Vitamin B6 status in pregnancy by xiangpeng


									Vitamin                                             B6 status                                           in pregnancy
Sigfried              Heller,’                   Richard                  M.       Salkeld2                    and          Wilhelm             F.      K#{246}rner2

                                       ABSTRACT                                The     vitamin     B6 status of 493             pregnantwomen     was investigated            by means     of
                                       the    erythrocyte                          glutamate-oxaloacetate         transaminase          (EGOT)        activation        test.   Of the 458
                                       women         with                    uncomplicated           pregnancies,        40 to 60% were            found       to be suboptimally         supplied
                                       with    vitamin                       B6 in order        to saturate       EGOT        in comparison       with      a group       of over 300 male and
                                       female      blood                     donors.      Mothers       of higher      gravidity      were slightly       more    deficient      with  respect     to
                                       enzyme                 saturation        than       those                       of lower        gravidity.          In the      whole        group         there    was    otherwise                                             no
                                       correlation                  between       vitamin                          status
                                                                                                                  B6           and     various        clinical     parameters             during        pregnancy         and
                                       delivery.               Nevertheless,          if one                       assumes        that     a good         maternal        vitamin status
                                                                                                                                                                           B6                 is of value     to the
                                       offspring,                it is suggested          that                      pyridoxine          supplementation      is necessary          in 50%      of the pregnant
                                       women                 in        order         to     maintain                normal        coenzyme           saturation          of the enzymes   tested.           Am.     J.
                                       Clin.         Nutr.        26:          1339-1348,                      1973.

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    The      existence       of                              a vitamin                      B6 deficiency                        pregnancy
                                                                                                                                   in                           has been      reported   to be beneficial
pregnancy           has been                                 suspected                      since     Willis                 et not
                                                                                                                                 al.     only               in cases of hyperemesis (1), but also in
(I)     used      pyridoxine                                   empirically                       over     30                     pre-eclamptic
                                                                                                                             years                                  toxemia (3,      21) and   placental
ago      to               alleviate          the                        symptoms                       of     morning vascular                            sclerosis     (22).  On the other   hand, has it
sickness                   in       pregnant                            women.                      Subsequently,     been                       stated               that           there               is      little            evidence                     that
McGanity                        et      al.         (2)       showed     with         that
                                                                             administration         patients
                                                                                                        of    pyridoxine        in amounts       ade-
hyperemesis           gravidarum          had     low        blood           quate
                                                                          urea            to normalize           the tryptophan        load test has
levels      which    exhibited      a prolonged           rise after       the
                                                                             any       clinical        effect      in normal       pregnancy       (23,
administration         of alanine        and    which         could       be 24).      No       correlation          has been      found     between
corrected         by   giving    pyridoxine          orally.        Sprince dietary         status       during       pregnancy     and either       the
et       al.         (3),             Vandelli                     (4),           and             Wachstein                      and
                                                                                                                                  clinical            outcome                   (25)   or the                     birth           weight              of the
Gudaitis                  (5,          6)           then                showed                     that              milder,     babies              (26).    With                a previously                              well-fed                popula-
nonsymptomatic                                   forms                  of        vitamin                    B6            defi- tion,          even           severe           famine                 conditions                     had         remark-
ciency                could                 be            detected                   by           indirect                 meansably             little          effect          on              birth              weights                      or         on
such      as               the          increase                       in urinary                 excretion       of
                                                                                                                perinatal                     in            mortality                              Holland                    (27).           Maternal
xanthurenic                           acid     after                    oral  loading                of trypto- size is the most      important                                                               single          determinant                         of
phan   (tryptophan                                    load              test    (7,         8)),
                                                                                            which      could    birth     weight (28)      and                                                     a contributory                                factor            is
be normalized                                  by      prior               pyridoxine                     administra-         the          adequate                  nutrition                   of the            mother                   during              her
tion.          Later,                increased                    excretion                  of      other            trypto- own             childhood                     (29).                Animal              studies                   show              no
phan           metabolites                          was           found              also          to     be         correct- effect   on the                              litters           of supplemented                                    animals
able         by      pyridoxine                           supplements                        (9-12).                          compared    with                            those            on a normal       diet                           (30).
    A deficiency                               was           also              suggested                  by         the       low In           view           of       these             conflicting                       opinions,                 it was
vitamin    B6 blood                                 levels             in the         mother                 (13-17),            considered                      valuable                   to         study                the         vitamin                  B6
the        low        urinary                  4-pyridoxic                         acid           (PA)         excretion         status      of    a large                           group              of women                            at various
after          pyridoxine                           administration                                (18),           and          also
                                                                                                                                 stages       of      pregnancy                                     using        the                    erythrocyte
by       a comparison       of the                                       tryptophan          metabolism                          gl utamate-oxaloacetate                                           t ransaminase                           (E .C.
of      pregnant      women    with                                         that    in experimentally                                        L-aspartate:2-oxoglutarate                                              amino-
induced                   dietary                   deficiency                        of          vitamin             inB6       transferase)                    (EGOT)-activation                              test.          This        test            is
man               (19).              Recently,                          Contractor                        and                  a
                                                                                                                           Shane         more             specific              and              sensitive                   measure                  of        the
(20),        using     direct                                  fluorometric            analysis       in
                                                                                                    vitamin                                               B6         status               (31)             than              the         tryptophan
contrast         to previous                                  indirect       methods,        showed load                                        test,           which                is         also          abnormal                      in        various
the       blood       levels                                 of      pyridoxal-5’-phosphate
(P-5’-P),       the   coenzyme                                     form     of vitamin          B6,
                                                                                                                                    ‘University         Obstetric                               Clinic,   T#{252}bingen, West                           Ger-
be   significantly                             lower               in pregnant                          women                than
                                                                                                                                 many.          2Department                                of     Vitamin     and Nutrition                                     Re-
in nonpregnant                                women                  or in men.                                                  search,             F.        Hoffmann-La                         Roche                &      Co.,         Ltd.,           Basel,
       The            administration                              of           pyridoxine                         during         Switzerland.

