Buku Pedoman Penyusunan LitRev PSGD-PST

Nutrients 2021, 13, 1924 11 of 20

Furthermore, Coprobacillus spp. has been linked to the regulation of ACE2 in the murine
gut [136], being the ACE2 a transmembrane protein that counteracts ACE, which receptors
are found within epithelium cells of the gut. Thus, changes in the gut microbiota may
alter the ability of the virus to gain cellular entry into the gut [137]. Other studies support
Zuo’s findings, detecting more potential pathogens in the gut microbiota of 30 SARS-CoV-2
hospitalized patients [138].

Furthermore, recent studies found how the gut composition is significantly altered
in COVID-19 patients independently of whether patients had received medication [139].
Authors suggested that reinforcing beneficial gut species depleted in COVID-19 could
serve as a novel way to mitigate severe disease, underscoring the importance of managing
patients’ gut microbiota during and after COVID-19 [139]. These changes in the micro-
bial profile after the pathogenesis of the COVID-19 were also found in patients during
the hospitalization, suggesting an early affection of the microbial profile [140]. Despite
this, more studies are necessary, as it seems that the gut microbiome is involved in the
magnitude of COVID-19 severity possibly via modulating host immune responses. Thus,
for anticipatory purposes, diagnosing gastrointestinal symptoms that precede respiratory
problems during COVID-19 could be necessary to improve early detection and treatment.
Further research should assess the composition of the gut microbiota and its metabolic
products in the context of COVID-19, which could help to determine new biomarkers of
the disease, helping identify new therapeutic targets [141].

Despite the intestinal microbiota and its composition depends on genetic and epige-
netic factors [142], nutrition has shown to be a factor that is capable of acutely modifying its
composition [143]. Interventions have been shown to have a positive and significant effect
on human health [144]. In addition, dietary supplements like fiber and probiotics have been
shown to improve microbial derangements in health [145], but the precise mechanisms
of how nutrition and dietary supplements modulate the gut microbiome remain to be
determined.

8. Physical Activity and COVID-19

Previous authors have shown how older patients, with comorbidities, cardiovascular
risk factors, and systemic diseases have a poorer prognosis with the coronavirus infec-
tion [146,147]. In the absence of actual effective treatment, the control of these pathologies
is basic and essential. In this line, physical activity has been shown a positive effect on
these diseases and a decrease in all-cause mortality [148,149]. Specifically, COVID-19 pa-
tients are characterized by a large inflammatory response [150], hypoxemia [151], impaired
respiratory function [152], where the angiotensin-converting enzyme 2 has been proposed
as the receptor for SARS-CoV-2 protein in the alveolar epithelial cells in the lungs [153], all
these factors associated with critical and fatal illnesses. In this line, exercise was associated
with decreases in inflammatory markers [154], decreases in basal minute ventilation and
increased oxygen uptake [155], a reduced upper respiratory tract infections incidence and
duration [156], and a shift in the renin-angiotensin system towards angiotensin 1–7 which
may reduce the severity of the clinical outcome of COVID-19 infection [157].

Several authors highlighted the importance of metabolic health as a modulator of
illness severity, emphasizing how metabolic complications related to inactivity and obe-
sity were fully operating to favor COVID-19 diffusion [158]. In this line, it was shown
how weaker and debilitated muscle strength was associated with a higher risk of severe
COVID-19 [159]. The association between muscle strength and COVID-19 severity is
related to the essential role of muscle in health and disease [160]. Poor skeletal muscle
functions negatively affect the immune response, motor function, respiratory function,
and metabolic stress when facing acute infection [161,162]. All these factors have been
previously identified as a COVID-19 severity modulator [163].

Cardiorespiratory fitness has been proposed to be beneficial in COVID-19 since it
allows a greater inflammatory response control and potentially enhancing antiviral host
responses following infection [164]. In this line, higher cardiorespiratory fitness levels

Nutrients 2021, 13, 1924 12 of 20

are related to a lower hospitalization due to COVID-19 [165]. It is known how physical
activity modulates immune system functions, presenting moderate physical activity an as-
sociation with cardiorespiratory fitness, increasing immune system capacity, and reducing
inflammation [166]. In this regard, a sedentary lifestyle was found as an independent risk
factor for mortality in COVID-19 hospitalized patients. This fact represents an important
finding and proposes the utility of exercise in the prevention of severe COVID-19 presen-
tations [167]. In addition, the walking pace has been identified as a potential risk factor
for severe COVID-19, with slow walkers having a high-risk profile [168]. Physical activity
and cardiorespiratory fitness have clear preventive potential on several chronic diseases
that are considered to be risk factors for COVID-19 outcomes and counteract aging-related
processes that may also be associated with higher COVID-19 risk [169]. Maximal exercise
capacity is independently and inversely associated with the likelihood of hospitalization
due to COVID-19.

In the actual situation, where vaccines are starting to administrate to the population,
also physical exercise could have a critical role. Previous authors demonstrated how
an acute stressor in close temporal proximity to immune challenge could enhance the
response to delayed-type hypersensitivity and antibody response to vaccination [170].
Specifically, acute exercise-induced stress before influenza vaccination (preferably high-
intensity exercise) might enhance antibody responses [171,172]. Beyond vaccination, the
COVID-19 pandemic has taught us the importance of preventive lifestyle actions. Physical
activity is presented as a safe and potential preventive measure, especially for the most
vulnerable groups [173].

Finally, given the ongoing novelty of COVID-19, some authors proposed the eval-
uation of both inflammatory response and physical function (handgrip strength) for pa-
tients recovering from COVID-19 since it provides new information into the recovery
process [174]

9. Practical Statements

The main findings of the present and their practical applications are summarized in
the following key points and Table 1.

• The COVID-19 lockdown promoted unhealthy dietary changes (inactivity, daily intake,
snacks, alcohol), increasing body mass and fat, and showing obesity-overweight
people poor diet habits.

• Obesity is a risk factor for COVID-19.
• A healthy balanced diet is an integral part of personal risk management.
• Vitamins C and D improve health-related outcomes in COVID-patients.
• Sufficient vitamin intake and an active lifestyle are strongly recommended as a pre-

ventive measure to the general population.
• There is a large prevalence of malnutrition among hospitalized patients with COVID-19.
• Nutritional support and rehabilitation exercise are needed to avoid muscle atrophy

and sarcopenia in COVID-19 hospitalized patients. They should be considered as an
integral part of the therapeutic approach.
• Deficient states of vitamin C, D, B12 selenium, iron, ω-3, and medium and long-chain
fatty acids increase the probability of hospitalization and mortality from COVID-19.
• The gut microbiome profile is altered due to COVID-19, being involved in the magni-
tude of COVID-19 severity via modulating host immune responses.
• A healthy gut microbiome serves as a preventive and protective factor, appropriate
nutrition and probiotics are good strategies for its enhancement.
• Active lifestyle and physical activity allow a lower risk, and mortality rate in COVID-19
patients, due to its positive effect on metabolic health and inflammation.

Nutrients 2021, 13, 1924 13 of 20

Table 1. Nutritional interventions in COVID-19.

Recommendation Nutritional Intervention
Avoid
Daily products
Include
Snacks
Prevent Deficient states
Keep Alcohol
Avoid
Keep Carbohydrates <60 % of total caloric value to avoid insulin
resistance, hyperglycemia, and acute respiratory

distress syndrome.
2 g/kg/day and must not exceed 150 g/day for

critically COVID-19 patients.

Proteins 1.3 g/kg day to reduce muscle loss due to systemic
inflammation and improve respiratory muscle
strength.

Fats 1.5 g/kg/day

Fluids For stable patients in ICU: 30 mL/kg/day of fluid
for adult and 28 mL/kg/day for elderly

Vitamin C

Vitamin D

Vitamin B12

Selenium

Iron

ω-3, and medium and long-chain fatty acids

Adequate gut microbiome profile

Physical Activity Intervention

Inactivity

Active lifestyle

Finally, the present review has certain limitations. First, the information regarding
the study aim has been presented with a low number of studies compared to traditional
reviews. This fact was due to the novelty of the review and the relatively short time since
the appearance of COVID-19. Based on the results presented, we would propose as future
research lines in this area the study of the effect of diets with a powerful anti-inflammatory
effect in patients with COVID-19 and the risk of COVID-19 infection; and to analyze the
effect of combinations of supplements with antioxidant and anti-inflammatory effects in
patients with COVID-19.

10. Conclusions

The present narrative review found how the COVID-19 lockdown promoted unhealthy
dietary changes and increases in body weight of the population, showing the obesity and
physical activity levels as risk factors for COVID-19. In addition, hospitalized COVID-19
patients presented malnutrition and deficiencies in vitamin C, D, B12 selenium, iron, ω-3,
and medium and long-chain fatty acids highlighting the potential health effect of vitamin
C and D interventions.

Author Contributions: Conceptualization, V.J.C.-S.; methodology, V.J.C.-S. and J.F.T.-A.; investiga-
tion, V.J.C.-S. and J.F.T.-A.; writing—original draft preparation, all authors; writing—review and
editing, all authors; supervision, V.J.C.-S. All authors have read and agreed to the published version
of the manuscript.

Funding: This research received no external funding.

Institutional Review Board Statement: Not applicable.

Nutrients 2021, 13, 1924 14 of 20

Informed Consent Statement: Not applicable.

Data Availability Statement: Not applicable.

Conflicts of Interest: The authors declare no conflict of interest.

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nutrients

Review

A Narrative Review of The Role of Foods as Dietary
Sources of Vitamin D of Ethnic Minority Populations
with Darker Skin: The Underestimated Challenge

Jing Guo 1,* , Julie A. Lovegrove 2 and David I. Givens 1
1 Institute for Food, Nutrition and Health, University of Reading, Reading RG6 6AR, UK;
[email protected]
2 Hugh Sinclair Unit of Human Nutrition and Institute for Cardiovascular and Metabolic Research,
University of Reading, Reading RG6 6AP, UK; [email protected]
* Correspondence: [email protected]; Tel.: +44-(0)118-378-8476; Fax: +44-(0)118-378-6595

Received: 15 November 2018; Accepted: 28 December 2018; Published: 3 January 2019

Abstract: In recent years, vitamin D deficiency has attracted attention worldwide. Especially many
ethnic minority populations are considered at high-risk of vitamin D deficiency, owing to a lesser
ability to synthesis vitamin D from sunlight (ultraviolet B), due to the skin pigment melanin and/or
reduced skin exposure due to coverage required by religious and cultural restrictions. Therefore,
vitamin D intake from dietary sources has become increasingly important for many ethnic minority
populations to achieve adequate vitamin D status compared with the majority of the population.
The aim of the study was critically evaluate the vitamin D intake and vitamin D status of the
ethnic minority populations with darker skin, and also vitamin D absorption from supplements
and ultraviolet B. Pubmed, Embaase and Scopus were searched for articles published up to October
2018. The available evidence showed ethnic minority populations generally have a lower vitamin
D status than the majority populations. The main contributory food sources for dietary vitamin D
intake were different for ethnic minority populations and majority populations, due to vary dietary
patterns. Future strategies to increase dietary vitamin D intake by food fortification or biofortification
needs to be explored, not only for the majority population but more specifically for ethnic minority
populations who are generally of lower vitamin D status.

Keywords: ethnic; vitamin D intake; vitamin D status; food fortification

1. Introduction

Humans can obtain vitamin D both from ultraviolet B (UVB) irradiation [1] and dietary sources [2].
Vitamin D, including cholecalciferol (vitamin D3) synthesis in the skin triggered by UVB and vitamin
D (vitamin D2 and vitamin D3) intake from diet (including dietary supplements), needs to undergo
two hydroxylation reactions for activation in the human body. The first occurs in the liver where
vitamin D is converted to 25-hydroxyvitamin D (25(OH)D) [3], and the second in the kidney to form
the physiologically active form vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D). Serum or plasma
25(OH)D concentration is commonly used as a measure of vitamin D status [3], as it is the main
circulating form of vitamin D. Serum or plasma 25(OH)D ≤ 25 nmol/L has been used to define vitamin
D deficiency [4] although higher values have been proposed [4].

Vitamin D is a key nutrient for normal bone growth and mineralisation. Recently, mounting
evidence shows that low vitamin D status is also associated with increased risk of cardiovascular
disease (CVD) and type 2 diabetes (T2D), which are the leading causes of morbidity and mortality in
the world [4]. Vitamin D deficiency is prevalent and has become a major health problem globally [5,6].

