The nutritional relevanceof micronutrients, omega-3 fatty acids and probioticsto women with the desire to have a baby, to pregnancyand the breastfeeding period

Literature Report

Summaries

of recent studies

Preface

During pregnancy and breastfeeding women have increased micronutrientrequirements. The adequate supply of essential vitamins, minerals andunsaturated fatty acids is an important prerequisite for a healthy pregnancy andthe development of embryo, fetus and infant. Current scienti�c studies show that,in a nutritional approach, the regular intake of probiotics can contribute to thebuildup and enhancement of the immune system and strengthen the normalfunctions of the gut micro�ora.

Just with a well-balanced diet alone it will be di�cult to ensure a micronutrientintake fully covering the need of the future mother. Numerous trials haveevaluated the e�ect of the supplementation of single or combinations ofmicronutrients related to speci�c pregnancy complications, such aspre-eclampsia, perinatal mortality and preterm births.

Probiotics

Omega-3 Fatty Acids

Micronutrients

123

Probiotics in primary prevention ofatopic disease

Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial.Kalliomäki M, Salminen S, Arvilommi H, et al. Lancet 2001;357(9262):1076-79.

Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial.Kalliomäki M, Salminen S, Poussa T, et al. Lancet 2003;361(9372):1869-71.

SummaryMany studies on the development of allergic diseases start from the hygiene hypothesis

which attributes the increased frequency of atopic dermatitis or other allergies in children

to a relatively reduced microbial exposure in the early months of life. Since, however, the

bacterial micro�ora of the gut belongs to the earliest and most essential stimulators of the

mucosa-associated lymphatic tissue (immune system), Kaliomäki et al. examined whether

the development of atopic diseases could be in�uenced by probiotics.

In this study more than 100 pregnant women with a positive family history of atopies

(including having atopic parents) received daily either probiotic cultures

(1 x 1010 CFU Lactobacillus GG) or placebo two to four weeks prenatally, and breastfeeding

mothers for 6 months postnatally. Infants who were not breastfed, postnatally received

probiotics in the �rst 6 months of life.

ResultsAfter 24 months, only 23% of the children in the probiotic group developed an atopic

eczema, whereas in the placebo group 46% of the children developed this atopic disease. In

the follow-up evaluation after 4 years these results were con�rmed. Compared with the

placebo group, in the probiotic group an atopic eczema was diagnosed in about half as

many children.

ConclusionThe supplementation of probiotics during and after pregnancy can prevent early atopic disease

in children at high risk.

Probiotics 1

40

30

20

10

%

Perinatal supplementation of probiotics and occurrence of an atopic dermatitis in children

After 2 years

46 %

After 4 years

23 %

46 %

26 %

obecalP Probiotics

Comparison of the frequency of atopic diseases in

children aged 2 or 4 years whose mothers had taken

during pregnancy and 6 months after delivery

placebo or probiotics.

E�ects of probiotics on immunityProbiotics: e�ects on immunityIsolauri E, Sütas Y, Kankaanpää P, et al. Am J Clin Nutr 2001;73(2 Suppl.):444S-50S.

SummaryThe gastrointestinal tract with a total surface area of approx. 400 m² is the largest organ of

the human immune system. Numerous current studies on the e�ects and functions of the

gut-associated immune system underline the relevance of the intestines to human health.

In this context a rising number of articles focus on the potentially bene�cial e�ects of

probiotics on the gut defence barrier and immunoregulation. Thus, for instance, probiotic

cultures can contribute to the regulation of an increased intestinal permeability in speci�c

intestinal dysfunctions, e.g. gastroenteritis, food allergies and in�ammatory bowel diseases.

The immunological e�cacy of probiotics is shown, among other things, by the stronger

immune response to microbial pathogens. In fact, in several studies phagocytosis could be

stimulated or an increased IgA release could be observed under the dietary e�ect of

probiotic cultures. The immunomodulating e�ect of a diet including probiotics plays an

especially important role in allergic diseases. In infants with cow’s milk allergy a probiotic

diet led to a signi�cant improvement of atopic dermatitis. Further studies with probiotic

bacteria and their fermentation products demonstrate a reduced formation of TNF-alpha

(tumor necrosis factor alpha) and increased formation of interferon gamma during oral

ingestion. The e�ect of probiotics could also reduce in�ammatory responses, enhance the

intestinal integrity and stabilize gut microecology.

