SEARCH

SEARCH BY CITATION

Keywords:

  • early pregnancy;
  • women's nutrition;
  • birth outcomes

Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Comments
  6. Conflicts of interest
  7. References

Current understanding of biologic processes indicates that women's nutritional status before and during early pregnancy may play an important role in determining early developmental processes and ensuring successful pregnancy outcomes. We conducted a systematic review of the evidence for the impact of maternal nutrition before and during early pregnancy (<12 weeks gestation) on maternal, neonatal and child health outcomes and included 45 articles (nine intervention trials and 32 observational studies) that were identified through PubMed and EMBASE database searches and examining review articles. Intervention trials and observational studies show that periconceptional (<12 weeks gestation) folic acid supplementation significantly reduced the risk of neural tube defects. Observational studies suggest that preconceptional and periconceptional intake of vitamin and mineral supplements is associated with a reduced risk of delivering offspring who are low birthweight and/or small-for-gestational age (SGA) and preterm deliveries (PTD). Some studies report that indicators of maternal prepregnancy size, low stature, underweight and overweight are associated with increased risks of PTD and SGA. The available data indicate the importance of women's nutrition prior to and during the first trimester of pregnancy, but there is a need for well-designed prospective studies and controlled trials in developing country settings that examine relationships with low birthweight, SGA, PTD, stillbirth and maternal and neonatal mortality. The knowledge gaps that need to be addressed include the evaluation of periconceptional interventions such as food supplements, multivitamin-mineral supplements and/or specific micronutrients (iron, zinc, iodine, vitamin B-6 and B-12) as well as the relationship between measures of prepregnancy body size and composition and maternal, neonatal and child health outcomes.

Women's nutrition, before and during pregnancy, may play a key role in reproductive health and is recognised as being important for optimising pregnancy outcomes.1,2 The availability and supply of nutrients to the developing fetus depends on maternal nutritional status which in turn depends on her nutrient stores, dietary intake and obligatory requirements. Most of the studies that have examined the importance of nutrition during pregnancy typically focus on the second and/or the third trimester by which time key processes such as organogenesis have been completed.3 Women's nutritional status just before conception and/or during early pregnancy (<12 weeks gestation), when women are typically unaware of their pregnancy status, may influence pregnancy outcomes by affecting critical developmental processes that begin early in pregnancy as well as the availability of nutrients. Animal studies suggest that periconceptional undernutrition may influence the hypothalamic-pituitary-adrenal axis which in turn influences outcomes such as pre-eclampsia and preterm delivery (PTD).4 Ensuring an adequate supply of nutrients to the fetus throughout gestation also depends on placental function which is determined in early pregnancy and may be influenced by maternal nutrition during early pregnancy.3,5 Maternal endocrine and metabolic responses that occur early in pregnancy in turn influence the supply and utilisation of available nutrients for the rapidly growing fetus later in pregnancy.6,7

Various aspects of maternal nutrition that are particularly relevant for the developing world and may influence pregnancy outcomes are shown in Figure 1. Women living in resource poor settings are often malnourished before pregnancy; they may be short as a result of early childhood malnutrition, and underweight and anaemic due to inadequate food intakes and infections. In some settings, overweight and obesity are also emerging concerns due to poor diet.8,9 Several observational studies have shown that measures of body size such as height, weight and body mass index (BMI) are associated with adverse birth outcomes such as low birthweight (LBW) and small-for-gestational age (SGA), although the exact timing of body measurement is unclear.10–12 Age at the time of conception and duration of inter-pregnancy interval are also important as they may influence the availability of nutrients at the time of conception and during early pregnancy. Adolescent girls who have not completed their own growth and development may be at increased risk of being shorter, lighter and/or depleted stores of energy and micronutrients such as iron, iodine and vitamin A; women with short inter-pregnancy intervals may also be at increased risk of nutrient deficiencies in resource poor settings.13,14 Various nutrients may influence pregnancy outcomes by altering both maternal and fetal metabolism due to their roles in modulating oxidative stress, enzyme function, signal transduction and transcription pathways that occur early in pregnancy,3,15 namely during the critical periods of preconception, conception, implantation, placentation and embryo- or organogenesis. Nutrients such as iron, zinc, iodine and long chain n-3 polyunsaturated fatty acids (LCPUFA) play critical roles in development of the brain and nervous system, whereas vitamins A, B-6, B-12 and folic acid influence oxidative pathways and methylation.

image

Figure 1. Conceptual framework of stages of pregnancy potentially impacted by nutrition. BMI, body mass index; LBW, low birthweight.

Download figure to PowerPoint

Nutrition during early pregnancy may affect placental function, which has been associated with adverse pregnancy outcomes such as pre-eclampsia, PTD and fetal growth restriction. Proposed mechanisms include lowered number and surface area of arterioles in tertiary villi and reduction in spiral artery formation as a result of impaired function of trophoblasts due to oxidative stress and/or inflammation.5 LCPUFA and iron status during early pregnancy have been shown to be inversely associated with placental weight and surface area of capillaries involved in gas exchange, respectively.16,17 Several micronutrients can also influence inflammation and oxidative stress early in pregnancy; vitamins A and D, zinc and fatty acids may influence immune function whereas vitamins C, E, B-6, B-12 and folic acid may reduce oxidative damage to the placenta. Nutrients such as vitamins A, B-6, B-12 and folic acid and zinc also affect embryogenenesis that occurs early in pregnancy and may be related to pregnancy loss and fetal malformations. These nutrients are involved are in several biochemical pathways such as the homocysteine pathway and influence processes such as methylation which in turn affects cell replication and differentiation.5 The most well-studied effect of periconceptional nutrition is the protective effect of folic acid in the first 28 days of pregnancy in reducing the risk of delivering infants with neural tube defect (NTD), which contribute to significant mortality and morbidity.18–20 Much less is known about other nutrients.

The objective of this paper, which is part of a series on the role of maternal nutrition for improving maternal, neonatal and child health outcomes (MNCH) that are significant public health problems in many developing countries, is to conduct a systematic review of the evidence on the role of nutrition before and during early pregnancy on maternal morbidity and mortality, pregnancy loss including stillbirths, birth defects, LBW, PTD and infant mortality.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Comments
  6. Conflicts of interest
  7. References

Search strategy

We identified published studies using PubMed and EMBASE search engines. The search was carried out by combining the results of three separate strategies using the following key concepts and related key words: (1) preconception and periconception terms (‘preconception’ or ‘periconception’ or ‘prepregnancy’ or ‘pre-pregnancy’ or ‘before pregnancy’), (2) nutritional terms (‘intervention’ or ‘nutrition’ or ‘micronutrient supplementation’ or ‘food fortification’ or ‘body mass index’ or ‘weight’ or ‘multivitamin’ or ‘multivitamin-mineral’ or ‘vitamin’ or ‘iodine’ or ‘zinc’ or ‘folic acid’ or ‘iron’), and (3) maternal, neonatal and child health outcomes of interest (‘low birth weight’ or ‘birth size’ or ‘birth weight’ or ‘intrauterine growth restriction’ or ‘preterm birth’ or ‘preterm delivery’ or ‘gestational age’ or ‘morbidity’ or ‘mortality’ or ‘growth’ or ‘nutritional status’ or ‘stillbirth’ or ‘pregnancy loss’ or ‘birth defects’ and ‘neonatal’ or ‘infant’ or ‘child’ or ‘children’ or ‘maternal’). We included all studies from 1950 to July 2011 with no language restriction but limited to ‘humans’. Additional studies were identified through hand search of references from previous review articles. The inclusion and exclusion criteria were as follows:

Inclusion criteria: (1) intervention and observational studies, (2) nutrition exposure (intervention or indicators of nutritional status) was measured right before (within 1 year of conception) and/or during early pregnancy (<12 weeks gestation), (3) studies that included MNCH outcomes (namely, maternal morbidity and mortality, pregnancy loss, stillbirths, birth defects, birth size, PTD, neonatal and infant mortality), and (4) appropriate comparison group.

Exclusion criteria: (1) animal studies, (2) nutrition exposure was assessed or began at later stages of pregnancy (beyond first trimester), (3) non-nutritional studies, (4) review articles, and (5) poorly defined comparison group (for, e.g. in programme evaluations, intervention of interest continued during pregnancy).

Data abstraction

The abstracts of all potential publications were reviewed independently by two co-authors (T. G. and A. Z.) initially to identify eligible publications for data abstraction. The senior author (U. R.) reviewed publications that were identified for inclusion by only one co-author to determine eligibility. Relevant study attributes (qualitative and quantitative) were abstracted from the selected publications using standardised forms developed for the overall project by one co-author (T. G.) and reviewed for accuracy by another co-author (F. G.) and the senior author (U. R.). We assessed the overall quality of evidence for the outcomes by the Grading of Recommendations, Assessment, Development and Evaluation criteria.21,22

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Comments
  6. Conflicts of interest
  7. References

A total of 441 titles were identified on PubMed and EMBASE searches, of which we carefully reviewed 62 articles that included five that appeared in the review articles but not in the PubMed search (Figure 2). Careful examination of these studies resulted in the inclusion of 45 articles20,23–66 most of which were based on observational studies (Table 1). The main reasons for excluding articles after completing abstraction were: (i) the intervention and/or exposure occurred after 12 weeks gestation,67–74 (ii) missing our outcomes of interest,75–83 and (iii) did not measure periconceptional exposures.84,85

image

Figure 2. Studies excluded and included in the review of the preconception nutrition and pregnancy outcomes. *Some studies had more than one publication. MNCH, maternal, neonatal and child health outcomes.