 The     American                    Journal               of Clinical               Nutrition 26:             DECEMBER                      1973, pp.          1339-1348.                       Printed           in U.S.A.
1340                                                                                                     HELLER                   ET        AL.

diseases                  (32,          33)            and         in      early           deficiency                 more donors                   was       concurrently                            assessed       by       means         of  the
                                                                                                                                  EGOT            activation          test.     We                  thought       that      this    apparently
sensitive                        than                 the           erythrocyte                           glutamate-
                                                                                                                                  healthy            population             should                     provide        reference           aEGOT
pyruvate                   transaminase                           (E.C.           2.6.1         .2.:      L-alanine:              values           reflecting            optimal                        vitamin B6 nutrition               in
2 -oxoglutarate                                     aminotransferase)                         (EGPT)-                             health;              values
                                                                                                                                                  ciEGOT           1.65    (mean + 2 SD) were
activation                       test (34).                  We          also          looked     for                any considered              normal;       1.66 to 1.69 marginal,          and values
correlation                         of            vitamin                   B6             deficiency                           1.70
                                                                                                                             with         (mean    + 2.5    SD) deficient. These values are in
                                                                                                                                agreement       with     those of other  investigators.       Reinken
various             clinical                  parameters.
                                                                                                                                (personal       communication)           found,         using    the    same
                                                                                                                                method        in a smaller         group   of nonpregnant            women
Material            and           methods                                                                                         who          were      not                   taking             oral           contraceptives,          a          mean
                                                                                                                           he considered
                                                                                                                                  ciEGOT      values1.50
                                                                                                                                                   of 135,  to be            and
Population                                                                                       within   the normal    range.    However,      a similar    study     by
    Four    hundred                              ninety-three      pregnant          women       Salkeld
                                                                                                at          et al. (manuscript       in preparation),       using     the
various stages      of                         pregnancy      were     investigated.       From same     method    in a group      of nonpregnant
                                                                                                                                         69               women,
the characteristics                             given in able
                                                          T      1, it can be seen that          showed     a mean aEGOT       of 1.53. On the other            hand,
they       represent                an          average           group.                                                          Sauberlich                et         al.         (35)         rarely            found             values                   >1.50     in
    Blood      was taken     from                               each       woman             on one             occasion          normal          subjects.
only    for vitamin       B6 status                               assessment.                No        attempt            was