Nutrients 2019, 11, 81; doi:10.3390/nu11010081 www.mdpi.com/journal/nutrients

Nutrients 2019, 11, 81 2 of 11

Especially ethnic minority populations (e.g., Asian, Black) with darker skin are considered as a
high-risk group for vitamin D deficiency, owing mainly to having less ability to synthesise vitamin D
from sunlight due to the skin pigment melanin and/or overall clothing required by their religion [7].
Furthermore, a resurgence of childhood rickets has recently highlighted the need for adequate vitamin
D status [8]. Several environmental factors (e.g., season, latitude, length of day) and personal
characteristics (e.g., skin melanin content, ageing) and human behaviour (e.g., sunscreen usage,
clothing) limit humans to derive vitamin D from UVB [9]. Therefore, vitamin D intake from the dietary
sources has become more important than before for contributing to vitamin D status.

In the current study, ethnic minority populations refer to populations within a community
which has different national or cultural traditions from the majority population, and with darker
skin. The main objective of the present review is to critically evaluate the vitamin D intake and
vitamin D status of ethnic minority populations with darker skin compared with majority populations,
and also vitamin D absorption from supplements and UVB of the ethnic minority populations is
reviewed. In addition, current strategies of increasing dietary vitamin D for ethnic minority populations
is considered.

2. Vitamin D Status and Vitamin D Intake of Ethnic Minority Populations

2.1. Methods

A review of the literature on vitamin D status, vitamin D intake in ethnic minority populations was
conducted using the online databases PubMed, Embase and Scopus by searching key words of ‘vitamin
D status’, ‘vitamin D intake’ and ‘ethnic’. Studies (observational studies, randomized controlled trials
(RCT)) published up to October 2018 (without language restriction) were searched. We excluded
studies on animals, or populations with a disease or medical condition. In addition, supplementary
hand searching of reference lists of previous review was conducted. Total 865 publications were
screened for this narrative review. Data were extracted from the studies if vitamin D status were
available for both majority population and ethnic minority populations.

2.2. Vitamin D Status of Ethnic Minority Populations

Studies reporting vitamin D status in different ethnic minority populations are presented in
Table 1 [10–24]. The study of Black et al. [12] reported vitamin D status in the West Australian
Pregnancy Cohort, which showed the vitamin D status of Caucasians to be significantly higher than
non-Caucasians (p < 0.001). Results from other studies [13,19,22,24] are consistent with the findings
from Black et al. [12]: Cauley et al. [13] reported vitamin D status in White, Black, Asian and American
Indian women of the Women’s Health Initiative Observational Study. The vitamin D status of the White
groups (60.8 nmol/L) was significantly higher than other ethnicities, and Black populations had the
highest number of people (70.5%) whose vitamin D status was lower than 63.6 nmol/L, while White
groups have the lowest number of people (30.7%). However, the results of Cauley et al. [13] may
be confounded by seasonal variability, as the seasonal variability of the vitamin D status was not
controlled. The study of Meyer et al. [19] measured vitamin D status in Norway and showed the mean
25(OH)D concentration was 74.8 (SD (standard deviation) = 23.7) nmol/L in persons born in Norway,
which was higher (p < 0.001) than those born in Pakistan. None of the Norwegian-born had 25(OH)D
levels below 12.5 nmol/L, whereas 9% and 21% of Pakistani men and women had 25(OH)D below
12.5 nmol/L, respectively. However, ethnicity was not defined in the Norwegian-born population.
The cross-sectional study of Schleicher et al. [22] assessed vitamin D status of different ethnicities
aged 12 years and above (including Mexican American, non-Hispanic Black, non-Hispanic White) at
five different time points (1988–1994, 2001–2002, 2003–2004, 2005–2006, 2007–2008 and 2009–2010).
The results showed the non-Hispanic Black population have the lower 25(OH)D concentrations and
more people with 25(OH)D level < 30 nmol/L than the Mexican American and non-Hispanic White,
another cross-sectional study of van der Meer et al. [24] measured vitamin D status of ethnicities in

Nutrients 2019, 11, 81 3 of 11

the Netherlands, and reported that Asian and mid/south Africans had lower 25(OH)D concentration
and a higher number of people whose 25(OH)D was < 25 nmol/L compared with other ethnicities.
Therefore, the above evidence highlights the potential higher risk of vitamin D deficiency in some
ethnic minority populations.

The most common cause of rickets is vitamin D deficiency [25]. There was a high prevalence of
rickets in children in industrialised Europe and North America in the 19th and early 20th centuries [26],
this situation was reversed by human consumption of a variety of vitamin D fortified foods and use of
cod liver oil by the late of 1930s. However, in Europe in the 1950s, for food products except breakfast
cereals and margarine, it was forbidden to fortify with vitamin D because of cases of vitamin D toxicity
in newborns [26]. Consequently, vitamin D fortified products became less available. Unfortunately,
rickets has made a resurgence in Europe [27] and also around the world [8], particularly among Asian
and Africa ethnic minorities [8,28]. The study of Robinson et al. [29] defined the demographic and
clinical characteristics of rickets in Australia, and reported the most prominent regions of origin were
India (37%), Africa (33%), and the Middle East (11%), while only 4% were white Australian children.
Furthermore, in an earlier UK survey [30] in the West Midlands, paediatricians identified 24 cases of
symptomatic vitamin D deficiency in children (≤5 year) and reported an incidence of rickets of 38 and
95 per 100,000 per annum in South Asian and Black children, with only 0.4 per 100,000 per annum in
white children.

2.3. Vitamin D Status in Different Seasons of Ethnic Minority Populations

Season of the year influences vitamin D status [31]. The study of Hypponen and Power [27]
showed that the prevalence of hypovitaminosis D in the UK was especially high in the winter and
spring seasons [27]. There are a few studies [10,20,21,23] which reported vitamin D status in different
ethnicities in winter. For example Nerhus et al. [20] reported that the ethnic minority population
had significantly lower serum 25(OH)D concentrations (mean 29.5 nmol/L, SD = 16.3) in winter than
participants from the majority of the population (mean 50.4 nmol/L, SD = 19.1) in Norway, although
serum 25(OH)D of different ethnic minorities was not investigated separately. In addition, the study of
Adebayo et al. [10] reported ethnic differences in serum 25(OH)D concentration in winter in Southern
Finland (60◦ N), with the mean serum 25(OH)D concentrations in Finnish women (mean 60.5 nmol/L,
SD = 16.6) being significantly higher than in East African women (mean 51.5 nmol/L, SD = 15.4).
In the UK, the study of Tripkovic et al. [23] reported South Asian participants had much lower serum
25(OH)D concentrations (mean 27.7 nmol/L) than White European participants (mean 60.3 nmol/L) in
winter. More specifically, Sacheck et al. [21] compared the serum 25(OH)D values of children in winter
across different ethnicities (White, Black, Hispanic or Latino, Asian) in the US. The results showed
white children had significantly higher mean serum 25(OH)D concentrations (mean 61.9 nmol/L) than
all other children (44.7 nmol/L, 51.9 nmol.L and 46.9 nmol/L for Black, Hispanic or Latino, Asian,
respectively). Furthermore, Haggarty et al. [18] investigated the influence of seasonal changes on
plasma 25(OH)D in pregnant Caucasian women in Scotland. They found that the highest 25(OH)D
values were in summer (53.1 nmol/L, 95% CI (confidence intervals): 50.0, 56.7), and the lowest in
winter (34.4 nmol/L, 95% CI: 31.8, 37.2). Also, the greatest proportion of participants whose plasma
25(OH)D was < 25 nmol/L was observed in winter. Another UK study by Darling et al. [14] which
compared serum 25(OH)D.

The results showed serum 25(OH)D concentrations of Asians were lower than Caucasians
throughout the year with the proportion of participants whose serum 25(OH)D < 25 nmol/L was much
higher in Asians (53.5–80.8%) than Caucasians (0.8–10.0%). In addition, the study reported a lack of
seasonal changes on 25(OH)D concentrations in the Asian population. Furthermore, vitamin D status
are associated with other factors (such as: age, gender, higher latitude, obesity and socioeconomic
status) [5], but there are limited evidence of the effects of those influencing factors for the different
ethnic minority populations compared with the majority populations, which needs further research
to clarity.

Nutrients 2019, 11, 81

Table 1. Summary of studies investigating the vitamin D status (25(OH

Study/Country Study Design Ethnic Minority Population a, n

Adebayo et al., 2018/Finland [10] Randomised controlled trial East African, n = 47
Aloia et al. 2008/US [11] Finnish, n = 69
Randomised controlled trial
Black et al., 2014/Australia [12] Black, n = 62
Prospective cohort study
(Western Australian White, n = 76

Preganancy Cohort Study) Caucasian (classified if both
parents were Caucasian), n = 887

Non-Caucasian (classified if at
least one parent was of an
alternate ethnicity), n = 158

White, n = 780

Cauley et al., 2011/US [13] Case control study nested Black, n = 758
witthin the prospecitve cohort Hispanic, n = 382

sudy of WHI-OS Asian, n = 224

American Indian, n = 88

Darling et al., 2013/UK [14] Longitudinal study Caucasian, n = 128

Gallagher et al., 2012 and 2013/US Randomised controlled trial South Asian, n = 43
[16,17] Caucasian, n = 97
South Asian, n = 24
Caucasian, n = 80
South Asian, n = 26
Caucasian, n = 79
South Asian, n = 24

Black, n = 110

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H)D concentration) in ethnic minority populations (in alphabetic order).

Study Participants, Age, BMI Season Vitamin D Intake 25(OH)D Concentration
(µg/day) (nmol/L)
Women, 41 years, 29.4 kg/m2 Winter
Winter Mean SD/95% CI Mean SD/95% CI
Women, 33 years, 23.8 kg/m2
All seasons 11.3 5.1 52.2 14.0
Men and women, 18–65 years, 27.3
kg/m2 8.4 4.1 60.5 16.6

Men and women, 18–65 years, 26.8 2.0 NA 39.7 NA
kg/m2
2.1 NA 5738.0 Reference
Male and Female, 14–17 year, 21.4–23.0
kg/m2

Male and Female, 14–17 years, All seasons −15.2 −19.1, −11.3 b
21.4–23.0 kg/m2
60.8 24.0
Postmenopausal women, 66 years, All seasons
27.5 kg/m2 43.7 21.5
All seasons
Postmenopausal women, 62 years, 53.0 21.0
30.5 kg/m2 All seasons
62.3 24.3
Postmenopausal women, 63 years, All seasons
29.0 kg/m2 50.0 25.5
All seasons
Postmenopausal women, 65 years, 2.4 2.0 72.1 26.1
24.7 kg/m2 Summer 2.2 1.8 26.2 9.9
Summer 2.1 1.5 59.5 25.6
Postmenopausal women, 63 years, Autumn 2.0 1.4 20.9 11.8
29.5 kg/m2 Autumn 2.6 1.8 44.5 18.0
Winter 2.0 2.0 19.7 10.6
Premenopausal women, 38 years, 26 Winter 2.5 1.9 53.2 23.9
kg/m2 Spring 1.6 1.1 22.1 11.3
Spring
Women, 67 years, 32.7 kg/m2 All seasons 33.0 NA

Nutrients 2019, 11, 81

Table 1

Study/Country Study Design Ethnic Minority Population a, n

Gallagher et al., 2014/US Randomised controlled trial White, n = 163
[15] Black, n = 79
White, n = 119

Caucasians, n = 1205

Haggarty et al., 2013/UK Prospective cohort study
[18]

Meyer et al., 2004/Norway [19] Prospective cohort study (Oslo Non-Caucasians (African, Asian
Nerhus et al., 2015/Norway [20] Health Study) and Indian), n = 42

Schleicher et al., 2016/US [22] Prospective cohort study Born in Norway, n = 866
Sacheck et al., 2017/US [21] (Thematically Organized Born in Pakistan, n = 176
Tripkovic et al., 2017/UK [23] Ethnic minority (Turkey, Africa
Psychosis Study) and Latin-America), n = 40

Cross-sectional: NHANES Norwegians, n = 102
(2009-2010) Mexican American, n = 1388
Non-hispanic Black, n = 1229
Randomised controlled trial Non-hispanic White, n = 3174

Randomised controlled trial White, n = 244
Black, n = 85
Hispanic or Latino, n = 135
Asian, n = 53
South Asian, n = 90
White, n = 245

Lightest skin Western, n = 110

van der Meer et al., 2008/The Cross-sectional Turkish and North African, n = 223
Netherlands
[24] Asian and Mid/South African
(darkest skin types), n = 280

NA: not available; CI: Confidence Intervals; SD: Standard Deviation; NHANES: National H
a Ethnic minority populations refer to populations within a community which has different na
difference in serum 25(OH)D concentrations from the reference category of categorical varia

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1. Cont.