Download figure to PowerPoint

Table 1.  Description of intervention and observational studies of periconceptional nutrition and maternal and child health outcomes
ReferenceDesign, nLocationPopulationIntervention/exposureOutcomes
  • a

    Reported significant associations.

  • BMI, body mass index; BW, Birthweight; CHD, congenital heart defects; CL, cleft lip; CLP, cleft lip with cleft palate; CP, cleft palate; FFQ, food frequency questionnaire; GA, gestational age; IUGR, intrauterine growth restriction; LAZ, length-for-age z-score; LBW, low Birthweight; LWZ, length-for-weight z-score; NTD, neural tube defects; OFC, oro-facial cleft; PIH, pregnancy induced hypertension; PTD, preterm delivery; RCT, randomised controlled trial; SGA, small-for-gestational age; WAZ, weight-for-age z-score.

Intervention trials
Berry et al., 199920Community-based intervention, 247 831ChinaWomen preparing for marriage who underwent a physical examination and were later registered with a monitoring system that records prenatal care and deliveryDaily supplement containing 400 µg folic acidNTDa
Chaouki and Benmiloud, 199430Community-based intervention, 1536AlgeriaWomen who were planning to be pregnantOral iodised oil 1–3 months before conception or during the first trimesterStillbirths, BWa, PTD
Chen et al., 200831Community-based intervention, 52 043ChinaResident women planning a pregnancy who volunteered to participate in follow-upDaily multivitamin supplement, containing 23 vitamins and microelements (including folic acid)NTDa
Czeizel et al., 1992, 199432,33RCT, 7540HungaryWomen (<35 years) planning a pregnancy (in most cases their first) who qualified for the Hungarian Family Planning Program trial in 1984Vitamin supplement (containing 12 vitamins including 0.8 mg of folic acid, four minerals and three trace elements) or a trace element supplement (containing copper, manganese, zinc and a very low dose of vitamin C) daily for ≥1 month before conception and until the date of the second missed menstrual period or laterNTDa, BW, GA, LBW, PTD, early pregnancy loss, stillbirth
Indian Council of Medical Research Collaborating Centres and Central Technical Co-ordinating Unit, 200038Double-blind, RCT, l466IndiaNon-pregnant women who had previously given birth to a child with open NTD and planned to have another childMultivitamin supplement (ferrous sulphate, calcium phosphate, vitamins A, D, B-1, B-2, B-6 and C, nicotinamide, zinc and folic acid) or placebo (ferrous sulphate and calcium sulphate) for ≥1 month prior to conception up to 3 month after conceptionRecurrence of NTDa, early pregnancy loss, stillbirth
Kirke et al., 199239Double-blind, RCT, 354IrelandNon-pregnant women who had previously given birth to a child with an NTD and planned to have another childFolic acid supplement, multivitamins without folic acid, or folic acid plus multivitamins for ≥2 month prior to conception until the third missed menstrual periodRecurrence of NTDa
Laurence et al., 198142Double-blind, RCT, 111WalesNon-pregnant women (<35 years) who had had a previous pregnancy complicated by a fetal NTD4 mg folic acid/day or placebo from the time contraceptive use was stopped until 6 weeks after a missed menstrual periodRecurrence of NTDa
Medical Research Council Vitamin Study Research Group, 199144Multicenter randomised double-blind prevention trial, 1817UKWomen at high risk of having a pregnancy with an NTD, because of a previous affected pregnancyFolic acid, other vitamins, both or neitherNTDa
Vergel et al., 199062Community-based intervention, 81CubaNon-pregnant women with a history of a previous NTD birth5 mg folic acid/day for not less than one menstrual period before conception until the 10th week of pregnancyRecurrence of NTDa
Observational studies     
Bitsko et al., 200723Case–control, 395USCases: mothers of infants/fetuses with ≥2 unrelated major birth defects affecting ≥2 different organ systems; Controls: random sample of liveborn, non-malformed infants born in the same time period to residents of the same geographical areaSelf-report of vitamin supplementation including ≥4000 µg folic acid ≥3 times/week periconceptionally (3 months before and after conception) or during the first trimesterMultiple congenital anomalies
Bower and Stanley, 199225Case–control, 154AustraliaCases: women who had infants/fetuses with an NTD; Controls: Women who had infants/fetuses with malformations other than NTDs or mothers of liveborn infants without malformationsSelf-report of vitamin supplement use in the 3 months before conception and the first 6 weeks of pregnancyNTD
Bower et al., 200624Case–control, 1053AustraliaCases: women who had infants/fetuses with an OFC, CHD, urinary tract defect, limb reduction defect, or other major birth defect; Controls were a random sample selected from the Midwives' Notification SystemSelf-report of vitamin supplementation periconceptionally, consumption of 174 foods and beverages (6 months before pregnancy), and consumption of any of a list of specific foods fortified with folic acid (6 months before pregnancy)Birth defects other than NTD
Bukowski et al., 200926Prospective cohort, 34 480USWomen who had singleton births at 20–42 weeks gestationSelf-report (during the first trimester) of preconceptional folate supplementation with or without multivitamins (≥1 year and <1 year)Pre-eclampsia, SGA, PTDa
Burris et al., 201027Retrospective cohort, 2464USNon-Hispanic white and black mothers of non-malformed infants who participated in the Slone Epidemiology Center Birth Defects StudyPericonceptional multivitamin use ≥4 times per week, containing at ≥2 water-soluble and two fat-soluble vitamins consumed during the period including the 28 days before and 28 days after the last menstrual periodBWa, weight for GA, GA
Catov et al., 200929Prospective cohort, 28 601DenmarkPregnant women early in gestationMultivitamin or folate-only supplement use during a 12-week periconceptional period (4 weeks prior 8 weeks after the last menstrual period)Pre-eclampsiaa
Catov et al., 201128Prospective cohort, 35 897DenmarkPregnant women early in gestationMultivitamin or folate-only supplement use during a 12-week periconceptional period (4 weeks prior 8 weeks after the last menstrual period)SGAa, PTDa
De Weerd et al., 200334Prospective cohort, 240the NetherlandsNon-pregnant women who became pregnant during the observation periodBody weight was measured and venous blood samples were assayed for several micronutrients (vitamins A, E, B-1, B-2, B-6, B-12, folate and iron)Pregnancy loss, BWa
Deierlein et al., 201135Prospective cohort, 363USMothers of infants who were not preterm and were not diagnosed with illnesses related to infant growthSelf-report of maternal pre-pregnancy BMI (underweight, normal, overweight, obese)WAZ, LAZ, LWZ
Ehrenthal et al., 201136Retrospective cohort, 16 582USWomen who delivered singleton pregnancies that were not <20 weeks gestationSelf-report of maternal pre-pregnancy BMI (underweight, normal, overweight, obese)PIHa
Han et al., 201137Retrospective cohort, 830South KoreaPregnant women in their second and third trimestersSelf-report of maternal pre-pregnancy BMI (underweight, normal, overweight, obese)LBWa, PTDa
Krapels et al., 200440,41Case–control, 409NetherlandsCases: mothers of a child with non-syndromic OFC; Controls: women with non-affected child of the same ageDietary intake according to FFQ 14 months after index birth to estimate preconception diet; Periconceptional vitamin from 4 weeks before and 8 weeks after conceptionOFC
Liu et al., 201143Retrospective Cohort, 5047ChinaWomen who had single, nulliparous pregnancies and delivered in one of three hospitals in the Shenyang areaPre-pregnancy BMIPre-eclampsiaa, PTD, SGAa, stillbirth
Murrin et al., 200745Prospective cohort study, 1048IrelandPregnant women, 14–16 weeks gestation attending their first antenatal visitSelf-report of pre-pregnancy BMI (<25, 25–30, >30)BW
Oddy et al., 200946Case–control, 710AustraliaCases: mothers of infants/fetuses born with a congenital anomaly; Controls: liveborn infants born >20 weeks gestationSelf-report of maternal pre-pregnancy BMI (underweight, normal, overweight, obese)heart defects, conotruncal defects, NTDs, urinary tract defects, OFCs, limb reduction defects
Ota et al., 201147Prospective cohort, 3022VietnamPregnant women with singleton pregnanciesSelf-report of pre-gestational BMI (low: <18.5, normal: 18.5–24.9, high: ≥25.0)SGAa, large-for-gestational age
Phithakwatchara and Titapant, 200748Retrospective cohort, 660ThailandPregnant women at risk for gestational diabetesPre-pregnancy BMI based on medical records, women with BMI ≥ 27 were compared with women with a BMI of 20–25Pre-eclampsiaa, LBW, PTD
Rayco-Solon et al., 200549Retrospective cohort, 2977GambiaWomen who had spontaneous vaginal births at home or at the primary care clinic with the assistance of a midwifeMonth of birth (determines changes in maternal weight because of fluctuation in rains)GAa
Ronnenberg et al., 200251Case–control, 458ChinaFemale textile workers who experienced at least one clinically recognised pregnancy during follow up; Cases: ended in fetal death <100 day gestation or livebirth; Controls: ended in a livebirthHomocysteine, folate, and vitamins B-6 and B-12 concentrations were measured in plasma obtained before conceptionPregnancy lossa
Ronnenberg et al., 2002, 200450,54Prospective cohort, 405ChinaNon-pregnant women textile workers, newly married, aged 21–34Homocysteine, folate, and vitamins B-6 and B-12 concentrations were measured in plasma obtained before conceptionLBW, SGAa, BW, IUGR, GA, PTD, infant length, head circumference
Ronnenberg et al., 200353Prospective cohort, 575ChinaNon-pregnant women textile workers, newly married, aged 21–34Examined maternal BMI prior to preconception (moderately underweight or severely underweight vs. normal BMI)BWa, LBWa, BW ratio, IUGR, GA, PTD, infant head circumference and length, ponderal index
Ronnenberg et al., 200752Prospective cohort, 364ChinaNon-pregnant women textile workers, newly married, aged 21–34Homocysteine, folate, and vitamins B-6 and B-12 concentrations were measured in plasma obtained before conceptionPregnancy lossa
Shaw et al., 199556Case–control, 1089USCases: mothers of infants/fetuses with an NTD; Controls: mothers of singleton infants without NTDsSelf-report of vitamin supplement use containing folic acid 3 months before/after conceptionNTDa
Shaw et al., 199957Case–control, 829USCases: mothers of infants/fetuses with an NTD; Controls: mothers of singleton infants without NTDsNutrient intake according to FFQ, self-report of supplemental vitamin containing folic acid beginning 3 months before conceptionNTDa, spina bifida, isolated CPa
Shaw et al., 200255Case–control, 1860USCases: mothers of infants/fetuses with a congenital anomaly; Controls: mothers of liveborn infants with no major congenital anomaliesWomen's report of use of a vitamin supplement that contained folic acid in the period 1 month before conception through 3 months after conceptionConotruncal defects, isolated CL, CLP, or CP, NTD, limb deficiency defectsa
Timmermans et al., 200958Prospective cohort, 6353the NetherlandsPregnant womenSelf-reported folic acid supplement use (0.4–0.5 mg/day) during first 8 weeks of pregnancyLBWa, SGAa, GA, PTD,
van Beynum et al., 201059Case–control, 3012the NetherlandsCases: mothers of infants with isolated or complex heart defects, without any related syndrome or genetic abnormality; Controls: mothers of infants with a known chromosomal or genetic defect or with other non-folate related congenital malformationsSelf-report of folic acid supplementation (≥400 µg/day) starting at least 4 weeks prior to conception and continuing up to 8 weeks thereafterCHDs
van Driel et al., 200860Case–control, 281the NetherlandsCases: families with children with a CHD; Controls: families with children without a congenital malformation or chromosomal abnormalitySelf-report of periconceptional use of folic acid supplements and completion of a validated FFQ on dietary folic acid and vitamin B-2 intake 17 months after index pregnancyCHD
Velie et al., 199961Case–control, 859USCases: mothers with NTD-affected infants/fetuses; Controls: randomly selected non-malformed infantsSelf-report of preconceptional use of vitamin, mineral, and food supplements and completion of a FFQNTD
Vujkovic et al., 200763Case–control, 381the NetherlandsCases: mothers of a child with CL or CLP; Controls: mothers of non-malformed childrenMaternal nutritional intakes assessed 14 months after index birth to estimate preconception intakeCL, CLPa
Werler et al., 199364Case–control, 3078US and CanadaCases: mothers of infants/fetuses with NTD; Controls: mothers of infants/fetuses with other major malformation, excluding OFCsSelf report of multivitamin use containing ≥2 vitamins, one which was water soluble taken 28 days before and after conceptionNTDa
Yazdy et al., 200765Pre–post, 420 832USWomen giving birth in 54 states in the US (and DC)Impact of folic acid fortification (pre vs. post-fortification)OFCa
Yeh and Shelton, 200766Retrospective cohort, 1342USWomen who delivered live-born twins in Western upstate New YorkMaternal pre-pregnancy BMI (underweight, normal, overweight, obese) based on information from birth certificatesmean twin BW, GA