ConclusionProbiotic cultures support the physiological intestinal functions. Furthermore they are able

to protect against microbial pathogens and modulate the immune system, thus reducing

the risk of atopic disease.

Probiotics 1

Probiotics: treatment option of bacterial vaginosis inpregnancy

Ingestion of probiotics: optional treatment of bacterial vaginosis in pregnancyShalev E. Isr Med Assoc J 2002;4(5):357-60.

SummaryDuring pregnancy, bacterial vaginosis is diagnosed in 15 to 23% of women with the course

of the disease being asymptomatic in up to 50% of cases. The presence of potentially

pathogenic microorganisms in the vaginal micro�ora frequently remains undiscovered.

Treatment of this infection, however, is indicated as women with bacterial vaginosis are at

an increased risk of premature rupture of the membranes, preterm labor and preterm

delivery. Moreover, fever during or after delivery (postpartum endometritis and wound

infections) was observed more frequently in women with bacterial vaginosis. The

therapeutic standard of bacterial vaginosis is the oral administration or topical

application of antibiotics (metronidazol, clindamycin). But antibiotic therapy usually is

not started before the second trimester in order to avoid possible risks to the fetus

which can develop even at a low dose.

Recent studies point out an extended and well-tolerated treatment option with probiotics.

Thus, for instance, the dietary intake of speci�c probiotic cultures may have a favorable

e�ect on the stabilization of the normal vaginal micro�ora.

In a double-blind, randomized study including 46 women investigators could achieve a

bene�cial e�ect on the vaginal micro�ora with a dietary probiotic supplement

(Lactobacillus acidophilus). During the study period, the women consuming the yoghurt

that contained L. acidophilus (n=23) had a signi�cantly increased number of positive

vaginal cultures with L. acidophilus and a signi�cant reduction of episodes of bacterial

vaginosis. In the control group (n=23, eating pasteurized yoghurt) no such e�ects could be

observed.

ResultsProbiotic cultures are a well-tolerated, safe treatment option for bacterial vaginosis inpregnant women. They are promising as an adjunct to therapy contributing to a healthyvaginal micro�ora, especially before pregnancy or during the �rst trimester of pregnancy.

ConclusionProbiotic microorganisms stabilize the vaginal micro�ora and may contribute to theprevention and treatment of bacterial vaginosis.

Probiotics 1

Therapeutic measures for the preventionof allergic diseasesTherapeutic measures for prevention of allergic rhinitis/asthma development.Stanaland BE. Allergy Asthma Proc 2004;25(1):11-5.

SummaryThe development of asthma and allergic disease involves not only genetic but also external

factors. Such factors include, among other things, diet and environmental conditions. At a

meeting on the occasion of the Eastern Allergy Conference in Palm Beach (Florida) in May

2003, the therapeutic measures for prevention of allergic disease were presented by

Dr. Brett E. Stanaland from the University of South Florida.

An important measure, already in pregnancy, is the supplementation of the maternal diet

with probiotics. Also during the breastfeeding phase which should last at least 4 to 6

months, the supplementation of the diet with probiotics is to be recommended to

breastfeeding mothers. Another nutritional measure includes a diet for mother and child

which is rich in antioxidants and omega-3 fatty acids. A su�cient supply can bene�cially

in�uence the modulation of the immune system.

Moreover, during the �rst months of life cow’s milk and other highly allergenic foods

should not be components of the child’s menu. Also the avoidance of dust-mite exposure

and nicotine as well as a smokefree environment are essential measures of prevention.

ConclusionTherapeutic measure for the prevention of allergic disease should already be taken during

the prenatal and early infantile phase. An adequate supply of probiotics, antioxidants and

omega-3 fatty acids is essential as these nutritional substances in�uence the early

modulation of the immune system.