Study Participants, Age, BMI Season Vitamin D Intake 25(OH)D Concentration
(µg/day) (nmol/L)
Women, 67 years, 30.2 kg/m2 All seasons
Women, 35 years, 32.5 kg/m2 All seasons Mean SD/95% CI Mean SD/95% CI
Women, 33 years, 28.8 kg/m2 All seasons 39.0 NA
3.7 3.5, 3.9 37.4 30.7, 43.9
Pregnant women, 31 years, NA Winter 3.8 3.6, 4.1 31.0 23.0, 39.2
Spring 3.9 3.6, 4.2 34.4 31.8, 37.2
Summer 4.0 3.7, 4.4 39.7 36.7, 42.9
Autumn 53.1 50.0, 56.7
33.7 30.6, 37.2

Pregnant women, 39 years, NA All seasons 17.1 NA

Men and women, adults, NA All seasons 74.8 23.7
Men and women, adults, NA All seasons 25.0 13.6

Men and women, 28 years, 26.1 kg/m2 Winter 29.5 16.3

Men and women, 28 years, 24.6 kg/m2 Winter 50.4 19.1

Men and women, ≥12 years, NA All seasons 53.9 52.2, 55.5

Men and women, ≥12 years, NA All seasons 46.0 41.6, 50.5

Men and women, ≥12 years, NA All seasons 75.0 72.5, 77.4

Winter 61.9 NA

Boy and girl, 11 years, 21.5 kg/m2 Winter 44.7 NA
Winter 51.9 NA

Winter 46.9 NA

Women, 43 years, 24.0 kg/m2 Winter 27.7 NA
60.3 NA

Men and women, 18–65 years, All seasons 58.0 49.0, 68.0
25.3–28.7 kg/m2

Men and women, 18–65 years, All seasons 33.0 28.0, 39.0
25.3–28.8 kg/m2

Men and women, 18–65 years, All seasons 29.0 25.0, 34.0
25.3–28.9 kg/m2

Health and Examination Survey; WHI-OS: Women’s Health Initiative- Observational Study.
ational or cultural traditions from the majority population, and with darker skin. b Estimated
ables or per unit increase of continuous variables.

Nutrients 2019, 11, 81 6 of 11

2.4. Vitamin D Intake of Ethnic Minority Populations

The work of Kiely and Black indicated that dietary vitamin D intakes are inadequate to meet
Dietary Reference Intake, which may vary according to gender, age and country fortification
practices [32]. Whilst it is known that dietary patterns vary between different ethnic minority
populations [33], there is very limited evidence on the vitamin D intake of different ethnicities. Dietary
vitamin D intake was reported to be higher in the US and Canada than most of European countries
except Nordic countries, due to mandatory fortification in North America [32]. In Finland where
mandatory fortification takes place [34], the study of Adebayo et al. [10] showed a higher mean dietary
vitamin D intake by women of East African origin (11.2 µg/d, SD = 5.8) than Finish participants
(8.4 µg/d, SD = 4.1). The main contributory food sources for dietary vitamin D intake for both East
African and Finish participants were fortified fluid milk products and fortified fat spreads. There
was a higher intake of fortified fluid milk products in East African group than Finnish group, which
may resulted in higher vitamin D dietary intake in the East African group. In the UK, vitamin D
fortification of foods is not mandatory [4]. The study of Darling et al. [14] reported that vitamin D
intake was slightly higher in Caucasian than Asian sections of the population in the UK throughout
the year. Vitamin D intakes from the diet were 1.6–2.2 µg/d and 2.1–2.6 µg/d for South Asians and
Caucasians, respectively [14], which was much lower than vitamin D intake of subjects in the Finnish
study [10]. In addition, no influence of seasonal changes in dietary vitamin D intake for both South
Asians and Caucasians was seen. The main sources of vitamin D in the diet (flour, grains and starches;
meat and meat products; fish and fish products, milk and milk products; egg and egg products) were
the same for both groups but the proportions of the various foods were different for South Asians and
Caucasians. For example, flour, grains and starches contributed 21.8–33.0% and 24.2–26.6% to total
vitamin D dietary intake for South Asians and Caucasians, respectively. In the UK National Diet and
Nutrition Survey (NDNS) [5], the mean daily vitamin D dietary intake for adults (19–64 years) was
2.8 µg, which was in line with results of Darling et al. [14], however, data in NDNS was not specific
analysed for different ethnic minority populations in the UK, which could be done in the future.

2.5. Vitamin D Status Response to Vitamin D Supplementation of Ethnic Minority Populations

There is limited evidence on the impact of vitamin D supplementation on the vitamin D status of
racially diverse populations (Table 2). The study of Adebayo et al. [10] investigated ethnic differences
of serum 25(OH) D to vitamin D3 supplementation of 10 or 20 µg/d through a 5-month RCT in
East African and Finnish women, and found no ethnic differences in the response to either 10 or
20 µg/d vitamin D3 supplementation. In addition, studies of Gallagher et al. [16,17] compared the
effect of vitamin D3 supplementation at different doses (10, 20, 40, 60, 80, 100 and 120 µg/d) in African
American Women with Caucasian women in the US. The findings agreed with Adebayo et al. [10] that
effect of vitamin D3 supplementation on serum 25(OH)D concentration is not dependent on race.

Nutrients 2019, 11, 81

Table 2. Summary of randomised controlled trials investigating vitamin D status (2
population (in alphabetic order).

Study/Country Study Duration Ethnic Minority Study Participants, Age, BM
Population a, n

Adebayo et al. 5-month East African, n = 47 Women, 41 years, 29.4 kg/m
2018/Finland [10] Finnish, n = 69 Women, 33 years, 23.8 kg/m

Aloia et al. 2008/US 6-month Black, n = 62 Men and women, 18–65 years,
[11] White, n = 76 kg/m2

Men and women, 18–65 years,
kg/m2

Gallagher et al. 2012 1-year Black, n = 110 Women, 67 years, 32.7 kg/m
& 2013/US [16,17] White, n = 163 Women, 67 years, 30.2 kg/m

Gallagher et al. 1-year Black, n = 79 Women, 35 years, 32.5 kg/m
2014/US [15] White, n = 119 Women, 33 years, 28.8 kg/m

White, n = 244 Boy and girl, 11 years, 21.5 kg

Sacheck et al. 1-year Black, n = 85
2017/US [21] Hispanic or Latino, n = 135

Asian, n = 53

Tripkovic et al. 12-week South Asian, n = 90 Women, 43 years, 24.0 kg/m
2017/UK [23] White, n = 245

NA: not available; BMI: Body Mass Index; a Ethnic minority populations refer to population
population, and with darker skin; b Juice supplemented with 15 µg vitamin D3.

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25(OH)D concentration) response to vitamin D supplementation in ethnic minority

25(OH) D Concentration nmol/L

MI Season Vitamin D Baseline Endpoint
Winter Supplementation
m2 Winter Mean SD/95% CI Mean SD/95% CI
m2 Winter 10 µg/ day
, 27.3 20 µg/ day 52.2 14.0 +10.0 +19.2%
10 µg/ day
20 µg/ day +17.1 +32.7%

97.9 (21.0) µg over 3 visits 60.5 16.6 +8.5 +14.1%

+10.7 +17.7%

39.7 NA

, 26.8 Winter 76.0 (28.4) µg over 3 visits 57.8 NA

m2 All seasons 10–120 µg/day 33.0 NA 125.0 NA

m2 All seasons 10–120 µg/ day 39.0 NA 117 NA

m2 All seasons 60 µg/ day 37.4 30.7, 43.9 97.6 90.4, 104.8
m2 All seasons
31.0 23.0, 39.2 107.8 95.4, 120.1

g/m2 Winter 50 µg/ day 61.9 NA

Winter 50 µg/ day 44.7 NA +54.4 7.0

Winter 50 µg/ day 51.9 NA

Winter 50 µg/ day 46.9 NA +35.0 5.4

m2 Winter 27.7 NA 60.1 49.7, 70.5 b
60.3 NA 87.9 82.3, 93.5 b

ns within a community which has different national or cultural traditions from the majority

Nutrients 2019, 11, 81 8 of 11

In contrast, an RCT [21] supplemented different ethnic children (White, Black, Hispanic or Latino,
Asian, Multiracial or other) with vitamin D3 at three different doses (15, 25 or 50 µg/d) for 6 months.
The results showed similar responses across ethnicities for the 15 µg/d and 25 µg/d doses but the
Asian group had the lowest response (mean ± SE increase of 35.0 nmol/L ± 5.4 nmol/L) to the
50 µg/d dose group, while Black children had the greatest response to supplementation (mean ± SE
increase of 54.4 nmol/L ± 7.0 nmol/L). Furthermore, the study of Aloia et al. [11] used a 6-month RCT
to investigate the effect of vitamin D3 supplementation on serum 25(OH)D concentration in African
Americans and White groups. The results showed both groups achieved the target of 75 nmol/L
by week 18, but the vitamin D3 dose needed to achieve that value was 50% higher in the African
Americans. However, the study of Gallagher et al. [15] found a greater dose response in African
Americans than white women after 12-month vitamin D supplementation (up to 60 µg/d). Tripkovic
et al. [23] also found a greater response to vitamin D supplementation (15 µg/d for 12 week) in
South Asian women than white European women. However, in the studies [11,15,21,23] that reported
different effects of vitamin D supplementation in different ethnicities, there was a lower baseline
25(OH)D concentrations in Black and Asian population compared with white people, which may have
influenced the different response.

Therefore, future studies on investigating vitamin D status response to vitamin D supplementation
for ethnic minority populations need to design the RCT with same serum/plasma 25(OH)D
concentration at baseline.

2.6. Vitamin D Synthesis from Sunlight Exposure of Ethnic Minority Populations

Skin pigmentation absorbs UVB radiation [35], consequently people with darker skin are
susceptible to less UVB absorption. Compared with Caucasians, there is evidence that Asians require
approximately threefold longer periods of sunlight exposure because of the protective pigmentation in
their skin and Africans need six times the same exposure, to achieve the same serum/plasma 25(OH)D
concentration [36]. Furthermore, extensive coverage by garments is practised by some ethnic minority
populations due to religious or cultural needs [9], which may add more potential risk of vitamin D
deficiency for those ethnic minority populations. In addition there is evidence that some ethnicities
may have less sunlight exposure time than Caucasians. Darling et al. [14] showed Caucasians had a
significant higher UVB exposure than Asian group (95% CI: 0.3–3.9 SED (standard erythemal dose)) in
the UK over the year. Although the reasons could not be assessed in the study of Darling et al. [14],
which may be clarified in the future studies.

3. Current Strategies and Limitations

Only few foods are naturally rich in vitamin D (e.g., egg yolk, oily fish and wild mushroom),
but vitamin D content are highly variable even in those foods considered the richest sources [37].
For example, the study of Mattila et al. [38] measured vitamin D2 in different mushroom species,
and found that there was a significant variation (0.21–29.82 µg/100 g of fresh weight). For
animal derived products, vitamin D concentrations may vary between different produced systems.
For instance, wild salmon had nearly double the vitamin D content of farmed salmon [39]; vitamin
D3 in organic and free range eggs was significantly higher than in indoor eggs [40]. It is therefore
difficult to meet the vitamin D dietary recommendation solely by natural foods. Food fortification is
a potentially effective strategy to increase vitamin D intake and circulating plasma/serum 25(OH)D
concentrations on a population-wide basis. The recent meta-analysis [41] evaluated evidence from
sixteen studies and showed a mean individual intake of 11 µg/d from fortified foods (range 3–25 µg/d)
increased plasma/serum 25(OH)D concentration by 19.4 nmol/L (95% CI: 13.9, 24.9), which confirmed
the efficacy of vitamin D fortified foods on circulating concentrations of 25(OH)D. Currently, however,
food fortification policy varies between different countries [30]. For instance, there is mandatory
fortification of milk with vitamin D in Canada and Finland, while milk is mostly voluntarily fortified
in the US [30,34]. Furthermore, to our knowledge, no studies have investigated the effect of different

Nutrients 2019, 11, 81 9 of 11

vitamin D fortified foods on increasing vitamin D status for ethnic minority populations. The review
by Cashman et al. [34] suggested that vitamin D should be fortified in a wider range of foods, not only
a single staple, to accommodate dietary diversity. This conclusion is especially important to different
ethnicities to ensure an adequate vitamin D dietary intake. For example, milk is not widely consumed in
India, Jordan or China [42], fortification of wheat flour may be therefore more efficacious in preventing
vitamin D deficiency [43]. Therefore, more studies are needed to investigate the effect of vitamin D
fortified foods on vitamin D status and human health, especially for the high risk group, such as ethnic
minority populations.

