Background
Review
Methods
Study inclusion parameters | Study exclusion parameters |
---|---|
- Human studies from 1950 to July 2015, with no language restriction | - Studies with nutrient interventions commencing during, but not before pregnancy |
- Blinded and unblinded randomised trials | - If time of intervention was unclear |
- Community-/population-based studies | - Poorly defined control or comparison groups |
- Ongoing randomised trials studies with published methodologies, but awaiting trial closure | - Observational human studies |
- Clear definition of nutrient intervention | |
- Indication of period of periconceptional supplementation | |
- Definition of outcome variables (maternal, fetal, or infant outcomes). | |
- Studies in non-pregnant women prior to ascertainment of pregnancy | |
- Starting early in first trimester up to 28 days after last menstrual period | |
- Individually randomised or population-based studies |
Results and discussion
Trial structures and outcome assessments
Trial design
The non-pregnant cohort
The pregnant cohort
The infant cohort
Generating mechanistic hypotheses as a trial basis
Maternal (biochemical, endocrine factors, and plasma volume) |
- Specific mineral deficiencies and impaired metabolic pathways [82] |
- Limited macronutrients required for fetal growth [82] |
- Adiposity [83] |
- Oxidative stress associated with deficiencies of specific micronutrient antioxidant activities [84] |
- Infection with transcriptional inflammatory response through IL-6 receptor alpha and prostaglandin response leads to cervical ripening and uterine contractions [85] |
- Homocysteine metabolic effects on obstetrical vascular disease or placental spiral artery function [86] |
- Interferon tau and progesterone effects on selective nutrient transport to the uterine lumen, with cell signalling pathways effecting, migration, and protein synthesis in trophectoderm [64] |
- Urinary metabolites measured at the end of the first trimester and increased risk of negative birth outcomes [87] |
- Biochemical markers of early placentation and downstream resistance to uterine arterial flow [77] |
- Sex-specific effects of first trimester progesterone levels [52] |
Placental (growth, morphology, vascularisation and function) |
- Alterations of number and surface area of arterioles in tertiary villi, and factors controlling endothelial re-modelling and trophoblast cell turnover from immature villi to conductance villi and gas exchanging terminal villi [16] |
- Impaired molecular signalling networks [91] |
- Reduced transfer capacity due to impaired utero-placental flow and fetal nutrient uptake [92] |
- Iron associated with markers of vasculopathy and placental growth factor excess [96] |
- Alterations in placental phenotype and availability of placental hormone receptors and effects of hormones on the morphology, transport capacity and endocrine function of the placenta [56] |
- Decreased nitric oxide bioavailability through low dietary arginine substrate and antioxidant supply [82] |
- Interference with folate homeostasis in malaria infected placentae [97] |
Fetal (embryonic, fetal growth factors and endocrine axes) |
- Periconceptional undernutrition accelerating fetal hypothalamic-pituitary-adrenal (HPA) axis activation [54], mediated by different influences of maternal glucocorticoid on maturation of the fetal HPA axis, via placental 11-beta-hydroxysteroid dehydrogenase isozymes. Fetal exposure to glucose, fatty acids, and micronutrients, with resultant increased fetal insulin secretion, could influence development of the HPA axis controlling infant appetite [57] |
