Risk of eczema, wheezing and respiratory tract infections in the first year of life: A systematic review of vitamin D concentrations during pregnancy and at birth.

BACKGROUND: Allergic conditions and respiratory tract infections (RTIs) are common causes of morbidity and mortality in childhood. The relationship between vitamin D status in pregnancy (mothers), early life (infants) and health outcomes such as allergies and RTIs in infancy is unclear. To date, studies have shown conflicting results.
OBJECTIVE: This systematic review aims to gather and appraise existing evidence on the associations between serum vitamin D concentrations during pregnancy and at birth and the development of eczema, wheezing, and RTIs in infants. DATA SOURCES: PubMed, MEDLINE, ProQuest, Scopus, CINAHL, Cochrane Library and Academic Search Premier databases were searched systematically using specified search terms and keywords. STUDY SELECTION: Articles on the associations between serum vitamin D concentrations during pregnancy and at birth and eczema, wheezing, and RTIs among infants (1-year-old and younger) published up to 31 March 2019 were identified, screened and retrieved.
RESULTS: From the initial 2678 articles screened, ten met the inclusion criteria and were included in the final analysis. There were mixed and conflicting results with regards to the relationship between maternal and cord blood vitamin D concentrations and the three health outcomes-eczema, wheezing and RTIs-in infants.
CONCLUSION: Current findings revealed no robust and consistent associations between vitamin D status in early life and the risk of developing eczema, wheezing and RTIs in infants. PROSPERO registration no. CRD42018093039.

Introduction

Allergic diseases and respiratory tract infections (RTIs)–whether upper respiratory tract infections (URTIs) or lower respiratory tract infections (LRTIs)–are among the most common causes of morbidity and mortality in childhood [1, 2]. Over the years, occurrences of allergic diseases and RTIs in children have continued to rise [3-5]. The trend is apparent among the infant age group [6-8]. Worldwide, it was estimated that 30%–60% of infants suffered from allergic conditions such as eczema and wheezing [8, 9].

Previously, the prevalence of allergic diseases was most common in Europe, but in recent decades, the same phenomenon has been observed in Asia [10, 11]. A cross-sectional study in Malaysia found that the prevalence of eczema among infants aged two years and younger was 65% [12]. An earlier study reported that approximately 37% of those aged one year and younger experienced the same condition [9]. Other Asian countries such as Korea, Indonesia, Japan and Thailand reported a prevalence of eczema ranging between 5% and 23% [13-16]. On the other hand, RTIs (particularly LRTIs) are a leading cause of hospital admission among infants. A survey conducted in a Malaysian city found that 88% of hospital admissions due to LRTI involved infants aged 1 year and younger, with the median age being 8 months [17]. Likewise, 69.6% of LRTI hospital admissions in Korea involved children younger than three years, with the majority being infants [18].

The early presentation of these conditions indicates that prenatal factors such as environmental exposures during the gestational period may have a role in the development of allergic diseases in infancy [19, 20]. Among the various environmental factors that contribute to allergic diseases and RTIs, vitamin D status has gained much research interest, given its purported immuno-modulatory properties [21]. Low vitamin D levels in pregnant mothers are said to have adverse consequences on the immune system development of infants in early life. [22]. Similarly, high levels of maternal vitamin D during pregnancy were associated with lower occurrences of eczema and RTIs in infants [16, 23, 24]. In contrast, several studies did not support this association and have shown conflicting results [25, 26]. To date, the extent vitamin D levels during pregnancy and early postnatal period (e.g., cord blood) affect the development of allergic diseases and RTIs in infants remains unclear. Prior reviews were heterogeneous in their sample characteristics and methods. Some included a wide range of age groups while assessing allergic diseases and RTI outcomes (e.g. 0 to 7 years) while some employed diverse tools in the measurement of serum vitamin D and dietary intake [4, 24, 27].

The lack of conclusive empirical evidence among a more focused age group (e.g., infants aged one year and younger) has implications on health policy and clinical practice. For instance, questions of when should vitamin D be provided as a form of intervention—earlier or later—and whether it is more beneficial to prescribe vitamin D to a woman during her pregnancy or to her two-year-old child remain. In some countries, vitamin D has been recommended as supplementation for pregnant women and infants and foods were supplemented with vitamin D. This is because vitamin D deficiency is prevalent among pregnant women and infants ranging from 45% to 90% in pregnant women and 61% to 96% in infants [28]. This is likely due to inadequate sun exposure, vitamin D dietary and exclusive breast milk intake.

However, in countries that receive more sunlight (e.g., countries with equatorial climate), the necessity of vitamin D supplementation for pregnant women and infants has been questioned. Compared to previous reviews, we added to existing knowledge by summarising the data differently. We narrowed down the endpoint (age gap) to enable a clearer and more focused understanding on the impact of vitamin D levels in pregnancy and early life (cord blood) on health outcomes in the first year of life. Given the alarming trend of allergic diseases and RTIs in infancy—with vitamin D levels as a potential risk factor—we undertook a systematic review to determine the relationship between vitamin D (25(OH)D) concentrations during pregnancy and at birth (e.g., cord blood) with eczema (including atopic dermatitis), wheezing and RTIs (URTIs and LRTIs) in the first year (12 months) of life. This review focused on serum 25hydroxyvitamin D (25(OH)D) instead of vitamin D dietary intake as clinically, serum 25(OH)D represents the cumulative effect of dietary intake of vitamin D and sunlight exposure [29].

Methods

This review was designed according to the PICOS (Participants, Intervention, Comparison, Outcomes and Study Design) criteria (Table 1) and The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [30] (Fig 1). The review protocol has been registered with the International Prospective Register of Systematic Reviews [PROSPERO Registration no; CRD42018093039].

Table 1

PICOS criteria employed to design the systematic review.

Criteria	Description
Participants	Pregnant women and their infants aged ≤12months.
Intervention/exposure	Serum 25(OH)D concentrations during pregnancy and early postnatal (cord blood).
Comparison	Analysis of serum 25(OH)D concentrations during pregnancy and early postnatal (cord blood) either by mean, median, interquartile or cut-off values such as deficiency, sufficient and insufficient.
Outcomes	Eczema, wheezing and RTIs of infants aged ≤12months.
Study design	Randomised controlled trial (RCT), non-RCT, observational cohort and case control study.

Fig 1

PRISMA flow diagram.

Data sources and literature search

The PubMed, MEDLINE, ProQuest, Scopus, CINAHL, the Cochrane Library and Academic Search Premier databases were used to search for studies published until March 31, 2019. The search was performed on May 1, 2019. Articles investigating associations between serum vitamin D concentrations during pregnancy and at birth (cord blood) and the development of allergic eczema, wheezing, and RTIs in infants were identified systematically. The keywords used in the search were “vitamin D” AND (wheezing OR atopic dermatitis OR eczema OR respiratory infections). In addition, all related keywords, MeSH terms, text words and search terms were used in the literature search (S1 Table).

Study selection and data extraction

The goal of the search strategy was to identify studies that reported the associations between serum vitamin D concentrations during pregnancy and at birth (cord blood) and the development of allergic eczema (including atopic eczema/dermatitis), wheezing and RTIs (including URTIs and LRTIs) among infants in the first year (12 months) of life. Allergic eczema, wheezing and RTIs in infants (in the 12 months of life) is defined as outcomes, which were diagnosed either by health professional officers, assessed by established questionnaires or tools or parental reports. The following inclusion criteria were applied: (1) Primary research which includes randomised controlled trial (RCT), non-RCT, observational cohort and case-control study designs, and; (2) studies that examined the associations between serum 25(OH)D concentrations during pregnancy or at birth (cord blood) and the development of allergic eczema, wheezing and RTIs among infants in the first year (12 months) of life. Meanwhile, the exclusion criteria were as follows: (1) study subjects were more than one-year old (>12 months); (2) studies that involved animals; (3) review articles, conference papers and dissertations; (4) ecological studies; (5) non-English papers, and; (6) studies published as only abstracts without full-texts.

The database search identified titles and abstracts that were independently screened and reviewed by two authors. Results were then compared, and disagreements were resolved by discussion and by consulting a third author when necessary. The following information was extracted from the selected papers: Author (s); year of publication; study population; sample size; study location; study design; parental allergy history; exposure; week of pregnancy during measurement of vitamin D, how the outcomes were assessed, which either (1) were diagnosed by health professional officers (including parental reports); (2) assessed by established questionnaires or tools such as ‘SCORing Atopic Dermatitis’ (SCORAD) index or (3) parental reports (based on parent observation or perception); and summary of the association for exposure and results of the outcomes (eczema, wheezing and respiratory infections). The original authors of the papers were contacted whenever further clarification of the study results or other details were required.

Assessment of risk of bias

The Cochrane Collaboration’s tool was used to assess the risk of bias in randomised control trials [31]. Meanwhile, the Eight-Star Newcastle-Ottawa Scale (NOS) for Cohort studies was used to assess the risk of bias in observational studies [32] (S2 Table).

Data synthesis and analysis

Mean, median, odd ratios (OR) and relative risks (RR) of the outcomes were regarded as primary measures of exposure and outcomes effect. However, other calculations/statistics, such as quartiles were presented in this review. Final results and scoring of selected papers were tabulated, summarised and elaborated in a narrative manner.

Results

A total of 2678 articles were initially identified from the databases. Following title and abstract screening, 32 full-texts were analysed. Out of 32 studies, ten met the inclusion criteria. Twenty-two were then removed because the outcome measurement was not specific to those one-year-old and younger, or it was performed on subjects older than one year. Fig 1 illustrates the flow diagram of literature search (PRISMA).

Study characteristics

All the ten papers selected were prospective cohort studies conducted in western, high-income nations [7, 33–41]. Some studies assessed multiple outcomes. Six studies measured the associations between vitamin D concentrations in pregnancy and allergic eczema, five measured wheezing as the outcome and six measured RTIs. Methods of outcome assessment were diverse. Most studies relied on parental reports (n = 7) while some used standardised tools (n = 3) to determine eczema: ‘SCORing Atopic Dermatitis’ (SCORAD) index [7], ‘UK Working Party’s diagnostic criteria’ [33] and ‘Hanifin and Rajka criteria’ [41]. Six studies measured maternal serum 25(OH)D concentrations, while four studies measured cord serum 25(OH)D as their exposure component. In terms of measurement timing, one study conducted its assessment in the stage of early pregnancy (first trimester) [34], another in mid-pregnancy (second trimester) [38] and four studies in late pregnancy (third trimester) [33, 35–37].

A further five studies reported the ethnic backgrounds of their study subjects [7, 33, 34, 40, 41]. For instance, in Gale et al. (2008), all participants were Caucasians, and in Morales et al. (2011), 97% were Caucasians. Jone et al. (2012), Camargo et al. (2010) and Palmer et al. (2015) included various ethnic groups but Caucasians still comprised the majority of the study subjects. Meanwhile, age of subjects ranged between 0 to 12 months when outcomes (wheezing, allergic eczema or RTIs) were measured. Most studies reported either odd ratios (OR) or relative risks (RR) with the 95% confidence interval except for one study that reported only p-values [36]. Detailed descriptions of the ten studies are presented in Table 2.

Table 2

Characteristics of studies included in the final analysis (n = 10).