We identified six intervention trials20,30,33,38,39,42,44,62,76 and seven observational studies26,29,34,36,43,48,51,52 that examined the relationship between preconception and/or periconception maternal nutritional status and maternal morbidity and pregnancy loss including stillbirth. In the case of child outcomes, we included nine intervention trials20,30–33,38,39,42,44,62 and 28 observational studies23–28,34,35,37,40,41,43,45–50,53–61,63–66 that examined the effects on birth defects, birth size and PTD. We did not find any studies that examined maternal or neonatal mortality. The key findings are described by outcome in the following sections and additional details are available on request.

Maternal health

Four observational studies26,29,43,48 examined the effects of prepregnancy and/or periconceptional nutrition on the risk of developing pre-eclampsia later in pregnancy. Phithakwatchara and Titapant48 reported that the risk of pre-eclampsia was significantly increased [odds ratio (OR): 3.87 [95% confidence interval (CI) 2.09, 7.25]] in overweight Thai women (pre-pregnancy BMI ≥ 27 kg/m2) compared with normal weight women (BMI of 20–25 kg/m2), after adjusting for the confounding factors. This study used data from a retrospective review of medical records of the pregnant women who were at risk of gestational diabetes. Similar findings were reported in a large study of singleton nulliparous pregnancies delivered in three hospitals in Shenyang, China using data obtained from medical records.43 Compared with normal weight women (18.5 ≤ BMI < 24 kg/m2), overweight (24 ≤ BMI < 28 kg/m2) and obese women (BMI ≥ 28 kg/m2) had significantly increased risks [adjusted risk ratio (RR): 5.7 [95% CI 4.0–8.1] and 3.0 [95% CI 2.2–4.1]] of pre-eclampsia. Ehrenthal et al.36 also found that prepregnancy BMI (based on self-report) was positively associated with the risk of pregnancy-induced hypertension.

In a secondary analysis of a large prospective cohort study, Bukowski et al.26 found no significant association between duration of preconceptional folate supplementation and the risk of pre-eclampsia (OR: 1.05 [95% CI 0.85, 1.31]) or placental abruption (OR: 0.80 [95% CI 0.55, 1.14]). In contrast, regular consumption of multivitamin supplements during the periconceptional period was associated with a 22% reduced risk of pre-eclampsia [hazards ratio (HR): 0.78 [95% CI 0.60, 0.99]] in a study using data from the Danish National Birth Cohort (1997–2003).29

Pregnancy loss

De Weerd et al.34 evaluated the relation between maternal periconceptional biochemical and haematological parameters and early pregnancy loss in a prospective study of 240 women in the Netherlands. Women were recruited before pregnancy and body weight measurements and blood samples were taken preconceptionally and at 6 and 10 weeks amenorrhea. Prepregnancy weight was positively associated with the risk of early pregnancy loss (P < 0.05) but relationships with concentrations of several biomarkers of vitamin status were non-significant in this well-nourished population. In contrast, findings from an observational study of Chinese women textile workers suggest that preconception micronutrient status may be negatively associated with pregnancy loss.51,52 Ronnenberg et al.51 found that suboptimal preconception folate and vitamin B-6 status, especially when they occurred together, was associated with an increased risk of clinical spontaneous abortion (P for trend = 0.06 and 0.07, respectively) in a case–control analysis in which cases (n = 49) were women with a clinically recognised pregnancy who experienced a fetal death before 100 days' gestation and controls (n = 409) were women who maintained a pregnancy that ended in a livebirth. Ronnenberg et al.52 also found that compared with women in the lowest quartile of vitamin B-6 levels, those in the third and fourth quartiles were more likely to conceive (adjusted HR: 2.2 [95% CI 1.3, 3.4], HR: 1.6 [95% CI 1.1, 2.3], respectively), and the risk of early pregnancy loss in conceptive cycles was lower in the fourth quartile (OR: 0.5 [95% CI 0.3, 1.0]). This analysis was done in the subsample of 364 women who conceived at least once during the period 1996–1998. Liu et al.43 did not find any significant differences in the risk of stillbirth by categories of prepregnancy BMI.

Five intervention trials33,38,39,42,44 evaluated the effect of periconceptional folic acid on miscarriages and/or stillbirths and found no significant differences. These trials were conducted primarily in developed countries among women at risk of delivering a child with NTD and have been described below. One trial that was conducted in Algeria, evaluated the effect of providing iodised oil in women either before or during the first trimester of pregnancy and reported a non-significant reduction in the incidence of stillbirths when compared with women who received no intervention.30

Birth defects

We found eight intervention trials20,31–33,38,39,42,44,62 and 14 observational23–25,40,41,46,55–57,59–61,63–65 studies that evaluated the relationship between maternal preconceptual and periconceptional nutrition and risk of birth defects, especially NTD. Czeizel et al.32,33 compared the risk of NTD births among women receiving vitamin supplement (containing 0.8 mg folic acid) and those receiving trace-element supplements daily from at least 1 month before conception and until the date of the second missed menstrual period or later in a randomised controlled trial (RCT) among 7540 Hungarian women (<35 years) and showed significant reductions (P < 0.05) in congenital malformations (13.3/1000 and 22.9/1000 in the vitamin and trace-element group, respectively) and the first time occurrence of NTD (6 vs. 0 NTD cases in the trace-element and vitamin supplement group). The MRC Vitamin Study Group44 also evaluated the effects of supplementation with folic acid or a mixture of seven other vitamins (A, D, B-1, B-2, B-6, C and nicotinamide) around the time of conception in a large multicenter double blind RCT of 1817 women in the UK and other countries and reported a 72% reduction in the incidence of NTDs in the folic acid group (RR: 0.28 [95% CI 0.12, 0.71]) but no significant protective effect for the other vitamins group (RR: 0.80 [95% CI 0.32, 1.72]) when compared with a placebo. Intervention trials in China, India and Ireland have shown similar results.20,31,38,39