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made       to      follow     the                               status            of       individual              women
throughout         the pregnancy.                                                                                                 Results
                                                                                                                                       As       can         be          seen              in Table 2 and                     Fig.         1 which
EGOT         activation                      test
                                                                                                                                  include                  all               uncomplicated                       pregnancies,                                  the
    The determination                                  of the EGOT      activity,    which                                was
                                                                                                                                  mean            aEGOT                       lay             within                   the          normal                       and
carried   out according                                  to the method        of Stanuloval                                       et
al. (31), is based    on                             the transamination         of aspartic                               acid
to        2-oxo-glutaric                       acid                        The
                                                               (cr-ketoglutaric                 acid).
                                                                                                                                  TABLE     2
resulting        oxaloacetate         is enzymatically             converted to                                                   Mean EGOT                          week              of pregnancy
malate        by     NADH4ependent          malate        dehydrogenase.
The      consumption          of NADH,        ascertained          by measuring
the decrease          in the absorption      at 334 nm, corresponds                                                                       Week of                                                                                        No.            of
to the amount           of oxaloacetate             which      in turn reflects                                                          pregnancy                                 Mean                          SD                       cases
the degree     of EGOT        activity.
    Hemolyzed,          washed          erythrocytes           are       incubated                                                                                                     1.67                                                         3
with      and   without       additional           pyridoxal-5       ‘-phosphate                                                                                                                                0.23                           40
                                                                                                                                               7-12                                    1.64
(P-5’-P).     The     ratio    of the           increased        activity        (with                                                                                                 1.59                     0.27                           42
P-5’-P)    to              the     original                   activity          (without             P-5’-P)   is the
                                                                                                                                            19-24                                      1.68                     0.31                           51
activation                coefficient                      (ciEGOT),             which            is a measure      of
                                                                                                                                            25-30                                      1.67                     0.27                           70
the vitamin  B6 status.                                                                                                                                                                1.64                     0.28                          142
    In order   to provide                                       a basisfor             comparison,                  the
                                                                                                                                            37-42                                      1.59                     0.36                          110
vitamin    B6 status    of                                     300   male                 and          female        blood

 TABLE                1
 Characteristics                        of      subjects

                                                               Characteristic                               Minimum                               Maximum                                        Mean                                    SD

 At first       consultation                         Age,       years                                                17                                     44                                      28.5                                  5.9
                                                     No.       of previous                                               0                                       6                                       1.4
                                                     No.     of previous                                                 0                                       5                                       0.24

 During            this                              Hemoglobin,                   g/100          ml                     8.3                                 19.1                                      13.10                                  1.29
       pregnancy                                     Birth       weight,           g                             2,500                                5,380                                    3,337                                    578
                                                     Birth       length,           cm                                25.0                                   57.0                                    50.1                                      2.8


                                                                                                                  Proteinuria                                         Glucosuria                                        Acetonuria

