Impact of maternal iron and zinc intake on low birth weight risk: a nested case—control study

Introduction

According to the World Health Organization (WHO) criterion (De Costa et al., 2021), low-birth-weight (LBW) infants are defined as newborns weighing less than 2,500 g in the first hour after birth, independent of gestational age. Because of immature development and many complications, LBW is closely related to neonatal death, developmental delays, and long-term chronic diseases in offspring (Shinzawa et al., 2019). Studies have shown that LBW accounts for 15–20% of all live births and more than 80% of all neonatal deaths worldwide; it is still an important public health indicator for assessing the health of infants and young children (Blencowe et al., 2019). The overall prevalence of LBW of Chinese children younger than 6 years was 5.15% in 2013, with 4.57% in boys and 5.68% in girls (Shen et al., 2021). However, the potential mechanisms for LBW remain unclear. Therefore, identifying modifiable risk factors to provide evidence for the primary prevention of LBW is particularly meaningful.

Maternal nutritional status during pregnancy is an important modifiable factor associated with their health and affects the next generation’s growth and development. Adequate nutrition particularly important for the growth, development, and maintenance of normal physiological functions in LBW infants is mainly obtained from the diet. Micronutrient deficiency occurs if the body has insufficient reserves preconception and insufficient supplies after pregnancy. The main function of trace element iron is to transport oxygen and carbon dioxide, participate in tissue respiration, and promote biological redox reactions (Berggren et al., 2015; Tussing-Humphreys et al., 2012). Zinc is the second most abundant trace element in the body after iron; it is especially abundant in the liver, kidney, retina, bone, and muscle tissue and fluid, and is involved in the regulation of cell function and vitamin A metabolism in the body (Dusek, Jankovic & Le, 2012). Zinc deficiency in fetuses can lead to growth restriction and sexual organ dysfunction (Khoushabi et al., 2016).

In recent years, the scientific community has been widely concerned about the biological effects of various trace elements during pregnancy and their relationship with the origin of life, heredity, growth and development, congenital disabilities, and other maternal and infant health outcomes. However, available studies on the relationship between iron or zinc intake during pregnancy and LBW have not systematically covered the period preconception and the entire pregnancy (Chang, Li & Xu, 2018; Siyoum & Melese, 2019; Palma et al., 2008; Yadav et al., 2020; Imdad & Bhutta, 2012; Haider et al., 2013; Cogswell et al., 2003; Peña Rosas et al., 2015; Bánhidy et al., 2011; Negandhi et al., 2014; Iannotti et al., 2008; Xie, Chen & Pan, 2001; Goldenberg et al., 1995; Zahiri Sorouri, Sadeghi & Pourmarzi, 2016; Osendarp et al., 2000; Carducci, Keats & Bhutta, 2021; Warthon-Medina et al., 2015). Some of the studies that have assessed total iron/zinc intake did not separately model the relationships between iron/zinc from food and that from dietary supplements. Moreover, previous studies have not considered the synergistic effects of iron and zinc intake on the risk of LBW. Therefore, this study aimed to investigate the effects of iron and zinc daily intake preconception and during pregnancy on the risk of delivering LBW babies and to assess whether there is an interaction between iron and zinc intake on the risk of LBW.

Materials & Methods

Results

Associations of maternal dietary zinc intake with the odds of LBW

As shown in Table 4, there was a positive relationship between zinc intake and the risk of LBW. Compared with quartile 4 (highest) and quartile 1 (lowest) of dietary zinc intake during pregnancy and at the third trimester, the adjusted OR for LBW was 1.22 (1.01–1.46) and 1.20 (1.01–1.43), respectively, and the test for trend was significant for both (P < 0.001). Additionally, in quartile 1 of zinc intake during pregnancy, the second and third trimesters showed a significantly higher preterm LBW risk than in quartile 4, and the trend test was significant. However, no significant association was observed between zinc intake and term LBW either preconception or when stratifying by the trimesters of pregnancy. There was no relationship between zinc intake below RNI and the risk of LBW, preterm LBW, and term LBW (Table 5).

Table 4:

Associations of maternal dietary zinc intake with the odds of LBW.