Observational studies have also shown the protective effect of folic acid in reducing birth defects. Shaw et al.56 found that women who consumed a folic acid-containing supplement in the 3 months before conception had a lower risk of having an NTD-affected pregnancy (OR: 0.65 [95% CI 0.45, 0.94]) when compared with non-users. Werler et al.64 also found that daily periconceptional intake of 0.4 mg of folic acid was associated with a 60% reduction in the risk of occurrent NTDs in a case–control study where cases were mothers of infants/fetuses with NTD while controls consisted of mothers of infants/fetuses with other major malformation, excluding oro-facial clefts (OFC). The exposure was defined as consumption of multivitamin supplements containing ≥2 vitamins including folic acid 28 days before and after conception. In contrast, Bower and Stanley25 did not find an association between periconceptional vitamin supplementation and NTDs in a case–control study in Australia. Recall bias and small sample size may have been limitations. We also found a case–control study61 in which higher preconceptional zinc intake was associated with a reduced risk for NTD (quintile 5 vs. quintile 1, OR: 0.65 [95% CI 0.43, 0.99]) cases were 430 NTD-affected fetuses/infants, and controls were 429 randomly selected non-malformed infants.

A few studies have examined the relationship between preconceptional nutrition and other birth defects such as cleft palate and congenital heart defects (CHD). Vujkovic et al.63 assessed maternal preconceptional nutritional intakes in a case–control study of 203 mothers of a child with a cleft lip or cleft palate and 178 mothers with non-malformed offspring and found that the Western dietary pattern, for example, high in meat, pizza, legumes and potatoes, and low in fruits, was associated with a high risk of a cleft lip or cleft palate (OR: 1.9 [95% CI 1.2, 3.1]). Bower et al.24 found no association between folic acid supplement use during the periconceptional period and risk of birth defects other than NTD. Cases were women whose infants had OFC (n = 62), CHD (n = 151), urinary tract defects (n = 117), limb reduction defects (n = 26) or other major birth defects (n = 119). There were 578 control women. Van Driel et al.60 in a case–control study of Dutch women also found no significant differences in periconceptional use of folic acid supplements and dietary intakes of total energy, folate, and vitamin B-2 between case (infants with CHD) and control-mothers, but reported a significant interaction between genetics and folic acid supplement use during the periconceptional period (P = 0.008); the OR [95% CI] of the mothers carrying the MTHFR AC and CC genotypes in the supplemented vs. the non-supplemented group was 1.8 [95% CI 1.01–3.1] vs. 0.6 [95% CI 0.3–1.1], respectively. A case–control study in the Netherlands40,41 also showed a trend towards risk reduction for OFC with increasing dietary intake of thiamine (P = 0.04) and pyridoxine (P = 0.03) among women who consumed folic acid supplements periconceptionally. Finally, Yazdy et al.65 reported a significant decline in OFC prevalence following folic acid fortification (prevalence risk: 0.94 [95% CI 0.92, 0.96]) based on retrospective cohort analysis of US birth certificate data from 45 states and the District of Columbia in which births were compared during the pre-fortification period (January 1990–December 1996) and post-fortification period (October 1998–December 2002).

Birth size

We identified two intervention trials30,33 and 14 observational studies26,27,34,35,37,43,45,47,48,50,53,54,58,66 that examined the relationship between prepregnancy and/or periconceptual nutrition and birth size. Chaouki and Benmiloud30 evaluated the benefits of providing oral iodised oil to women just before conception or during the first trimester in a study conducted in a region of endemic goiter in Algeria. The offspring of treated women (n = 1536) had significantly higher birthweight (+6.25%) when compared with non-treated women. Czeizel et al.33 found no significant differences in the risk of LBW when they compared women who received folic acid containing supplements before 12 weeks gestation with those who received a supplement containing only trace elements (copper, manganese and zinc) and vitamin C. Mean birthweight was much higher in both groups compared with the general population.

Several observational studies have examined the association with maternal nutritional status based on anthropometric measurements such as weight and height and/or vitamin supplement use during the periconceptional period and birth size. Liu et al.43 reported an increased risk of delivering a SGA infant (adjusted RR: 1.7 [95% CI 1.1, 2.6]) among underweight women (BMI < 18.5 kg/m2) in a retrospective study of Chinese women. Ronnenberg et al.53 reported similar findings in a prospective cohort study that examined the relationship between pre-pregnancy BMI and birth outcomes among 20- to 34-year-old Chinese women (n = 575); infants born to mothers who were underweight before pregnancy (BMI ≤ 18.5 kg/m2) were at increased risk for fetal growth deficits. Being underweight was also associated with smaller infant head circumference and lower ponderal index. Prepregnancy weight (P < 0.01; partial r2 = 0.24) was positively associated with infant birthweight in a prospective study of 240 women in whom measurements were obtained preconceptually in the Netherlands.34 Most recently, a large prospective study from Vietnam47 also reported a significantly higher risk of delivering a SGA infant (adjusted OR: 1.95 [95% CI 1.52–2.50], P < 0.01) among women who were underweight before conception (BMI < 18.5 kg/m2) compared with those with BMI between 18.5 and 23.0 kg/m2. There were no significant differences for the group with higher BMI (>23 kg/m2). Similarly, no significant differences were reported in the risk of LBW (OR: 0.57 [95% CI 0.29, 1.14]) by maternal overweight (BMI ≥ 27 kg/m2) in a retrospective study of Thai women.48

Ronnenberg et al.54 also assessed the association between preconception anaemia and iron status and infant growth and pregnancy outcomes and found that preconception anaemia, particularly iron-deficiency anaemia, was associated with reduced infant growth (lower birthweight). The risks of LBW and fetal growth restriction (defined as <85% of a birthweight ratio calculated as the observed birthweight*100/mean birthweight of infants with the same gestational age within the cohort) were significantly greater among women with moderate anaemia compared with non-anaemic controls (OR: 6.5 [95% CI 1.6, 26.7], P = 0.009 and OR: 4.6 [95% CI 1.5, 13.5], P = 0.006, respectively). A few studies, primarily in developed countries have also examined the relationship between periconceptional multivitamin use and birth size. In a retrospective cohort study of non-Hispanic white (n = 2331) and non-Hispanic black (n = 133) mother–infant pairs, Burris et al.27 assessed the association of maternal periconceptional multivitamin use and infant birthweight disparities between infants delivered by whites and those delivered by their African American women counterparts. Multivitamin use was associated with a 536 g increased birthweight (P = 0.001) among African Americans; no association between multivitamin use and birthweight or gestational age was found among white subjects. This study used a more restrictive definition of periconceptional as the period between 28 days prior to the date of the last menstrual period to 28 days after last menstrual period. In a population-based prospective cohort study, Timmermans et al.58 evaluated the impact of self-reported folic acid supplement (0.4–0.5 mg/day) and found that periconceptional folic acid supplementation (<8 weeks of gestation) was associated with higher placental (13 g [95% CI 1.1, 25.5]) and birthweight (68 g [95% CI 37.2, 99.0]); reduced risks for LBW (OR: 0.43 [95% CI 0.28, 0.69]) and SGA (OR: 0.40 [95% CI 0.22, 0.72]) were observed for women who started supplementation preconceptionally, compared with those who did not use folic acid. A significant interaction by parity was also observed, with larger differences in birthweight by supplement use among multiparous compared with nulliparous women. The adjusted risk for a SGA birth was also significantly reduced among regular users of multivitamins during the periconceptional period (<12 weeks gestation) regardless of their prepregnancy BMI (HR: 0.83 [95% CI 0.73, 0.95]) compared with non-users in the Danish National Birth Cohort Study (n = 35 897).28

Preterm delivery/gestational age

We found two intervention trials30,33 and 11 observational studies26–28,37,43,48–50,53,54,58,66 that examined the relationship between preconceptual or periconceptional nutrition and gestational age and/or risk of PTD. There were no significant differences in the incidence of PTD in the large intervention trial in Hungary that examined the benefits of providing folic acid containing supplements before 12 weeks of gestation, but both groups received other micronutrients like zinc. Chaouki and Benmiloud30 found no differences in PTD among women who received iodised oil during the first trimester of pregnancy.

Rayco-Solon et al.49 evaluated the effect of preconceptional undernutrition among rural Gambian women who experience annual fluctuations in energy balance and found significantly shorter gestational ages for pregnancies conceived in September to November (when lower weights are recorded) than those from better-fed months (38.6 vs. 39.0 weeks; log-rank χ2 = 17.4, P < 0.0001). Data were obtained prospectively in this study. Liu et al.43 obtained measures of body size (weight and height) before 12 weeks gestation from health records and found that the adjusted odds of early PTD (<34 weeks) was significantly elevated (RR: 3.4 [95% CI 1.2, 9.4]) among obese women (BMI > 28 kg/m2) when compared with normal weight women (18.5 < BMI < 24); there were no differences in the risk of PTD (<37 weeks) by maternal prepregnancy size in contrast to findings from earlier observational studies.37,48,53,58,86–88 Han et al.37 found that high pre-pregnancy maternal BMI (>25 kg/m2) increased the risk of PTD (OR: 2.85 [95% CI 1.20, 6.74]) in a study of Korean women.