4. Conclusions

Dark skinned ethnic minority populations generally have a lower vitamin D status than the
majority of the population. The main contributory food sources for dietary vitamin D intake were
different for ethnic minority populations and majority populations, due to different dietary pattens.
Future strategies to increase dietary vitamin D intake by food fortification needs to be explored,
specifically for ethnic minority populations. In addition, public health policy and practice needs to
have an increased awareness of vitamin D deficiency in ethnic minority populations, and address the
dietary strategies for those population in the future.

Author Contributions: J.G. and D.I.G. developed the concept. J.G. conceived and wrote the manuscript. J.A.L
and D.I.G. critically appraised the document at all stages. All authors critically reviewed the approved the final
version of the manuscript.

Funding: This research received no specific grant from any funding agency, commercial or non-for-profit sectors.
J.G. was supported by the Barham Benevolent Foundation and University of Reading.

Conflicts of Interest: The authors declare no conflict of interest.

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© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Wilkins et al. Journal of Health, Population and Nutrition (2021) 40:20
https://doi.org/10.1186/s41043-021-00241-2

REVIEW ARTICLE Open Access

Maternal nutrition and its intergenerational
links to non-communicable disease
metabolic risk factors: a systematic review
and narrative synthesis

Elizabeth Wilkins1, Kremlin Wickramasinghe1, Jessie Pullar1, Alessandro R. Demaio2, Nia Roberts3,
Karla-Maria Perez-Blanco4, Katharine Noonan5 and Nick Townsend6*

Abstract

Background: Non-communicable diseases (NCDs) are the leading cause of death and disability globally, while
malnutrition presents a major global burden. An increasing body of evidence suggests that poor maternal nutrition
is related to the development of NCDs and their risk factors in adult offspring. However, there has been no
systematic evaluation of this evidence.

Methods: We searched eight electronic databases and reference lists for primary research published between 1
January 1996 and 31 May 2016 for studies presenting data on various dimensions of maternal nutritional status
(including maternal exposure to famine, maternal gestational weight gain (GWG), maternal weight and/or body
mass index (BMI), and maternal dietary intake) during pregnancy or lactation, and measures of at least one of three
NCD metabolic risk factors (blood pressure, blood lipids and blood glucose) in the study population of offspring
aged 18 years or over. Owing to high heterogeneity across exposures and outcomes, we employed a narrative
approach for data synthesis (PROSPERO= CRD42016039244, CRD42016039247).

Results: Twenty-seven studies from 10 countries with 62,607 participants in total met our inclusion criteria. The
review revealed considerable heterogeneity in findings across studies. There was evidence of a link between
maternal exposure to famine during pregnancy with adverse blood pressure, blood lipid, and glucose metabolism
outcomes in adult offspring in some contexts, with some tentative support for an influence of adult offspring
adiposity in this relationship. However, the evidence base for maternal BMI, GWG, and dietary intake of specific
nutrients during pregnancy was more limited and revealed no consistent support for a link between these
exposures and adult offspring NCD metabolic risk factors.

Conclusion: The links identified between maternal exposure to famine and offspring NCD risk factors in some
contexts, and the tentative support for the role of adult offspring adiposity in influencing this relationship, suggest
the need for increased collaboration between maternal nutrition and NCD sectors. However, in view of the current
scant evidence base for other aspects of maternal nutrition, and the overall heterogeneity of findings, ongoing
monitoring and evaluation using large prospective studies and linked data sets is a major priority.

* Correspondence: [email protected]
6Department for Health, University of Bath, Bath BA2 7AY, UK
Full list of author information is available at the end of the article

© The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if
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The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the
data made available in this article, unless otherwise stated in a credit line to the data.

Wilkins et al. Journal of Health, Population and Nutrition (2021) 40:20 Page 2 of 11

What is already known and what this review adds on the development of NCDs operates at multiple stages
We identified several non-systematic, narrative reviews throughout the life-course, and moreover, between gen-
that focused largely on the developmental origins of erations. Specifically, it seems that sub-optimal maternal
metabolic risk factors and NCD outcomes [1–6]. In nutrition before and during pregnancy can induce
terms of reviews that discussed evidence, two supported changes in foetal development that predispose offspring
a link between maternal undernutrition and overnutri- in later life to immediate NCD metabolic risk factors
tion and offspring NCDs. In contrast, a recent systematic such as raised blood pressure, high blood lipid levels,
review of maternal overnutrition found no consistent impaired glucose tolerance, and overweight/obesity, and
support for a link with cardiovascular risk factors in in turn NCDs [1, 2, 5, 6, 10].
adult offspring [7].
A number of narrative reviews have explored this
To our knowledge, this is the first systematic review to relationship, with the focus on the underlying theory
examine the relationship between various dimensions of and potential mechanisms [1–6]. Discursive reviews of
maternal nutritional status during pregnancy or lactation the evidence on maternal undernutrition during preg-
and blood pressure, blood lipids, and glucose metabol- nancy have suggested a link with offspring risk of
ism in adult offspring. Our findings support an associ- NCDs [5, 6]. Reviews of the evidence on maternal
ation between maternal gestational exposure to famine overnutrition have been more mixed, with some find-
and offspring metabolic NCD risk factors in some con- ing a link with the development of offspring NCDs
texts, but reveal no consistent support for a relationship and risk factors [5, 6], and others finding no consist-
between maternal gestational weight gain (GWG), ma- ent associations [7]. To our knowledge, no study has
ternal weight or body mass index (BMI), or maternal systematically reviewed the relationship between vari-
dietary intake and offspring NCD risk factors. Our find- ous dimensions of maternal nutritional status during
ings also show some tentative support for an influence pregnancy and lactation and the development of
of adult offspring adiposity in the maternal exposure to metabolic risk factors for NCDs in adult offspring.
famine—offspring NCD risk factor relationship. Import-
antly, our review exposes the paucity of the current evi- Such a review is needed to identify critical windows
dence base and considerable heterogeneity across and intervention focus points for NCD prevention, and
studies. to inform the future work of maternal nutrition and
NCD sectors. It is also an appropriate time to conduct
Background such a review, given the declaration by the United Na-
Malnutrition represents one of the greatest global health tions General Assembly of 2016 to 2025 as the Decade
challenges of our time. In 2015, approximately 462 mil- of Action on Nutrition [11], the respective SDG targets
lion adults worldwide were underweight and 264 million to end all forms of malnutrition and reduce premature
women of reproductive age were affected by iron- NCD mortality by one third by 2030 [12], and the
amenable anaemia, while 1.9 billion adults were either current international focus on collaboration across dif-
overweight or obese [8]. This co-existence of undernu- ferent sectors. Accordingly, this paper aims to systemat-
trition and over-nutrition, or ‘double burden of malnu- ically assess the evidence on the relationship between
trition’, is of particular concern in lower middle-income maternal nutritional status during pregnancy and lacta-
countries (LMIC). tion and three metabolic NCD risk factors—elevated
blood pressure, high blood lipid levels, and impaired glu-
Meanwhile, unprecedented rates of economic and in- cose tolerance—in adult offspring.
come growth, urbanisation, and globalisation have led to
a rapid rise in the burden of non-communicable diseases Methods
(NCDs), principally cardiovascular disease (CVD), can-
cers, chronic respiratory diseases, and diabetes. NCDs Search strategy and selection criteria
are now the world’s leading cause of death and disability, We conducted a systematic review following PRISMA
responsible for 71% of deaths and 60% of disability- guidelines (Additional file 1) [13]: PROSPERO regis-
adjusted life years (DALYs) globally in 2015, with the tration numbers: CRD42016039244, CRD42016039247.
burden of premature deaths from these diseases also felt We searched CINAHL, Cochrane Database of System-
disproportionately in low- and lower middle-income atic Reviews, Cochrane Register of Controlled Trials,
countries (LLMIC) [9]. Database of Abstracts of Reviews of Effects, MEDL
INE, EMBASE, Web of Science, and Global Health
Unhealthy diets constitute the largest behavioural risk for all studies that included primary data published
factor for NCDs, with 30% of global NCD deaths and between 1 January 1996 and 31 May 2016. We also
18% of NCD DALYs attributable to dietary risk factors reviewed the reference lists of reviews identified dur-
[9]. Mounting clinical, experimental, and epidemiological ing screening and of included papers. We did not re-
evidence suggests that the influence of dietary nutrition view grey literature. We used English search terms

Wilkins et al. Journal of Health, Population and Nutrition (2021) 40:20 Page 3 of 11

(Additional file 2) but placed no restrictions on the Data extraction
publication language, populations assessed, or study From each included full-text study, EW and JP ex-
design. tracted information on study type; nature of sample,
including sample size and percentage male; offspring
The study population was adult offspring (age 18 years age; maternal nutrition exposure measures; offspring
and over). The exposure variable was maternal nutri- metabolic risk factor outcomes; and results. Ambigu-
tional status during pregnancy or lactation. We defined ities were resolved by group consensus. Where data
maternal nutritional status broadly to include maternal were unclear or incomplete, the authors were con-
exposure to famine (measured by proxy indicators, such tacted by email, and the study excluded if the infor-
as the official daily rations for the population aged 21 mation was unavailable.
years and over combined with birth date); maternal ges-
tational weight gain (GWG); maternal weight and/or We used a modified, design-specific versions of the
body mass index (BMI); and maternal dietary intake. Newcastle-Ottawa scale to assess the quality of included
The outcome variable was NCD metabolic risk factors in studies (Additional file 3). The scoring system was based
adult offspring. Specifically, we studied three NCD meta- on the selection of study groups, comparability of
bolic risk factors: blood pressure, blood lipid levels/me- groups, ascertainment of exposure and outcome mea-
tabolism, and blood glucose levels/metabolism (the sures, and methods to control for confounders.
specific outcome indicators for each study are presented
in Table 1). We did not study outcome measures of off- The main outcomes extracted were differences in
spring overweight/obesity, taking the view that the very blood pressure, blood lipid, and glucose metabolism in-
large volume of studies on this outcome merited a separ- dicators for offspring of mothers with different levels of
ate, future systematic review. a given nutritional indicator (see Table 1 for the specific
outcome indicators for each study). We also planned,
We included records if they presented summary where possible, to investigate how the findings were in-
estimate data on one or more indicators of maternal fluenced by the specific risk factor outcome, offspring
nutritional status during pregnancy or lactation, and sex, gestational timing of exposure, and adult offspring
measures of at least one of the three NCD metabolic adiposity. We assessed within-study variability in our
risk factors for offspring aged 18 years or over. We quality scoring when considering the repeatability of
excluded studies if they did not include a measure of measuring instruments. Owing to the heterogeneity of
maternal nutritional status, or did not include a the design and outcome measures of included studies, a
measure of one of the three NCD metabolic risk fac- meta-analysis was not conducted. Instead, narrative syn-
tors in adult offspring, were not primary research, or thesis of data was conducted by EW, with studies
were conducted in animals. In addition, we did not grouped by outcome measure. We used Microsoft Excel
include studies that focused on mothers with pre- to calculate simple descriptive statistics.
existing medical conditions, or a diagnosis of pre-
eclampsia or gestational diabetes during pregnancy, Ethical clearance
since we were interested in the link between mothers’ Ethical clearance was not required as this is a systematic
nutritional status and offspring NCD metabolic risk review of literature, and anonymised data were used
factors in the general population. A specific focus on throughout.
the interaction between nutrition and underlying
medical conditions in this relationship would have Results
added a level of complexity due to the range of We identified 23,291 records from our database
possible medical conditions. search and 214 records from other sources, yielding
21,659 records after the removal of duplicates. Fol-
Jessie Pullar (JP), Karla-Maria Perez-Blanco (KP), and lowing initial screening of these 21,659 records, we
Katharine Noonan (KN) independently screened the reviewed 116 full-text articles, 27 of which met our
titles and abstracts of the initial 21,659 records. The inclusion criteria (Fig. 1).
Cohen’s κ statistic was calculated at 10% intervals
(approximately every 2000 papers) to check percentage The included studies were published between 1996
agreement. Once Cohen’s κ exceeded 0.75 (excellent and 2015 and included 62,607 participants in total.
agreement [41]), KP, and KN screened all remaining Overall, ten countries were represented: seven from the
records. Uncertainties were brought to JP, Kremlin World Health Organization’s (WHO) European Region,
Wickramasinghe (KW), and Nick Townsend (NT), and two from the Western Pacific Region, and one from the
disagreements were resolved by group consensus. Eliza- Region of the Americas. When classified by World Bank
beth Wilkins (EW) and JP then reviewed all records se- income group, there were seven high-income economies,
lected for full text review, resolving any uncertainties by two upper-middle-income economies, and one lower-
group consensus with KW and NT. middle-income economy. Seventeen studies were cohort