ProbioticsOmega-3 Fatty Acids1 2

Therapeutic measures duringpregnancy and breastfeeding

according to Brett E. Stanaland

Diet rich in antioxidants and omega-3 fatty acids

Breastfeeding during the�rst 4 months of life

Avoidance of dust-mite exposure

Ingestion of probiotics during pregnancy and breastfeeding

Avoidance of nicotine and/or tobacco smoke exposure

Avoidance of the early feedingof dairy products and highlyallergenic foods (e.g. nuts)

Essential fatty acids are enhancers of thebene�cial e�ects of probioticsEssential fatty acids as possible enhancers of the bene�cial actions of probiotics.Das UN. Nutrition 2002;18(9):786-9.

The in�uence of polyunsaturated fatty acids on probiotic growth and adhesion.Kankaanpää PE, Salminen SJ, Isolauri E, et al. FEMS Microbiol Lett 2001;194(2):149-53.

SummaryThe favorable e�ect of probiotics on the modulation of the immune system has been

documented in many studies. For example, probiotics are able to reduce the release of

in�ammatory signal substances as a response to allergens. This feature is relevant to the

development and severity of atopic conditions.

Since polyunsaturated fatty acids also play a major role as immune modulators, Kankaanpää

and colleagues examined the potential interaction between probiotics and fatty acids.

In their study it was demonstrated that polyunsaturated fatty acids, such as omega-3 fatty

acids, may promote the mucus adhesion of probiotics.

The authors therefore conclude that the combination of long-chain polyunsaturated fatty

acids and probiotics represents a protective barrier against atopic diseases.

FazitOmega-3 fatty acids support the adhesion and bene�cial health-enhancing e�ects of

probiotics. Supplementing the diet with omega-3 fatty acids and probiotics in pregnancy

and the breastfeeding period can substantially contribute to the modulation of the infant’s

immune system and thus reduce the allergy risk.

ProbioticsOmega-3 Fatty Acids1 2

Fish oil supplementation in pregnancy and neonatalallergen-speci�c immune responses in infants at highrisk of atopyFish oil supplementation in pregnancy modi�es neonatal allergen-speci�c immune responses and clinical outcomes in infants at high risk of atopy: a randomized, controlled trialDunstan JA, Mori TA, Barden A, et al. J Allergy Clin Immunol 2003;112(6):1178-84.

Maternal �sh oil supplementation in pregnancy reduces interleukin-13 levels in cord blood of infants at high risk of atopyDunstan JA, Mori TA, Barden A, et al. Clin Exp Allergy 2003;33(4):442-8.

SummaryThe dramatic increase in asthmatic and allergic diseases in the past 20 to 30 years is an

important reason for the intensive research on potential factors which may help prevent

allergies. It is striking to see that within this period the amount of antiin�ammatory

omega-3 fatty acids taken in with the food has dropped, whereas the percentage of

omega-6 fatty acids in the diet has increased.

Theoretically, the supplemental intake of omega-3 fatty acids should lead to a reduction in

allergy frequency. As the predisposition towards allergic immune responses already exists

before birth, it seems sensible to initiate immune modulation using omega-3 fatty acids

during pregnancy.

In this randomized, placebo-controlled study 98 atopic, pregnant women were included.

From the 20th week of gestation until delivery 52 women received �sh oil (3.7 g omega-3

PUFAs per day), 46 received placebo. In the group with �sh oil supplementation the

examination of the newborn babies showed signi�cantly higher proportions of omega-3

PUFAs in neonatal erythrocyte membranes. All neonatal cytokine responses to all

allergens tended to be lower in the �sh oil group. At 1 year of age infants in the �sh oil

group (n=40) were signi�cantly less likely to have an allergic response to speci�c

allergens, e.g. to egg, compared with the placebo group.

ConclusionThe adequate dietary supply of pregnant women with omega-3 fatty acids can signi�cantly

reduce the risk of the development and the severity of infant allergy. The modulation of the

immune system is bene�cially in�uenced already in the prenatal phase.