Using a case–control design, Ronnenberg et al.50 found that elevated homocysteine (≥12.4 µmol/L) during the preconceptional period was associated with a higher risk of PTD (OR: 3.6 [95% CI 1.3, 10.0], P < 0.05). The risk of PTD was also 60% lower among women with serum vitamin B-12 ≥258 pmol/L than among vitamin B-12-deficient women (OR: 0.4 [95% CI 0.2, 0.9], P < 0.05). Similar reductions were seen with among vitamin B-6-deficient women (OR: 0.5 [95% CI 0.2, 1.2]), but they were not statistically significant. Folate status was not associated with PTD. In contrast, Bukowski et al.26 reported that preconceptional folate supplementation that was prospectively recorded in the first trimester of pregnancy was associated with significant reductions in the incidence of early spontaneous PTD (HR: 0.22 [95% CI 0.08, 0.61], P = 0.004). Regular periconceptional multivitamin use was associated with reduced risk of PTD in non-overweight women (HR: 0.84 [95% CI 0.73, 0.95]) who participated in the Danish Birth Cohort Study.28 We did not find any reports of controlled trials in developing country populations where there is greater risk of inadequate nutrient intakes.

Comments

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Comments
  6. Conflicts of interest
  7. References

The majority of studies identified in our review were observational with few well-designed intervention trials. The overall quality of evidence was low for most outcomes with the exception of the benefits of maternal preconception folic acid for reducing the risk of NTD, which was high (Table 2) and based on several well-designed intervention trials. The most recent meta-analysis by De-Regil et al.89 that included five intervention trials32,33,38,39,42,44 confirmed the findings of an earlier review18 that estimated a 72% reduction in the risk of NTD (RR: 0.28 [95% CI 0.13, 0.58]). These findings have led to recommendations promoting the use of supplements and/or fortified foods containing folic acid by women of reproductive age (WRA) in many countries. The universal fortification of staple foods such as flour and ready-to-eat cereals in countries such as the US, Canada, Chile and Costa Rica has been linked to significant reductions in the incidence of NTD in these countries.90,91 Some of the studies we reviewed also suggest that increased intakes of folic acid and other nutrients are associated with reduced risk of other congenital birth defects.40,41,63,65 Unpublished findings based on follow-up of offspring in the SINO-US NTD prevention project have shown that daily consumption of 400 µg of folic acid during the periconceptional period was associated with reduced infant mortality among infants without major birth defects (RR = 0.78 [95% CI 0.72, 0.85]) and improved linear growth.92,93 There were no differences in behaviour and cognitive development during early childhood in the same study population94,95 in contrast to a recent study in which maternal consumption of supplements containing folic acid during the periconceptional period (4 weeks before pregnancy to <8 weeks gestation) was associated with a significant reduction (20%) in the risk of moderate language delay among the offspring (singleton non-intrauterine growth restriction) at 3 years of age in a Norwegian birth cohort.96 Finally, no benefit was reported in a recent meta-analysis of four trials that examined the effects of were periconceptual folic acid supplementation on stillbirths (RR: 0.96 [95% CI 0.51, 1.83]); all trials were conducted among women with a history of NTD in a previous pregnancy.89

Table 2.  Quality assessment and summary of findings
No. of studiesStudy designQuality assessmentQualitative summary of findings
LimitationsConsistencyGeneralisable to resource-poor populationsGeneralisable to intervention of interest
  1. BMI, body mass index; LBW, low Birthweight; NTD, neural tube defects; RCT, randomised controlled trial; SGA, small-for-gestational age.

Pre-eclampsia: overall quality of evidence = very low
4Three prospective cohort, one retrospective cohortUnclear if measures of exposure were restricted to preconception and/or the first trimester of pregnancy only; no intervention trialsNoUS, Denmark and overweight Thai women at risk for gestational diabetes; ChinaTwo studies examined periconceptional multivitamin use.One of two large studies showed reductions in pre-eclampsia in multivitamin users; one study from China showed positive associations with overweight
Two studies examined prepregnancy BMI.
Pregnancy loss: overall quality of evidence = low
10Six intervention trialsBlinding unclear for some trials; studies among women with history of NTDNoAlgeria (high risk of endemic goiter)Iodised oil.No significant differences for in stillbirth
Ireland, Hungary, UK, India and ChinaFive of six studies provided multivitamins containing folic acid.
Four observational studiesRecall and selection bias the Netherlands, ChinaBiomarkers of nutritional status (water soluble vitamins and iron) in samples collected just before and/or in early pregnancy.One prospective study in China found associations between vitamin status and pregnancy loss whereas the one from Netherlands found no associations.
• Two prospective cohort
• One retrospective cohort
• One case–controlPrepregnancy BMI.One study showed no differences in stillbirth by maternal BMI.
Birth defects: overall quality of evidence = high
22Eight intervention trials YesIreland, Hungary, UK, India, ChinaPreconceptional use of supplements containing folic acid with other micronutrients72% reduction in NTD among women who consumed folic acid containing supplements during the periconceptional period
14 Case–controlRecall bias and small sample size for some studies Many studies in North America, Europe, Australia, and ChinaRegular use of multivitamin supplements, dietary intakes, folic acid fortificationMixed findings with suggestion of benefit of NTD and other birth defects as well
Birthweight (g): overall quality of evidence = low
7Two intervention trialsBlinding unclear for study in Algeria and allocation was broken early in Hungarian RCTNoAlgeria (has endemic goiter), Hungary (low risk of deficiencies)Iodised oil.Significantly higher birthweight for iodine but no differences for multivitamin group but control group also received selected nutrients (Cu, Zn, Iron and Mg)
Multivitamin supplements containing folic acid and several other vitamins.
 Five observational studiesExposures varied from prepregnancy body size to micronutrient statusNothe Netherlands, US, China, IrelandStudies examined blood tests, supplementation (folic acid, multiple micronutrient) and pre-pregnancy BMIUnderweight is positively associated with birthweight
• Three prospective cohort
• Two retrospective cohort
LBW (<2500 g): overall quality of evidence = low
6One intervention trialAllocation was broken early in Hungarian RCTNoHungary (low risk of deficiencies)Multivitamin supplements containing folic acid and several other vitaminsNo significant differences
Five observational studiesRecall and selection bias especially in retrospective studies.NoKorea, Thailand, Netherlands, ChinaBiomarkers of nutritional status, preconceptional multivitamin supplement use and pre-pregnancy BMIAll prospective studies suggest benefit of periconceptional micronutrient status or supplement use
• Three prospective cohort
• Two retrospective cohortExposures varied from prepregnancy body size to micronutrient status.
SGA: overall quality of evidence = low
8Five prospective cohort,Recall and selection bias especially in retrospective studies.NoChina, Vietnam, US, Netherlands, DenmarkStudies examined blood tests, supplementation (folic acid, multiple micronutrient) and pre-pregnancy BMIPericonceptional use of multivitamin supplements is associated with reduced risk of SGA in developed countries.
Three retrospective cohortVarying definitions for exposures and outcomes.
Low BMI (<18.5 kg/m2) before or during early pregnancy is associated with increased risk of SGA in prospective studies.
Gestational age (weeks): overall quality of evidence = low
7One intervention trialAllocation was broken early in Hungarian RCTNoHungary (low risk of deficiencies)Multivitamin supplements containing folic acid and several other vitaminsNo differences
Six observational studiesRecall and selection bias especially in retrospective studies. US, China and GambiaStudies examined blood tests, multiple micronutrient supplementation, pre-pregnancy BMI, and time of yearMixed findings
• Three prospective cohort
• Three retrospective cohortFew well-designed studies by specific exposure (BMI, supplement use and micronutrient).
Preterm delivery: overall quality of evidence = low
8Two intervention trialsBlinding unclear for study in Algeria and allocation was broken early in Hungarian RCTNoAlgeria (has endemic goiter), Hungary (low risk of deficiencies)Iodised oil.No differences in both trials
Multivitamin supplements containing folic acid and several other vitamins.
Six observational studiesRecall and selection bias especially in retrospective studies US, the Netherlands China and Korea, ThailandMultivitamin-mineral supplement use (3) and pre-pregnancy BMI (3)Two of three prospective studies show benefit of periconceptional micronutrient supplement.
• Three prospective cohort
Two studies indicate increased risk among overweight women.
• Three retrospective cohort

Overall, we found few studies from developing country settings where maternal malnutrition is common. Short interpregnancy interval, which has the potential to result in maternal depletion of nutrients including folate, iodine and iron, has been associated with increased risk of adverse outcomes such as fetal growth restriction and developmental abnormalities.13,14 For example, severe iodine deficiency during pregnancy has been associated with adverse pregnancy outcomes including cretinism97 and although we found a few intervention studies30,69,74 that suggest that providing iodine during early pregnancy to women living in iodine deficient areas improve birth size, we had to exclude some of them because the exact nature and timing of the intervention was unclear. Universal salt iodisation has been a successful strategy towards the elimination of iodine deficiency disorders but the importance of iodine in settings where mild-moderate iodine deficiency exists has not been studied adequately and appropriate intervention in WRA may have the potential to improve MNCH outcomes. Several intervention trials have also shown that the provision of weekly iron-folic acid supplements to WRA in developing country populations can improve iron status and reduce the risk of anaemia73,75,76,78–80,82 but few have evaluated the benefits of these interventions for pregnancy outcomes. This is a major gap given the high prevalence of iron deficiency and anaemia in WRA (before and during pregnancy) in many developing countries and our understanding of the mechanisms that suggest that iron status during the periconceptual period may be as important as iron status during the latter half of pregnancy for improving MNCH outcomes.3 We found only one observational study that showed that anaemia during the preconception period in WRA is associated with increased risk of unfavourable pregnancy outcomes and reduced infant growth.54 The major cause of anaemia is iron deficiency, however, deficiencies of other micronutrients such as folate, vitamins B-6 and B-12 can also cause anaemia, indicating that the inclusion of these nutrient may be beneficial. Periconceptional anaemia may influence the synthesis of hormones and thus adversely affect infant growth.3,98 The current review, including mostly observational studies in developed countries, suggests that preconceptional and periconceptional intake of vitamin and mineral supplements or dietary intake of such nutrients may reduce the risk of adverse outcomes such as PTD and LBW.

