The prevalence of hypovitaminosis D and its risk factors in pregnant women and their newborns in the Middle East: A systematic review

Abstract Background Pregnant women and newborns are at risk for vitamin D deficiency (VDD). Also, poor health outcomes for pregnant women with VDD are reported in the published literature. Objective The aim of this systematic review was to estimate the prevalence of hypovitaminosis D and the associated risk factors for hypovitaminosis D in Middle Eastern pregnant women and their newborns. Results The prevalence of circulating 25-hydroxyvitamin D (25(OH)D) < 50 nmol/L as a marker of vitamin D status in pregnant women and their newborns was between 24.5-98% and 22-100%, respectively. The prevalence of 25(OH) D < 25 nmol/L in pregnant women and their newborns was over a wide range between 16.7-80% and 22-82%, respectively. Predictors for low maternal and neonatal 25(OH)D concentrations included decreased vitamin D synthesis due to reduced exposure to sunlight and decreased nutritional intake of vitamin D. A predictor of low neonatal 25(OH)D concentrations included maternal vitamin D status and the correlation between vitamin D concentrations in maternal and cord blood. Conclusion The high prevalence of VDD in the pregnant women of the Middle East underscores the necessity of implementing national prevention and intervention strategies. A clear policy for clinicians and healthcare workers is needed for screening and maintaining sufficient vitamin D status during pregnancy.


Introduction
Vitamin D deficiency (VDD) is a global public health problem in all age groups (1). There are four recent meta-analyses showing that pregnant women and newborns are at a risk for VDD (2)(3)(4)(5). A number of studies have reported that pregnancy alone increases the risk of VDD (6). Results of two recent meta-analyses showed that there was a significant relationship between maternal VDD and adverse maternal, fetal, and postnatal outcomes (7,8).
The countries of the Middle East -Bahrain, Cyprus, Egypt, Iran, Iraq, Israel, Jordan, Kuwait, Lebanon, Oman, Palestine, Qatar, Saudi Arabia, Syria, Turkey, United Arab Emirates, and Yemen have a high incidence of VDD and rickets (43)(44). Although the Middle East has a hot, sunny and arid climate; and is located within the latitudes from 12N-42 N; both of which allow for vitamin D synthesis from ultraviolet B (UVB) rays for most months of the year and for more than 8 hr/day (45), there exists significant VDD. Therefore it is important to determine the mother's vitamin D status and associated factors during pregnancy in order to prevent neonatal VDD and related complications (46)(47)(48).
A number of recent reviews have included the rapidly growing body of literature on vitamin D during pregnancy. However, because few studies conducted in the Middle East and North Africa were population-based, extrapolation to the vitamin D nutritional status of pregnant women and their neonates in that region is limited (44). In the past five yr, only one review focused on maternal and OR "Iraq" OR "Israel" OR "Jordan" OR "Kuwait" OR "Lebanon" OR "Egypt" OR "Cyprus" OR "Oman" OR "Qatar" OR "Saudi Arabia" OR "Syria" OR "Turkey" OR "United Arab Emirates" OR "Yemen").
The period of publication was from 2000 to 2017. Publications were searched and reference lists were hand-searched. The confirmed sources were examined using a data extraction form. Based on the protocol, we reviewed all crosssectional studies, prospective studies, and casecontrol studies, which had been conducted on the status of vitamin D in pregnant women and their newborns in the Middle East in the desired time limit.

The process of study selection
Study selection was performed in three phases: In the first phase, titles were scanned according to the selection criteria. The accepted titles were entered into the abstract review phase to identify studies for eligibility. In the next phase, abstracts were reviewed; the study was excluded if the reviewer found that the study met one or more exclusion criterion/criteria. The last phase was performed to determine if the full texts should be included for data extraction. In total, 1,857 articles were investigated, of which, 1,722 papers were excluded due to the lack of consistency with the goals of the study; as for example, studies on the general population (teenage, children, men, or breastfeeding women), and studies that provided no new empirical data (reviews, editorial letters, and brief items). Moreover, 12 papers were ruled out due to lack of access to the original article; for instance, because of the type of language (Turkish or Arabic language).
Finally, 51 papers were included in this study ( Figure 1).