Omega-3 Fatty Acids 2

High maternal plasma DHA during pregnancy isdirectly associated with neonatal sleep-statepatterningHigher maternal plasma docosahexaenoic acid during pregnancy is associated with more mature neonatal sleep-state patterningCheruku SR, Montgomery-Downs HE, Farkas SL. Am J Clin Nutr 2002;76(3):608-13.

SummaryThe role of omega-3 fatty acids for metabolism and cell growth has been impressively

reported in numerous studies. The polyunsaturated fatty acids have an e�ect on many

physiological processes and are essential building-blocks of the membranes of all body cells.

In particular the phospholipid composition of the brain and the retina is characterized by a

high content of omega-6 and omega-3 fatty acids, especially of docosahexaenoic acid (DHA).

A su�cient supply of these fatty acis according to the special requirements is important for

the functional maturation of tissues during the embryonic and neonatal period. However,

the fetus is to a great extent depending on the placental supply. This is why in pregnancy,

above all in the last trimester, long-chain fatty acids are selectively transferred from the

maternal circulation to the fetus.

In the study by Cheruku and colleagues the association between materal plasma DHA

concentration and the neonatal sleep pattern as a marker for functional integrity of the

central nervous system was determined. On the basis of the median plasma DHA level (by

weight of total fatty acids) on the day of delivery, the study participants were divided into 2

groups: one group with high DHA levels (>3% DHA by weight of total fatty acids) and one

group with low DHA (≤3% DHA by weight of total fatty acids). On the �rst and second day

after delivery, the neonatal sleep-state patterns were assessed by means of the Motility

Monitoring System (MMS) using a sensor pad recording the infant’s respiration and body

movements.

ResultsThe investigators found a signi�cant correlation between maternal DHA plasma levels and

the sleep patterns of the newborns. Children whose mother had a high plasma DHA

concentration had less active sleep and a more favorable relation between active sleep and

quiet sleep. Also, and especially on the second day after birth, the neonates of mothers with

high DHA levels showed markedly longer periods of wakefulness (48.2%) compared to

neonates of mothers with low DHA levels (28.33%).

ConclusionAn adequate supply of docosahexaenoic acid to pregnant and breastfeeding women has a

substantial e�ect on the nature of neonatal sleep patterns which may be interpreted as a

sign for CNS maturity.

Omega-3 Fatty Acids 2

Relationship between diet, DHA content inmother’s milk and postpartum depressionSeafood consumption, the DHA content of mothers’ milk and prevalence rates of postpartum depression:a cross-national, ecological analysis.

Hibbeln JR. J A�ect Disord 2002;69(1-3):15-29.

SummaryIn pregnancy, nutrients for the fetus are all transferred from the maternal organism. This

is also true of docosahexaenoic acid (DHA), an omega-3 fatty acid which is essential for

neurological development. Since the DHA requirements of both the fetus and the neonate

are very high, a DHA de�ciency may occur during pregnancy or shortly after delivery in

the maternal body.

Several studies indicate that an inadequate dietary supply of DHA to the mother may

increase the risk of postpartum depression. DHA is the omega-3 fatty acid which is

especially abundant in �sh oil. Therefore it is assumed that in countries with a high

consumption of seafood the incidence of postpartum depression may be clearly reduced.

In order to examine on a broad basis the association between diet during pregnancy and

the prevalence of postpartum depression, 41 studies on this subject from 23 countries

including 14,542 women were evaluated. All studies used the Edinburgh Postpartum

Depression Scale (EPDS) for the subjects’ assessment. This scale was developed especially to

estimate and compare the frequency and severity of postpartum depression.

ResultsThe prevalence rate of postpartum depression varied between 0.5% in Singapore and 24.5%

in South Africa. The mean prevalence rate amounts to 12.4%. Basically authors noted that a

high national consumption of seafood was strongly associated with low prevalence rates.

Similarly they found that a high DHA content in mother’s milk predicts a low frequency of

postpartum depression. The DHA content in mother’s milk again is closely related to the

seafood consumption and is a marker for the maternal omega-3 fatty acid status. Due to

current study results therefore the intake of at least 300 mg DHA daily is recommended for

pregnant women.

ConclusionThe adequate dietary supply of omega-3 fatty acids, above all of DHA, to pregnant women

can signi�cantly lower the risk of developing postpartum depression.