Wilkins et al. Journal of Health, Population and Nutrition (2021) 40:20 Page 4 of 11

Table 1 Summary of study characteristics

Site Study Number of Age of Exposure Outcome

design participants adult

offspring at

follow-up

De Rooij Netherlands Cohort 672 58 Famine Glucose metabolism (FPG, 120
et al. [14] minute glucose)

De Rooij Netherlands Cohort 783 58 Famine Blood pressure (SBP, DBP)
et al. [15] Blood lipids
Glucose metabolism

Huang China Cohort 33247 (total 32 Famine Blood pressure (prevalence of
N=35025) hypertension)
et al. [16]

Li et al. [17] China 2959 (total 43–45 Famine Glucose metabolism: FPG,
N=7874) prevalence of hyperglycemia

Ravelli et al. Netherlands Cohort 702 51–55 Famine Glucose metabolism (FPG, 30
[18] minute glucose, 120 minute
glucose)
Blood lipids

Roseboom Netherlands Cohort 739 51–55 Famine Blood pressure (SBP, DBP)
et al. [19]

Roseboom Netherlands Cohort 704 50 Famine Blood lipids (total cholesterol,
et al. [20] LDL, HDL, LDL:HDL, Apo-A1,
Apo-B)

Stanner Russia Cross- 549 52–53 Famine Blood pressure: SBP, DBP
et al. [21] sectional

Stein et al. Netherlands Cohort 971 56–62 Famine Blood pressure (SBP, DBP,
[22] prevalence of hypertension)

Wang et al. China Cross- 2420 (total 52–53 Famine Blood pressure: (SBP, DBP,
[23] sectional N=6445) prevalence of hypertension)
Blood lipids
Glucose metabolism

Zheng China Cross- 3696 (total 44–51 Famine Blood pressure (SBP, DBP,
sectional N=5040) prevalence of hypertension)
et al. [24] Blood lipids
Glucose metabolism

Loos et al. Belgium Cross- 800 18–34 GWG, ppBMI Glucose metabolism (FPG, fasting
[25] sectional plasma proinsulin, fasting plasma
insulin, HOMA-IR, HOMA)

Mamun Australia Cohort 2271 21 GWG Blood pressure (SBP, DBP)
et al. [26]

Hochner Israel Cohort 1130 32 GWG, ppBMI Blood pressure (SBP, DBP)
et al. [27] Blood lipids
Glucose metabolism

Hrolfsdottir Denmark Cohort 308 19–20 GWG Blood pressure (SBP, DBP)
et al. [28] Blood lipids
Glucose metabolism

Mi et al. China Cross- 627 41–47 GWG Blood pressure(SBP, DBP,
[29] sectional BMI prevalence of hypertension)
Blood lipids
Glucose metabolism

Scheers- Sweden Cohort 9816 18.3 GWG Blood pressure (SBP, DBP,
Andersson prevalence of hypertension)
et al. [30]

Webb et al. Guatemala Longitudinal 450 21–29 GWG, BMI, dietary Blood pressure (SBP, DBP)
[31] intake (protein
and micronutrient
supplementation)

Hochner Israel Cohort 1130 32 GWG, ppBMI Blood pressure (SBP, DBP)
et al. [27] Blood lipids
Glucose metabolism

Wilkins et al. Journal of Health, Population and Nutrition (2021) 40:20 Page 5 of 11

Table 1 Summary of study characteristics (Continued)

Site Study Number of Age of Exposure Outcome

design participants adult

offspring at

follow-up

Loos et al. Belgium Cross- 800 18–34 GWG, ppBMI Glucose metabolism (FPG, fasting
[25] sectional plasma proinsulin, fasting plasma insulin, HOMA-IR, HOMA)

Mi et al. China Cross- 627 41–47 GWG, BMI Blood pressure (SBP, DBP)
[29] sectional Blood lipids
Glucose metabolism

Webb et al. Guatemala Longitudinal 450 21–29 GWG, BMI, dietary Blood pressure (SBP, DBP)
[31] intake (protein
and micronutrient
supplementation)

Campbell UK Cohort 253 40.6 Maternal dietary Blood pressure (SBP, DBP)
et al. [32] intake: protein,
animal protein,
fat, carbohydrate,
calcium, vitamin
A, thiamine,
riboflavin, niacin,
vitamin C

Conlisk Guatemala Longitudinal 429 24.4 Maternal dietary Glucose metabolism (FPG)
intake: protein
et al. [33] and micronutrient
supplementation

Danielsen Denmark Cohort 428 20 Maternal dietary Blood pressure (SBP, DBP)
et al. [34] intake: GI, GL Blood lipids
Glucose metabolism

Macleod UK RCT 118 22–23 Maternal dietary Blood pressure (SBP, DBP)

et al. [35] intake: protein Blood lipids

and carbohydrate Glucose metabolism

supplementation

Roseboom Netherlands Cohort 739 50 Maternal dietary Blood pressure (SBP, DBP)
et al. [36] intake: protein/
carbohydrate ratio

Rytter et al. Denmark RCT 243 18–19 Maternal dietary Blood lipids (total cholesterol, LDL, HDL, TAG, Apo-A1,

[37] intake: fish oil Apo-B)

supplementation

Rytter et al. Denmark RCT 180 19 Maternal dietary Blood pressure (SBP, DBP)
[38] intake: fish oil
supplementation

Rytter et al. Denmark Cohort 443 19–20 Maternal dietary Blood pressure (SBP, DBP)
[39] intake: fish oil
supplementation

Shiell et al. UK Cohort 626 27–30 Maternal dietary Blood pressure (SBP, DBP)
[40] intake: meat and
fish consumption
plus low
carbohydrate

Webb et al. Guatemala Longitudinal 450 21–29 GWG, BMI, dietary Blood pressure (SBP, DBP)
[31] intake (protein
and micronutrient
supplementation)

GWG, gestational weight gain; BMI, body mass index; ppBMI, pre-pregnancy body mass index; GI, GlycFPG = Fasting Plasma Glucose; SBP, systolic blood pressure;
DBP, diastolic blood pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein; TAG, triacylglycerides; HOMA-IR, homeostatic model assessment for
insulin resistance

studies, seven were case-control studies, and three were Each of the included studies addressed one or more
randomised-controlled trials (RCTs). In total, there were of four maternal nutrition exposures: maternal expos-
16 high-quality and 11 medium-quality studies ure to famine, maternal GWG, maternal weight or
(Additional file 4), indicating a low risk of bias overall. BMI, and maternal dietary intake. No studies

Wilkins et al. Journal of Health, Population and Nutrition (2021) 40:20 Page 6 of 11

Fig. 1 PRISMA flow diagram of systematic review results

measured maternal nutritional status during lactation. lipids [15, 20, 23, 24], and impaired glucose metabolism [14,
The characteristics of included studies are summarised in 18, 23, 24] in fetally exposed versus non-exposed offspring.
Table 1; more in-depth findings are presented in the There was no clear evidence of a difference in the nature of
Supplementary Table 1 (Additional file 5). the relationship for different NCD risk factor outcomes.

Maternal exposure to famine From the included studies, there was no clear evi-
Eleven studies examined the association between mater- dence of differences by sex of the offspring. Of the
nal exposure to famine (measured by proxy indicators, four papers that stratified findings by sex, two stud-
such as the official daily rations for the population aged ies—both of the Chinese famine—observed signifi-
21 years and over combined with birth date) and NCD cantly higher blood pressure and blood lipids in
metabolic risk factors in adult offspring. Six of these exposed versus non-exposed female but not male off-
studies were of high quality and five were of medium spring [23, 24]; one study of the Dutch famine found
quality. There were six cohort studies of the Dutch fam- the reverse, namely significantly lower high-density li-
ine of 1944–1945, four studies of the Great Chinese fam- poproteins (HDL), which is associated with higher
ine of 1958–1961, and one study of the 1941–1944 NCD risk, in exposed versus not exposed male but
Leningrad siege. Seven of the eleven studies reported on not female offspring [15]; while another study of
offspring blood pressure outcomes, five on blood lipid blood pressure outcomes in offspring of mothers ex-
outcomes, and seven on glucose metabolism outcomes. posed to the Dutch famine revealed no significant sex
Four of the eleven studies, including the single study of the differences [22]. There was no clear evidence from
Leningrad siege, found no significant differences in blood the included studies of differences by timing of gesta-
pressure [15, 16, 19, 21], blood lipids [21], or indicators of tional exposure. Of the five studies—all of the Dutch
glucose metabolism [15, 21] between offspring exposed to famine—that stratified results by gestational timing of
famine in utero and unexposed offspring. Conversely, seven exposure, two found that offspring blood pressure
studies, five of the Dutch famine and two of the Chinese outcomes were independent of the timing of gesta-
famine, revealed significantly higher blood pressure and/or tional exposure to famine [14, 19], two found a more
prevalence of hypertension [22–24], adversely altered blood atherogenic blood lipid profile in offspring exposed to
famine in early compared to later gestation [14, 20],

Wilkins et al. Journal of Health, Population and Nutrition (2021) 40:20 Page 7 of 11

and one found that offspring exposed to famine in insulin and homeostatic model assessment for insulin
later gestation had the highest rates of impaired glu- resistance (HOMA-IR) (for men only), and significant
cose tolerance [18]. negative associations between GWG30 and adult off-
spring total cholesterol and low-density lipoprotein
However, there was some tentative support for a role (LDL) cholesterol levels [28]. The other study found
of adult offspring adiposity in influencing the maternal positive relationships between unadjusted maternal
exposure to famine—offspring NCD risk factor relation- GWG and adult offspring blood pressure and triglycer-
ship. Of the studies that measured the influence of adult ide concentrations, although these associations were at-
offspring adiposity or indicators of postnatal nutritional tenuated to non-significance following adjustment for
abundance [15, 17, 18, 20–22], several supported a role adult offspring BMI [27]. The remaining five studies
of this variable in the relationship between maternal ex- found no significant relationship between maternal
posure to famine and NCD risk factors in adult off- GWG and offspring blood pressure [26, 29–31], blood
spring. A study of the Chinese famine found evidence lipids [29], or glucose metabolism [25, 29].
that the association between foetal exposure to severe
famine and the risk of adult hyperglycemia seemed to be There was no clear difference in the results of included
exacerbated in subjects who consumed an energy-dense studies according to specific NCD metabolic risk factor
diet as adults [17]. A study of the Dutch famine found outcome. Only two studies reported results stratified by
that the relationship between gestational exposure to sex, but the findings were not consistent. There was insuf-
famine and adult hypertension was attenuated following ficient evidence from the included studies to draw conclu-
adjustment for adult waist circumference, with authors sions about the role of gestational timing of exposure in
suggesting that this demonstrated a potential mediating the GWG-NCD risk factor relationship. Three studies ex-
role for this variable in the association [22], and another plored the influence of offspring adiposity [26–28]. Of
study of the Dutch famine found that while in utero ex- these, two cohort studies from Israel and Denmark re-
posure to famine was associated with glucose tolerance spectively found that the significant positive associations
at all adult body mass indices, the highest plasma glu- between GWG and offspring NCD risk factors were sig-
cose concentrations were found in those exposed partici- nificantly attenuated following adjustment for offspring
pants who became obese in adulthood [18]. It is also adult BMI and leptin levels respectively [27, 28]. In the
worth noting that while the study of the Leningrad Siege remaining Australian cohort study, the association be-
found no difference between subjects exposed to famine tween GWG and offspring blood pressure, while not sig-
in utero versus infancy in glucose tolerance, insulin con- nificant in itself, was consistent in size with the
centration, blood pressure, lipid concentration, or coagu- association of maternal GWG with offspring BMI and of
lation factors, the authors did find evidence, in female offspring BMI with their blood pressure, further support-
subjects, of a significantly stronger association between ing an influence of adult adiposity in the relationship [26].
obesity and systolic and diastolic blood pressure in those
subjects who had been exposed to famine in utero, Maternal weight/body mass index (BMI)
which they interpreted as suggesting that foetal exposure Four studies investigated the association between mater-
to famine and adult obesity may operate in synergy to nal weight or BMI prior to or during pregnancy and off-
increase the risk of hypertension [21]. spring NCD risk factors [25, 27, 29, 31]. These studies
examined maternal BMI as a continuous variable and
Maternal gestational weight gain (GWG) did not analyse results for ‘low’ and ‘high’ maternal BMI
Seven studies examined the relationship between ma- specifically. All were of high quality. Three examined
ternal GWG and NCD metabolic risk factors in adult blood pressure outcomes [27, 29, 31], two blood lipid
offspring [25–31]. Four of these also examined the im- outcomes [27, 29], and three glucose metabolism out-
pact of maternal BMI [25, 27, 29, 31]. Six studies were comes [25, 27, 29]. The findings were mixed. Two stud-
of high quality and one was of medium quality. Six ies revealed significant inverse associations between
measured offspring blood pressure outcomes, three maternal BMI and offspring NCD risk factors [25, 29].
blood lipid outcomes, and four glucose metabolism One of these—a cross-sectional study from China—
outcomes. Overall, only two of the seven studies re- found significant inverse associations between maternal
vealed a significant association between measures of BMI at 15 weeks’ gestation and total cholesterol, LDL
maternal weight gain during pregnancy and offspring cholesterol, 120-min glucose, and 12-min insulin, al-
NCD metabolic risk factors [27, 28]. One of these—a though it found no significant associations with offspring
Danish cohort study of 308 19–20-year-old males— blood pressure, HDL cholesterol, or fasting glucose or
found significant positive associations between GWG insulin levels [29]. The other—a cross-sectional study
during the first 30 weeks of gestation (GWG30) and from Belgium—revealed significant inverse associations
adult offspring systolic blood pressure (SBP), plasma between maternal pre-pregnancy BMI (mppBMI) and