Data extraction, data elements, and quality assessment
Each study was evaluated using a data extraction form. We developed a data extraction form to collect key indicators of each study, including study design, definition of VDD and vitamin D insufficiency, as well as assays used and characteristics of the study population. We extracted data on these indicators as reported in the articles. We collected data from the included studies and organized the results in a table format. The study outcomes are presented in the Results section.
We assessed the study quality by using data reported on representativeness and validity. A study was considered representative if: (1) this feature of the study was explicitly addressed in the corresponding full-text article, or (2) any statement made by the authors suggested that the actual sample reflected the target population. Validity was evaluated using information about the (25(OH)D) measure (e.g., participation of the laboratory in the International Vitamin D Quality Assessment Scheme, DEQAS) (50).
At any point, any disagreement between reviewers was resolved by means of meeting and discussion among all authors to establish a consensus. Table I shows the studies conducted to estimate VDD for pregnant women and newborns in Iran, Turkey, and Arabic countries. Estimates are reported using various assay methodology for the measurement of circulating 25-hydroxyvitamin D (25(OH)D) concentration, which serves as the indicator of vitamin D status. This metabolite (25(OH)D) is difficult to measure, with large variations between methods and among laboratories even when the same methods are used (51). This review revealed that the prevalence of (25(OH)D) concentration < 50 nmol/L in pregnant women and their newborns was between 24.5-98% and 22-100%, respectively. The prevalence of (25(OH)D) concentration < 25 nmol/L in pregnant women and their newborns was over a wide range between 16.7-80% and 22-82%, respectively (Table II).

Results
A number of factors can limit the cutaneous production of vitamin D and dietary sources of vitamin D (52), especially in pregnant women (53). As shown in Tables II and III, predictors for low maternal and neonatal (25(OH)D) concentrations included decreased vitamin D synthesis, likely due to reduced exposure to sunlight and decreased nutritional intake of vitamin D.

In this section, vitamin D status in mothers and their newborns and predictors for low maternal and neonatal (25(OH)D) concentrations in the Middle
East will be discussed in detail.

Vitamin D status in mothers and their newborns
A US-based study from California reported extensive vitamin D insufficiency and deficiency during pregnancy that particularly affected mothers and their newborns (53) Our review revealed the prevalence of (25(OH)D) concentrations < 50 nmol/L in pregnant women and their newborns was over a wide range, but at minimum, more than a third-to-half of the women and their newborns had frank VDD, and more than 75% had either deficiency or insufficiency. Our findings of VDD in mothers and their newborns in the Middle East are consistent with the previous systematic review that had shown a high prevalence of hypovitaminosis D among pregnant women (9,49,102,103). Results of this study are similar to other studies in the United States and Europe. In more recent reports,  (1,25(OH) 2 D) are so highly correlated. This is also found in the neonate at birth, but beyond the neonatal period this relationship no longer exists (114).

Factors influencing vitamin D status in newborns including the correlation between 25(OH)D concentrations in maternal and cord blood
Newborns receive their vitamin D via the placenta throughout pregnancy in the form of 25(OH)D (46). Eight studies in this review have shown a strong positive correlation between maternal and fetal circulating 25(OH)D concentrations (6,47,57,67,71,73,89,93). The results of this review are consistent with other systematic reviews of studies reporting serum (25(OH)D) concentration in maternal and newborn populations in the Americas, Europe, Eastern Mediterranean region, South-East Asia, Western Pacific, and African countries (49). Most of the investigators have reported that there is a positive and strong correlation between maternal and cord blood (25(OH)D) concentrations (33,110,(115)(116)(117), and this is supported by recent studies from many countries, including India (103), the United Kingdom (118), Greece (119), and the US (110,117,120). Not surprisingly, these studies further demonstrated a high prevalence of VDD in mother-infant pairs at birth.