Author	Study setting	Study design, participant	Exposure	Parental allergy/ atopy history	Period of exposure assessment	Outcomes	How the outcome was assessed	Age during outcome assessment
Gazibaraa, 2016 [38]	Rotterdam, Netherlands (51°55’N)	Cohort study 3019 mother–child pairs	Maternal 25(OH)D serum	Reported	2nd trimester Median of gestation = 20.5 (IQR: 18.1–24.9) weeks	• Eczema	• Parent reported	• At 6 months (mo)
								• At 12 mo
Palmer, 2015[41]	Adelaide, Australia (34°51’ S)	Cohort study 270 mother–child pairs	25(OH)D cord blood	Reported	Delivery	• RTIs	• Parent reported	• At 12 mo
						• Atopic eczema	• Hanifin & Rajka criteria
Baiz, 2014 [39]	Pontiers (46° 35’N) Nancy (48° 41’N), France	Cohort study 2002 mother–child pairs	25(OH)D cord blood	Reported	Delivery	• Wheezing	• Parent reported	• At 12 mo
						• Atopic eczema	• Parent reported
De Jongh, 2014 [37]	Southampton, UK, (50°54’N)	Cohort study 2025 mother–child pairs	Maternal 25(OH)D serum	Not reported	At week 34 of gestation	• Wheezing	• Parent reported	• At 6 mo
						• URTIs	• Parent reported	• At 12 mo
						• LRTIs	• Parent reported
Skowrońska-Jóźwiak, 2014 [36]	Poland	Cohort study 102 mother–child pairs	Maternal 25(OH)D serum	Not reported	3rd trimester	• RTIs	• Parent reported	• At 12 mo
Weisse, 2013[35]	Leipzig, Germany (51°40’N)	Cohort study 378 mother–child pairs Ethnicity: not reported	Maternal 25(OH)D serum	Reported	3rd trimester At week 34 of gestation	• Atopic eczema	• Parent reported	• At 12 mo
Jones, 2012 [7]	Perth, Australia (31°57’S)	Cohort study 231 mother–child pairs	25(OH)D cord blood	Reported	Delivery	• Wheezing	• Parent reported	• At 12 mo
						• Atopic eczema	• SCORAD severity index
Morales, 2012 [34]	4 study areas: Menorca Island, Valencia, Sabadell and Gipuz-koa in Spain (39°N, 39°N, 41°N, 44°N)	Cohort study 1724 mother–child pairs Ethnicity; 97% white, 3% others	Maternal 25(OH)D serum	Reported	Early pregnancy Mean of gestation = 12.6 (SD ±2.5) weeks	• LRTIs	• Parent reported	• At 12 mo
						• Wheezing	• Parent reported
Camargo, 2010 [40]	Wellington (41°S), Christchurch (43°S), New Zealand	Cohort study 922 newborns	25(OH)D cord blood	Not reported	Delivery	• RTIs	• Parent reported	• At 3 mo
Gale, 2008 [33]	Southampton, UK (50°54’N)	Cohort study 596 mother–child pairs Ethnicity: 100% white	Maternal 25(OH)D serum	Not reported	3rd trimester Median of gestation = 32.6 (IQR: 32.0–33.4) weeks	• Atopic eczema	• UK Working Party’s diagnostic criteria	• At 9 mo
						• RTIs	• Parent reported

Quality assessment

Of the ten cohort studies, nine could be regarded as good (high) quality [7, 33–35, 37–41], and one was scored to be of moderate or fair quality [36]. Details summary of quality appraisal is illustrated in Table 3.

Table 3

Summary of quality assessment of the included studies using the Newcastle-Ottawa scale.

	Selection				Comparability	Outcome
	Representativeness of the exposed cohort	Selection of the non-exposed	Ascertainment of exposure	Demonstration that outcome of interest was not present at start of study	Comparability of cohorts on the basis of the design or analysis controlled for confounders	Assessment outcome	Follow up long enough for outcomes to occur	Adequacy of follow up of cohorts
Palmer et al. (2015)	*	*	*	*	*	*	*	*
Jones et al. (2012)	*	*	*	*	*	*	*	*
Baiz et al. (2014)	*	*	*	*	*		*	*
Camargo et al. (2010)	*	*	*	*	*		*	*
Weisse et al. (2013)	*	*	*	*	*		*
Gale et al. (2008)	*	*	*	*		*	*	*
Gazibara et al. (2016)	*		*	*	*		*
De Jongh et al. (2014)	*		*	*	*		*
Morales et al. (2012)	*		*	*	*		*
Skowrońska-Jóźwiak et al. (2014)	*		*	*			*

Good quality: 3 or 4 stars in selection domain AND 1 or 2 stars in comparability domain AND 2 or 3 stars in outcome/exposure domain.

Fair quality: 2 stars in selection domain AND 1 or 2 stars in comparability domain AND 2 or 3 stars in outcome/exposure domain.

Poor quality: 0 or 1 star in selection domain OR 0 stars in comparability domain OR 0 or 1 stars in outcome/exposure domain.

Vitamin D status

The average concentration of serum 25(OH)D during pregnancy ranged between 50.0 to 73.6 nmol/L, while in the early postnatal period (cord blood) it ranged between 44.0 to 58.4 nmol/L. This might be due to the differences in the timing of exposure assessment and methods of reporting. Six studies reported median with interquartile range, with the quartiles and quintiles being either natural or pre-set [33–35, 37, 39, 40]. Three studies reported mean and standard deviation for the serum 25(OH)D levels [7, 38, 41]. One study categorised serum 25(OH)D levels into three groups: deficient (< 50 nmol/L), insufficient (50.0–75.0 nmol/L) and sufficient (> 75.0 nmol/L). To determine the associations between exposure (vitamin D concentrations during pregnancy or at birth) and outcomes (eczema, wheezing or RTIs), some studies used quartiles and quintile while some employed cut-off values while categorising vitamin D levels, such as deficient (25.0–40.0, < 50.0 nmol/L), sufficient (50.0–74.9, >75.0 nmol/L), severe deficiency (≤25.0 nmol/L), insufficient (50.0–75.0 nmol/L) and optimal (≥75.0 nmol/L). These variations rendered comparison across studies difficult. In addition, there has been no consensus on the threshold value for an optimal level of vitamin D.

Vitamin D and eczema in the first year (12 months) of life

Six studies examined maternal or cord serum 25(OH)D levels in relation to eczema in infants aged one and younger. Three studies reported on the association during pregnancy, while the other three studies reported in cord blood [7, 33, 35, 38, 39, 41]. All were ranked as high quality based on the NOS (refer Table 4). Out of the three studies that assessed vitamin D levels in pregnancy, two had their measurement conducted in late pregnancy (28–42 weeks of gestation) and gave conflicting results [33, 35]. Gale et al. (2008) reported that higher maternal serum 25(OH)D concentrations in late of pregnancy led to higher risks of eczema in 9-month-old infants (Adjusted OR = 3.26, 95% CI = 1.15–9.29). Whereas, Weisse et al. (2013) found no significant association between maternal serum 25(OH)D concentrations in late pregnancy and eczema in infants aged 0–1 year (Adjusted OR = 0.89, 95% CI = 0.63–1.32, P-value = 0.614). Nevertheless, Weisse et al. (2013) adjusted for parental allergy history in the analyses but the assessment of the eczema relied on parental report. Whereas Gale et al. (2008) did not report they had adjusted for parental allergy history, but they used the established tool to assess the eczema outcomes. On the other hand, a study conducted by Gazibara et al. (2016) in mid-gestation (median 20.5 (IQR, 18.1–24.9) weeks of gestation) reported that the 25(OH)D levels were not associated with eczema in infants (parental allergy history was accounted in the analyses, and the eczema outcome was based on parental reports).

Table 4

Studies included in the analysis of 25 (OH)D during pregnancy or cord blood with the development of eczema in the first year (12 months) of life.

Author	serum 25(OH) D levels	Result findings	Conclusion
Gazibaraa, 2016 [38]	Mean (SD) maternal 25(OH) D level = 65.5 (43.7) nmol/L	Eczema (0–1 y); N = 614	No association between maternal serum 25(OH)D levels in 2nd trimester and the risk of eczema in the first year of life.
		OR (95% CI)
	Severely deficient = <25.0 nmol/L	<25.0 nmol/L: 0.91 (0.55–1.49)
	Deficient = 25.0–49.9 nmol/L	25.0–49.9 nmol/L: 0.98 (0.74–1.31)
	Sufficient = 50.0–74.9 nmol/L	50.0–74.9 nmol/L: 0.92 (0.72–1.17)
	Optimal ≥75.0 nmol/L	≥75.0 nmol/L: reference
		P for trend: 0.940
Palmerb, 2015[41]	Mean (SD) 25(OH)D cord blood level	Eczema at 1 year: N = 265	Risk of eczema at 1 year of age decreased (12% reduction in risk) as cord blood 25(OH)D concentrations increased; a 10 nmol/L rise.
	= 57.0 (24.1) nmol/L	Adjusted RR (95% CI) in relation to 10 nmol/L rise 25(OH)D cord blood: 0.88 (0.81–0.96)
		P-value = 0.002
Baizc, 2014 [39]	Median (IQR) 25(OH)D cord blood level = 17.8 (15.1) ng/ml+	Atopic eczema at 1 year: N = 239	No association between cord blood 25(OH)D levels and the risk of eczema in the first year of life.
		Adjusted OR (95% CI) in relation to 5 ng/ml+ rise 25(OH)D cord blood = 0.84 (0.71–1.00)
		P-value = 0.050
Weissed, 2013[35]	Median (IQR) maternal 25(OH)D level = 22.19 (14.40–31.19) ng/ml+	Atopic eczema (0–1 y)	No association between maternal serum 25(OH)D levels in 3rd trimester and atopic eczema in the first year of life.
		Symptoms (N = 272)
	Q1: 6.13–14.39 ng/ml+	Maternal 25(OH) D, quartiles: n (%)
	Q2: 14.40–22.19 ng/ml+	Q1: 10 (15.2)
	Q3: 22.20–32.19 ng/ml+	Q2: 8 (11.0)
	Q4: 32.20–60.80 ng/ml+	Q3: 6 (9.5)
		Q4: 7 (10.0)
		Adjusted OR (95% CI) 0.89 (0.63–1.32); P = 0.614
		Diagnosed (N = 272)
		Maternal 25(OH) D, quartiles: n (%)
		Q1: 4 (6.1)
		Q2: 9 (12.3)
		Q3: 7 (11.1)
		Q4: 7 (10.0)
		Adjusted OR (95% CI): 1.16 (0.79–1.71); P = 0.451
Jonese, 2012 [7]	Mean (SD) 25(OH)D cord blood level = 58.4(SD, 24.1) nmol/L	Eczema at 1 year; N = 193	Risk of eczema at 1 year of age decreased (14% reduction in risk) as cord blood 5(OH)D concentrations increased; a 10 nmol/L rise.
		Adjusted OR (95% CI) in relation to 10 nmol/L rise 25(OH)D cord blood: 0.86 (0.74–0.99)
		P-value = 0.042
GaleNA, 2008 [33]	Median (IQR) maternal 25(OH)D level = 50.0 (IQR: 30.0–75.3) nmol/L	Eczema (0–9 mo); OR (95%CI) N = 440	High maternal serum 25(OH)D level (>75 nmol/l) in 3rd trimester have a higher risk of atopic eczema in the first year of life.
	Q1: < 30 nmol/L (reference)	Q1: 1.0 (reference)
		Q2: 0.59 (0.14–2.50)
	Q2: 30–50 nmol/L	Q3: 0.79 (0.21–3.00)
	Q3: 51–75 nmol/L	Q4: 3.26 (1.15–9.29)
	Q4: > 75nmol/L

a Adjusted for maternal age, maternal pre-pregnancy body mass index, maternal education level, maternal history of eczema, allergy and asthma, parity, smoking, pet keeping, psychological distress, folate level, seasonal, gestational age at birth, birth weight, breastfeeding, vitamin D supplementation at the age 2 months.

b Adjusted for parity, gender, maternal smoking, and vitamin D supplementation.

c Adjusted for city, mother’s age, maternal history of allergy, pre-pregnancy body mass index, any smoking during pregnancy, any passive smoke exposure during the first 3 years of life, number of siblings, household income, newborn’s sex and weight, season of birth, and exclusive breast-feeding for 4 months or longer.

d Adjusted for child sex, number of siblings, cord blood total IgE, family history of atopy, breastfeeding, UV intensity of month of birth and vitamin D supplementation during the 1st year of life.

e Adjusted for season of birth, infant gender, pet ownership, maternal age and maternal ethnicity.