Dietary zinc intake (mg/d)	NBW (7,510)	LBW (n = 565)					Term-LBW (37≥weeks)			Preterm-LBW (<37 weeks)
		Cases	ORa (95% CI)	P-value	ORc (95% CI)	P-value	Cases	ORc (95% CI)	P-value	Cases	ORc (95% CI)	P-value
Preconception
Q1 <5.34	1,878	232	1.29 (1.20–1.40)	<0.001**	1.05 (0.95–1.17)	0.360	47	0.93 (0.76–1.14)	0.483	185	1.08 (0.96–1.22)	0.208
Q2 5.34–6.79	1,877	123	1.07 (0.94–1.23)	0.306	0.96 (0.82–1.13)	0.617	31	0.81 (0.60–1.08)	0.160	92	0.98 (0.82–1.17)	0.824
Q3 6.79–8.52	1,878	103	0.96 (0.73–1.27)	0.785	0.98 (0.72–1.33)	0.900	19	0.64 (0.35–1.17)	0.147	84	1.02 (0.73–1.43)	0.115
Q4 ≥ 8.52	1,877	107	Ref.		Ref.		29	Ref.		78	Ref.
P for trend			<0.001		0.019			0.975			0.005
During pregnancy
Q1 <6.71	1,877	243	1.39 (1.27–1.51)	<0.001**	1.22 (1.01–1.46)	0.034*	51	0.92 (0.64–1.33)	0.654	192	1.34 (1.09–1.63)	0.004**
Q2 6.71–8.40	1,878	140	1.15 (1.05–1.26)	0.002**	1.10 (0.91–1.32)	0.315	29	0.81 (0.52–1.24)	0.342	111	1.09 (0.88–1.34)	0.442
Q3 8.40–10.39	1,877	90	0.88 (0.79–1.02)	0.888	0.93 (0.67–1.28)	0.661	22	0.88 (0.47–1.65)	0.689	68	0.94 (0.65–1.36)	0.742
Q4 ≥ 10.39	1,878	92	Ref.		Ref.		24	Ref.		68	Ref.
P for trend			<0.001		<0.001			0.658			<0.001
First trimester
Q1 <6.46	1,877	231	1.34 (1.23–1.45)	<0.001**	1.02 (0.85–1.17)	0.808	47	0.81 (0.59–1.10)	0.185	184	1.21 (0.99–1.48)	0.063
Q2 6.46–8.13	1,878	137	1.19 (1.04–1.36)	0.012*	1.11 (0.93–1.33)	0.253	31	0.80 (0.55–1.19)	0.257	106	1.07 (0.89–1.27)	0.456
Q3 8.13–10.09	1,878	100	1.03 (0.77–1.37)	0.838	0.91 (0.67–1.24)	0.547	23	0.83 (0.44–1.54)	0.56	77	0.94 (0.66-1.34)	0.732
Q4 ≥ 10.09	1,877	97	Ref.		Ref.		25	Ref.		72	Ref.
P for trend			<0.001		0.055			0.855			0.002
Second trimester
Q1 <6.76	1,877	244	1.38 (1.27–1.49)	<0.001**	1.14 (0.95–1.37)	0.160	50	0.95 (0.67–1.34)	0.772	194	1.24 (1.01–1.51)	0.036*
Q2 6.76–8.50	1,878	135	1.20 (1.05–1.37)	0.009**	1.07 (0.90–1.28)	0.451	28	0.82 (0.54–1.25)	0.354	107	1.12 (0.92–1.37)	0.264
Q3 8.50–10.57	1,877	92	0.98 (0.73–1.32)	0.889	0.93 (0.68–1.29)	0.656	24	0.91 (0.49–1.69)	0.764	68	0.94 (0.65–1.35)	0.740
Q4 ≥ 10.57	1,878	94	Ref.		Ref.		24	Ref.		70	Ref.
P for trend			<0.001		0.002			0.866			<0.001
Third trimester
Q1 <6.74	1,877	243	1.38 (1.27–1.50)	<0.001**	1.20 (1.01–1.43)	0.040*	50	0.99 (0.71–1.38)	0.952	193	1.28 (1.05–1.55)	0.013*
Q2 6.74–8.49	1,878	146	1.25 (1.10–1.43)	0.001**	1.15 (0.98–1.36)	0.094	31	0.92 (0.62–1.36)	0.678	115	1.21 (1.00–1.45)	0.044*
Q3 8.49–10.56	1,878	83	0.89 (0.66–1.21)	0.459	0.88 (0.64–1.23)	0.443	22	0.94 (0.50–1.75)	0.846	61	0.87 (0.60–1.26)	0.462
Q4 ≥ 10.56	1,877	93	Ref.		Ref.		23	Ref.		70	Ref.
P for trend			<0.001		<0.001			0.511			<0.001

DOI: 10.7717/peerj.19896/table-4

Notes:

aOR^a univariate analyses.

cOR^c adjusted for weight gain during pregnancy, father’s BMI, total energy intake, monthly income per capita, maternal education level, smoking, maternal employ, multivitamin supplement, gestational hypertension, history of premature birth, reproductive history and dietary iron intake.