Omega-3 Fatty Acids 2

Supplementation of long-chain unsaturated fattyacids in pregnancy and lactationPerinatal supply and metabolism of long-chain polyunsaturated fatty acids: importance for the early development of the nervous systemLarque E, Demmelmair H, Koletzko B. Ann N Y Acad Sci 2002;967:299-310.

Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy and lactation augments children‘s IQ at 4 years of ageHelland IB, Smith L, Saarem K, et al. Pediatrics 2003;111(1):e39-44.

SummaryLong-chain polyunsaturated fatty acids (PUFA), such as arachidonic acid (AA) and

docosahexaenoic acid (DHA), are essential structural lipid components of biomembranes. In

particular during the last trimester of pregnancy and in the �rst months of the prenatal

period, the need for these fatty acids is very high, as in these periods major growth and

developmental processes take place. In pregnancy long-chain PUFAs (polyunsaturated fatty

acids) are preferentially transferred from mother to fetus across the placenta. Breastfed

children receive long-chain fatty acids through the breast milk. Aiming to con�rm the role of

the prenatal supply of PUFAs, a number of double-blind randomized studies with

PUFA-enriched infant formula were made. In detail, the e�ect on the development of vision

and cognitive performance was assessed. On the basis of the data evaluated, it may be

concluded that long-chain PUFAs in the early prenatal period are potentially to be

considered essential micronutrients and are able to favorably in�uence the development. An

expert panel of the Child Health Foundation recommend the supplementation of maternal

diet with long-chain PUFAs during pregnancy and lactation.

The su�cient dietary supply with omega-3 fatty acids, above all DHA, has bene�cial e�ects

on the cognitive functions of the growing child lasting long beyond the actual

supplementation period. In a randomized double-blind study by Helland and colleagues

(2003), 84 children at four years of age were tested with the Kaufman Assessment Battery for

Children (K-ABC) for intelligence and cognitive performance. The mothers of the intervention

group had received cod liver oil with a high content of omega-3 fatty acids and DHA from

the 18th gestational week until three months after delivery. Mothers in the control group

had received corn oil during the same period of time.

ResultsThe children of mothers who had taken cod liver oil in pregnancy showed markedly superior

scores in all subscales of the test. The superiority in the Mental Processing Composite

(a measure for the child’s intelligence) was signi�cant.

ConclusionOmega-3 fatty acids, especially DHA, have a sustained in�uence on the cognitive

performance of the child. The Child Health Foundation recommends the supplementation

of long-chain unsaturated fatty acids in pregnancy and lactation.

Omega-3 Fatty Acids 2

Fish oil supplementation in high riskpregnancies

Omega-3 Fatty Acids

Randomised clinical trials of �sh oil supplementation in high risk pregnancies. Fish Oil Trials In Pregnancy (FOTIP) Team.Olsen SF, Secher NJ, Tabor A, et al. BJOG 2000;107(3):382-95.

SummaryNumerous trials report that the dietary supply of omega-3 fatty acids may favorably

in�uence the course of pregnancy. Therefore it is strongly assumed that also in high risk

pregnancies the su�cient supply of omega-3 fatty acids may reduce the frequency of

potential complications. The authors of this multicenter trial tested whether the early

supplementation of �sh oil reduces the risk of preterm delivery, intrauterine growth

retardation, pre-eclampsia and pregnancy-induced hypertension.

In total, 1,647 pregnant women at 19 European research sites who had a known history

of the pregnancy-associated complications mentioned or of twin pregnancies,

participated in this project. The women were divided into 6 subgroups, 4 prophylactic

and 2 therapeutic groups. The subjects of the prophylactic groups (n=724) received

from the 20th gestational week 2.7 g �sh oil (1.3 g eicosapentaenoic acid, 0.9 g

docosahexaenoic acid) daily. In the control group 753 women received daily olive oil.

In the subgroups for the assessment of therapeutic e�ects, all 142 women ingested daily

6.1 g �sh oil (2.9 g eicosapentaenoic acid, 2.1 g docosahexaenoic acid) or olive oil from

the 33rd gestational week.