NA Not reported for adjusted cofounder.

+ 1ng/ml is equivalent 2.496 nmol/L.

N = study size n = number of cases.

Further, three studies addressed the association between cord blood 25(OH)D concentrations and the eczema outcome in the 12 months of life in infants [7, 39, 41]. Two studies reported that cord blood 25(OH)D concentrations were significantly contributed to the risk of eczema in the first 12 months of life in infants [7,41]. Both studies, Jones et al. (2012) and Palmer et al. (2015), used the established tool to assess the eczema outcomes. In contrast, Baiz et al. (2014) defined the outcome of eczema based on parental report did not find a significant association between cord blood 25(OH)D concentrations and the eczema outcome in the 12 months of life in infants. However, these three studies adjusted for family allergy history in their analyses [39, 41]. Detailed descriptions are available in Tables 2 and 4.

Vitamin D and wheezing in the first year (12 months) of life

Four studies reported the association between serum 25(OH)D concentrations and wheezing in the first year of life. They found that the wheezing outcome for all studies were based on parental reports. Two assessed 25(OH)D levels during pregnancy and two assessed 25(OH)D levels in cord blood [7, 34, 37, 39]. All were ranked as good (high) quality based on the NOS (Table 3). Morales et al. (2011) studied 1724 mother–child pairs in Spain and found no association between maternal serum 25(OH)D in early pregnancy and wheezing at the age of 1 year (P trend = 0.441). This was in line with Jone et al.’s (2012) findings using cord blood. On the contrary, Baiz et al. (2014) demonstrated that higher vitamin D concentrations in cord blood reduced the risk of wheezing in infants. De Jongh et al. (2014) assessed wheezing at two stages (0–6 months and 6–12 months). The risk of wheezing was reduced by 36% when mothers had less than 25.0 nmol/L of vitamin D concentrations (RR = 0.64 95% CI = 0.44–0.95; P = <0.0001). This was applied to 0-6-month-old infants, while no association was found among those aged 6–12 months. Detailed descriptions are available in Table 5.

Table 5

Studies included in the analysis of 25 (OH)D during pregnancy or cord blood with the development of wheezing in the first year (12 months) of life.

Author	Finding of serum 25(OH) D levels	Finding of the association	Conclusion
Baizc, 2014 [39]	Median (IQR) 25(OH)D cord blood level = 17.8 (IQR 15.1) ng/ml+	Wheezing at 1 year: N = 239	High levels cord blood 25(OH)D levels decreased the risk of wheezing at the age of 1 year.
		Adjusted OR (95% CI) in relation to 5 ng/ml+ rise 25(OH)D cord blood: = 0.67 (0.54–0.81)
		P-value < 0.001
De Jonghf, 2014 [37]	Median (IQR) maternal 25(OH)D level = 59.0 (40.6–84.3) nmol/L	RR (95% CI)	Low maternal serum 25(OH)D levels decreased the risk of wheezing at 0–6 months but not at 6–12 months.
	Q1: < 25 nmol/L	Wheezing (0–6 mo) n/N = 525/2021
	Q2: 25–49 nmol/L	Q1: 0.64 (0.44–0.95)
	Q3: 50–74 nmol/L	Q2: 0.72 (0.61–0.87)
	Q4: ≥75nmol/L (reference)	Q3: 0.96 (0.81–1.15)
		Q4: Reference
		P = 0.000
		Wheezing (6–12 mo) n/N = 601/1946
		Q1: 1.10 (0.80–1.52)
		Q2: 1.21 (1.03–1.43)
		Q3: 1.17 (0.98–1.39)
		Q4: Reference
		P = 0.163
Jonese, 2012 [7]	Mean (SD) 25(OH)D cord blood level = 58.4 (SD, 24.1) nmol/L	Wheezing at 1 year: N = 231	No risk of wheezing related to cord blood 25(OH)D concentrations at the age of 1 year.
		Adjusted OR (95% CI) in relation to 10 nmol/L rise 25(OH)D cord blood:
		1.00 (0.98–1.01)
		P-value = 0.731
Moralesg, 2012 [34]	Median (IQR) maternal 25(OH)D level = 29.5 (22.5–37.1) ng/ml+	Wheezing (0–1 y); (N = 1724)	No association between maternal serum 25(OH)D levels in early of pregnancy and the risk of wheezing in the first year of life.
	Q1: < 21.9 ng/ml+ (reference)	Adjusted OR (95% CI)
		Q1: 1.0 (reference)
	Q2: 21.9–29.1 ng/ml+	Q2: 1.04 (0.78–1.40)
	Q3: 29.2–37.0 ng/ml+	Q3: 0.96 (0.71–1.29)
	Q4: >37.0 ng/ml+	Q4: 0.91 (0.67–1.23)
		P trend = 0.441

c Adjusted for city, mother’s age, maternal history of allergy, pre-pregnancy body mass index, any smoking during pregnancy, any passive smoke exposure during the first 3 years of life, number of siblings, household income, newborn’s sex and weight, season of birth, and exclusive breast-feeding for 4 months or longer.

f Adjusted for child sex, birth weight, and gestational age, maternal age, maternal education level, parity, ethnicity, breastfeeding duration, maternal smoking in pregnancy and maternal pre-pregnancy body mass index.

e Adjusted for season of birth, infant gender, pet ownership, maternal age and maternal ethnicity.

g Adjusted for child sex, maternal education level, siblings at birth, breastfeeding duration, maternal smoking in pregnancy, day-care attendance, maternal asthma and maternal pre-pregnancy body mass index.

+ 1ng/ml is equivalent 2.496 nmol/L.

N = study size; n = number of cases.

Vitamin D and respiratory tract infections in the first year (12 months) of life

Six articles addressed the relationships between serum 25(OH)D concentrations and respiratory infections in the first year (12 months) of life. Four studies assessed 25(OH)D during pregnancy, and two assessed 25(OH)D in cord blood [33, 34, 36, 37, 40, 41]. Among the four studies that measured 25(OH)D during pregnancy, one assessed early pregnancy [34], and the rest in late pregnancy (28–42 weeks of gestation) [33, 36, 37]. Overall, the findings showed inconsistent results. Three studies did not show any association between vitamin D levels and respiratory infections [33, 37, 41]. However, Gale et al. (2008) found that children whose mothers were in the top quarter (of vitamin D level) were more likely to have been diagnosed with pneumonia or bronchiolitis than those whose mothers were in the bottom quarter (OR = 4.80, 95% CI = 1.01–22.73). In contrast, De Jongh et al. (2014) reported that mothers with serum 25(OH)D less than 50 nmol/L reported fewer lower respiratory infections in their children aged 0–6 months compared to mothers with serum 25(OH)D level more than 75nmol/L. However, the result may be attributable to residual confounding [37]. Nevertheless, both studies were ranked as ‘high quality’ using the NOS [33, 37].

The remaining three studies demonstrated associations between serum 25(OH)D concentrations and risks of respiratory infections in the first year of life [34, 37, 40]. Morales et al. (2011) reported that higher circulating maternal 25(OH)D concentrations in early pregnancy led to lower risks of LRTI. This corroborated the findings of Camargo et al. (2011) which measured cord blood 25(OH)D levels. Similarly, Skowronska-Jozwiak et al. (2014) found that vitamin D deficiency in late pregnancy increased the risks of respiratory infections (P = 0.003). Detailed descriptions are available in Table 6.

Table 6

Studies included in the analysis of 25 (OH)D during pregnancy or cord blood with the development of RTIs in the first year (12 months) of life.

Author	Finding of serum 25(OH) D levels	Finding of the association	Conclusion
Palmerb, 2015[41]	Mean (SD) 25(OH)D cord blood level = 57.0 (24.1) nmol/L	RTIs at 1 year (n/N = 45/267)	No association between 25(OH)D cord blood levels and RTIs at the age of 1 year.
		Adjusted RR (95% CI) in relation to 10nmol/L rise 25(OH)D cord blood = 1.07 (0.97–1.18)
		P-value = 0.18
Skowrońska-JóźwiakNA, 2014 [36]	Mean (SD) maternal 25(OH)D level = Not reported	RTIs (0–1 y) (N = 102)	Maternal 25(OH)D deficiency in 3rd trimester may increase the risk of respiratory infections in the first year of life.
	Deficient = <20.0 ng/ml+	>30.0 ng/ml+ vs <20.0 ng/ml+
		P = 0.003
	Insufficient = 20.0–30.0 ng/ml+
	Sufficient > 30.0 ng/ml+	>30.0 ng/ml+ vs 20.0–30.0 ng/ml+
		P = 0.004
		20.0–30.0 ng/ml+ vs < 20.0 ng/ml+
		P = 0.200
De Jonghf, 2014 [37]	Median (IQR) maternal 25(OH)D level = 59.0 (40.6–84.3) nmol/L	LRTI (0–6 mo)	Low maternal serum 25(OH)D levels decreased the risk of LRTI at 0–6 months but not at 6-12months.
		n/N = 288/2021
	Q1: < 25 nmol/L	Q1: 0.45 (0.24–0.84)
	Q2: 25–49 nmol/L	Q2: 0.63 (0.49–0.81)
	Q3: 50–74 nmol/L	Q3: 0.76 (0.58–0.99)
	Q4: ≥75nmol/L (reference)	Q4: Reference
		P = 0.000
		LRTI (6–12 mo) n/N = 368/1946
		Q1: 1.11 (0.72–1.71)
		Q2: 1.22 (0.97–1.54)
		Q3: 1.12 (0.87–1.42)
		Q4: Reference
		P = 0.155
Moralesg, 2012 [34]	Median (IQR) maternal 25(OH)D level = 29.5 (22.5–37.1) ng/ml+	LRTI (0–1 y) (N = 1693)	Higher maternal 25(OH)D concentrations in early of pregnancy decreased the risk of LRTI in the first year of life.
	Q1: < 21.9 ng/ml+ (reference)	Adjusted OR (95% CI)
		Q1: 1.0 (reference)
	Q2: 21.9–29.1 ng/ml+	Q2: 0.89 (0.67–1.19)
	Q3: 29.2–37.0 ng/ml+	Q3: 0.92 (0.70–1.23)
	Q4: >37.0 ng/ml+	Q4: 0.67 (0.50–0.90)
		P trend: 0.016
Camargoh, 2010 [40]	Median 25(OH)D cord blood (IQR) nmol/L	RTIs (0–1 y); n = 553	High levels 25(OH)D cord blood decreased the risk of RTIs among infants in the first year of life.
	N = 922: 44 (29–78) nmol/L	OR (95% CI)
	n = 180; <25.0 nmol/L: 19 (14–22) nmol/L
		<25.0 nmol/L: 2.04 (1.13–3.67)
		25.0–74.0 nmol/L: 2.16 (1.35–3.46)
	n = 491; 25.0–74.0 nmol/L: 41 (34–53) nmol/L
		≥75.0 nmol/L: reference
	n = 251≥75.0 nmol/L: 100 (87–124) nmol/L	P for trend: 0.030
GaleNA, 2008 [33]	Median (IQR) maternal 25(OH)D level = 50.0 (IQR: 30.0–75.3) nmol/L	LRTIs (pneumonia /Bronchiolitis);	Higher maternal serum 25(OH)D levels increased the risk of LRTIs BUT no association was seen in RTIs in the first year of life.
		(0–9 mo) N = 440
	Q1: < 30 nmol/L (reference)	OR (95%CI)
	Q2: 30–50 nmol/L	Q4: 4.80 (1.01–22.73)
	Q3: 51–75 nmol/L	Other quarters not reported.
	Q4: > 75nmol/L	Chest infections, Bronchitis/respiratory infections—reported no significant association—result not shown.