**P-value < 0.01.

*P-value < 0.05.

Table 5:

Maternal dietary zinc intake categorized by RNIs and the odds of LBW.

Dietary zinc intake (mg/d)	NBW (7,510)	LBW (n = 565)					Term-LBW (37≥weeks)			Preterm-LBW (<37 weeks)
		Cases	ORa (95% CI)	p-value	ORc (95% CI)	p-value	Cases	ORc (95% CI)	p-value	Cases	ORc (95% CI)	p-value
Preconception
Met the RNI	2,818	158	Ref.		Ref.		37	Ref.		121	Ref.
Below the RNI	4,692	407	1.44 (1.12–1.86)	<0.001**	1.11 (0.89–1.39)	0.362	89	0.97 (0.62–1.51)	0.382	318	1.20 (0.93–1.55)	0.162
During pregnancy
Met all the RNI	2,120	110	Ref.		Ref.		28	Ref.		82	Ref.
Below 1 trimester	519	30	1.11 (0.74–1.69)	0.624	1.00 (0.64–1.57)	1.000	8	0.94 (0.41–2.18)	0.884	22	1.02 (0.61–1.70)	0.940
Below 2 trimester	388	21	1.02 (0.80–1.30)	0.873	0.93 (0.71–1.22)	0.600	4	0.75 (0.42–1.34)	0.331	17	0.99 (0.73–1.33)	0.948
Below 3 trimester	4,483	404	1.20 (1.12–1.29)	<0.001**	1.01 (0.91–1.12)	0.850	86	0.85 (0.69–1.04)	0.121	318	1.08 (0.97–1.20)	0.156
First trimester
Met the RNI	2,329	121	Ref.		Ref.		30	Ref.		91	Ref.
Below the RNI	5,181	444	1.65 (1.34–2.03)	<0.001**	1.01 (0.77–1.32)	0.942	96	0.74 (0.43–1.27)	0.276	348	1.11 (0.82–1.51)	0.503
Second trimester
Met the RNI	2,725	147	Ref.		Ref.		37	Ref.		110	Ref.
Below the RNI	4,785	418	1.62 (1.33–1.96)	<0.001**	0.97 (0.74–1.27)	0.824	89	0.65 (0.39–1.12)	0.109	329	1.09 (0.81–1.47)	0.570
Third trimester
Met the RNI	2,732	143	Ref.		Ref.		37	Ref.		106	Ref.
Below the RNI	4,778	422	1.69 (1.39–2.05)	<0.001**	1.04 (0.80–1.36)	0.773	89	0.69 (0.41–1.16)	0.162	333	1.18 (0.88–1.59)	0.272

DOI: 10.7717/peerj.19896/table-5

Notes:

aOR^a univariate analyses.

cOR^c adjusted for weight gain during pregnancy, father’s BMI, total energy intake, monthly income per capita, maternal education level, smoking, maternal employ, multivitamin supplement, gestational hypertension, history of premature birth, reproductive history and dietary iron intake.

**P-value < 0.01.

*P-value < 0.05.

Figure 2 depicts the RCS curves for the associations between zinc intake and the risk of LBW preconception and during pregnancy. As the daily dietary zinc intake increases, the risk of LBW decreases rapidly and gradually levels off. In the third trimester, when the intake is less than 8.37 mg/d, the risk of LBW increases. When the intake is between 8.37 mg/d and 41.63 mg/d, zinc intake is a protective factor for LBW. When the intake is greater than 41.63 mg/d, the risk of LBW increases. Similar results were obtained in preconception, the first trimester, and the second trimester. respectively (P_Nonlinear <0.05).