Factors influencing Vitamin D status in mothers 4.3.1. Decreased vitamin D synthesis due to personal and environmental factors
In this review, personal factors associated with decreased vitamin D synthesis included lifestyle (6,47,55,76,85), and cultural conditions (6,76,85,86,93,101) due to greater coverage of the body with clothing that resulted in lower duration as well as less surface area exposed to the sun (121,122), less participation in outdoor activities (123), and the use of sunscreen, which blocks UVB radiation, and thus vitamin D synthesis in the skin (124). Similar results were observed in studies in the Middle East and countries with Muslim communities (125)(126).
Women residing in the Middle East and Southeast Asia tend to spend very little time in the sunlight due to cultural and social reasons (127). Studies in Nigeria and Gambia have shown that VDD in newborns at birth is rare when mothers' exposure to sunlight is unrestricted (128). Decreased time spent outdoors may be related to increasing urbanization and increasing time spent indoors at work. Shade reduces the amount of solar radiation by 60% and windowpane glass blocks UVB radiation (123).
Countries of the Persian Gulf region-Bahrain, Iran, Iraq, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates-have become increasingly modernized, resulting in lifestyle transformation based on technology, sedentary activity, and lack of sunlight. These factors have led to a higher prevalence of VDD (129). Besides urbanization, there are multiple factors that limit sunlight exposure such as the hot environment/weather (130), social norms, and religious habits (129)(130)(131). Women avoid going outdoors due to more urbanized lifestyles and aesthetic reasons; for example, the culture tends to favor a fair skin that is not suntanned. Therefore, even in the privacy of their own homes, women from such cultural background tend to avoid sun exposure (130). This is in marked contrast to the more Western cultures where tanning and darkening of the skin pigment among white/Caucasian women are considered to enhance their beauty. Cultural norms thus play a role in the time spent outdoors and in the sun, and both directly affect vitamin D status.
As mentioned earlier, sun exposure is also greatly affected by clothing styles that cover most of the body, which leads to reduced vitamin D production in the skin (129). Thus, limited sun exposure in the Middle East appears to be mostly due to cultural practices, clothing styles and limited outdoor activity (132). Other factors such as cloud cover of the sun (133), atmospheric pollution (121,133,134), geographic latitude (46), and season (122) are environmental factors influencing the amount of UVB radiation reaching earth (127). In this study, factors associated with vitamin D status included air pollution (98,73) and seasons (98,101). Our data indicate that exposure to ambient urban air pollution during pregnancy can significantly contribute to VDD in newborns at the time of delivery.
A cohort study in France reported an inverse correlation between air pollution and (25(OH)D) concentrations in cord blood (135). The association between air pollution and low vitamin D status has also been reported among children (133,136) and women (137,138). Historically, this was the basis of rickets in children living in industrialized Great Britain where air pollution prevented UVB from reaching beyond the coal and pollutant layer (139).
Air pollution decreases vitamin D synthesis in the skin in two ways: Pollution reduces the amount of UVB radiation reaching the skin (121) and also the amount of time that people are outdoor (140).
In a study of newborns in Amman, Jordan, Khuri-Bulos et al., reported that birth during winter months was associated with lower infant 25(OH)D concentrations (98). In a US cohort of 100 infants who were born at latitude 32°N, both the groups of African-American and Caucasian infants exhibited a seasonal variation in vitamin D status (46). An alternative explanation can be that when pregnancy was in winter, these infants accrued lower stores of vitamin D in utero (141). Other studies have shown that the prevalence of VDD during the winter months was higher than the summer months (119,(142)(143). Vitamin D status is typically low in the winter months due to variation in cutaneous photosynthesis of pre-vitamin D at higher latitudes above 30° (144). In addition, in the winter the mothers use warmer clothing and the less body surface exposure reduces the cutaneous synthesis of vitamin D (46).