ResultsThe intake of �sh oil reduced the risk of recurrent preterm deliveries in the prophylactic

trial groups from 33% to 21%. The mean pregnancy duration was 269 days with the

prophylactic administration of �sh oil. In the women of the therapeutic groups who had

received olive oil, investigators observed a mean pregnancy duration of 260 days. There

were no signi�cant e�ects on the other study parameters.

ConclusionIn high risk pregnancies the early dietary supplementation of omega-3 fatty acids can

signi�cantly reduce the recurrent risk of preterm delivery.

2

Occurrence of congenital heart defectsand maternal multivitamin use

Micronutrients 3Occurrence of congenital heart defects in relation to maternal multivitamin useBotto LD, Mulinare J, Erickson JD. Am J Epidemiol 2000;151(9):878-84.

SummaryCardiac defects occurring in at least one in 150 newborns are the most common group of

major congenital anomalies. The factors increasing the risk of an anomaly are known for few

defects only. Known risk factors include rubella infection or maternal diabetes mellitus.

Also the maternal multivitamin status seems to in�uence the occurrence of heart anomalies.

This was suggested by the results of current population-based studies.

However, in many cases not only the periconceptional supplementation but also the early

preconceptional dietary supplementation with micronutrients should be recommended

because many developmental processes in which a congenital defect may occur take place

in a very early stage of pregnancy. Therefore, already at the start of pregnancy vitamins,

minerals and trace elements should be administered at su�cient doses.

The association between the early supply of micronutrients based on the actual need and

the risk of congenital anomalies was determined in several studies, including the Atlanta

Birth Defect Case-Control study. In this population-based case-control study including

3,987 pregnant women, the incidence of congenital heart defects in children was analyzed

in relation to the maternal use of multivitamin combinations. Women who had

supplemented their diet 3 months before and after conception on a regular basis with

a multivitamin combination were assigned to a subgroup and compared to women who

had not taken any supplemental vitamins in this period.

ResultsIn the group of early multivitamin users the risk of the occurrence of congenital heart

defects could be reduced by 24%. In particular a signi�cant risk reduction was found for

common out�ow tract defects (-54%) and for ventricular septal defects (-39%).

ConclusionWith the intake of a combination of micronutrients before and during pregnancy the

incidence of heart anomalies can be reduced.

E�ect of vitamins E and C on oxidative stressand placental function in womenat risk of pre-eclampsia

Micronutrients

E�ect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trialChappell LC, Seed PT, Briley AL, et al. Lancet 1999;354(9181):810-6.

Vitamin C and E supplementation in women at risk of preeclampsia is associated with changes in indicesof oxidative stress and placental function

Chappell LC, Seed PT, Kelly FJ, et al. Am J Obstet Gynecol 2002;187(3):777-84.

SummaryPre-eclampsia is a relatively frequent complication of pregnancy characterized by symptoms

including proteinuria, hypertension and edema. It is a common cause of maternal mortality

and morbidity and may lead to preterm birth or still birth. The disorder occurs due to a

disturbance of microcirculation which, among other factors, results in an impaired placental

perfusion. The causes of pre-eclampsia have not yet been ultimately identi�ed, as one major

factor of pathophysiology oxidative stress is discussed. The plasma concentration of

ascorbic acid is low, and the formation of reactive oxygen species in the placenta is increased.

In a previous publication, Chappel and colleagues reported on a highly signi�cant

reduction of pre-eclampsia risk by supplementing 1,000 mg vitamin C and 400 IU vitamin E

per day (Chappel et al. 1999). In an additional evaluation of the study mentioned, the

authors determined whether and how vitamin supplementation in�uences indices of

placental dysfunction. Before the start of the study pregnant women were examined for

any risk factors. These comprised pre-eclampsia in previous pregnancies and abnormal

Doppler ultrasound �ndings in uterine arteries. In total, 79 pregnant women at high

pre-eclampsia risk received daily 1,000 mg vitamin C and 400 IU vitamin E (from

gestational week 16 women with a previous history, and from gestational week 20-22

women with normal test results). They were compared to 81 pregnant women at high risk

who received a placebo; 32 pregnant women at low risk served as controls.