Discussion

Pregnancy is a critical period for both the short- and long-term health effects of mothers and infants. To meet the needs of their own and fetal growth and development during pregnancy, pregnant women have an increased demand for various nutrients. However, in developing countries, women tend to pay more attention to the intake of macronutrients such as protein during pregnancy than some trace elements, increasing the risk of LBW (Haider & Bhutta, 2017; Parodi et al., 2018). It has been shown (Guilbert, 2003; Prasad, 2003) that more than 2 billion people worldwide are iron-deficient, and billions more are exposed to zinc deficiency, the vast majority of which occur in developing countries. Causes of micronutrient deficiencies include inadequate intake, poor absorption, impaired utilization, excessive loss, increased physiological requirements, or a combination of these factors. Inadequate intake could be the main cause of deficiency in developing countries (Gibson, 2006). A nutritional survey of pregnant women in western China implied (Mao et al., 2020) that the deficiency ratio of dietary iron, zinc, iodine, copper, and selenium was higher during pregnancy (P < 0.05). Iron plays a critical role in energy metabolism, regulation of DNA synthesis, cell proliferation and differentiation, and oxygen transport. Nearly half of pregnant women in the second and third trimesters consume less than their average dietary iron requirements (estimated average requirement, EAR). Iron absorption during pregnancy is a complex process and generally increases with the increase of gestational age. The incidence of iron deficiency anemia is high in women during pregnancy, with the highest prevalence in the second and third trimesters. Therefore, the WHO recommends iron supplementation during pregnancy to prevent birth related adverse outcomes in the future (Rahman et al., 2021). While prenatal iron supplementation has a beneficial effect on women with anemia, it has a controversial effect on women without anemia (Ribot et al., 2012); namely, in women with normal hemoglobin levels during pregnancy, daily iron supplementation may be harmful to fetal growth (Aranda et al., 2013). A cohort study (Shastri et al., 2015) revealed that women with the highest dose (>39.2 mg/day) of supplemental iron intake had an increased risk of term LBW compared with those with the lowest dose (≤36.6 mg/day) (RR = 1.89; 95% CI [1.26–2.83]). Pregnant women should not take iron supplementation if their hemoglobin levels exceed 110 g/L during the first and third trimesters and 105 g/L during the second trimester. Excessive or insufficient dietary iron in mothers can both increase the risk of low birth weight. Excessive iron can lead to endocrine disorders, such as hypothyroidism, elevated HbA1c levels and decreased adrenocorticotropic hormone levels, thereby affecting bone health (Chen et al., 2024; Yang et al., 2020). In plant-based diets, iron exists in the form of inorganic non-haem iron, which is less bioavailable than haem iron from animal foods sources, and this results in lower total iron absorption from vegetarian diets (Hurrell & Egli, 2010). Studies have shown that the bioavailability of iron can be enhanced by taking iron supplements orally, adjusting the diet, including increasing the intake of iron-rich foods such as meat, as well as through techniques like sprouting and fermentation (Abbaspour, Hurrell & Kelishadi, 2014).