- Placental metabolic alterations associated with the growth restricted fetus [89] |
- Pre-term birth frequency in the growth restricted fetus [98] |
- Altered fragility of chorioamniotic membrane [99] |
- Inadequate micronutrient supply [48] |
- One-carbon metabolic effects on methyl groups and DNA methylation [100] |
- Transport effects on methionine from the mother to the coelomic cavity and amniotic fluid [64] |
- Vitamin independent effect of homocysteine in the fetal metabolic cycle [64] |
- Thyroid hormone effects of mild/moderate iodine deficiency on cognitive ability and growth [102] |
- Fetal angiogenic and placental growth factors affecting newborn thyroid function [103] |
- Influence on development and activation of regulatory T cells in the human fetus [106] |
General mechanisms
Specific mechanisms
Selection of single versus multimicronutrient interventions
Trial country [reference] | Ca mg | Cu mg | Folic acid mg | I μg | Fe mg | Mg mg | Mn mg | Niacin mg | P mg | K mg | Se μg | Zn mg | Biotin μg | Vitamins | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
B1 mg | B2 mg | A μg | B12 μg | C mg | D IU | E mg | K μg | B5 mg | B6 mg | ||||||||||||||
Wales [20] | - | - | 4 | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - |
- | 2 | 0.4 | 150 | 30 | - | - | 18 | - | - | 65 | 15 | - | 1.4 | 1.4 | 240 | 2.6 | 70 | 200 | 1 | - | - | 1.9 | |
Hungary [30] | 125 | 1 | 0.8 | - | 60 | 100 | 1 | 19 | 125 | 100 | - | 7.5 | 200 | 1.6 | 1.8 | 1,800 | 4 | 100 | 500 | 1 | - | - | 2.6 |
Bangladesh [24] | - | - | 0.4 | - | 60 | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - |
India [25] | 240 | - | 4 | - | 120 | - | - | 15 | - | - | - | 10 | - | 2.5 | 2.5 | 1,200 | - | 40 | 400 | - | - | - | 2 |
Cuba [36] | - | - | 5 | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - |
Vietnam 1 [33] | - | - | 3.5 | - | 60 a | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - |
Netherlands [37] | - | - | 0.4b | ||||||||||||||||||||
China 1 [34] | - | - | 0.4 | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - |
100 | 2 | 0.4 | - | 10 | 30 | 3 | 14 | 77 | 4 | 30 | 10 | 100 | 1.4 | 1.4 | 169 | 3 | 60 | 200 | 8 | - | 4 | - | |
Burkina Faso [21] | - | - | 2.8 | - | 60 | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - |
Ireland [22] | 480 | - | 0.36 | - | 50 | - | - | 15 | - | - | - | - | - | 1.5 | 1.5 | 1,200 | - | 40 | 400 | - | - | - | 1 |
Algeria [38] | - | - | - | 240 | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - |
Multi-country 1 [23] | - | - | 4 | - | - | - | - | 13 | - | - | - | - | - | 1.5 | 1.5 | 1,200 | - | 40 | 400 | - | - | - | 1 |
Multi-country 2 [29]d | 280 | 4 | 0.4 | 250 | 20 | 65 | 2.6 | 36 | 190 | 200 | 130 | 15 | - | 2.8 | 2.8 | 800 | 5.2 | 100 | 1,000 | 20 | 45 | 7 | 3.8 |
Vietnam 2 c [26] | - | 2 | 2.8 | 150 | 60 | - | - | 18 | - | - | 65 | 15 | - | 1.4 | 1.4 | 800 | 2 | 70 | 600 | 10 | - | - | - |
Nepal [28] | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | 7,000 | - | - | - | 5 | - | - | - |
Single nutrient supplementation | Multimicronutrient supplementation |
---|---|
General points: | General points: |
(a) Potential negative interactions between multiple nutrients [107] (b) Identification of the gestational timing of specific nutrient effects (c) Allows specific hypotheses to be tested as single nutrient effects can be identified, e.g., calcium supplementation and pre-eclampsia [108], or folic acid and neural tube defects (d) Preferred for assessment of dose–response associations (e) Facilitates safety and adverse outcome assessments, e.g., infection risk with iron supplementation (NIH), or folate use and cancer risk [109] | (a) Nutrient synergisms