b Adjusted for parity, gender, maternal smoking, and vitamin D supplementation.

NA Not reported for adjusted cofounder.

f Adjusted for child sex, birth weight, and gestational age, maternal age, maternal education level, parity, ethnicity, breastfeeding duration, maternal smoking in pregnancy and maternal pre-pregnancy body mass index.

g Adjusted for child sex, maternal education level, siblings at birth, breastfeeding duration, maternal smoking in pregnancy, day-care attendance, maternal asthma and maternal pre-pregnancy body mass index.

+ 1ng/ml is equivalent 2.496 nmol/L.

h Adjusted for season of birth plus 14 potential confounders (study site, maternal age at birth, New Zealand Deprivation Index, maternal history of asthma, paternal history of asthma, gestational age, gender, child’s ethnicity, any smoking during pregnancy, any passive smoke exposure at 3 months of age, number of children younger 16 years in household at the time the child was 3 months old, endotoxin on bedroom floor at the time the child was 3 months old [in quartiles], damp musty smell in any room of home at the time the child was 3 months old, and duration of exclusive breastfeeding). NA Not reported for adjusted cofounder. N = study size; n = number of cases.

Discussion

This systematic review identified ten studies examining the associations between vitamin D concentrations (during pregnancy and at birth), allergic conditions (i.e., eczema and wheezing) and RTIs in the first year of life. Overall findings demonstrated no consistent associations, as results were mixed. The amount of existing research and evidence is rather limited, and comparisons across studies remains a challenge given the different timing and tools of assessment.

All the studies included in this review were conducted in high-income Western countries. None were from Asian countries. Three studies reported that the average vitamin D concentrations in pregnancy or at birth were deficient, whereas the remaining studies (seven studies) reported insufficient and sufficient (the majority were in the insufficient group). Serum vitamin D is preferable to determine individuals’ vitamin D levels instead of dietary vitamin intake alone as it represents the cumulative effect of vitamin D dietary intake and sun exposure [29, 42].

Further, many studies reported that populations living with insufficient sunshine either most of the year or at least one month (higher latitudes; western countries) have a high risk of vitamin D deficiency [43-45]. This deficiency is probably due to inadequate sun exposure; a major source of vitamin D. Nevertheless, studies in Asian countries (have sun exposure most of the time) reported a high prevalence of vitamin D deficiency in all age groups including children and pregnant women [46-50]. The high prevalence of vitamin D deficiency in Asian countries was probably due to clothing styles (wearing a full dress) and ethnicity [46]. These portrayed that the vitamin D concentrations are a biomarker of sun exposure rather than being the active molecule that is being studied. Although other molecules activated by the sun may confer benefits, the literature on this is scarce probably due to difficulties in analyses as it depends on the scale of the study, budget and ethical considerations. Also, there is a lack of studies in differentiating active and non-active molecules of vitamin D.

Association between serum vitamin D concentrations in pregnancy and eczema in the first year (12 months) of life

As mentioned earlier, the comparison of results across studies in this review was difficult. Among the reasons were differences in the timing of vitamin D measurement and the lack of adjustment for similar confounders, such as parental allergy history. Throughout pregnancy, vitamin D levels could fluctuate as a result of various factors (e.g., morning sickness, limited outdoor activity and supplement intake) [43]. Therefore, vitamin D levels measured at a single period point (e.g., first trimester) may not represent the actual serum pregnancy level. It is thus difficult to ascertain whether optimal vitamin D level in pregnancy for the investigated outcomes is a risk or vice versa. On the other hand, parental allergy history should be taken into account during analysis because the tendency to develop allergies is often genetic, with heritability estimates varying between 71% and 84% [51-53]. Although genome-wide association studies (GWAS) and meta-analyses of GWAS have begun to shed light on both common and distinct pathways that contribute to allergic diseases, genetic components were acknowledged to play a role in the pathophysiology of allergic eczema [54, 55].

Association between serum vitamin D concentrations in pregnancy and wheezing in the first year (12 months) of life

Our findings showed a lack of consistent data addressing the association between serum vitamin D concentrations in pregnancy and wheezing in the first year (12 months) of life. This contradicted a recent meta-analysis that reported no association between early life vitamin D levels and the risk of wheezing in later life [4]. Nevertheless, a number of earlier studies suggested that higher vitamin D levels in pregnancy lower the risk of wheezing during childhood [24, 27, 56]. In comparison, our review showed inconsistent findings. The potential explanation for this discrepancy, first, could be due to the differences in sample age; we focused on infants aged one year and younger while prior reviews included children between 0–7 years in which the huge age scale may dilute some information subsequently affected the outcome findings among infants population. Second, the serum 25(OH)D levels in studies were measured at different times points and measured only once. The inconsistency in the measurement time point might introduce errors in exposure assessment, but out of 4, 3 studies in this review measured at late pregnancy (at 34 weeks of gestation and birth (cord blood), thus the measurement timing should not substantially bias our findings. Nevertheless, measured 25(OH)D levels only once might not adequately reflect the long-term exposure and might attenuate any possible association of not only wheezing but also other interest in this study (eczema and RTIs) in the first year (12 months) of an infant’s life.

Association between serum vitamin D concentrations and respiratory tract infections in the first year (12 months) of life

Earlier systematic reviews indicated a protective role of vitamin D in early life against RTIs, where inverse associations were found between vitamin D levels and RTIs among infants [24, 27]. However, current findings did not support this due to several possible explanations. Firstly, the current review focused on infants aged 0–1 year, while prior reviews included a wider age-range (e.g. 0 to 7 years). In order to know whether it is more beneficial to prescribe vitamin D earlier (e.g. during pregnancy) or later (e.g. postnatal period or infants) as a form of intervention, a more focused age group (e.g. infants one year and younger) is needed. This evidence seems to be important as it has implications on health policy and clinical practice. Secondly, the outcome of RTIs in all studies was reported by parents in which the likelihood of misclassification could occur for example parents might report wheezing as respiratory infections while wheeze can also be associated with allergic conditions [57].

Strengths and limitations of this review

This review has several strengths. First, it was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Second, most studies were rated as good (high) quality—except for one—based on the NOS assessment for cohort studies. Third, our review focused on children aged 12 months and younger. By narrowing down the age range, we reduced the discrepancies of magnitude and latitude of other variables which may affect the outcomes. Accordingly, it could also more closely reflect the importance of vitamin D in utero exposure on the extra-skeletal health of children, in this context, infant allergy and respiratory infections. Fourth, vitamin D level is measured by objective biomarker (maternal or cord serum) in which it reflects the cumulative vitamin D obtained from diet and sun exposure.

Meanwhile, the main limitation of this review was that some outcomes, such as respiratory infections were based on parental reports. This could have caused bias given that self-reports are not always accurate compared to established tools or medical diagnoses. In addition, all studies involved performed single and not repeated measurements, which may not truly represent the vitamin D levels throughout the entire course of pregnancy. Likewise, all selected studies were derived from Western, high-income and mainly Caucasian populations. Lastly, we did not assess or analyse the heterogeneity of tools and timing across selected studies beyond mere description.

Conclusion

Overall, evidence on the impacts of vitamin D exposure in utero and in cord blood on the risks of eczema, wheezing and respiratory infections in the first year (12 months) of life is equivocal and inconclusive. This systematic review highlighted that existing data on maternal vitamin D concentrations and eczema, wheezing, and respiratory infections among infants aged 12 months and younger are limited, with no study representing the Asia Pacific region. To form a better understanding and enable a more robust scientific conclusion, more studies using appropriate and comparable methodologies are needed. These include employing randomised control trials or cohort study design with a larger sample size, and measuring the outcomes based on medical diagnoses or established clinical tools to ensure accuracy. In addition, study subjects should comprise a more specific and targeted age group. Measuring vitamin D at multiple period points (instead of single measurement) with appropriate statistical analyses will provide a better understanding of the relationship between the exposure and outcome. Future studies on the role of vitamin D in pregnancy and the early postnatal period in the aetiology of eczema, wheezing and RTI in infants are needed particularly in the Asia Pacific region, as the incidence of infant allergies and respiratory infections is on the rise. Therefore, future intervention study requires a robust study design and appropriate evaluation.

This table shows the search terms used for PubMed, MEDLINE, ProQuest, Scopus, CINAHL, the Cochrane Library and Academic Search Premier.

(PDF)

Click here for additional data file.

This table shows the PRISMA checklist.

(PDF)

Click here for additional data file.

7 Nov 2019

PONE-D-19-24730

Maternal vitamin D status during pregnancy and the risk of eczema, wheezing and respiratory tract infections in the first year of life: a systematic review

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Reviewer #1: “Maternal vitamin D status during pregnancy and the risk of eczema, wheezing and respiratory tract infections in the first year of life: a systematic review”

The current study aims to systematically review the literature published until March 2019 on maternal vitamin D status in pregnancy and the development of eczema, wheezing and respiratory tract infections in the offspring within the first year of life. Although the literature search is comprehensive and includes a large number of databases, the rationale for the review in the context of previous studies is unclear, and the presentation of results is not reader friendly. The study also includes studies of cord blood vitamin D, which is not reflected in the title or objectives.