Zinc is an essential trace element and is very important for the normal development of the fetus during pregnancy. Zinc deficiency has become a major nutritional and health problem worldwide (Roohani et al., 2013). Considering the differences in ethnicity, living environment, eating habits, and economic status, zinc deficiency in mainland China shows regional variability, and zinc deficiency levels in different pregnancies are not all the same (Liang et al., 2019). Zinc is involved in maintaining many important physiological functions in the human body, such as promoting growth and development, enhancing immunity, and promoting wound healing. Zinc is involved in many processes, such as cells (Grzeszczak, Kwiatkowski & Kosik-Bogacka, 2020). Zinc-binding proteins and zinc transporters are involved in the distribution and transport of zinc in the body, and they regulate and maintain zinc homeostasis in the body through various mechanisms (Baltaci & Yuce, 2018). Zinc deficiency can decrease the activity of Cu–Zn superoxide dismutase (SOD) (Abolbashari et al., 2018) and increase serum homocysteine levels (Jing et al., 2015), which may be the pathological basis for LBW in childbirth. The absorption and bioavailability of zinc are influenced by many factors. The two main factors affecting zinc absorption are dietary zinc intake and phytates, which together account for more than 80% of the variation in zinc absorption (Hambidge et al., 2010). Because of the wide range of biological functions of zinc and its importance to human health, the WHO recommends using zinc-rich foods when adequate zinc intake is not possible in the general diet. Zinc can be obtained from various sources, including food, fortified foods and supplements. Taking zinc supplements is a convenient and effective option for treating zinc deficiency and maintaining healthy levels of zinc (Devarshi et al., 2024). Iron deficiency and zinc deficiency often occur together during pregnancy (Nishiyama et al., 1999). Combining iron and zinc supplementation in women with iron deficiency in early pregnancy could have more benefits than iron therapy alone. The recovery of serum ferritin in pregnant women is more effective when iron and zinc are combined 1:1 (Saaka, Oosthuizen & Beatty, 2009). The possible reason may be that zinc promotes the formation of IGF-1, which along with erythropoietin, is required for hematopoiesis (Ten Have, van der Lely & Lamberts, 1997). Additionally, it has been reported that iron loading reduces divalent metal transport-1 (DMT1) expression, resulting in reduced iron absorption. However, zinc can increase DMT1 mRNA expression (Yamaji et al., 2001), which may also be a potential mechanism for the interaction between dietary iron deficiency and zinc deficiency observed in this study. In this nested cohort study, we observed that women with low dietary iron intake preconception and during pregnancy had a significantly increased risk of delivering LBW infants, with a dose–response relationship, especially for preterm LBW infants. Similarly, significant inverse associations with LBW were found for lower dietary zinc intake during pregnancy. Moreover, the positive additive and multiplicative scale interactions between low dietary iron and zinc intake and LBW were observed preconception and during different trimesters of pregnancy. This is the first study that comprehensively examined the effects of dietary iron and zinc intake on LBW infants from the preconception period through the entire gestational period.