enhance potential benefits [110] (b) Theoretical need for multiple nutrients from early in gestation, and for normal placentation (c) Balanced supply of carbohydrates, lipids, proteins and vitamins is critical to meet fetal and maternal energy needs, and for substrates for metabolic pathways [104, 111] (d) Unlikely single nutrient intervention will improve placental function, as combined deficiencies are common in low resource settings, and combination of nutrients potentially ameliorates several underlying nutrient deficiencies (e) Requirement for ideal mixture of functional amino acids and micronutrients to regulate key metabolic pathways [82] (f) Optimal nutrition from early in pregnancy may help ameliorate need for advanced therapies of neonatal care in low resource settings (g) Greater increase in body stores of nutrients than with single nutrient supplementation |
For iron: | Specific multimicronutrient effects: |
(a) Targets pre-existing iron deficiency anaemia and addresses need to enter pregnancy with adequate iron stores [112] (b) Data from experimental animals that iron status early in gestation may effect auditory responsiveness [113] (c) Assessment of specific interactions related to safety, e.g., iron-infection interactions influencing susceptibility to infection [14] | (a) Vitamins B2, B6, B12, magnesium and iron combined with folic acid may have greater protective effect in reducing risk of neural tube defects [30, 35, 114] (b) Benefits in improving content of breast milk for several nutrients [115] (c) Nutrient-nutrient synergisms may enhance iron absorption [116] (d) Folate and other vitamins measured longitudinally in pregnancy have values mostly below recommended levels [64], and accelerated breakdown suggested in addition to haemodilution [117] (e) Observational studies for less growth restriction and reduced pre-term birth with regular periconceptional multivitamins [118] (f) Evidence for improved birth weight with later gestational supplementation [8] |
For folate: | |
(a) Specific maternal and fetal metabolic enzyme polymorphisms can be targeted (e.g., methyl tetrahydrofolate reductase) [64] (b) Folate requirements increase steeply once the chorioallantoic placenta is formed and the fetal heart starts perfusion (about 22 days after fertilisation) (c) Folate and vitamin B12 linked to utero-placental vascular resistance [119] | |
For iodine: | |
(a) Mild to moderate iodine deficiency may influence cognitive development [102] | |
Placental and genetic | |
(a) Specific nutrients may be involved in expression of genes involved in placental function and cell cycle processes [120] (b) Identification of factors controlling trophoblast turnover from immature to mature villi |
Cohort size and composition
Population of women of child-bearing age (n) a | 15 – 19 yrs | 20 – 24 yrs | 25 – 29 yrs | 30 – 34 yrs | 35 – 40 yrs | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Fertility rates | Fertility rates | Fertility rates | Fertility rates | Fertility rates | |||||||||||
P1 | P2 | P3 | P1 | P2 | P3 | P1 | P2 | P3 | P1 | P2 | P3 | P1 | P2 | P3 | |
54.6 | 23.5 | 8.2 | 76.2 | 75.4 | 53.0 | 37.2 | 52.7 | 64.8 | 15.0 | 24.5 | 34.5 | 3.2 | 5.8 | 14.8 | |
1,000 | 55 | 24 | 8 | 76 | 75 | 53 | 37 | 53 | 65 | 15 | 24 | 35 | 3 | 6 | 15 |
2,000 | 110 | 48 | 16 | 152 | 150 | 106 | 74 | 106 | 130 | 30 | 48 | 70 | 6 | 12 | 30 |
3,000 | 165 | 72 | 24 | 228 | 225 | 159 | 111 | 159 | 195 | 45 | 72 | 105 | 9 | 18 | 45 |
4,000 | 220 | 96 | 32 | 304 | 300 | 212 | 148 | 212 | 260 | 60 | 120 | 140 | 12 | 24 | 60 |
5,000 | 275 | 120 | 40 | 380 | 375 | 265 | 185 | 265 | 325 | 75 | 144 | 175 | 15 | 30 | 75 |