Wilkins et al. Journal of Health, Population and Nutrition (2021) 40:20 Page 8 of 11

proinsulin, β-cell function, fasting insulin (for females total cholesterol and HDL cholesterol (borderline), but
only), and insulin resistance (for females only), but not not with LDL cholesterol, blood pressure, or glucose
with fasting plasma glucose [25]. Neither of these studies metabolism [34]. There was insufficient information
found significant associations between maternal GWG from these diverse studies to draw conclusions about
and offspring risk factor outcomes. A cohort study from differential effects by sex and/or gestational timing of
Israel revealed a significant positive association between exposure, nor about the influence of adult offspring
mppBMI and offspring blood pressure, although this adiposity.
was attenuated to non-significance after adjusting for
adult offspring BMI [27]. The final longitudinal study Discussion
found no significant relationship between maternal non- This systematic review reveals considerable heterogen-
pregnant BMI (≥5.5 months post-partum) and offspring eity in findings across studies of the impact of various
blood pressure [31]. There is insufficient evidence aspects of maternal nutritional status during pregnancy
from this small number of heterogeneous studies to on NCD risk factors in adult offspring. There is evidence
suggest differences in the effect of maternal BMI by of a link between maternal exposure to famine during
offspring risk factor type. Only one study reported pregnancy and adverse blood pressure, blood lipid, and
results by sex [25]. glucose metabolism outcomes in adult offspring in some
contexts. The evidence base for maternal BMI and
Maternal dietary intake GWG is more limited and currently reveals no consist-
Ten studies examined the relationship between various ent support for a link between either of these exposures
aspects of maternal dietary intake on the blood pressure and adult offspring NCD metabolic risk factors. Simi-
of adult offspring. Five were of high quality, and five of larly, there is no indication from the currently limited
medium quality. The findings were again heterogeneous. evidence base of a relationship between the absolute
Of the five studies that measured levels of maternal pro- levels of specific maternal dietary nutrients and off-
tein and carbohydrate intake [31–33, 35, 36], only one— spring NCD risk factor outcomes, although there is
a longitudinal study from Guatemala—found a signifi- some tentative support for a possible link between
cant association with offspring NCD risk factors [33]. the balance of protein and carbohydrate in the mater-
This study revealed an inverse relationship between pre- nal diet and offspring blood pressure. This warrants
natal energy intake from supplement and adult fasting further investigation. There is insufficient evidence
plasma glucose, although only in women. However, of from the included papers to assess the influence of
the three studies that examined the link between the bal- offspring sex or gestational timing of exposure. The
ance of protein and carbohydrate in the maternal diet findings do, however, show some tentative support for
and offspring blood pressure, all revealed a significant an influence of offspring adiposity in the maternal ex-
association [32, 36, 40]. One—a cohort study from posure to famine—offspring NCD risk factor relation-
Scotland—found that when mothers’ animal protein in- ship, with several studies reporting stronger
take was below 50g/day, an increase in carbohydrate in- associations for offspring with high adult adiposity, or
take was linked with higher offspring blood pressure, a significant attenuation of associations when control-
while at high daily protein intakes above 50g, greater ling for this variable.
carbohydrate intake was associated with lower offspring
blood pressure [32]. A Dutch cohort study also reported To our knowledge, this is the first study to systematic-
a significant inverse association between the ratio of pro- ally review the evidence on the relationship between
tein/carbohydrate in mothers’ diets and offspring SBP, in maternal nutrition during pregnancy and the develop-
the third trimester specifically [36], while a second Scot- ment of three key NCD metabolic risk factors in adult
tish cohort study found that increasing maternal con- offspring. Our finding of a link between maternal expos-
sumption of meat and fish in the context of a high ure to famine and offspring NCD risk factors in some
protein-low carbohydrate diet in the second half of preg- contexts is consistent with the findings of existing narra-
nancy was linked with significantly higher adult offspring tive reviews on the topic [5, 6]. This relationship could
blood pressure [40]. Of the three studies (two RCTs and be driven by the ‘predictive adaptive response hypoth-
one cohort study from the same authors in Denmark) esis’, a form of developmental plasticity in which in
that examined maternal gestational fish oil supplementa- utero and early life conditions prompt the development
tion, none found a significant association with offspring of a phenotype which is adaptive in a ‘predicted’ later life
blood pressure [38, 39], blood lipids [37, 39], or glucose environment [42]. However, where the predicted envir-
metabolism [39]. A single Danish cohort study that mea- onment does not match the offspring’s actual later life
sured maternal glycemic index (GI) during pregnancy environment (e.g. where the in utero/early life environ-
found a significant positive relationship with offspring ment is nutritionally scarce, but the later life environ-
ment is nutritionally rich), the phenotype developed (e.g.

Wilkins et al. Journal of Health, Population and Nutrition (2021) 40:20 Page 9 of 11

one suitable for a nutritionally scarce environment) can In terms of individual studies, the risk of residual con-
be maladaptive, leading to deleterious health conse- founding is a major source of bias. Important potential
quences in adulthood [42]. The mechanisms underlying confounders include fixed genetic variants common to
this plasticity are likely to be multifactorial, but could in- both mothers and offspring, as well as shared postnatal
clude alterations in cell number and/or cell type [43, 44], dietary and lifestyle factors. Whilst ethical considerations
altered maternal hypothalamic-pituitary-adrenal axis restrict the use of strict RCTs to minimise confounding
activity [45], epigenetic regulation of gene expression in dietary studies, sibling comparison studies present an
[46, 47], and reduced oxidative capacity [48]. opportunity to reduce confounding due to familial/gen-
etic factors. There was considerable loss to follow-up in
The absence of evidence from our included studies many cohort studies, a trade-off of the need for long
of a link between maternal BMI and GWG align with follow-up periods in the assessment of NCD risk factor
the results of a recent non-systematic review, which outcomes. A further source of bias relates to the ascer-
found no consistent associations between maternal tainment of maternal nutritional exposures. Most exist-
BMI and CVD risk factors in adults [7]. Our findings ing famine studies lack reliable information about the
in several papers of stronger associations between ma- food intake of individuals during the famine period.
ternal exposure to famine and offspring NCD risk fac- Moreover, associations are complicated by the absence
tors in offspring with high adult adiposity, and the of appropriate tools to measure dietary intake accurately
attenuation of associations when controlling for adult in humans.
adiposity, are consistent with the hypothesis that the
impact of development in utero depends strongly on One of the main contributions of this systematic re-
the postnatal environment [42]. Where poor in utero view is its exposure of the paucity of the current evi-
nutrition is combined with later life exposure to obe- dence base on the intergenerational links of maternal
sogenic environments, the effects in terms of off- nutrition during pregnancy and NCD risk factors in
spring’s NCD risk factors and outcomes are likely to adult offspring. Existing studies are drawn dispropor-
be most severe. This is particularly concerning given tionately from high-income countries, particularly in the
the rapid nutritional transitions taking place within European Region, which limits the generalisability of the
many developing countries at present. findings. Moreover, while a number of studies have ex-
amined the effects of maternal gestational exposure to
One key observation to emerge from this systematic famine, our search revealed no records investigating the
review is that of inconsistencies in the results of papers effects of chronic energy deficiency, arguably a more
apparently measuring the same maternal nutrition prevalent problem in LMICs today. There are also rela-
exposure and offspring NCD risk factor. Such mixed tively few studies investigating maternal BMI, GWG,
findings may stem from differences in sample popula- and specific dietary factors, making it difficult to draw
tion, study design including offspring age at follow-up, clear conclusions about the role of these influences on
variation in definitions or measurements, confounding offspring NCD risk factors. Furthermore, no studies ex-
variables, and contextual factors, particularly postnatal amined the impact of maternal nutrition during lacta-
environmental life exposures. For the famine studies, for tion. Each of these constitute priority areas for future
instance, the fact that significant associations were research, particularly the area of nutrition during lacta-
observed for most studies of the Chinese and Dutch tion given the potential capacity of good nutrition during
famines but not the Leningrad siege might reflect the this time period to offset negative effects of poor nutri-
fact that the former two famines were preceded and tional exposure in utero [49]. Future studies that stratify
followed by sufficient nutrition, whereas the population results by sex and gestational timing of exposure and the
exposed to the latter was largely malnourished before measurement of postnatal environmental factors will be
the siege and remained malnourished for an extended important, as will research to elucidate the biological
period afterwards [21]. mediators and mechanisms underlying the observed
associations.
The main strengths of this review lie in its systematic
approach and comprehensive scope. Our methodology This systematic review reveals considerable heterogen-
was designed to capture all studies on a wide range of eity in findings across studies. The evidence supports a
maternal nutrition exposures and three of the four link between maternal exposure to famine during preg-
main NCD metabolic risk factors. To our knowledge, nancy and offspring NCD metabolic risk factors in some
this is true of no other study to date. One consequence contexts, with some tentative support for an influence of
of this broad scope, however, is the inclusion of hetero- adult offspring adiposity in this relationship. Based on
geneous exposure and outcome measures, which limit an admittedly more limited evidence base, there is no
our ability to synthesise findings. Moreover, the large consistent support for relationships between maternal
volume of data returned precludes an in-depth analysis GWG, maternal BMI, or maternal dietary intake and
of each risk factor.

Wilkins et al. Journal of Health, Population and Nutrition (2021) 40:20 Page 10 of 11

NCD risk factors in adult offspring. Overall, our findings Availability of data and materials
support calls for increased collaboration between mater- Not applicable.
nal nutrition and NCD sectors but suggest that a greater
focus on research is needed to identify how these two Declarations
sectors can work together to support each other’s aims.
Ethics approval and consent to participate
Conclusion and recommendations Not applicable.
Despite calls for increased collaboration and integration of
policies and programmes between the maternal nutrition Consent for publication
and NCD sectors, there remains weak evidence on the link. Not applicable.
Findings of a link between maternal exposure to fam-
ine during pregnancy and offspring NCD risk factors in Competing interests
some contexts, plus some evidence of a role of adult adi- We declare no competing interests. The authors alone are responsible for
posity in influencing this relationship, suggest there is po- the views expressed in this article and they do not necessarily represent the
tential for significant co-benefits from collaboration. views, decisions, or policies of the institutions with which they are affiliated.
However, more research and evidence are needed to inform
how NCD and maternal health sectors can work together Author details
to achieve the Sustainable Development Goals (SDGs). 1Centre on Population Approaches for NCD Prevention, University of Oxford,
Oxford, UK. 2VicHealth, Carlton, Victoria, Australia. 3Health Library, Nuffield
Abbreviations Department of Population Health, University of Oxford, Oxford, UK. 4Centre
BMI: Body mass index; DALYs: Disability-adjusted life years; GWG: Gestational on Migration, Policy and Society (COMPAS), University of Oxford, Oxford, UK.
weight gain; GWG30: Gestational weight gain during the first 30 weeks of 5Department of Health, Western Australia, Perth, Australia. 6Department for
gestation; GI: Glycemic index; HDL: High-density lipoproteins; HOMA- Health, University of Bath, Bath BA2 7AY, UK.
IR: Homeostatic model assessment for insulin resistance; LLMIC: Low- and
lower middle-income countries; LDL: Low-density lipoprotein; LMIC: Lower Received: 13 February 2018 Accepted: 23 March 2021
middle-income countries; mppBMI: Maternal pre-pregnancy BMI; NCDs: Non-
communicable diseases; RCTs: Randomised-controlled trials; References
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life

Review

Nutrient and Dietary Patterns in Relation to the
Pathogenesis of Postmenopausal Osteoporosis—A
Literature Review

Bolaji Lilian Ilesanmi-Oyelere 1,2,* and Marlena C. Kruger 1,2
1 School of Health Sciences, College of Health, Massey University, Tennent Drive, Palmerston North 4442,
New Zealand; [email protected]
2 Riddet Institute, Massey University, Palmerston North 4442, New Zealand
* Correspondence: [email protected]

Received: 1 September 2020; Accepted: 23 September 2020; Published: 25 September 2020

Abstract: Postmenopausal women tend to be susceptible to primary osteoporosis due to its association
with oestrogen deficiency. There is emerging evidence that an unhealthy dietary pattern drives
an increase in the risk of postmenopausal osteoporosis (PO), whereas a healthy dietary pattern
may decrease its occurrence. In this narrative literature review, we sought to review the role of
nutrient and dietary patterns in the pathogenesis of PO. Therefore, we searched and reported all
research articles from 2001 to May 2020 in Web of Science, Cinahl and Scopus that have researched a
relationship between nutrient and/or dietary patterns and postmenopausal osteoporosis. Nutrients
such as calcium, phosphorus, magnesium and vitamin D have been proven to be beneficial for
bone health. Meanwhile, for the dietary patterns, foods such as dairy products especially milk,
fibre and protein-rich foods, e.g., meat were directly linked to a positive association with bone mineral
density (BMD). Likewise, fruits, vegetables and probiotic and prebiotic foods were reported for its
positive relationship with BMD. Therefore, aside from physical activity, nutrition and diet in adequate
proportions are suggested to be an important tool for ameliorating osteoporosis and bone health
issues in older age.