ResultsIn the placebo group at high pre-eclampsia risk, clear signs of oxidative stress and

placental dysfunction were observed. In the high-risk group with vitamin supplementation,

risk markers of pre-eclampsia improved signi�cantly: The ascorbic acid plasma levels as

well as the markers of oxidative stress and placental function reached almost the values

of the low-risk group. Plasma levels of vitamin E in the intervention group were 30%

above the levels of the group that had not taken any vitamin supplement.

ConclusionAntioxidant supplementation in women at risk of pre-eclampsia reduced this risk as well as

the oxidative stress, and improved placental function.

3

E�ects of periconceptional multivitaminsupplementation on pregnancy outcomes

Micronutrients

Pregnancy outcomes in a randomised controlled trial of periconceptional multivitamin supplementation. Final report.Czeizel AE, Dudás I, Métneki J. Arch Gynecol Obstet 1994;255(3):131-9.

SummaryNumerous studies con�rm that the periconceptional supplementation of a multivitamin-

folic acid combination may reduce the occurrence of neural tube defects. But beside the

preventive e�ect on the development of fetal diseases, also other bene�cial impacts are

possible.

There is some evidence for the fact that an optimal vitamin supply is not only critical to a

healthy course, but also to the very occurrence of pregnancy itself.

In the present study, the e�ects of a periconceptional supplementation of a combination

of trace elements, compared to a multivitamin-folic acid combination, on the desired

occurrence of pregnancy were assessed. In total, 3.953 subjects received a daily

multivitamin combination containing 0.8 mg folic acid from the 28th day before the

expected fertile days until the timepoint of the second missed menstrual period. In the

control group, 3,952 study participants received a dietary supplement of trace elements

during the same period of time. The series of study examinations included the recording

of the number of pregnancies and the occurrence of neural tube defects.

ResultsMultivitamin-folic acid supplementation signi�cantly increased the rate of conceptions

amounting to 71.3% compared to 67.9% in the group who had received only trace

elements. Furthermore, the occurrence of neural tube defects was reduced in the

multivitamin group.

ConclusionThe periconceptional supplementation of a multivitamin-folic acid combination improved

fertility. The occurrence of neural tube defects was reduced at the same time.

3

Correlation between plasma homocysteine levels,folate status and MTHFR gene mutation in womenwith recurrent spontaneous abortion

Micronutrients

Plasma homocysteine levels correlated to interactions between folate status and methylene tetrahydrofolatereductase gene mutation in women with unexplained recurrent pregnancy loss

Kumar KS, Govindaiah V, Naushad SE, et al. J Obstet Gynaecol. 2003;23(1):55-8.

SummaryHyperhomocysteinemia is a risk factor for recurrent spontaneous abortion. This disorder

is related either to a hereditary defect in the methionine-homocysteine pathway or it

might be acquired as a result of de�ciencies of vitamin B12 and folic acid.

The genetic predisposition as well as the dietary supply of the micronutrients mentioned

seem to have an equal impact on pathogenesis. The reasons are that, on the one hand, both

vitamins contribute to the conversion of homocysteine to methionine, and, on the other, the

metabolic reaction is catalyzed by the methylene tetrahydrofolate reductase (MTHFR) enzyme.

This study aimed to assess the correlation between folate level and homocysteine

concentration as well as the e�ects of hereditary MTHFR defects on the development

of hyperhomocysteinemia.

Study participants were 24 women who in their history had three or more consecutive

recurrent pregnancy losses prior to the 22nd week of gestation. Before start of the study,

all subjects and their partners had been screened for chromosomal anomalies, and the

female subjects additionally underwent ultrasound and hormonal status tests. Another

group including 24 females who had already completed one successful pregnancy and did

not have any early abortion in their history served as control.

ResultsIn a total of 37.5% of the women with previous recurrent spontaneous abortions

signi�cantly lower folate levels were measured, while in the control group only 20.8%

of women had a folate de�ciency. The highest values of homocysteine concentration

were found in women experiencing recurrent pregnancy loss with both the hereditary

enzyme defect and folate de�ciency.