Outcome measurements
Study activity | Non-pregnant | Pregnant | Placenta | Post-partum | Child (birth – 24 months) |
---|---|---|---|---|---|
Health history and assessment | Exclusion criteriaa Demographic and socio-economic status; Food security, dietary and drug history; Morbidity, obstetric and reproductive histories; BP; mental health; workload | Uterine artery pulsatility (UtAPI) and resistance indices (UtARI) at 28–32 w gestation;b BP; Ultrasound: 1st trimester: gestational and yolk sac development; 2nd/3rd: biparietal diameter, HC, AC, FL; LMP; drug use | History of pre-eclampsia | Mental health | Gestational assessment, infant feeding practices, neuro-behavioural assessments, fat-free mass oto-acoustic emissions; drug use |
Anthropometry c | Wt, Ht, MUAC, Skin-fold thickness, BMI, ultrasound of abdominal visceral fat | Wt, Ht, MUAC | Wt, diameter | Wt, Ht, MUAC, BMI | Wt, recumbent Lt, crown-rump Lt; head, upper arm, abdominal circumference |
Haematology | Baseline anaemia | Hb, MCHC, MCV, red cell distribution width | Cord Hb, ferritin, sTfR | Hb, cord clamping time | Hb at 3, 6 12 months |
Biochemistry | Iron biomarkers,d sera and RBC folate, micronutrient profiling, metabolome | Iron biomarkers, sera and RBC folate; amino acids, lipids, fatty acids, renal function, gluconeogenesis, anti-oxidant profile,e metabolome | Ratio plasminogen-activator inhibitor (PAI)-1: PAI-2,f uterine-artery Doppler waveform at 18–22 weeks gestation,f cord blood metabolitesg | Iron biomarkers, micronutrients, amino acids, lipids, fatty acids, breast milk composition | Iron and folate biomarkers, amino acids, lipids, fatty acids, micronutrients, anti-oxidant profile,e metabolome |
Endocrinology | Adipose tissue-secreted hormones (adipokines): leptin, visfatin, resistin, apelin, omentin, sex steroids, growth factors | Cortisol, progesterone, oestradiol, thyroid function, pregnancy associated plasma protein-A (PAPP-A); free β-human chorionic gonadotrophin (β-hCG) | Cord placental growth factor (PlGF); soluble FMS-like tyrosine kinase-1 (sFlt1)h | Adipokines | Hormonal growth factors, glucose homeostasis |
Infection | Blood/stool samples, STIsi HIV, bacterial vaginosis, vaginal microbiome | Bacterial vaginosis, STIs | Chorioamnionitis, malaria histology | Bacterial vaginosis, vaginal microbiome | Gut helminths, malaria, respiratory, diarrhoea, HIV, health attendances, fecal microbiome, thymic size |
Inflammation | CRP, AGP | CRP, AGP | Specific maternal-cord antibody titres | CRP, AGP | CRP, AGP |
Genotype profile | Blood storage | - | Micro RNAsj | - | Blood storage, micro RNAs |
Study contact | Health history and assessment | Haematology | Biochemistry | Anthropometry | Infection and inflammation screena |
---|---|---|---|---|---|
Screening | Demographicsb | - | - | - | - |
Randomisation | Reproductive,c general health, blood pressure, temperature, dietary,e drugs | Sera for iron biomarkers,d Hb if pallor or symptomatic | Blood for sera and genotype | Wt, Ht, BMI, MUAC | Malaria if symptomatic, vaginal, STI (syndromic) |
Non-pregnant cohort
| |||||
- Weekly visitsf | T0 C and morbidity,g side effects, compliance, | - | - | - | RDT for malaria if symptoms/febrile |
- Cross-sectional survey | T0 C and morbidity, side effects | - | - | - | All for malaria microscopy |
- Participant unscheduled visits | T0 C and morbidity, side effects | - | - | - | If symptoms |
- End assessment survey | T0 C and morbidity, side effects | Hb, iron biomarkers | Nutritional biomarkersh | Wt, Ht, MUAC | Malaria RDT and microscopy, BV, CRP, vaginal microbiome and lactoferrin, trichomonas |