We found few well-designed studies that carefully examined the relationship between maternal size and body composition during the periconceptional period with adverse pregnancy outcomes such as stillbirth, PTD and LBW. Recent reviews and meta-analyses have concluded that balanced protein-energy supplementation during pregnancy was associated with reduced stillbirth rates and LBW, but none of the studies examined the effect of these interventions before and during the first trimester of pregnancy.99 Several observational studies especially in developed countries have examined the relationship between maternal BMI and adverse pregnancy outcomes, but most of them used data that were obtained after delivery or based on medical records obtained during pregnancy making it difficult to ascertain the quality of the data and exact timing of measurement.12,86,88,100 Nevertheless, these studies do suggest that overweight and/or obesity is associated with increased risk of pregnancy complications such as gestational diabetes and hypertensive disorders which in turn influence subsequent maternal and child health and well-being.87 The Institute of Medicine, which recently revised the US guidelines for gestational weight gain (GWG) based on the concerns about the obesity epidemic, also concluded that the risk of SGA was greater among women who had low GWG and low prepregnancy BMI and that there was strong evidence of a U shaped relationship between low GWG and PTD in normal and underweight women.11 These findings have important policy implications for industrialised countries such as the US as well as countries like Mexico that are facing the dual burden of malnutrition, that is, undernutrition that manifests as stunting during early childhood and contributes to short maternal stature combined with overweight as a result of the nutrition transition. Careful examination of the relationship between prepregnancy body size and composition and MNCH outcomes in developing country settings using well-designed prospective cohort studies is needed to develop appropriate interventions.

Overall, the paucity of intervention trials, especially in developing country settings is striking. The majority of the studies in our review were observational in design, which make inferences of causality difficult especially when the exposure was based on maternal recall. Only a third of the studies measured the exposure, that is, nutritional status and/or intakes using a prospective cohort study design. Key limitations include the inability to determine if the outcomes are specifically the result of preconceptional supplementation because women who consumed nutrient supplements before and during early pregnancy continued to take them through delivery, recall bias (in the case of retrospective studies) and differences in the timing of exposure. There is no clear definition of the ‘periconceptional’ period; we used <12 weeks, that is, first trimester which has been used by others and typically in many settings especially developing countries, most women do not identify and/or seek antenatal care before 12 weeks. Some studies clearly state that they measured nutrient intakes and/or status before pregnancy (maternal recall or prospectively) but the periconception period ranged from 1 month prior to the last menstrual period to 4 to 12 weeks of gestation. We also excluded several studies because they either used a slightly different definition, namely <16 or 20 weeks gestation, and/or the timing of the intervention was not clear.

In summary, there is evidence supporting the importance of nutritional status before and during early pregnancy to reduce the risk of adverse pregnancy outcomes especially birth defects and to a lesser extent, PTD and LBW. Little is known about outcomes such as stillbirths and maternal and infant mortality. The limited available evidence suggests improving prepregnancy maternal nutritional status will improve MNCH outcomes, although there are emerging concerns of overweight and obesity. There is a need for RCTs that evaluate the benefits of preconceptional nutritional interventions to confirm the findings from observational studies. These studies will need large sample sizes and should evaluate interventions such as providing supplements that contain nutrients such as iron, zinc, iodine and/or a combination of several micronutrients in addition to providing folic acid, targeted use of fortified foods and or behaviour modification to improve intakes. The dissemination of messages about the importance of a healthy diet and lifestyle before and during pregnancy along with messages about family planning that address timing and spacing of pregnancies have the potential to optimise MNCH outcomes in many settings. Evaluation of innovative approaches such as counselling newly wed mothers101 is also lacking and will help guide programme implementation.

Conflicts of interest

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Comments
  6. Conflicts of interest
  7. References

