difference of
8.9%
Reduction of 35.7%
22% in 4,400 IU arm 29.4 in 400 IU arm
Rate difference of 7.4%
Reduction of 25.2%
Fig. 1 Kaplan-Meier survival estimates. Error bars indicated 95% CI estimates at intervals of 1, 2, and 3 years. The hazard ratio for the time to first event of asthma or recurrent wheeze was 0.8 (95% CI, 0.6–1.0; p = 0.051). Adapted from Litonjua AA, Carey VJ, Laranjo N, Harshfield BJ, McElrath TF, O’Connor GT, et al. [59]
Current Recommendation for Vitamin D Supplementation During Pregnancy
At this time, based on RCT data, we suggest that all pregnant women maintain a circulating 25(OH)D concentration of at least 40 ng/mL during the earliest time points of pregnancy. This will ensure maximum protection from pregnancy com- plications, including preeclampsia in the mother and asthma formation in the infant. To achieve this, intakes of at least 4000 IU/d vitamin D3 will be required because of variable individual abilities to convert vitamin D to 25(OH)D [50].
These supplements have proven to be safe in thousands of patients over the past 15 years, as not a single adverse event has been observed. Further, this level of supplementation lies within the safe intake level as defined by The Endocrine Society [7].
Vitamin D Requirements of the Mother/Infant Dyad During Lactation
Breast milk has long been held as the “perfect” food for the human neonate with one caveat: it contains insufficient vitamin D for nursing neonates to maintain minimal circulating levels of 25(OH)D, and thus skeletal integrity. When compared with formula-fed infants, solely breastfed infants are at increased risk of developing rick- ets [65, 66]. This is especially true in African American breastfed infants [67].
Vitamin D activity in “normal” lactating women’s milk is known to be in the range of 5–80 IU/L, depending on the method of assay [68–70]; however, the vitamin D content of human milk can be greatly increased by maternal oral vitamin D supple- mentation [68, 69] and/or increasing solar exposure of the mother [71]. Infants solely breastfed by women with vitamin D intakes of 400 IU/d typically attain a circulating 25(OH)D concentration in the marginally sufficient-to-severely defi- cient (<5.0 ng/ml) range [72]. Therefore, to address this risk of deficiency, vitamin D supplementation of all breastfeeding infants beginning within a few days of birth has been recommended by both the American Academy of Pediatrics (AAP) [73]
and the Institute of Medicine (IOM) [74]. Although this has been the recommenda- tion for decades, it is rarely followed for various reasons, with low compliance ranging from 2% to 19% [75–77], leaving the nursing infant at significant risk for vitamin D deficiency.
The amount of vitamin D required by a lactating woman to normalize her own vitamin D status and ensure adequate vitamin D concentrations in her milk for her breastfeeding infant is predicted by known pharmacokinetics about vitamin D