Keywords: nutrient patterns; dietary patterns; postmenopausal osteoporosis; bone health;
postmenopausal women

1. Introduction

Osteoporosis is a major public health concern with the ageing populations [1]. Worldwide,
8.9 million fractures occur annually which results in an osteoporotic fracture every 3 s [2].

Postmenopausal osteoporosis is a condition on the rise amongst aged women as the world
demography experiences marked ageing of the population. Globally, New Zealand is amongst one
of the most affected by the burden of the disease. Postmenopausal osteoporosis is characterized by
increased low-grade inflammation contributing to low bone mass and degradation of bone mineral
content resulting in bone loss and/or fractures [1,2].

Although the pathogenesis of osteoporosis is multifactorial, key drivers include oestrogen
deficiency, poor dietary habits, chronic inflammation, smoking, excessive alcohol consumption and
sedentary lifestyle. However, diet regulates the composition and function of the human gut microbiota
with recent evidence suggesting that the gut microbiome plays essential roles in the host energy
homeostasis, immune system enablement and metabolic function and health [3].

Menopausal hormone replacement therapy (HRT) has been employed in the treatment of
menopausal treatments. However, its risks have also been documented which include increased

Life 2020, 10, 220; doi:10.3390/life10100220 www.mdpi.com/journal/life

Life 2020, 10, 220 2 of 13

occurrence of breast cancer, stroke, venous thromboembolism (VTE) and risk of coronary artery disease
but the “timing hypothesis” has been suggested for a possible amelioration if administered early in
menopause [4].

Nutraceuticals, also known as alternative pharmaceuticals products made from plants and foods
which have medicinal properties, are non-hormonal natural therapies or approach to menopausal
symptoms. These include phytoestrogenic plants or isoflavones, antioxidants, dietary supplements
and fortified dairy products [5].

Nutrition and lifestyle changes are essential in promoting health and in the prevention of metabolic
diseases such as osteoporosis. Many nutrients are known to interact with each other thereby influencing
their bioavailability and absorption [3]. Several key nutrients are known to affect bone mineral content
(BMC) and bone mineral density (BMD). These nutrients, however, occur together in foods and dietary
patterns, therefore the need to study the diet in its entirety. Unhealthy dietary patterns are known to
be associated with some chronic diseases such as diabetes and cardiovascular disease [4]. Likewise,
nutrients such as calcium and vitamin D are well-established as nutritional drivers in the maintenance
of normal bone metabolism. Additionally, nutrients such as potassium, zinc, magnesium, iron, copper,
vitamin C and vitamin K are micronutrients rich in fruits and vegetables that are beneficial for bone
metabolism. However, the overall effects of dietary choices on bone health are not well understood
and therefore need further research and discussion.

There are two main holistic methodologies used in describing and quantifying nutrient and/or
dietary patterns/habits: 1. The a posteriori (data-driven) dietary pattern approach, i.e., the use of
statistical methods such as principal component analysis (PCA) or factor analysis, reduced rank
regression (RRR), cluster analysis and partial least square to generate dietary patterns from data
collected; and 2. The a priori dietary pattern approach, i.e., the use of created or predefined dietary
indexes on the basis of existing knowledge in nutrition usually complying with dietary guidelines and
recommendations [5].

The aim of this review was to investigate and discuss the reported relationships observed between
nutrient and dietary patterns and bone health status (BMD, bone biomarkers and fracture risks) in
postmenopausal women.

2. Current Evidence and Status of Knowledge

2.1. The Relationship between Nutrient Patterns and Postmenopausal Osteoporosis

Research shows there is a relation between nutrient patterns and postmenopausal osteoporosis;
however, results from studies are heterogeneous and therefore no conclusive nutrient pattern has been
proposed. To date, only two studies have explored the relationship between nutrient patterns and
bone health exclusively in postmenopausal women.

The first study by Karamati et al., 2014 indicated that a nutrient pattern (NP1) high in folate,
fiber, vitamin B6, potassium, vitamin A, vitamin C, β-carotene, vitamin K, magnesium, copper and
manganese was positively associated with lumbar spine BMD. These nutrients are particularly rich
in fruits and vegetables. These antioxidant micronutrients are important for the formation and
maintenance of bone cells and the structure required for normal bone metabolism. However, they failed
to find any correlation with the well-known nutrients that are important for bone health in their
NP2 which was high in vitamin B2, protein, calcium, phosphorus, zinc, vitamin B12, vitamin D and
low in vitamin E. The explanation was that although protein intake levels have been associated with
bone health benefits, the influence of protein intakes generally depends on a balanced whole diet in
terms of acid-producing potential. Acid/base balance is important to avoid urinary calcium loss with
acid-forming foods such as processed meat, shellfish and pastries. The NP3 with high intakes of dietary
fats and low intakes of carbohydrate, vitamin B1 and fiber was likewise not correlated with BMD [6].

The second study by Ilesanmi-Oyelere et al., 2019 found a positive association between NP1
(characterised by high riboflavin, phosphorus, calcium, sugars, potassium, vitamin B6, carbohydrate

Life 2020, 10, 220 3 of 13

and magnesium) and lumbar spine, femoral neck and whole-body BMD. These nutrients are particularly
rich in eggs, lean meats, milk, milk products and some fruits and vegetables. NP2 (high in dietary fats,
vitamin E, alpha and beta carotene) was negatively associated with BMD while NP3 (also characterised
by high fat, protein, zinc and cholesterol with low intakes of alpha and beta carotene and vitamin C)
was not associated with BMD at all sites (Table 1).

Life 2020, 10, 220

Table 1. Nutrient patterns and bone min

Study, Location and Participants Information Diet Nut
Design Assessment/Method
160 postmenopausal NP1 was hig
Factor analysis women, age 50–85 years Validated 168-item potassium, vita
BMD/BMC food frequency copper and m
1135 adults, median age B2, protein, calc
Postmenopausal Iranian 62 years questionnaire/LS BMD and vitamin D
women, Iran, and FN BMD by DXA in total fat, mo
cross-sectional 101 postmenopausal fatty acids and
women, age 54–81 years Validated food
North West Adelaide frequency/BMD by DXA levels of
Health Study, Australia,
3-day diet diary/LS, FN Mixed-sourc
cross-sectional and hip BMD by DXA niacin, s

“Bug‘n’Bones” study, Animal-sourc
New Zealand, cholesterol and
cross-sectional in β-carotene, l

NP1 high in rib
potassium

magnesium an
acids, vitam
cholesterol a

Fractures

Bordeaux sample of the 934 women and 548 men, 24-h dietary recal and a (1) Nutrient-d
Three-City Study, France, aged 68–95 y food frequency iron, B vitam
unsaturated f
longitudinal questionnaire/Hip, wrist,
and vertebrae fracture; iron; (3) southw
self-reported incidence alcohol, calciu

BMD = bone mineral density; BMC = bone mineral content; LS = lumbar spine; FN

neral density in postmenopausal women. 4 of 13
Ref.
trient Patterns Generated Main Results

gh in folate, total fiber, vitamin B6, NP1 which was associated with high intakes Karamati et al.,
amin A, C, K, β-carotene, magnesium, of fruits and vegetables and low intakes of 2014 [6]
manganese. NP2 was high in vitamin cereal was significantly positively correlated
cium, phosphorus, zinc, vitamin B12, with lumbar spine BMD but not the femoral Melaku et al.,
neck. NP2 and NP3 were not significantly 2017 [7]
and low in vitamin E. NP3 was high
onounsaturated fatty acids, saturated associated with BMD at any of the sites. Ilesanmi-Oyelere
et al., 2019 [8]
polyunsaturated fatty acids with low Mixed-source nutrient pattern was positively
carbohydrate and vitamin B1. associated with BMD. No independent and
statistically significant associations between
ce pattern was high in phosphorus, animal- and plant-sourced nutrient patterns
starch/dextrins and riboflavin.
ced pattern high in palmitoleic acid, and BMD were found
d omega-6. Plant-sourced pattern high
lutein and zeaxanthin and vitamin C. NP1 was positively correlated with the spine,
hip and femoral neck BMD while NP2 was
boflavin, phosphorus, calcium, sugars,
m, vitamin B6, carbohydrate and negatively correlated with hip and
nd NP2 high in dietary fats and fatty whole-body BMD.
min E and NP3 high in fats, protein,
and low levels of vitamin C, α- and

β-carotene.

dense; high in calcium, phosphorus, Pattern (1) was inversely associated with risk Samieri et al.,
mins, vitamin C and E, protein and of wrist and overall fractures; pattern (3) was 2013 [9]
fats. (2) retinol, vitamin B-12, folate, inversely associated with risk of hip fracture
western French high in proteins, fats,
um, phosphorus, vitamin D and B12

N = femoral neck; DXA = dual energy X-ray absorptiometry; NP = nutrient pattern.

Life 2020, 10, 220 5 of 13

2.2. Dietary Pattern Analyses and Bone Health in Postmenopausal Osteoporosis

Generating dietary patterns with correlated foods are important to investigate diet due to the
complexity and interaction of various nutrients and foods. Studies have used dietary patterns generated
from foods to give a view of the association between dietary intakes and BMD/BMC, bone biomarkers,
osteoporosis and fractures (Table 2).

Traditional Western-style diets that are characterised by processed foods high in salt, fats and
sugar have been researched and positively associated with osteoporosis as is evidenced in six studies
that explored dietary patterns and bone health status [10–14]. Similarly, energy-dense foods such as
white rice, wheat and grains have been associated with the risk of fractures during postmenopause [15].
These patterns of foods have therefore been labelled “unhealthy” and are known to drive the risk of
many metabolic diseases including osteoporosis and consequently fractures.

On the other hand, foods such as milk, low-fat dairy, fruit, vegetables and nutrient-dense foods
have been associated with high BMD and lower risk of osteoporosis or fractures. These food patterns
have been termed “healthy” and/or “prudent” dietary patterns.