Major comments

The introduction should reflect more strongly that this is a systematic review. Previous reviews and meta-analysis on the current topic need to be summarized and referenced before they appear in the Discussion (refs 26, 43, 44), and there should be a clear description of what the current study contributes. The focus on RTI in the Asia-Pacific region creates some expectations that this review will add evidence from non-western populations, but this does not seem to be the case. It is unclear why the atopic march is brought up, as the current study is limited to infants < =12 months. Greater emphasize could be placed on the potential role of maternal vitamin D status in the etiologies of eczema, wheezing and RTI in the offspring.

Also, the introductory description of the occurrence and time trends in eczema, wheezing and RTI in infants should be more precise with an appropriate choice of references, e.g. references 1 and 2 seem a bit arbitrary (USA) or old (WHO) for documenting the current situation. Judging from the titles, references 3-5 to do not appear to be primary sources of data showing an increase in the rates of over time. General statements such as “…54.7% have been diagnosed with RTIs in early life” is supported by a study from a regional hospital in Cameroon, which is insufficient. The reference list is incomplete with several journal names missing, so revision is needed.

Search strategy and PICOS criteria (Table 1): the objective of the study is to review literature on maternal vitamin D status, but 4 of 10 included studies have assessed vitamin D status in cord blood. The title/scope/Table 1 PICOS statement and study selection criteria could be changed to reflect the inclusion of studies of vitamin D status measured at birth, or these 4 studies should be excluded from the paper. The PICOS statement for “outcome” should include children and age group.

Search terms (Table S1): It seems that the literature search could have been more targeted by including terms for pregnancy, infants or human studies (ref Table S1 PICO). The very broad search may explain why so few studies (10 of 2678 records) were included in the end. It is unclear if search terms were MeSH and/or text words, and why vitamin D deficiency, but not excess (which has also been associated with the outcomes of interest) was included, or chemical forms of vitamin D.

Data extraction (line 131): data on the adjustment for maternal confounders other than parental history should also be extracted and considered when interpreting results and inconsistencies, e.g. were results adjusted for other nutrients of potential importance (e.g. fatty acids or folate) as referenced papers seem to indicate.

Results/study characteristics: it would be helpful if the summary included number of studies vs publications for each outcome, and how these outcomes were assessed (e.g. maternal report or clinical diagnosis) before describing ethnicity of the study populations.

Results in text: reference category needs be mentioned when reporting relative-risk estimates.

Results: Table 2 does not seem space efficient, or reader friendly. Maybe better if split into 2 tables (separate for study characteristics and results where similar outcomes are grouped together)

Results/vitamin D status (line 180-182): a mean value of 14 nmol/L seems unlikely, please verify.

Minor comments:

Results: information regarding exclusion criteria in first paragraph is better suited under Methods.

Results: Some parts of the Table 2 is confusing and may have errors. It seems that LRTI at 15 months is included (Camargo et al 2010) although the study selection criteria is <= 12 months.

Under summary statistics for exposure, what is meant by “(Median 25(OH)D cord blood (IQR) nmol/L = n; 922”?

Abstract: unclear what level of maternal vitamin D that seems to be protective (line 36-37). Also not possible to conclude that evidence is inconsistent due to low number of studies.

Line 189-190: unclear definitions

Line 184: incomplete sentence

Reviewer #2: Overall this is an excellent piece of work and that helps to answer an important question. I think the methodology is in keeping with best practice, and the manuscript is largely well written with appropriate conclusions drawn from the results. The main reason for "major revision" is that I feel there should be assessment and reporting of how outcomes were defined/measured in the the methods and results section. As the authors state in the discussion, this can significantly impact the results and as such should be discussed. If that was adjusted, in addition to some other minor points below, then I would think the manuscript would be ready for publication.

Please see more specific feedback below;

Abstract;

- Clear and well written

Introduction

- The paragraph that begins Page 3, Line 58 is confusing. The paragraph starts with a description of the “atopic march” concept, and then says “similar patterns were observed in RTI cases”. However RTI cases in early life do not lead to more severe persistent RTI cases in later life, so I do not think there is a similar pattern to atopic march.

I think what the authors are trying to say is that atopic disease and RTI are both common in early life, and important causes of morbidity as atopic disease can “march” on to more severe, persistent atopic disease and RTI is a leading cause of hospital admission. If so, I agree with that, but I think the paragraph needs reworking.

- This is a minor point, but the final paragraph of the introduction would have more of an impact of it consisted of the 2 sentences. The one the starts “to this day …” (page 4, line 82) and “this systematic review aimed …” (page 4 line 85). The points re importance of measuring serum vitamin D rather than dietary is important and valid, but could be worked into the previous paragraph.

Methods

- well done

- clear question, followed best practice, registered prospectively

- Please reference the table with the search terms in the data sources paragraph so that readers know it is available.

- assessment of definition of each outcome is important as this is a potential source of heterogeneity (i.e was eczema /wheezing/RTI parent report, doctor diagnosed, or assessed by the trial team)

Results

- Please reference the PRISMA diagram at the start of the results section, so that readers know that is available for them to look at. Same for PRISMA checklist

- need to incorporate comment on how each outcome was assessed. See feedback above

Discussion

- minor point; page 22, line 261 “- when put together-“ would be better to have “,” rather than “-“ (i.e , when put together,)

- page 23, line 280; It would be good to briefly outline what the results of prior systematic reviews are, that this review contradicts

- page 23, line 283; matured should be mature

- page 23, line 284; there is a full stop missing before “Second”

- page 23, line 285; this is an important point (method of outcome assessment) but should not be mentioned for the first time here. It should be incorporated into both methods and results.

Conclusion

- Page 24; Line 314; Include examples of what more appropriate and comparable methodologies would include (i.e multiple measurements of vitamin D, with statistical analysis involving … and outcomes assessed …)

Reviewer #3: This is a well written perspective that discusses the evidence for maternal vitamin D levels controlling the incidence of eczema, wheezing and respiratory tract infections in infants before one year of life. The maternal levels were measured at times ranging from during the first trimester to ‘at birth’ with measures in the cord blood. Vitamin D levels from a single sample were sometimes published as absolute amounts but in other studies only defined into categories. Another limitation was that some outcomes were based on parental reports and were not necessarily nurse or doctor defined. Ten studies were scrutinised in full, all of which included primarily western/Caucasian populations. Measures of maternal vitamin D were considered as a possible determinant of infant eczema, wheezing or respiratory tract infections; the discussion for this study did not consider vitamin D levels of the infant per se as a possible contributor to allergic outcomes. Perhaps vitamin D deficiency during the first year of life is as important as the level before birth.

The review is informative and suggests that no robust association between maternal vitamin D and infant allergy exists. If an effect exists, it is minor and can be detected only inconsistently in studies. It will be interesting if the authors perform a similar analysis in the Malaysian population; such a study would be very informative due to the latitude of Malaysia and the Malaysians recruited to the study will have obtained their vitamin D levels from significant sun exposure. Many of the other studies reported included populations living at higher latitudes. As inferred in line 89, there is a growing awareness that vitamin D levels are a biomarker of recent sun exposure rather than being the active molecule in the condition under study. Any association of vitamin D levels with a condition cannot infer that vitamin D is the causal molecule. Instead, other sun-induced molecules may be responsible for the benefit found. In a revised manuscript, this argument should be included in the Discussion.

Line 151, remove with.

Line 184, something is missing, Three what?

Line 280, references are required for the prior systematic reviews.

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Reviewer #1: No

Reviewer #2: Yes: Shivanthan Shanthikumar

Reviewer #3: No

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19 Dec 2019

“Author Response”

We would like to express our sincere gratitude to the esteemed reviewers for their useful comments. We have now revised the manuscript according to the reviewers’ suggestions, and sincerely hope that the manuscript is now suitable for publication in Plos One.

Editor Comments

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

Thank you for highlighting this. We had amended it accordingly.

2. *Please include in your methods section, the dates included in your search and the dates during which you performed your search.

The information that is requested already been updated in method section; Line 104-106

“The following databases were used to search for studies published until March 31, 2019; PubMed, MEDLINE,

ProQuest, Scopus, CINAHL, the Cochrane Library and Academic Search Premier. This search was performed on May 1,

2019.”

3. *Please explain whether you assessed the heterogeneity of the manuscripts.

Thank you for pointing that out. We did not use any scoring to assess heterogeneity. However, from the definition of

outcomes evaluation, assessment for heterogeneity is by evaluating the 10 papers ( 8 studies reported the

measurement of the outcomes were by parental reported and only 2 reported using established scoring tool. Hence

because of that, we updated as limitation.

Comments from Reviewer 1

1. The current study aims to systematically review the literature published until March 2019 on maternal vitamin D status in pregnancy and the development of eczema, wheezing and respiratory tract infections in the offspring within the first year of life. Although the literature search is comprehensive and includes a large number of databases, the rationale for the review in the context of previous studies is unclear, and the presentation of results is not reader friendly. The study also includes studies of cord blood vitamin D, which is not reflected in the title or objectives.

Thank you for pointing that out. We appreciate the reviewer comments and we have revised some sentences, words,

title and objectives of the review. We have amended the title; “Risk of eczema, wheezing and respiratory tract

infections in the first year of life: a systematic review of vitamin D concentrations during pregnancy and at birth”

We also have updated the amendment and revision to PROSPERO with registration no. CRD42018093039.

2. The introduction should reflect more strongly that this is a systematic review.

We acknowledged your input and the introduction had been revised accordingly to show this is a systematic review.

3. Previous reviews and meta-analysis on the current topic need to be summarized and referenced before they appear in

the Discussion (refs 26, 43, 44), and there should be a clear description of what the current study contributes.

Thank you for pointing that out. The information have been added accordingly in the introductory section; Line 71-

75. “To this day, it is still unclear to what extent the vitamin D levels during pregnancy or early postnatal (e.g, cord

blood) affects the development of allergic diseases and RTIs in infants. Prior reviews have included a wide range of

age while assessing allergic diseases and RTI outcomes (e.g 0 to 5 years old), and employed different methods in

vitamin D measurement; serum 25(OH)D and dietary intake (4, 23, 26).

4.The focus on RTI in the Asia-Pacific region creates some expectations that this review will add evidence from non-western populations, but this does not seem to be the case.

Thank you for highlighting this. It would be a good input if studies had been conducted in Asia Pacific region. We did

not found any. A study conducted in Japan had to be excluded as had met our exclusion criteria.

5. It is unclear why the atopic march is brought up, as the current study is limited to infants < =12 months.

Thank you for pointing that out. We take note it and we had removed it.

6. Greater emphasize could be placed on the potential role of maternal vitamin D status in the etiologies of eczema, wheezing and RTI in the offspring.

Thank you for highlighting this. Noted that vitamin D has potential role in bone’s health, other musculoskeletal health

such as rickets, cardiovascular disease, diabetes and certain cancers. However it is not strong enough to show the

association of high vitamin levels and the eczema status. Thus we could not put a greater emphasize literature on this

issue.

7. Also, the introductory description of the occurrence and time trends in eczema, wheezing and RTI in infants should be more precise with an appropriate choice of references, e.g. references 1 and 2 seem a bit arbitrary (USA) or old (WHO) for documenting the current situation. Judging from the titles, references 3-5 to do not appear to be primary sources of data showing an increase in the rates of over time. General statements such as “…54.7% have been diagnosed with RTIs in early life” is supported by a study from a regional hospital in Cameroon, which is insufficient.