-Focus groups/interviews | Knowledge and acceptability | - | - | - | - |
Pregnant cohort
| |||||
- First AN attendance i at 13–16 wks | T0 C and morbidity, ultrasound, blood pressure, drugs (IPTp), supplement, compliance, side effects | Hb, iron and folate biomarkers | Urine glucose and protein | Wt, Ht, MUAC | Malaria RDT and microscopy, CRP and AGP, BV, HIV, STI (syndromic), vaginal lactoferrin and microbiome, trichomonas |
- Second AN attendance at 32–36 wks | T0 C and morbidity, blood pressure, drugs (IPTp) | Hb if pallor or symptomatic | Urine glucose and protein | Wt, Ht | Vaginal lactoferrin and microbiome, other infections if symptoms |
- Unscheduled visits | T0 C and morbidity | Hb if pallor or symptomatic | - | Wt | Other infections if symptoms |
- Delivery | T0 C and morbidity, stillbirths | - | - | Wt | Placental histology for chorioamnionitis and malaria |
Infant follow-up
| |||||
-Live births | Gestational age | - | - | Wt, length, HC | - |
-Cross-sectional postnatal survey | Infant feeding, morbidity, health visits | Hb, iron biomarkers | - | Wt, length, MUAC | Malaria |
Adherence assessment
Trial location (reference) | Double blind | Tablet regimen | Supplement duration | Adherence assessment method | Side effects monitored | Adherence |
---|---|---|---|---|---|---|
Wales [20] | Yes | Daily | Not reported a | Serum folate cut-off | Yes | 73 % Not assessed in controls |
Yes | Daily | Mean 10.9 weeks pre-conception to 11 weeks post-conception | Two weekly home tablet counts | Yes | 88 %. | |
Median 24.1 weeks | Supplement clinic attendance 72 % | |||||
Hungary [30] | No | Daily | Up to 9 months pre-conception to 3 months gestation | Three monthly tablet counts | Yes | 71.5 % full course |
8.9 % no supplementsb | ||||||
19.6 % partial supplementsc | ||||||
Bangladesh [24] | Yes | Daily | Maximum 9 months | Monthly sachet counts | Yes | 57.7 ± 26.9 %d |
Mean 72.9 days | ||||||
India [25] | Yes | Daily | ≥1 month pre-conception – 3 months post-conception | Three monthly tablet counts | Yes | 34 % lost to follow-up before conception |
Cuba [36] | No | Daily | One menstrual period before conception − 10 weeks gestation | Not reported | No | 19.8 % partial supplementsc |
55.1 % no supplementsb | ||||||
Vietnam 1 [33] | No | Weekly vs daily | Up to 9 months | Tablet purchases | No? | 50-92.5 %, variable with period of follow-up |
Netherlands [37] | No | Daily | Not reported | Self-reported | No? | 29.6 % reported not using |
China 1 [34] | No | Daily | Maximum 38 months | Monthly bottle counts | No | 81–87 % periconceptionale |
74–75 % late usef | ||||||
68–78 % discontinuedg | ||||||
No | Daily | At least 3 months pre-conception. Mean 149.8 days pre- and 49.3 days post-conception | Monthly capsule counts | No | 85.7 % – 93 % compliance | |
Burkina Faso [21] | Yes | Weekly | Maximum 18 months | Directly observed intake | Yes | Trial in progress |
Ireland [22] | Yes | Daily | At least 2 months pre-conception | Tablet counts and blood testsh | Yes | Not reported |
Algeria [38] | No | Single dosage | Either 1–3 months pre-conception, or 1–3 months gestation | Directly observed | Not applicable | 100 %i |
Multi-country 1 [23] | Yes | Daily | Continuous until 12th week gestation | Three monthly capsule counts | Yes | 7 % discontinued;g 3–8 % took 50–79 %; 0.8 % took <50 % |
Multi-country 2 [29] | No | Daily | Not reported | Self-reported sachet use | Yes | Trial in progress |
Vietnam 2 [26] | Yes | Daily | Maximum 18 months | Two weekly capsule counts | Yes | Trial in progress |
Nepal [28] | Yes | Weekly | ≤3.5 years | Directly observed | No? | >75 % pregnant ≥ 50 % |
62 % non-pregnant ≥ 50 % |