Life 2020, 10, 220

Table 2. Dietary patterns and bone

Study, Location and Participants Information Diet Assessment/Method
Design
4928 postmenopausal Validated 131-item food-frequency
Factor analysis women, aged 56 ± 12 y Questionnaire/FN BMD, total hip BMD,
BMD/BMC
LS BMD by DXA
Co-twin controlled study,
United Kingdom,
cross-sectional

Annual health check-up 293 postmenopausal Modified validated simple food
program, Japan, women, aged 60 ± 6 y frequency questionnaire (FFQ)/33%
cross-sectional
Radial BMD by DXA

Postmenopausal Iranian 160 women, aged 50–85 y Validated 168-item food frequency
women, Iran, questionnaire/LS BMD and FN BMD
cross-sectional
by DXA

2-y prospective study of 282, 212, and 202 women Validated 80-item food frequency
postmenopausal women, at baseline, year 1 and questionnaire/Hip BMD (FN,

China, cross-sectional year 2, respectively, aged trochanter, and Ward’s) LS BMD,
50–65 y at baseline TB BMD by DXA

Brazilian postmenopausal 156 women, aged ≥ 45 y; 3-day food diary/LS BMD, total femur
women with osteoporosis, mean age 68 ± 9 y BMD, FN BMD, TB BMD by DXA

Brazil, cross-sectional

Bone Biomarkers 3236 women, aged 50–59 y Validated 98-foods FFQ/Bone
resorption biomarkers: urine fPYD: Cr
Aberdeen Prospective
Osteoporosis Screening and fDPD:Cr ratios; bone formation
biomarker: serum P1NP
Study, Scotland,
cross-sectional

Canadian Multicenter 754 women, 318 men, Food frequency questionnaire/Bone
Osteoporosis Study, aged 63 ± 11 y resorption biomarkers: CTX; bone
Canada, longitudinal formation biomarker: BAP; PTH; blood
samples collected in year 5 of study

health in postmenopausal women. Main Results 6 of 13
Ref.
Dietary Patterns Generated

(1) Fruit and vegetables, (2) high intake of Pattern (3) was inversely Fairweather-Tait
alcohol, (3) traditional English, (4) dieting, associated with FN BMD et al., 2011 [10]

(5) low meat intake Pattern (2) was inversely Sugiura et al.,
associated with BMD and pattern 2011 [11]
(1) Carotene, (2) retinol,
(3) β-cryptoxanthin (3) was positively associated Karamati et al.,
with BMD 2012 [12]
(1) Folate, total fiber, vitamin B-6,
potassium, vitamins A, C, and K, Pattern (1) was directly Chen et al.,
β-carotene, magnesium, copper, and associated with LS BMD 2015 [13]
manganese; (2) vitamin B-2, protein,
calcium, phosphorus, zinc, vitamin B-12, Pattern (1) was inversely de França et al.,
vitamin D, and low vitamin E; (3) total fat, associated with hip and LS BMD; 2016 [14]
MUFAs, SFAs, PUFAs, and low pattern (2) was directly associated

carbohydrate and vitamin B-1 with hip BMD.

Pattern (1): rice, cooked wheat food, fried Pattern (4) was inversely
food and other grains, and fruits; pattern associated with total femur and

(2): milk and root vegetables TB BMD

(1) Healthy; high in vegetables, fruit and
fresh juices, and tubers (2) red meat and
refined cereals; (3) low-fat dairy; (4) sweet
foods, coffee, and tea; (5) Western; high in
snacks, pizzas and pies, soft drinks and fats

(1) Healthy foods with high intakes of fruit Pattern (1) was inversely Hardcastle et al.,
and vegetables (2) processed foods, (3) associated with bone 2011 [15]
bread and butter, (4) fish and chips, (5) resorption biomarkers
snack foods with high intakes of Langsetmo et al.,
confectionery, crisps, nuts and sauces Pattern (1) was inversely 2016 [16]
associated with CTX in women
(1) Prudent, high in vegetables, fruit, and PTH in men; pattern (2) was
whole grains, and legumes and (2) Western, directly associated with BAP and

high in soft drinks, potato chips and CTX in women
French fries, processed meats, and desserts

Life 2020, 10, 220

Table 2

Study, Location and Participants Information Diet Assessment/Method
Design

Osteoporosis

Korean Health and 735 postmenopausal 24-h recall/Osteoporosis by LS and
Nutrition Examination women, aged 64 ± 9 y femur (FN, trochanter, intertrochanter,
Survey 2008–2010, Korea,
Ward’s, and total) BMD T-score
cross-sectional by DXA

Korean Genome and 1464 postmenopausal 103-food item, semiquantitative food
Epidemiology Study, women, 4-y follow-up frequency questionnaire
Korea, longitudinal
(SQFFQ)/Osteoporosis incidence by
Fractures SOS T-score at the mid-radius and tibia

Canadian Multicenter shaft by ultrasound
Osteoporosis Study,
Canada, longitudinal 3539 postmenopausal Self-administered FFQ/Low-trauma
women, aged 67 ± 8 y and fractures by year 10 of study by
Cluster Analysis self-reported interviews
1649 men, aged ≥50 y
(64 ± 10 y)

Framingham 562 women and 345 men, Validated FFQ/FN BMD, Ward’s area
Osteoporosis Study, aged 69–93 y BMD, and trochanter BMD by Lunar

United States, dual photon absorptiometry; 33%
cross-sectional radius shaft BMD by Lunar

single-photon absorptiometry

In CHIANTI Study, Italy, 434 women, aged 65–94 y 236-foods European Prospective
longitudinal (75 ± 7 y) Investigation into Cancer and

Nutrition (EPIC) questionnaire/Total
and trabecular BMD at 4% and cortical

BMD at 38% tibia by pQCT; BMD
variation over 6 y

BMD = bone mineral density; BMC = bone mineral content; LS = lumbar spine; FN = femo
TB = total body; fPYD = free pyridinoline; fDPD = free deoxypyridinoline; Cr = creatinine; CT
SOS = speed of sound; IBW = ideal body weight; pQCT = peripheral quantitative computed

7 of 13

2. Cont. Main Results Ref.

Dietary Patterns Generated

(1) Meat, alcohol, and sugar; (2) vegetables Pattern (4) was inversely Shin and Joung
and soy sauce; (3) white rice, kimchi, and associated with risk of 2013 [17]

seaweed; (4) dairy and fruit osteoporosis and pattern (3) was Park et al.,
directly associated with risk 2012 [18]
of osteoporosis

(1) Traditional (high in rice, kimchi and Pattern (2) was inversely
vegetable intake, (2) dairy (high in dairy associated with and patterns (1)
and (3) were directly associated
products, milk and green tea intake),
(3) Western (high in fat, sugar and bread) with risk of osteoporosis

(1) Nutrient-dense Pattern (1) was inversely Langsetmo et al.,
(2) energy-dense (Western) associated with risk of fracture in 2011 [19]

men and women

(1) Meat, dairy, and bread; (2) meat and Cluster (6) was directly Tucker et al.,
sweet baked products; (3) sweet baked associated with FN BMD, Ward’s 2002 [20]
products; (4) alcohol; (5) candy, (6) fruit, BMD, and trochanter BMD when

vegetables, and cereal compared with clusters 2–4 in
men; cluster (5) was inversely
associated with FN BMD, Ward’s
BMD, and radius BMD when
compared with cluster (6) in men

cluster (5) was negatively
associated with radius BMD
when compared with clusters (1),

(2), (4), and (6) in women.

(1) Lower intake of energy (30 kcal/kg IBW) Cluster (2) was directly Pedone et al.,
and bone-related nutrients; (2) higher associated with cortical BMD and 2011 [21]
intake of energy (44 kcal/kg IBW) and inversely associated with cortical
bone-related nutrients BMD loss over 6 y compared with

cluster (1)

oral neck; DXA = dual energy X-ray absorptiometry; FFQ = food frequency questionnaire;
TX = C-terminal telopeptide; BAP = bone alkaline phosphatase; PTH = parathyroid hormone;
d tomography.

Life 2020, 10, 220 8 of 13

2.3. Dietary Patterns Score/index and Bone Health in Postmenopausal Osteoporosis

Some studies have used the dietary pattern score/index in association with BMD/BMC,
bone biomarkers and fractures in postmenopausal women as is shown in Table 3. The Mediterranean
score indicates compliance with the Mediterranean diet. A traditional Mediterranean diet is rich in
the intake of vegetables, fruit, nuts and olive oil but low in saturated fats, moderately high intake of
fish, low to moderate intake of dairy and lesser intake of meat and poultry as well as moderate intake
of wine [22–24]. In general, the Mediterranean diet score/index was directly associated with BMD
and inversely associated with fracture risk [22,23]. Meanwhile, the Healthy Eating Index (HEI) that
measures the quality of diet and how well a particular set of foods aligns with the dietary guidelines for
Americans has been reported as having no significant association for both the HEI 2005 and 2010 [25,26].
However, Zheng et al., 2014 reported an inverse association between HEI 2005 and hip fracture risk.
Furthermore, a study by De Jonge et al., 2015 reported a direct association between the BMD Diet Score
and the Healthy Diet Indicator with femoral neck BMD in a large number of postmenopausal women
based in the Netherlands [24].

On the other hand, the Dietary Inflammatory Index (DII) that assesses the inflammatory potential
of a diet was inversely associated with BMD as was shown by two separate studies from the United
States of America and Iran [25,26], these indicating the relationship between inflammation and
bone degeneration.

Life 2020, 10, 220

Table 3. Dietary pattern score/index and

Study, Location Participants’ Information Diet Assessment/Method
and Design
BMD/BMC 100 premenopausal (aged Validated semi-quantitative
34 ± 7 y), 100 postmenopausal FFQ/Calcaneus BMD by DXA
Southern Spain women (aged 54 ± 6 y) women, aged
study, Spain, Validated semi-quantitative
cross-sectional 18–65 y FFQ/FN BMD and LS BMD

Postmenopausal women, 160 postmenopausal women, by DXA
Iran, cross-sectional aged 50–85 y

The Rotterdam Study, 2932 women and 2211 men, 170 food items
Netherlands, longitudinal aged ≥ 55 y at baseline semi-quantitative FFQ/FN
BMD by DXA, at baseline and
and cross-sectional (median: 67 y; IQR: 61–73 y)
three subsequent visits

The women’s Health 160,191 women between BMD of the total hip, lumbar
Initiative, USA, 50–79 y spine (L2–L4), and total body

observational study and Women’s Health Initiative
clinical trial (WHI) FFQ/Total hip, LS and

Bone Biomarkers total body BMD by DXA

NHANES 1999–2002, 827 postmenopausal women 24-h dietary recall
United States, aged ≥ 45 y interview/Bone formation:
cross-sectional serum BAP; bone resorption:

Osteoporosis urinary N-telopeptide
or creatinine

Fifth Korean National 847 postmenopausal women 24-h dietary
Health and Nutritional recall/Osteoporosis and
osteopenia based on WHO
Examination Survey
(2010), Korea, BMD T-score criteria
cross-sectional

bone health in postmenopausal women. 9 of 13
Ref.
Dietary Patterns Score/Index Main Results
Generated

Mediterranean Diet MDS was directly associated with Rivas et al.,
A Score (MDS) BMD in all subjects 2013 [23]

Dietary Inflammatory DII inversely associated with Shivappa et al.,
Index (DII) LS BMD 2016 [27]

BMD Diet Score Directly associated with FN BMD

d Healthy Diet Indicator Directly associated with FN BMD, De Jonge et al.,
but three times weaker than BMD 2015 [28]

Diet Score

r

y Dietary Inflammatory Less inflammatory dietary pattern Orchard et al.,
Index (DII) was associated with less BMD loss 2017 [29]

in postmenopausal women.

: Healthy Eating Index 2005 No association was found Hamidi et al.,
2011 [25]

Mean Nutrient Adequac Ratio No association was found Go et al.,
Dietary Diversity Score 2014 [30]
Inversely associated with risk of
Calcium source assessmen osteoporosis and osteopenia
Food Group Intake Pattern
Milk, anchovy, and sea mustard
were inversely associated with risk

of osteoporosis and osteopenia

No association was found

Life 2020, 10, 220

Study, Location Participants’ Information Table 3
and Design Diet Assessment/Method
Fractures
549 women pairs and Validated 79-item
China, case–control 177 men pairs, age-matched; food-frequency questionnaire

Three-City Study, aged 55–80 y (FFQ)/Hip fracture
France, longitudinal
932 women and 550 men, FFQ and 24-h dietary
aged ≥ 67 y at baseline, recall/Hip, vertebral, and
wrist fractures; self-reported
8 y follow-up every biennial interview

Women’s Health Initiative 90,014 postmenopausal WHI FFQ/Total and
observational study, women, aged 50–79 y (63 ± 7) hip fracture
United States, at baseline, 16–21 y follow-up
longitudinal

BMD = bone mineral density; BMC = bone mineral content; LS = lumbar spine; FN = femoral
Mediterranean diet score; DII = dietary inflammatory index; WHI = women’s health initiativ

10 of 13

3. Cont. Main Results Ref.

Dietary Patterns Score/Index
Generated

e Healthy Eating Index 2005 Inversely associated with hip Zeng et al.,
fracture risk 2014 [31]

Mediterranean Diet Score No significant association Feart et al.,
2013 [22]

Alternate Alternate Mediterranean score
Mediterranean Score inversely associated with hip

fracture risk

Healthy Eating Index 2010 No significant association Haring et al.,
No significant association 2016 [26]
Alternative Healthy Eating
Index 2010

Dietary Approaches to Stop No significant association
Hypertension

neck; DXA = dual energy X-ray absorptiometry; FFQ = food frequency questionnaire; MDS =
ve; WHO = World Health Organisation.