Thank you for highlighting this. We had removed that points and we had amended it.

8. The reference list is incomplete with several journal names missing, so revision is needed.

Thank you for pointing that out. We had revised and had corrected it.

9. Search strategy and PICOS criteria (Table 1): the objective of the study is to review literature on maternal vitamin D status, but 4 of 10 included studies have assessed vitamin D status in cord blood. The title/scope/Table 1 PICOS statement and study selection criteria could be changed to reflect the inclusion of studies of vitamin D status measured at birth, or these 4 studies should be excluded from the paper. The PICOS statement for “outcome” should include children and age group.

Thank you for the reviewer comment and suggestion. We had revised it and had made necessary changes. We have

amendment the title and had been changed accordingly. The title/scope/Table 1 PICOS statement and study selection

criteria had been updated and had amended in PROSPERO.

10. Search terms (Table S1): It seems that the literature search could have been more targeted by including terms for pregnancy, infants or human studies (ref Table S1 PICO). The very broad search may explain why so few studies (10 of 2678 records) were included in the end.

Thank you for the suggestion. We used a larger search term to ensure we did not miss the evidence by specifically.

Having specific search term, we afraid it may reduce paper that will be selected.

11. It is unclear if search terms were MeSH and/or text words, and why vitamin D deficiency, but not excess (which has also been associated with the outcomes of interest) was included, or chemical forms of vitamin D.

Thank you for pointing that out. We used MESH term and this had already explicitly in line 109-111.

12. Data extraction (line 131): data on the adjustment for maternal cofounders other than parental history should also be extracted and considered when interpreting results and inconsistencies, e.g. were results adjusted for other nutrients of potential importance (e.g. fatty acids or folate) as referenced papers seem to indicate.

Thank you for highlighting this. we had added in the table result accordingly.

13. Results/study characteristics: it would be helpful if the summary included number of studies vs publications for each outcome, and how these outcomes were assessed (e.g. maternal report or clinical diagnosis) before describing ethnicity of the study populations.

Thank you for highlighting this. The information that is required already been updated. “Methods of outcome

assessment were diverse. Most studies relied on parental reports (n=8 studies) while some used standardized tools

(n=2 studies). The two tools used to determine eczema were the ‘SCORing Atopic Dermatitis’ (SCORAD) index (7)

and the modified version of the UK Working Party’s diagnostic criteria (35).

14. Results in text: reference category needs be mentioned when reporting relative-risk estimates.

Thank you for highlighting this. The information that is required already been updated.

15. Results: Table 2 does not seem space efficient, or reader friendly. Maybe better if split into 2 tables (separate for study characteristics and results where similar outcomes are grouped together)

Thank you for highlighting this. We appreciate the reviewer suggestion and we have simplified the table accordingly.

15. Results/vitamin D status (line 180-182): a mean value of 14 nmol/L seems unlikely, please verify.

Thank you for pointing that out. We take note it and had revised and made necessary changes. Line 186-187.

“The average concentration of serum 25(OH)D during pregnancy ranged 50.0 to 73.6 nmol/L and early postnatal (in

cord blood) ranged from 44.0 to 58.4 nmol/L.”

16. Results: information regarding exclusion criteria in first paragraph is better suited under Methods.

Thank you for the reviewer comment. The information has been removed and changes has been made accordingly in

Method section.

17. Results: Some parts of the Table 2 is confusing and may have errors. It seems that LRTI at 15 months is included (Camargo et al 2010) although the study selection criteria is <= 12 months.

Thank you for pointing that out. Thank you for the reviewer comment. The information had been removed and

changes has been made accordingly.

18. Under summary statistics for exposure, what is meant by “(Median 25(OH)D cord blood (IQR) nmol/L = n; 922”?

Thank you for pointing that out. The information had been added.

19. Abstract: unclear what level of maternal vitamin D that seems to be protective (line 36-37). Also not possible to conclude that evidence is inconsistent due to low number of studies.

Thank you for pointing that out. We had revised and had made necessary changes accordingly. Line 39-42

“Studies on the associations between vitamin D concentrations during pregnancy and at birth and the mentioned

outcomes among infants were found limited. Nevertheless, there is conflicting evidence showing the risk of eczema,

wheezing and RTIs with vitamin D concentration in early life.”

20. Line 189-190: unclear definitions

Thank you for pointing that out. We have gone through and make necessary changes. Line 193 – 196.

“In determining the associations between exposure (vitamin D concentrations during pregnancy or early postnatal)

and outcomes (allergic eczema, wheezing or RTIs), some studies used quartiles and quintile while some employed

cut-off values with different presentation of vitamin D concentration categorizations, such as deficient (25.0-40.0, <

50.0 nmol/L),…”

21. Line 184: incomplete sentence

Thank you for pointing that out. The information had been added. Line 190-191. “Three studies reported mean and

standard deviation for the serum 25(OH)D results…”

Comments from Reviewer 2

1. Overall this is an excellent piece of work and that helps to answer an important question. I think the methodology is in keeping with best practice, and the manuscript is largely well written with appropriate conclusions drawn from the results.

The main reason for "major revision" is that I feel there should be assessment and reporting of how outcomes were defined/measured in the methods and results section. As the authors state in the discussion, this can significantly impact the results and as such should be discussed. If that was adjusted, in addition to some other minor points below, then I would think the manuscript would be ready for publication.

Thank you for pointing that out. We appreciate the reviewer suggestion and we have corrected and make necessary

changes. The outcomes were defined as in Line 162 – 165.

2. Abstract - Clear and well written

Thank you for the comment.

3. Introduction:

- The paragraph that begins Page 3, Line 58 is confusing. The paragraph starts with a description of the “atopic march” concept, and then says “similar patterns were observed in RTI cases”. However RTI cases in early life do not lead to more severe persistent RTI cases in later life, so I do not think there is a similar pattern to atopic march. I think what the authors are trying to say is that atopic disease and RTI are both common in early life, and important causes of morbidity as atopic disease can “march” on to more severe, persistent atopic disease and RTI is a leading cause of hospital admission. If so, I agree with that, but I think the paragraph needs reworking. This is a minor point, but the final paragraph of the introduction would have more of an impact of it consisted of the 2 sentences. The one the starts “to this day …” (page 4, line 82) and “this systematic review aimed …” (page 4 line 85).

Thank you for pointing that out. We have gone through and make necessary changes. We have removed the

information of “atopic march” paragraph. This has been amended and comment were incorporated in introduction

section (Line 58-62).

The points re importance of measuring serum vitamin D rather than dietary is important and valid, but could be worked into the previous paragraph.

Thank you for highlighting this. We had revised and had amended accordingly. Line 76- 79.

“Clinically, serum 25hydroxyvitamin D (25(OH)D) is used as a marker of vitamin D level because it represents the

cumulative effect of dietary intake of vitamin D and sunlight exposure (27). Thus, dietary intake alone might not be a

good indicator of overall vitamin D levels as ultraviolet B-rays induces skin formation of vitamin D.”

4. Methods

- well done

- clear question, followed best practice, registered prospectively

- Please reference the table with the search terms in the data sources paragraph so that readers know it is available.

- assessment of definition of each outcome is important as this is a potential source of heterogeneity (i.e was eczema /wheezing/RTI parent report, doctor diagnosed, or assessed by the trial team)

Thank you for the comment. We take note it and had referenced the table with the search terms as in line 111.

The description on how outcomes were assessed by the studies had been updated as in line 162– 165.

5. Results

- Please reference the PRISMA diagram at the start of the results section, so that readers know that is available for them to look at. Same for PRISMA checklist.

- Need to incorporate comment on how each outcome was assessed. See feedback above

Thank you for pointing that out.

We take note it and had referenced the PRISMA diagram at the start of the results section as stated in line 155 –

Figure 1. Figure 1 is the PRISMA diagram.

6. Discussion

- minor point; page 22, line 261 “- when put together-“ would be better to have “,” rather than “-“ (i.e , when put together,)

Thank you for pointing that out and the suggestion. We have corrected it. Line 294.

- page 23, line 280; It would be good to briefly outline what the results of prior systematic reviews are, that this review contradicts

Thank you for pointing that out. We have gone through and make necessary changes. Line 308-310.

“Previous reviews indicated a preventive role of vitamin D in early life against wheezing and RTIs; inverse

associations were found between vitamin D levels in early life and wheezing and/or RTIs among infants (23, 26).”

- page 23, line 283; matured should be mature

Thank you for pointing that out and the suggestion. We have corrected it.

- page 23, line 284; there is a full stop missing before “Second”

Thank you for pointing that out and the suggestion. We have corrected it.

- page 23, line 285; this is an important point (method of outcome assessment) but should not be mentioned for the first time here. It should be incorporated into both methods and results.

Thank you for pointing that out. We have gone through and make necessary changes. We added information of method of the outcome assessment in Result/study characteristic section. Line 163 – 171.

7. Conclusion

- Page 24; Line 314; Include examples of what more appropriate and comparable methodologies would include (i.e multiple measurements of vitamin D, with statistical analysis involving … and outcomes assessed …)

Thank you for pointing that out. We have gone through and added a few points. Line 354-359.

“These include employing randomized control trial or cohort study design with a larger sample size, and measuring

the outcomes based on medical diagnosis or established clinical tools to ensure its’ accuracy. In addition, the study

subjects should comprise a more specific and targeted age group….”

Comments from Reviewer 3

1. This is a well written perspective that discusses the evidence for maternal vitamin D levels controlling the incidence of eczema, wheezing and respiratory tract infections in infants before one year of life. The maternal levels were measured at times ranging from during the first trimester to ‘at birth’ with measures in the cord blood. Vitamin D levels from a single sample were sometimes published as absolute amounts but in other studies only defined into categories.

Noted with thanks.

2. Another limitation was that some outcomes were based on parental reports and were not necessarily nurse or doctor defined.

I agree with your comment and this is highlighted in our limitation section.

3. Ten studies were scrutinised in full, all of which included primarily western/Caucasian populations. Measures of maternal vitamin D were considered as a possible determinant of infant eczema, wheezing or respiratory tract infections; the discussion for this study did not consider vitamin D levels of the infant per se as a possible contributor to allergic outcomes. Perhaps vitamin D deficiency during the first year of life is as important as the level before birth.

The review is informative and suggests that no robust association between maternal vitamin D and infant allergy exists. If an effect exists, it is minor and can be detected only inconsistently in studies. It will be interesting if the authors perform a similar analysis in the Malaysian population; such a study would be very informative due to the latitude of Malaysia and the Malaysians recruited to the study will have obtained their vitamin D levels from significant sun exposure.

Your constructive suggestions is noted and the study among infant in Malaysia will be conducted in near future.

4. Many of the other studies reported included populations living at higher latitudes. As inferred in line 89, there is a

growing awareness that vitamin D levels are a biomarker of recent sun exposure rather than being the active

molecule in the condition under study. Any association of vitamin D levels with a condition cannot infer that vitamin D

is the causal molecule. Instead, other sun-induced molecules may be responsible for the benefit found. In a revised manuscript, this argument should be included in the Discussion.