ConclusionThe early diagnosis of hyperhomocysteinemia may contribute to initiating treatment,

e.g. with folic acid supplementation, to ensure a healthy course of pregnancy.

3

Folic acid supply and occurrence of neural tubedefects in the infant

Micronutrients

Folate intake and the risk of neural tube defects: an estimation of dose-responseMoore LL, Bradlee ML, Singer MR, et al. Epidemiology 2003;14(2):200-5.

SummarySeveral trials could show that with the supplementation of multivitamin-folic acid

combinations in the periconceptional period and in early pregnancy, the risk of neural

tube defects could be reduced signi�cantly. However, study results do not provide any

clear data concerning the optimal folic acid dose and the proper time point for the start

of such supplementation. Therefore, in 23,228 pregnant women data on diet and vitamin

intake in the early second trimester of pregnancy were collected during the course of

pregnancy. The case-related endpoint of each survey was the prenatal diagnosis of a

neural tube defect or birth. The daily total folic acid intake (from diet plus supplements)

was measured as DFE (dietary folate equivalents) units. Here 1 DFE means 1 µg folic acid

from the diet or 0.5 µg folic acid from supplements or 0.6 µg from folate-enriched foods.

0.8

0.6

0.4

0.2

Prevalence rate

Folic acid intakeper day expressed in μg

1st to 5th week of gestation

Conception

0 200 400 600 1000 1200

Prevalence rate of neural tube defects

800

ResultsFor each additional folic acid intake, i.e. each additional 500 DFE consumed per day, the

prevalence of neural tube defect decreased by 22% (95% con�dence internal [CI] 0.47-1.09)

per 1,000 pregnancies.

ConclusionThe risk of fetal neural tube defects declines markedly with modest increased total folic acid

consumption in early pregnancy. Risk reduction is clearly correlated with the total dose of

additional folic acid consumed.

3

Micronutrients 3Maternal vitamin D status during pregnancyand childhood bone mass at age 9 years:a longitudinal studyMaternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study.Javaid MK, Crozier SR, Harvey NC, et al. Lancet 2006; 367: 36-43

SummaryVitamin D de�ciency during pregnancy may lead to a reduced bone mineral contentof the child. This de�ciency still exists years later and is likely to have an e�ect on therisk of osteoporosis in future years of life.

In this retrospective cohort study investigators examined the maternal vitamin D statusduring pregnancy and the later bone mass of the child. For the longitudinal study, dataof 198 children were evaluated who were born in 1991 and 1992. The maternal bodybuild, nutrition and vitamin D status during pregnancy were assessed in relation to thechildren’s bone mass and body size at the age of 9 years.

Vitamin D de�ciency of the mother during pregnancy was proven: 18% of them had ade�cient (<11 μg/l 25(OH)-vitamin D) and 31% an insu�cient vitamin D status(11 µg/l to 20 μg/l 25(OH)-vitamin D).

A low maternal vitamin D concentration (<20 μg/l 25(OH)-vitamin D), especially duringthe late months of pregnancy, was associated with a reduced childhood whole-bodybone mineral content (BMC) also beyond the 9th year of life. When mothers had ade�cient vitamin D status (<11 μg/l 25(OH)-vitamin D), their children showed astatistically signi�cant decrease of bone mass.

ConclusionThe study results show that the maternal vitamin D status during pregnancy isassociated with a sustained reduction of bone mineral content in the o�spring duringchildhood. Vitamin D supplementation of pregnant women could lead to enhancedbone-mineral accrual and reduce the risk of osteoporotic fracture in their children.

Maternal serum vitamin D levelsduring pregnancy

Childhood whole-body BMC1 atthe age of 8-9 years

gk 40.1l/gµ 11 <

gk 41.1l/gµ 02-11

gk 61.1l/gµ 02 >

1 BMC = Bone mineral content

Orthomol pharmazeutischeVertriebs GmbH

Herzogstr. 30 40764 LangenfeldGermanyexport@orthomol.de www.orthomol.com

We Value Your Health!

2051

4907

05

/10