The authors declare no conflicts of interests.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Comments
  6. Conflicts of interest
  7. References
  • 1
    Chavarro JE, Rich-Edwards JW, Rosner BA, Willett WC. Iron intake and risk of ovulatory infertility. Obstetrics and Gynecology 2006; 108:11451152.
  • 2
    Ebisch IM, Thomas CM, Peters WH, Braat DD, Steegers-Theunissen RP. The importance of folate, zinc and antioxidants in the pathogenesis and prevention of subfertility. Human Reproduction Update 2007; 13:163174.
  • 3
    Cetin I, Berti C, Calabrese S. Role of micronutrients in the periconceptional period. Human Reproduction Update 2010; 16:8095.
  • 4
    Bloomfield FH, Oliver MH, Hawkins P, Holloway AC, Campbell M, Gluckman PD, et al. Periconceptional undernutrition in sheep accelerates maturation of the fetal hypothalamic-pituitary-adrenal axis in late gestation. Endocrinology 2004; 145:42784285.
  • 5
    Cetin I, Alvino G. Intrauterine growth restriction: implications for placental metabolism and transport. A review. Placenta 2009; 30 (Suppl A):S77S82.
  • 6
    King JC. Physiology of pregnancy and nutrient metabolism. American Journal of Clinical Nutrition 2000; 71:1218S1225S.
  • 7
    Kind KL, Moore VM, Davies MJ. Diet around conception and during pregnancy – effects on fetal and neonatal outcomes. Reproductive Biomedicine Online 2006; 12:532541.
  • 8
    Kelishadi R. Childhood overweight, obesity, and the metabolic syndrome in developing countries. Epidemiologic Review 2007; 29:6276.
  • 9
    Prentice AM. The emerging epidemic of obesity in developing countries. International Journal of Epidemiology 2006; 35:9399.
  • 10
    Kelly A, Kevany J, de Onis M, Shah PM. A WHO collaborative study of maternal anthropometry and pregnancy outcomes. International Journal of Gynecology & Obstetrics 1996; 53:219233.
  • 11
    Rasmussen KM, Yaktine A (eds). Weight Gain During Pregnancy: Reexamining the Guidelines. Washington, DC: National Academy Press, 2009.
  • 12
    Han Z, Mulla S, Beyene J, Liao G, McDonald SD, Knowledge Synthesis G. Maternal underweight and the risk of preterm birth and low birth weight: a systematic review and meta-analyses. International Journal of Epidemiology 2011; 40:65101.
  • 13
    Smith GC, Pell JP, Dobbie R. Interpregnancy interval and risk of preterm birth and neonatal death: retrospective cohort study. British Medical Journal 2003; 327:313.
  • 14
    Smits LJ, Essed GG. Short interpregnancy intervals and unfavourable pregnancy outcome: role of folate depletion. Lancet 2001; 358:20742077.
  • 15
    McArdle HJ, Ashworth CJ. Micronutrients in fetal growth and development. British Medical Journal 1999; 55:499510.
  • 16
    Hindmarsh P, Geary M, Rodeck C, Jackson M, Kingdom J. Effect of early maternal iron stores on placental weight and structure. Lancet 2000; 356:719723.
  • 17
    Magnusardottir AR, Steingrimsdottir L, Thorgeirsdottir H, Hauksson A, Skuladottir GV. Red blood cell n-3 polyunsaturated fatty acids in first trimester of pregnancy are inversely associated with placental weight. Acta Obstetricia et Gynecologica Scandinavica 2009; 88:9197.
  • 18
    Lumley J, Watson L, Watson M, Bower C. Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects. Cochrane Database of Systematic Reviews 2001; 4:CD001056.
  • 19
    Persad VL, Van den Hof MC, Dube JM, Zimmer P. Incidence of open neural tube defects in Nova Scotia after folic acid fortification. Canadian Medical Association Journal 2002; 167:241245.
  • 20
    Berry RJ, Li Z, Erickson JD, Li S, Moore CA, Wang H, et al. Prevention of neural-tube defects with folic acid in China. New England Journal of Medicine 1999; 341:14851490.
  • 21
    Atkins D, Eccles M, Flottorp S, Guyatt GH, Henry D, Hill S, et al. Systems for grading the quality of evidence and the strength of recommendations I: critical appraisal of existing approaches The GRADE Working Group. Biomedcentral Health Services Research 2004; 4:38. doi:10.1186/1472-6963-4-38.
  • 22
    Walker N, Fischer-Walker C, Bryce J, Bahl R, Cousens S. Standards for CHERG reviews of intervention effects on child survival. International Journal of Epidemiology 2012; 1:i21i31.
  • 23
    Bitsko RH, Reefhuis J, Romitti PA, Moore CA, Honein MA. Periconceptional consumption of vitamins containing folic acid and risk for multiple congenital anomalies. American Journal of Medical Genetics 2007; 143A:23972405.
  • 24
    Bower C, Miller M, Payne J, Serna P. Folate intake and the primary prevention of non neural birth defects. Australian and New Zealand Journal of Public Health 2006; 30:258261.
  • 25
    Bower C, Stanley FJ. Periconceptional vitamin supplementation and neural tube defects; evidence from a case-control study in Western Australia and a review of recent publications. Journal of Epidemiology and Community Health 1992; 46:157.
  • 26
    Bukowski R, Malone FD, Porter FT, Nyberg DA, Comstock CH, Hankins GDV, et al. Preconceptional folate supplementation and the risk of spontaneous preterm birth: a cohort study. PLoS Medicine 2009; 6:e1000061.
  • 27
    Burris HH, Mitchell AA, Werler MM. Periconceptional multivitamin use and infant birth weight disparities. Annals of Epidemiology 2010; 20:233.
  • 28
    Catov JM, Bodnar LM, Olson J, Olsen S, Nohr EA. Periconceptional multivitamin use and risk of preterm or small-for-gestational-age births in the Danish National Birth Cohort. American Journal of Clinical Nutrition 2011; 94:906912.
  • 29
    Catov JM, Nohr EA, Bodnar LM, Knudson VK, Olsen SF, Olsen J. Association of periconceptional multivitamin use with reduced risk of preeclampsia among normal-weight women in the Danish national birth cohort. American Journal of Epidemiology 2009; 169:13041311.
  • 30
    Chaouki ML, Benmiloud M. Prevention of iodine deficiency disorders by oral administration of lipiodol during pregnancy. European Journal of Endocrinology 1994; 130:547551.
  • 31
    Chen G, Song X, Ji Y, Zhang L, Pei L, Chen J, et al. Prevention of NTDs with periconceptional multivitamin supplementation containing folic acid in China. Birth Defects Research Part A: Clinical and Molecular Teratology 2008; 82:592596.
  • 32
    Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. New England Journal of Medicine 1992; 327:18321835.
  • 33
    Czeizel AE, Dudas I, Metneki J. Pregnancy outcomes in a randomised controlled trial of periconceptional multivitamin supplementation. Final report. Archives of Gynecology and Obstetrics 1994; 255:131139.
  • 34
    De Weerd S, Steegers-Theunissen R, De Boo T, Thomas C, Steegers E. Maternal periconceptional biochemical and hematological parameters, vitamin profiles and pregnancy outcome. European Journal of Clinical Nutrition 2003; 57:11281134.
  • 35
    Deierlein AL, Siega-Riz AM, Adair LS, Herring AH. Effects of pre-pregnancy body mass index and gestational weight gain on infant anthropometric outcomes. Journal of Pediatrics 2011; 158:221226.
  • 36
    Ehrenthal DB, Jurkovitz C, Hoffman M, Jiang X, Weintraub WS. Prepregnancy body mass index as an independent risk factor for pregnancy-induced hypertension. Journal of Women's Health 2011; 20:6772.
  • 37
    Han YS, Ha EH, Park HS, Kim YJ, Lee SS. Relationships between pregnancy outcomes, biochemical markers and pre-pregnancy body mass index. International Journal of Obesity (London) 2011; 35:570577.
  • 38
    Indian Council of Medical Research Collaborating Centres and Central Technical Co-ordinating Unit. Multicentric study of efficacy of periconceptional FA containing vitamin supplementation in prevention of open neural tube defects from India. Indian Journal of Medical Research 2000; 112:206211.
  • 39
    Kirke PN, Daly LE, Elwood JH. A randomised trial of low dose folic acid to prevent neural tube defects. The Irish Vitamin Study Group. Archives of Disease in Childhood 1992; 67:14421446.
  • 40
    Krapels IP, van Rooij IA, Ocke MC, van Cleef BA, Kuijpers-Jagtman AM, Steegers-Theunissen RP. Maternal dietary B vitamin intake, other than folate, and the association with orofacial cleft in the offspring. European Journal of Nutrition 2004; 43:714.
  • 41
    Krapels IP, van Rooij IA, Ocke MC, West CE, van der Horst CM, Steegers-Theunissen RP. Maternal nutritional status and the risk for orofacial cleft offspring in humans. Journal of Nutrition 2004; 134:31063113.
  • 42
    Laurence KM, James N, Miller MH, Tennant GB, Campbell H. Double-blind randomised controlled trial of folate treatment before conception to prevent recurrence of neural-tube defects. British Medical Journal (Clinical Research Edition) 1981; 282:15091511.
  • 43
    Liu X, Du J, Wang G, Chen Z, Wang W, Xi Q. Effect of pre-pregnancy body mass index on adverse pregnancy outcome in north of China. Archives of Gynecology and Obstetrics 2011; 283:6570.
  • 44
    Medical Research Council Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991; 338:131137.
  • 45
    Murrin C, Segonds-Pichon A, Fallon UB, Hannon F, Bury G, Loftus BG, et al. Self-reported pre-pregnancy maternal body mass index and infant birth-weight. Irish Medical Journal 2007; 100 (Suppl):2023.
  • 46
    Oddy WH, De Klerk NH, Miller M, Payne J, Bower C. Association of maternal pre-pregnancy weight with birth defects: evidence from a case-control study in Western Australia. Australian and New Zealand Journal of Obstetrics and Gynaecology 2009; 49:1115.
  • 47
    Ota E, Haruna M, Suzuki M, Anh DD, Tho LH, Tam NTT, et al. Maternal body mass index and gestational weight gain and their association with perinatal outcomes in Viet Nam. Bulletin of the World Health Organization 2011; 89:127136.
  • 48
    Phithakwatchara N, Titapant V. The effect of pre-pregnancy weight on delivery outcome and birth weight in potential diabetic patients with normal screening for gestational diabetes mellitus in Siriraj Hospital. Journal of the Medical Association of Thailand 2007; 90:229236.
  • 49
    Rayco-Solon P, Fulford AJ, Prentice AM. Maternal preconceptional weight and gestational length. American Journal of Obstetrics and Gynecology 2005; 192:11331136.
  • 50
    Ronnenberg AG, Goldman MB, Chen D, Aitken IW, Willett WC, Selhub J, et al. Preconception homocysteine and B vitamin status and birth outcomes in Chinese women. American Journal of Clinical Nutrition 2002; 76:13851391.
  • 51
    Ronnenberg AG, Goldman MB, Chen D, Aitken IW, Willett WC, Selhub J, et al. Preconception folate and vitamin B(6) status and clinical spontaneous abortion in Chinese women. Obstetrics and Gynecology 2002; 100:107113.
  • 52
    Ronnenberg AG, Venners SA, Xu X, Chen C, Wang L, Guang W, et al. Preconception B-vitamin and homocysteine status, conception, and early pregnancy loss. American Journal of Epidemiology 2007; 166:304312.