Thank you for the suggestions. I agreed that potentially there are other molecule that is activated by sun that may

confer benefits. However the literature on this is scarce. Nevertheless, despite some countries at the equator and

have sun exposure most of time, the population/ the subject can also be at risk of vitamin D insufficiency due to the

clothing style as reported by recent study, Quah et al. (2018).

5. Line 151, remove with.

Thank you for pointing that out. We have removed “with”.

6. Line 184, something is missing, Three what?

Thank you for pointing that out. We have added the missing sentence.

7. Line 280, references are required for the prior systematic reviews.

Thank you for pointing that out. We take note it, and had added the references.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

12 Feb 2020

PONE-D-19-24730R1

Risk of eczema, wheezing and respiratory tract infections in the first year of life: a systematic review of vitamin D concentrations during pregnancy and at birth

PLOS ONE

Dear Dr Majid,

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Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Comments to paper after first revision:

Although the methodology for the literature search seems solid, the revised manuscript and presentation of results seem to suffer from typos, errors and inconsistencies and leaves an untidy impression. Also, it still remains unclear what the current study adds compared with the previous reviews and meta-analyses referenced (refs 4, 23, 26); e.g. does the current study include more studies on wheeze in infants than the meta-analysis from 2018 (ref 4) or do you summarize the evidence differently?

The authors argue that previous reviews have included vitamin D intake, but this is not a problem as long as vitamin D intake and vitamin D status are presented as separate analyzes, which is usually the case –without knowing these studies in detail. Regarding the age restriction of all outcomes (RTI, eczema, wheeze) to infants, the rationale for doing this should be made more clear, especially because the authors conclude that the literature is limited and the outcomes of eczema and wheeze also occur in children after the first year of life. Some arguments now mentioned in the Discussion, could be moved to the Introduction. However, for vitamin D there is still a chance that prenatal exposure may play a role, due to vitamin D supplement recommendations to infants in some countries, and the introduction of complementary feeding which may be enriched with vit D.

Major comments/

The study rationale could be refined some more.

The manuscript needs proof reading from the very beginning, a few examples include the Abstract (line 29 – duplicate words, missing commas; line 36 missing “in” or “during”) and Introduction (line 50, grammar). Clarity is affected in some places, e.g. in the Introduction (line 57) – it is unclear if “allergy eczema” should read “allergy and eczema” or “allergic eczema”. There are now 2 tables labelled “Table 3”, including the second page of Table 2, which should be corrected.

The paper is currently missing some information on outcome definitions as part of the inclusion/exclusion criteria. What types of eczema, wheeze, and RTI were included in the analysis and how were the outcomes assessed? Results on eczema (Table2/Table 3) seem to be presented for both eczema and atopic eczema, and RTI (Table 5) seems to include several types, including LRTI (pneumonia/bronchiolitis), URTI, recurrent RTI, as well as symptoms of cough. Now the information is briefly mentioned in the Discussion (line 286, 287). Unclear why ”Pregnancy outcomes” are mentioned in Table 2/3 (ref 38).

Tables have improved, but the information seems to be provided in an inconsistent manner. If the information was not available, it should be explained somewhere. The conclusion should preferably reflect the conclusions of the authors of the review (not the conclusions found in the papers), and be reported in a similar manner for all papers to the extent possible.

Taking Table 3 as an example:

Gale et al: no sample size provided, sig results for Q4 not marked in bold (but some results marked in bold in Table 4)

Weisse et al: no sample size provided, unclear if adj ORs refer to highest vs. lowest category

Gazibara et al. unclear if “n” refers to no. of cases or study size

Baiz et al. sample size provided twice (n=239), unclear if the reported OR is per nmol/L of vitamin D or if exposure categories are missing

Summary of results: it is hard to follow at times. The authors could consider summarizing the number of studies reporting no/positive/negative associations for each outcome.

Discussion/Vit D & RTI: although sex of the child may affect the risk of RTI, sex is not expected to be associated with maternal vit D status or vit D status at birth, and therefore not a confounder by the usual definition. Thus, lack of adjustment for sex should not be considered a weakness of studies.

Minor comments

Reference no. 9 to document prevalence (lines 52, 56), is based on mathematical modelling and not original data, which should be stated explicitly

Table 4: could go in the supplement with Table S3

Tables 3-5 titles: Suggest changing for better clarity from “Studies included in the analysis between 25 (OH)D during pregnancy and cord blood and the development of … in the first year (12 months) of life” to “Studies included in the analysis of 25 (OH)D during pregnancy or cord blood with the development of … in the first year (12 months) of life”.

Discussion/Vitamin D status: unclear what is meant by “evidence has shown that vitamin D concentrations are a biomarker of sun exposure” because you also write that vitamin D concentrations reflect the “cumulative effect of vitamin D dietary intake and sun

exposure”

Reviewer #2: Thanks you for the revisions. I thin you addressed most of my concerns. There are a few minor points;

1. Page 10 - heading of the table is "Table 3 Characteristics of 10 studies included in the analysis between 25 (OH)D during pregnancy and cord blood and the development of eczema, wheezing and RTIs in the first year (12 months) of life (continue)" - should this be table 2 (not table 3)?

2. I think it would be good to include a column in Table 2 on how the each outcome was assessed, even if it is just health professional diagnosed or parent reported

3. I think the results section, under the headings Vitamin D and Eczema in the first year (12 months) of life, Vitamin D and wheezing in the first year (12 months) of life, and Vitamin D and respiratory infections in the first year (12 months) of life it would be good to comment on whether the method of outcome assessment could explain the conflicting results found.

Reviewer #3: This is an improved manuscript but the English spelling and phrases are very poor. Much of the manuscript requires rewriting. Many of the corrections required are listed below but perhaps an English writer should be consulted.

Line 36: During should be removed.

Line 50: continued to increase.

Introduction: 3rd sentence is repetitive of the 2nd sentence.

Line 56: years 2014 to 2015.

Line 57: ranged from xx

Line 62: The majority.

Line 64: second para, reword the sentence.

Line 66: ‘low’ vitamin D status

Line 68: remove ‘the’

Line 72: Cord blood does not represent early postnatal. In many places (for example line 107), cord blood is clearly stated as at birth, rather than early postnatal.

Line 81: remove course

Line 87: remove pool

Line 88: Low vitamin D levels are the risk factor

Line 129: ‘the’

Line 187: ranged ‘from’

Line 188: the meaning of ‘timing of exposure assessment’ is not clear

Line 210: Meaning of late of pregnancy?

Line 263: remove ‘There are’

Line 268: It is associations between X and Y

Lines 278-280: rewrite as meaning not clear

Line 282: populations

Lines 287-288: The literature is not scarce for the properties of other molecules induced by UV radiation. See Hart et al, Nat Rev Immunol 2011, and Hart et al, Annu Rev Pathol 2019.

Lines 288-290: not good English, please rewrite.

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Reviewer #2: Yes: Shivanthan ShanthikumarDr

Reviewer #3: No

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22 Mar 2020

Reviewer #1: Comments to paper after first revision:

1. Although the methodology for the literature search seems solid, the revised manuscript and presentation of results seem to suffer from typos, errors and inconsistencies and leaves an untidy impression.

Author Response: Thank you for highlighting this. We had amended it accordingly.

2. Also, it still remains unclear what the current study adds compared with the previous reviews and meta-analyses referenced (refs 4, 23, 26); e.g. does the current study include more studies on wheeze in infants than the meta-analysis from 2018 (ref 4) or do you summarize the evidence differently?

Author Response: The information that is requested already been updated in method section; Line 80-98

3. The authors argue that previous reviews have included vitamin D intake, but this is not a problem as long as vitamin D intake and vitamin D status are presented as separate analyzes, which is usually the case –without knowing these studies in detail. Regarding the age restriction of all outcomes (RTI, eczema, wheeze) to infants, the rationale for doing this should be made more clear, especially because the authors conclude that the literature is limited and the outcomes of eczema and wheeze also occur in children after the first year of life. Some arguments now mentioned in the Discussion, could be moved to the Introduction. However, for vitamin D there is still a chance that prenatal exposure may play a role, due to vitamin D supplement recommendations to infants in some countries, and the introduction of complementary feeding which may be enriched with vit D.

Author Response: The information that is requested already been updated in method section; Line 80-84; 92-95. This is further elaborated to highlight the importance of current literature review.

Major comments:

4. The study rationale could be refined some more.

Author Response: The information that is requested already been updated in method section; Line 80-84; 92-98.

5. The manuscript needs proof reading from the very beginning, a few examples include the Abstract (line 29 – duplicate words, missing commas; line 36 missing “in” or “during”) and Introduction (line 50, grammar). Clarity is affected in some places, e.g. in the Introduction (line 57) – it is unclear if “allergy eczema” should read “allergy and eczema” or “allergic eczema”. There are now 2 tables labelled “Table 3”, including the second page of Table 2, which should be corrected.

Author Response: Thank you for highlighting this. The manuscript was proofread. We had amended and corrected it accordingly.

6. The paper is currently missing some information on outcome definitions as part of the inclusion/exclusion criteria. What types of eczema, wheeze, and RTI were included in the analysis and how were the outcomes assessed? Results on eczema (Table2/Table 3) seem to be presented for both eczema and atopic eczema, and RTI (Table 5) seems to include several types, including LRTI (pneumonia/bronchiolitis), URTI, recurrent RTI, as well as symptoms of cough. Now the information is briefly mentioned in the Discussion (line 286, 287).

Author Response: The information that is requested already been updated in method section; Line 128-131; 148-151

7. Unclear why ”Pregnancy outcomes” are mentioned in Table 2/3 (ref 38).

Author Response: Thank you for highlighting this. We had removed it.

8. Tables have improved, but the information seems to be provided in an inconsistent manner. If the information was not available, it should be explained somewhere. The conclusion should preferably reflect the conclusions of the authors of the review (not the conclusions found in the papers), and be reported in a similar manner for all papers to the extent possible.

Author Response: Thank you for highlighting this. We had amended it accordingly.

9. Taking Table 3 as an example:

Gale et al: no sample size provided, sig results for Q4 not marked in bold (but some results marked in bold in Table 4)

Author Response: Thank you for highlighting this. We had corrected and bold it.

10. Weisse et al: no sample size provided, unclear if adj ORs refer to highest vs. lowest category

Author Response: The information already been updated.

11. Gazibara et al. unclear if “n” refers to no. of cases or study size

Author Response: Thank you for highlighting this. We had amended it. We also added a footnotes. N=study size; n=number of cases.

12. Baiz et al. sample size provided twice (n=239), unclear if the reported OR is per nmol/L of vitamin D or if exposure categories are missing

Author Response: We had removed it and the information been updated in the table.

13. Summary of results: it is hard to follow at times. The authors could consider summarizing the number of studies reporting no/positive/negative associations for each outcome.

Author Response: Thank you for the suggestions. We had amended it accordingly.

14. Discussion/Vit D & RTI: although sex of the child may affect the risk of RTI, sex is not expected to be associated with maternal vit D status or vit D status at birth, and therefore not a confounder by the usual definition. Thus, lack of adjustment for sex should not be considered a weakness of studies.

Author Response: Thank you for highlighting this. We had removed and amended it accordingly. Line 315-321.

Minor comments

15. Reference no. 9 to document prevalence (lines 52, 56), is based on mathematical modelling and not original data, which should be stated explicitly

Author Response: Thank you for highlighting this. We had amended it accordingly. Line 56-59.