Decreased dietary sources of vitamin D due to dietary habits and vitamin D replacement
The results of this review study showed that another predictor for low 25(OH)D concentrations included decreased dietary sources of vitamin D due to dietary habits and lack of vitamin D replacement (85,86,93,101). Dawodu and colleagues (2015), in the Global Exploration of Human Milk study, concluded that the prevalence of VDD in diverse populations appears to depend on sunlight exposure behaviors and vitamin D supplementation use (145). This is in support of the findings in this study. Vitamin D is a fat-soluble vitamin, which is found naturally only in a few foods, such as fishliver oils, fatty fish, egg yolks, liver, and mushrooms (146,147). Among the dietary sources, the only ones that seem to affect 25(OH)D synthesis are fish (85) and mushrooms (147) if consumed in sufficient quantity. Promoting fish and mushroom consumption in pregnant women may be reasonable with respect to 25(OH)D concentration (85); however, with the former, there is concern about heavy International Journal of Reproductive BioMedicine

Conclusion
The Middle East, in most of its geographic regions, has sufficient sunshine for the adequate photocutaneous synthesis of vitamin D; however, most of the Middle Eastern women cannot benefit from this source because of cultural practices, such as clothing and veiling among Muslim women, and spending most time indoors. The results of this study raise the concern that newborns in the Middle East are entering the world with a vitamin D deficiency that begins in utero, with documented consequences on later health such as low birth weight, small-for-gestational age (7,9), abnormal skeletal development, type 1 diabetes (35), abnormal immune development (37), wheezing, asthma (40), abnormal neurocognitive development (41), and the concern for epigenetic factors that can adversely affect health later in life (160).
The high prevalence of hypovitaminosis D in the Middle East underscores the necessity of implementing national preventive strategies. These strategies for the prevention of VDD in women and their newborns at birth begin with vitamin D sufficiency in women during pregnancy. The preventive strategies need to encompass public awareness and also guidelines for health care personnel concerning screening and supporting vitamin sufficiency (161). In most countries, there is no routine screening for VDD nor for insufficiency during pregnancy. A 2013 study and 2009 review have recommended that women with one or more risk factors for low serum 25(OH)D should be screened at the beginning of gestation and in mid-pregnancy and early in the antenatal period, especially for those with risk factors (47,116). Such screening programs already have been implemented in centers in the US with a positive effect (162).
Based on this current view, more than 75% of Middle Eastern women are either frankly vitamin D deficient or insufficient, which directly reflects their reduced exposure to sunlight and decreased dietary sources of vitamin D, thus making them significantly more likely to have lower 25(OH)D concentrations. These findings lend support to a screening of pregnant women and their newborns for VDD in all Middle Eastern women. If a mother has VDD or insufficiency and sunlight exposure is limited, an alternative for the pregnant woman International Journal of Reproductive BioMedicine Hypovitaminosis D in pregnant women and their newborns is vitamin D supplementation during pregnancy to ensure vitamin D sufficiency for both herself and for her newborn (33,163). Daily doses of 4,000 units/day are recommended for achieving vitamin D sufficiency throughout pregnancy (110,164). Because vitamin D status is inversely associated with obesity parameters, women with higher BMIs will need higher doses of vitamin D supplementation (165)(166)(167). Dietary intake alone is not sufficient to maintain normal vitamin D status because a considerable amount of vitamin D is acquired by cutaneous synthesis when exposed to sun (121,137). Therefore, public health awareness about the predictors of low maternal and neonatal 25(OH)D concentrations in the Middle East and also the need to encourage vitamin D sufficiency by modest sunshine exposure and adequate maternal vitamin D intake during pregnancy are needed.

Strengths and weaknesses of the study
A strength of our study was the use of a comprehensive search strategy with broad search terms. A potential weakness is that we restricted the review to studies published in the English language in two international electronic databases (Scopus, PubMed), so relevant studies may have been missed.