Few previous studies have investigated the effects of dietary iron intake preconception and during pregnancy on LBW. Most of the studies have focused on nutrient supplementation interventions and reported controversial results; thus, the evidence on whether dietary iron intake decreases the risk of LBW is still not established (Chang, Li & Xu, 2018). Most studies have reported that iron supplementation could decrease the risk of LBW. One prospective study (Chang, Li & Xu, 2018) reported that iron supplementation during the whole period of pregnancy reduced the risk of LBW (OR = 0.60; 95% CI [0.43–0.83]). However, the risk of LBW was 0.90 (95% CI [0.64–1.28]) and 0.77 (95% CI [0.58–1.03]) when iron supplementation was only given in the first trimester and in the middle-to-late pregnancy, respectively. One case–control study (Siyoum & Melese, 2019) in Ethiopia demonstrated that the lack of iron supplementation during pregnancy increased the risk of LBW infants (OR = 2.89; 95% CI [1.58–5.29]), and a case–control study in Spain similarly demonstrated (Palma et al., 2008) that 80 mg ferrous sulfate supplementation was associated with a lower risk of LBW (OR = 0.58; 95% CI [0.34–0.98]). A matched case–control study (Yadav et al., 2020) in Nepal indicated that iron and folic acid consumption less than 60 days before delivery raised the risk of LBW (OR = 5.47; 95% CI [2.73–10.95]). One meta-analysis (Imdad & Bhutta, 2012) revealed that routine daily iron supplementation during pregnancy resulted in a significant reduction of 20% in the incidence of LBW in the intervention group compared with the control group (RR = 0.80; 95% CI [0.71–0.90]). Another meta-analysis (Haider et al., 2013) indicated that for every 10 mg increase in iron dose/day, up to 66 mg/day, the birth weight increased by 15.1 (6.0 to 24.2) g (P for linear trend = 0.005), and the relative risk of LBW decreased by 3% (RR = 0.97; 95% CI [0.95–0.98]) for every 10 mg increase in dose/day (P for linear trend <0.001). One randomized controlled trial (Cogswell et al., 2003) showed that iron supplementation from enrollment to 28 weeks of gestation led to a significantly higher mean birthweight (206 ± 565 g; P = 0.010) and a significantly lower incidence of LBW infants (4% compared with 17%; P = 0.003). However, other three studies (Imdad & Bhutta, 2012; Haider et al., 2013; Cogswell et al., 2003; Peña Rosas et al., 2015; Bánhidy et al., 2011) observed that iron supplementation alone during pregnancy was not associated with LBW (RR = 0.78, 95% CI [0.56–1.02]), and there was no higher rate of LBW in newborns of anemic pregnant women who received iron supplementation. Studies investigating the relationship between dietary zinc intake and the risk of LBW are also conflicting (Negandhi et al., 2014; Iannotti et al., 2008; Xie, Chen & Pan, 2001; Goldenberg et al., 1995; Zahiri Sorouri, Sadeghi & Pourmarzi, 2016; Osendarp et al., 2000; Carducci, Keats & Bhutta, 2021; Warthon-Medina et al., 2015). Four of the eight studies reported that zinc supplementation reduced the risk of LBW. One case–control study (Negandhi et al., 2014) in India reported that low zinc intake (<5.39 mg/dL) showed a significant association with the risk of LBW. One randomized controlled trial in Peru (Iannotti et al., 2008) showed that zinc supplementation through pregnancy to 1 month after delivery was associated with greater weight (by 0.58 ± 0.12 kg; P < 0.001), but no effect was observed for linear growth. One randomized, double-blind trial (Xie, Chen & Pan, 2001) in western China demonstrated that zinc supplementation in the doses of five and 10 mg/day had no benefit, whereas the 30 mg/day dose resulted in great improvements in the infants’ birth weight (283.07 g, P = 0.016). Another randomized, double-blind placebo-controlled trial (Goldenberg et al., 1995) in USA demonstrated that daily zinc supplementation with 25 mg/day zinc sulfate in women with relatively low plasma zinc concentrations in early pregnancy was associated with greater infant birth weights (126 g, P = 0.03). However, other studies found no effect of zinc supplementation on infants’ birth weight. Namely, one study reported (Zahiri Sorouri, Sadeghi & Pourmarzi, 2016) that 15 mg zinc supplementation daily from 16 weeks of pregnancy until delivery did not improve birth weight (3,262 g vs. 3,272 g, P = 0.780). In addition, one zinc supplementation trial indicated that no differences were noted in infants birth weight (3,267 ± 461 g vs. 3,300 ±498 g) by prenatal supplement type (iron + folate + zinc vs. iron + folate; P > 0.05), and there were no differences in the rates of LBW. A placebo-controlled trial in Bangladesh (Osendarp et al., 2000) demonstrated that supplementation with 30 mg zinc during the last two trimesters of pregnancy did not improve infant birth weights. One meta-analysis (Carducci, Keats & Bhutta, 2021) revealed that low or high doses of zinc supplementation during pregnancy were not significantly associated with high birth weight. Similarly, another meta-analysis (Warthon-Medina et al., 2015) showed that zinc supplementation during pregnancy (mean dose of 26.8 mg/day) might not attenuate the risk of LBW (RR = 0.76; 95% CI [0.52–1.11]). To the best of our knowledge, few previous studies have addressed the correlation between LBW and iron/zinc dietary intake, and there have been no previous studies of iron and zinc dietary intake interactions on LBW. Our results indicated that the simultaneous low intakes of iron and zinc preconception/during pregnancy might have an additive effect on the risk of LBW. Given the rarity of research on the combined effects of iron and zinc intakes on infant birth weight, further studies are warranted to confirm and interpret these findings. There are several strengths and limitations to be acknowledged in our study. First, information on dietary iron and zinc intake was obtained from participants’ self-reports, which may have led to recall bias. Second, quantitative analysis of the interaction between dietary multivitamins and trace elements was not feasible. Thus, there could be potentially confounding effects. Therefore, strict quality control was maintained throughout the process, from questionnaire design to data entry, to minimize recall bias. Detailed information on demographic data, medical history, and lifestyle factors allowed us to adjust and control for the confounding factors. LBW and its subtypes were diagnosed based on the medical records rather than based on self-reports, which minimized the risk of potential disease misclassification; in addition, this is the first large-scale sample study to comprehensively, systematically, and deeply explore the co-effects of dietary zinc and iron intake on LBW, which has important guiding significance for the next stage of research.

Conclusions

Our study suggests that lower intakes of iron and zinc preconception and during pregnancy may increase the risk for LBW. This study also suggests that low intakes of iron and zinc during pregnancy synergistically affect the LBW risk. These findings imply the importance of promoting iron and zinc intakes preconception and during pregnancy to reduce the incidence of LBW in Lanzhou City. Future human studies with data on maternal biological markers, mineral intake, and genetics are warranted to confirm these findings and elucidate underlying mechanisms.

Supplemental Information