16. Table 4: could go in the supplement with Table S3

Author Response: Thank you for the suggestion.

17. Tables 3-5 titles: Suggest changing for better clarity from “Studies included in the analysis between 25 (OH)D during pregnancy and cord blood and the development of … in the first year (12 months) of life” to “Studies included in the analysis of 25 (OH)D during pregnancy or cord blood with the development of … in the first year (12 months) of life”.

Author Response: Thank you for the suggestion. We had amended it accordingly.

18. Discussion/Vitamin D status: unclear what is meant by “evidence has shown that vitamin D concentrations are a biomarker of sun exposure” because you also write that vitamin D concentrations reflect the “cumulative effect of vitamin D dietary intake and sun exposure”.

Author Response: Thank you for highlighting this. We had removed the sentence and the sentences were rephrased accordingly. Line 273-282.

Reviewer #2:

Thanks you for the revisions. I thin you addressed most of my concerns. There are a few minor points;

1. Page 10 - heading of the table is "Table 3 Characteristics of 10 studies included in the analysis between 25 (OH)D during pregnancy and cord blood and the development of eczema, wheezing and RTIs in the first year (12 months) of life (continue)" - should this be table 2 (not table 3)?

Author Response: Thank you for highlighting this. We had renumbered it accordingly.

2. I think it would be good to include a column in Table 2 on how the each outcome was assessed, even if it is just health professional diagnosed or parent reported

Author Response: Thank you for the suggestion. We had added it accordingly in Table 2.

3. I think the results section, under the headings Vitamin D and Eczema in the first year (12 months) of life, Vitamin D and wheezing in the first year (12 months) of life, and Vitamin D and respiratory infections in the first year (12 months) of life it would be good to comment on whether the method of outcome assessment could explain the conflicting results found.

Author Response: Thank you for the suggestion. We had added the information accordingly. Line 220-222; 226-227.

Reviewer #3:

This is an improved manuscript but the English spelling and phrases are very poor. Much of the manuscript requires rewriting. Many of the corrections required are listed below but perhaps an English writer should be consulted.

Line 36: During should be removed.

Line 50: continued to increase.

Introduction: 3rd sentence is repetitive of the 2nd sentence.

Line 56: years 2014 to 2015.

Line 57: ranged from xx

Line 62: The majority.

Line 64: second para, reword the sentence.

Line 66: ‘low’ vitamin D status

Line 68: remove ‘the’

Line 72: Cord blood does not represent early postnatal. In many places (for example line 107), cord blood is clearly stated as at birth, rather than early postnatal.

Line 81: remove course

Line 87: remove pool

Line 88: Low vitamin D levels are the risk factor

Line 129: ‘the’

Line 187: ranged ‘from’

Line 188: the meaning of ‘timing of exposure assessment’ is not clear

Line 210: Meaning of late of pregnancy?

Line 263: remove ‘There are’

Line 268: It is associations between X and Y

Lines 278-280: rewrite as meaning not clear

Line 282: populations

Lines 287-288: The literature is not scarce for the properties of other molecules induced by UV radiation. See Hart et al, Nat Rev Immunol 2011, and Hart et al, Annu Rev Pathol 2019.

Lines 288-290: not good English, please rewrite.

Author Response: Thank you for highlighting this. Noted with thank you. The manuscript was proofread. We had amended and corrected it accordingly.

Submitted filename: Response to reviewers.docx

Click here for additional data file.

17 Apr 2020

PONE-D-19-24730R2

Risk of eczema, wheezing and respiratory tract infections in the first year of life: a systematic review of vitamin D concentrations during pregnancy and at birth

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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Reviewer #1: (No Response)

Reviewer #3: (No Response)

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Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #3: Yes

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Reviewer #3: Yes

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Reviewer #1: Comments to paper after second revision.

The authors have done a thorough revision. The study rationale is much now clearer and the manuscript reads a lot better. Most of my comments have been addressed and tables have improved considerably. A few minor points remain regarding the reporting of the results.

Table 2: no apparent order of studies. Could be sorted by publication year.

The marking of significant ORs in bold does still not seem entirely consistent, e.g. in Table 4 significant ORs are unmarked for the studies by De Jongh (OR for Q2) and Baiz. In Table 5 the same applies to the studies by De Jongh (Q3) and by Camargo.

It remains unclear for some studies what unit/increase the ORs are reported for, e.g. Table 4 for the studies by Jones and by Baiz. In Table 5 the OR is reported for a 10 nmol/L increase in the study by Palmer, which is the preferable reporting style.

The reporting of the results from the study by Weisse (Table 3) are slightly confusing as the quartiles include case numbers and not ORs as for the other studies, and it remains unclear if the single OR estimate refers to any of the categories (low vs high or opposite) or a continuous effect.

I suggest changing “positive association” for the study by De Jongh to “Low maternal serum 25(OH)D levels decreased the risk of… ” which is more consistent with the reporting of other studies, and easier to understand.

Other comments

Line 87-88: Reference has been inserted as author/year, but should be a number to be consistent with style.

Title of Tables 4 and 5: suggest replacing "and cordblood" with "or cordblood" as in title of Table 3

The unit of vitamin D concentration (nmol/L) seems to be converted from the original units in the paper in one or more studies (e.g. Weisse 2013 reported in ng/mL) – should be mentioned under Methods if the reported units differ from the original study.

Reviewer #3: It is difficult to grasp the aims and originality of this analysis.

Lines 133-138 detail the aims of the analysis. However, after reading multiple times, I cannot distinguish the difference between aims 2 and 3. No effect is measured, all the studies included are associations.

The authors concluded that there were no associations between 25(OH)D levels during pregnancy and at birth, and 3 respiratory based outcomes in infants up to one year of age. The relevant discussion that address why this may be so has been removed from the document. 25(OH)D is a biomarker of being in the sun but it is not necessarily the active molecule for the outcomes investigated. This important point has been removed. Reasons for a lack of association requires discussion.

Lines 58, 274, 277, Asian countries not Asia countries

Line 58, remove while.

Line 55, prevalence is singular and requires a singular not plural verb.

**********

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Reviewer #1: No

Reviewer #3: No

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7 May 2020

We would like to express our sincere gratitude to the esteemed reviewers for their useful comments. We have now revised the manuscript according to the reviewers’ suggestions, and sincerely hope that the manuscript is now suitable for publication in Plos One. Also, we had sent for proofreading for this revised manuscript.

Below are the author response to the reviewer comments.

Comments from Reviewer 1

1. The authors have done a thorough revision. The study rationale is much now clearer and the manuscript reads a lot better. Most of my comments have been addressed and tables have improved considerably. A few minor points remain regarding the reporting of the results.

Author Response: Thank you for the comment. We had amended it accordingly.

2. Table 2: no apparent order of studies. Could be sorted by publication year.

Author Response: Thank you for the suggestion. We had sorted the information in Table 2 by the recent year of publication accordingly.

3. The marking of significant ORs in bold does still not seem entirely consistent, e.g. in Table 4 significant ORs are unmarked for the studies by De Jongh (OR for Q2) and Baiz. In Table 5 the same applies to the studies by De Jongh (Q3) and by Camargo.

Author Response: We appreciate the comments and we had bold the information and corrected it accordingly.

4. It remains unclear for some studies what unit/increase the ORs are reported for, e.g. Table 4 for the studies by Jones and by Baiz. In Table 5 the OR is reported for a 10 nmol/L increase in the study by Palmer, which is the preferable reporting style.

Author Response:We are sorry for the missing information. The information that is requested already been updated in the Table 4.

5. The reporting of the results from the study by Weisse (Table 3) are slightly confusing as the quartiles include case numbers and not ORs as for the other studies, and it remains unclear if the single OR estimate refers to any of the categories (low vs high or opposite) or a continuous effect.

Author Response: Thank you for highlighting this. We did re-checking the reporting result of Weisse et al. (2013) study. The study reported they performed multivariate logistic regression and presented case numbers in each quartiles instead of ORs as for the other studies. As regards to eczema outcome definition, the eczema was recorded as parental report of symptoms and also parental report of a doctor diagnosed. Therefore, there are two results of eczema were presented.

6. I suggest changing “positive association” for the study by De Jongh to “Low maternal serum 25(OH)D levels decreased the risk of… ” which is more consistent with the reporting of other studies, and easier to understand.

Author Response: Thank you for the suggestion. We had changed the sentence as suggested accordingly.

7. Line 87-88: Reference has been inserted as author/year, but should be a number to be consistent with style.

Author Response:Thank you for highlighting this. We had amended it accordingly. Line 88.

8. Title of Tables 4 and 5: suggest replacing "and cordblood" with "or cordblood" as in title of Table 3

Author Response: Thank you for the suggestion. We had changed the phrase as suggested in title of Table 4 and 5 accordingly.

9. The unit of vitamin D concentration (nmol/L) seems to be converted from the original units in the paper in one or more studies (e.g. Weisse 2013 reported in ng/mL) – should be mentioned under Methods if the reported units differ from the original study.

Author Response: Thank you for highlighting this. After further discussion among the authors, we had changed the converted ones to the original units in the papers. However, for clarity purposes for comparison (the ng/ml change to nmol/L), we put a footnote, 1 unit ng/ml equivalent to 2.496 nmol/L. The information already been updated in footnote each table accordingly.

Comments from Reviewer 3

1. It is difficult to grasp the aims and originality of this analysis. Lines 133-138 detail the aims of the analysis. However, after reading multiple times, I cannot distinguish the difference between aims 2 and 3. No effect is measured, all the studies included are associations.

Author Response: We are sorry for the confusion of the information. To avoid the misunderstanding, we had removed the goal of no.3 as our review summarized and elaborated the findings in a narrative manner.

2. The authors concluded that there were no associations between 25(OH)D levels during pregnancy and at birth, and 3 respiratory based outcomes in infants up to one year of age. The relevant discussion that address why this may be so has been removed from the document. 25(OH)D is a biomarker of being in the sun but it is not necessarily the active molecule for the outcomes investigated. This important point has been removed. Reasons for a lack of association requires discussion.

Author Response: Thank you for highlighting this. The information that is requested already been updated accordingly. Line 288-291.

3. Lines 58, 274, 277, Asian countries not Asia countries

Author Response: Thank you for highlighting this. We had amended it accordingly. Line 59, 277, 286, 289

4. Line 58, remove while.

Author Response: Thank you for highlighting this. We had removed ‘while’ at line 58.

5. Line 55, prevalence is singular and requires a singular not plural verb.

Author Response: Thank you for highlighting this. We had amended ‘were most common…’ to ‘was most common..’. Line 55.

Submitted filename: Response to reviewers.docx

Click here for additional data file.

15 May 2020

Risk of eczema, wheezing and respiratory tract infections in the first year of life: a systematic review of vitamin D concentrations during pregnancy and at birth

PONE-D-19-24730R3

Dear Dr. Majid,

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Maria Christine Magnus, MPH

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

3 Jun 2020

PONE-D-19-24730R3

Risk of eczema, wheezing and respiratory tract infections in the first year of life: a systematic review of vitamin D concentrations during pregnancy and at birth

Dear Dr. Majid:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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