  • 53
    Ronnenberg AG, Wang X, Xing H, Chen C, Chen D, Guang W, et al. Low preconception body mass index is associated with birth outcome in a prospective cohort of Chinese women. Journal of Nutrition 2003; 133:34493455.
  • 54
    Ronnenberg AG, Wood RJ, Wang X, Xing H, Chen C, Chen D, et al. Preconception hemoglobin and ferritin concentrations are associated with pregnancy outcome in a prospective cohort of Chinese women. Journal of Nutrition 2004; 134:25862591.
  • 55
    Shaw GM, Nelson V, Carmichael SL, Lammer EJ, Finnell RH, Rosenquist TH. Maternal periconceptional vitamins: interactions with selected factors and congenital anomalies? Epidemiology 2002; 13:625630.
  • 56
    Shaw GM, Schaffer D, Velie EM, Morland K, Harris JA. Periconceptional vitamin use, dietary folate, and the occurrence of neural tube defects. Epidemiology 1995; 6:219226.
  • 57
    Shaw GM, Todoroff K, Schaffer DM, Selvin S. Periconceptional nutrient intake and risk for neural tube defect-affected pregnancies. Epidemiology 1999; 10:711716.
  • 58
    Timmermans S, Jaddoe VWV, Hofman A, Steegers-Theunissen RPM, Steegers EAP. Periconception folic acid supplementation, fetal growth and the risks of low birth weight and preterm birth: the Generation R Study. British Journal of Nutrition 2009; 102:777785.
  • 59
    van Beynum IM, Kapusta L, Bakker MK, den Heijer M, Blom HJ, de Walle HE. Protective effect of periconceptional folic acid supplements on the risk of congenital heart defects: a registry-based case-control study in the northern Netherlands. European Heart Journal 2010; 31:464471.
  • 60
    van Driel LMJW, Verkleij-Hagoort AC, de Jonge R, Uitterlinden AG, Steegers EAP, van Duijn CM, et al. Two MTHFR polymorphisms, maternal B-vitamin intake, and CHDs. Birth Defects Research Part A: Clinical and Molecular Teratology 2008; 82:474481.
  • 61
    Velie EM, Block G, Shaw GM, Samuels SJ, Schaffer DM, Kulldorff M. Maternal supplemental and dietary zinc intake and the occurrence of neural tube defects in California. American Journal of Epidemiology 1999; 150:605.
  • 62
    Vergel RG, Sanchez LR, Heredero BL, Rodriguez PL, Martinez AJ. Primary prevention of neural tube defects with folic acid supplementation: Cuban experience. Prenatal Diagnosis 1990; 10:149152.
  • 63
    Vujkovic M, Ocke MC, van der Spek PJ, Yazdanpanah N, Steegers EA, Steegers-Theunissen RP. Maternal western dietary patterns and the risk of developing a cleft lip with or without a cleft palate. Obstetrics and Gynecology 2007; 110:378.
  • 64
    Werler MM, Shapiro S, Mitchell AA. Periconceptional folic acid exposure and risk of occurrent neural tube defects. Journal of the American Medical Association 1993; 269:12571261.
  • 65
    Yazdy MM, Honein MA, Xing J. Reduction in orofacial clefts following folic acid fortification of the U.S. grain supply. Birth Defects Research Part A: Clinical and Molecular Teratology 2007; 79:1623.
  • 66
    Yeh J, Shelton JA. Association of pre-pregnancy maternal body mass and maternal weight gain to newborn outcomes in twin pregnancies. Acta Obstetricia et Gynecologica Scandinavica 2007; 86:10511057.
  • 67
    Bodnar LM, Catov JM, Roberts JM, Simhan HN. Prepregnancy obesity predicts poor vitamin D status in mothers and their neonates. Journal of Nutrition 2007; 137:24372442.
  • 68
    Bodnar LM, Tang G, Ness RB, Harger G, Roberts JM. Periconceptional multivitamin use reduces the risk of preeclampsia. American Journal of Epidemiology 2006; 164:470477.
  • 69
    Cao XY, Jiang XM, Dou ZH, Rakeman MA, Zhang ML, O'Donnell K, et al. Timing of vulnerability of the brain to iodine deficiency in endemic cretinism. New England Journal of Medicine 1994; 331:17391744.
  • 70
    Catov JM, Bodnar LM, Ness RB, Markovic N, Roberts JM. Association of periconceptional multivitamin use and risk of preterm or small-for-gestational-age births. American Journal of Epidemiology 2007; 166:296303.
  • 71
    Felkner M, Suarez L, Hendricks K, Larsen R. Implementation and outcomes of recommended folic acid supplementation in Mexican-American women with prior neural tube defect-affected pregnancies. Preventive Medicine 2005; 40:867871.
  • 72
    Loffredo L, Souza J, Freitas J, Mossey P. Oral clefts and vitamin supplementation. The Cleft Palate-Craniofacial Journal 2001; 38:7683.
  • 73
    Snook Parrott M, Bodnar LM, Simhan HN, Harger G, Markovic N, Roberts JM. Maternal cereal consumption and adequacy of micronutrient intake in the periconceptional period. Public Health Nutrition 2009; 12:12761283.
  • 74
    Thilly C, Swennen B, Moreno-Reyes R. Maternal, Fetal and Juvenile Hypothyroidism, Birthweight and Infant Mortality in the Etiopathogenesis of the IDD Spectrum in Zaire and Malawi. New York: Cognizant Communication Corporation, 1994.
  • 75
    Angeles-Agdeppa I, Paulino LS, Ramos AC, Etorma UM, Cavalli-Sforza T, Milani S. Government-industry partnership in weekly iron-folic acid supplementation for women of reproductive age in the Philippines: impact on iron status. Nutrition Reviews 2005; 63:S116S125.
  • 76
    Berger J, Thanh HT, Cavalli-Sforza T, Smitasiri S, Khan NC, Milani S, et al. Community mobilization and social marketing to promote weekly iron-folic acid supplementation in women of reproductive age in Vietnam: impact on anemia and iron status. Nutrition Reviews 2005; 63:S95108.
  • 77
    Brough L, Rees G, Crawford M, Dorman E. Social and ethnic differences in folic acid use preconception and during early pregnancy in the UK: effect on maternal folate status. Journal of Human Nutrition and Dietetics 2009; 22:100107.
  • 78
    Khambalia A, O'Connor DL, Zlotkin S. Periconceptional iron and folate status is inadequate among married, nulliparous women in rural Bangladesh. Journal of Nutrition 2009; 139:11791184.
  • 79
    Khambalia AZ, O'Connor DL, Macarthur C, Dupuis A, Zlotkin SH. Periconceptional iron supplementation does not reduce anemia or improve iron status among pregnant women in rural Bangladesh. American Journal of Clinical Nutrition 2009; 90:12951302.
  • 80
    Norsworthy B, Skeaff CM, Adank C, Green TJ. Effects of once-a-week or daily folic acid supplementation on red blood cell folate concentrations in women. European Journal of Clinical Nutrition 2004; 58:548554.
  • 81
    Ross JA, Blair CK, Olshan AF, Robison LL, Smith FO, Heerema NA, et al. Periconceptional vitamin use and leukemia risk in children with Down syndrome. Cancer 2005; 104:405410.
  • 82
    Sirikulchayanonta C, Madjupa K, Chongsuwat R, Pandii W. Do Thai women of child bearing age need preconceptional supplementation of dietary folate? Asia Pacific Journal of Clinical Nutrition 2004; 13:6973.
  • 83
    Vir SC, Singh N, Nigam AK, Jain R. Weekly iron and folic acid supplementation with counseling reduces anemia in adolescent girls: a large-scale effectiveness study in Uttar Pradesh, India. Food and Nutrition Bulletin 2008; 29:186194.
  • 84
    Eisenhauer E, Uddin DE, Albers P, Paton S, Stoughton RL. Establishment of a low birth weight registry and initial outcomes. Maternal and Child Health Journal 2009; 15:921930.
  • 85
    Hoff GL, Cai J, Okah FA, Dew PC. Pre-pregnancy overweight status between successive pregnancies and pregnancy outcomes. Journal of Women's Health 2009; 18:14131417.
  • 86
    McDonald SD, Han Z, Mulla S, Beyene J. Overweight and obesity in mothers and risk of preterm birth and low birth weight infants: systematic review and meta-analyses. British Medical Journal 2010; 341:c3428.
  • 87
    Torloni MR, Betrán AP, Horta BL, Nakamura MU, Atallah AN, Moron AF, et al. Prepregnancy BMI and the risk of gestational diabetes: a systematic review of the literature with meta-analysis. Obesity Reviews 2009; 10:194203.
  • 88
    Torloni MR, Betran AP, Daher S, Widmer M, Dolan SM, Menon R, et al. Maternal BMI and preterm birth: a systematic review of the literature with meta-analysis. Journal of Maternal-Fetal and Neonatal Medicine 2009; 22:957970.
  • 89
    De-Regil LM, Fern·ndez-Gaxiola AC, Dowswell T, PeÒa-Rosas JP. Effects and safety of periconceptional folate supplementation for preventing birth defects. Cochrane Database of Systematic Reviews 2010; 10:CD007950.
  • 90
    Berry RJ, Bailey L, Mulinare J, Bower C, Dary O. Fortification of flour with folic acid. Food and Nutrition Bulletin 2010; 31:22S35S.
  • 91
    Chen LT, Rivera MA. The Costa Rican experience: reduction of neural tube defects following food fortification programs. Nutrition Reviews 2004; 62:S40S43.
  • 92
    Berry R, Li Z, Gindler J, Liu J, Zheng J, Correa A, et al. Infant Mortality among Children Whose Mothers Consumed Folic Acid during Early Pregnanc-Sino-US NTD Prevention Project. Atlanta, GA: Centers for Disease Control and Prevention, 2002.
  • 93
    Gindler J, Liu J, Berry R, Li Z, Correa A, Wang H, et al. Growth of Children Whose Motehrs Consumed Folic Acid Supplements during Early Pregnancy-Sino-U.S. NTD Prevention Project. Beijing: NCMIH, Peking University, 2002.
  • 94
    Liu J, Ren A, Bertrand J, Gindler J, Li Z, Berry R, et al. Folic Acid Use during Pregnancy and Children's Cognitive Ability-Sino-U.S. NTD Project. Atlanta, GA: Centers for Disease Control and Prevention, 2002.
  • 95
    Ren A, Liu J, Bertrand J, Gindler J, Li Z, Berry R, et al. Folic Acid Use during Pregnancy and Child Behavior-Sino-U.S. NTD Project. Atlanta, GA: Centers for Disease Control and Prevention, 2002.
  • 96
    Roth C, Magnus P, Schjølberg S, Stoltenberg C, Surén P, McKeague IW, et al. Folic acid supplements in pregnancy and severe language delay in children. Journal of the American Medical Association 2011; 306:15661573.
  • 97
    Zimmerman MB. The effects of iodine deficiency in pregnancy and infancy. Pediatric and Perinatal Epidemiology 2012; 26 (Suppl. 1):108117.
  • 98
    Allen LH. Biological mechanisms that might underlie iron's effects on fetal growth and preterm birth. Journal of Nutrition 2001; 131:581S589S.
  • 99
    Yakoob MY, Menezes EV, Soomro T, Haws RA, Darmstadt GL, Bhutta ZA. Reducing stillbirths: behavioural and nutritional interventions before and during pregnancy. Biomedcentral Pregnancy Childbirth 2009; 9 (Suppl 1):S3.
  • 100
    Bodnar LM, Siega-Riz AM, Simhan HN, Diesel JC, Abrams B. The impact of exposure misclassification on associations between prepregnancy BMI and adverse pregnancy outcomes. Obesity 2010; 18:21842190.
  • 101
    HEED Bangladesh. National Nutrition Program (NNP ). 2011. Contract No.: Document Number|. http://www.heed-bangladesh.com/index.php?option=com_content&view=article&id=61&Itemid=95[last accessed October 21, 2011].