         Percentage                 with urinary                   abnormalities                                             10                                                    3                                                1
                                                                                VITAMIN                     B6         STATUS                     IN      PREGNANCY                                                                                         1341

marginal                   range.                  No           trend               towards             a deficiency                   first           two               trimesters                    and           subsequent                             improve-
at term              was    apparent.                                The        meanaEGOT      values,      ment                                        (Table          5 and               Fig.         4). Mothers                          with             more
however,               hide     a spread                               of       values    some     of which previous                                                pregnancies                        showed      a                    slightly               poorer
fall        in the  deficient                                   or       marginal                    range.   Table                       3
                                                                                                                                       vitamin                B6          status          than              those           with             less.
and          Fig.  2 show                                the           percentage                       of uncompli-                       Normal                          pregnancies                         were         compared                                with
cated              cases             with            deficient                       or      marginal aEGOT                            pathological                            pregnancies                         (abortion,                               diabetes,
values               at             6-week                     intervals                     throughout                           preg-
                                                                                                                                      hydramnios,                             pre-eclampsia,                             Rh           incompatibility,
nancy.               At             least          one-third                         of      the       women                      were
                                                                                                                                     and               stillbirth).                      In           the            firstwo
                                                                                                                                                                                                                         t                  trimesters,
vitamin               B6            deficient                    in each                  6-week            group                 andmothers                     with               pathological                         pregnancies                            had          a
only          60%              or        fewer             (40%                at         midpregnancy)                        poorer
                                                                                                                             had                             vitamin                 B6     status                   than      mothers                          with         a
aEGOT                values                 within                   the       normal                range.             There normal                           pregnancy.                        In         the          last          trimester,                  how-
was         a slight                increase                   in     the           frequency                 of       vitamin ever,                   the          reverse              appeared                    to         be      the          case       (Table
B6 deficiency           until       the                                    24th      week,        followed       by and
                                                                                                                  6          Fig. 5), but    this  finding                                                                      is not            significant
a slight   reduction           in the                                      last    trimester.                    because        of the small number                                                                         of cases.                    When          the
   In    order       to       check                                        whether            this      apparent complications          were      considered                                                                                  individually
reduction                      was          due           to         the       premature                    delivery                   (Table
                                                                                                                                        of                   7),          stillbirth        (after      the   30th   week)       and

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mothers                 with   a high      aEGoT-values,                                                           the     per-
                                                                                                                             diabetes                              were          associated        with     a normal     vitamin
centage               of mothers      with     deficient                                              or           marginal B6       status(only       three      and     two       cases,                                                                      respec-
aEG0T-values             was                               calculated                       for   those       deliver- tively),        whereas          only      25%       of    mothers                                                                           with
ing    after     various                                 lengths      of                    pregnancy.             How-pre-eclamptic             toxemia        (four      cases)       had                                                                     a defi-
ever,     as Table 4 and                                  Fig. 3 show,                      the    percentage          cient     status.      Mothers        with     high     gravidity                                                                        (three
of         women                    in       each               group                who             were          deficient or                 more               previous              pregnancies)                            showed                   a slightly
remained                        almost                   constant                       at    approximately                         greater                  incidence   of vitamin B6 deficiency        than
45%,          except        for                    the      higher                        (
                                                                                     figure57%)     for the                         mothers                    of low gravidity.
women              delivering                            before                     the       31st          week,                 who Table                      8 shows     the correlation      coefficients
had          to       be            grouped                         together                  because                  of         their
small         number                     (14).
       A      comparison                            of           the      vitamin B6 status           of
mothers                with                        two           previous         pregnancies           with
that    of           those               with                   three       previous        pregnancies
showed,                   in         general,                    a      peak               deficiency                       in        the


                                                                                                                                                               0-6          7-12         13-18        19-24         25-30            31-36 7-42

              I-I-1-I-I-1-L                                                                                                                                        III      deficient

                           0-6              7-12        13-18 19-24          25-30 31-36           37-42                                                                                                             :
                                                                                                                                           FIG.            2. Percentage      of mothers                                             with        normal            preg-
            FIG.           1. Mean ciEGOT:                           week           of pregnancy.                                      nancies           in marginal     to deficient ciEGOT                                         range.

 TABLE               3
 Percentage                    of     mothers               with            normal            pregnancies                    in       normal,           marginal,                  and      deficient                cSEGOT                  range

                                                                                                     Percent           (number)                   of cas in each
                                                                                                                                                      es                           ciEGOT             range

             Week of                                                                                                                                                                                                            Marginal             +
            pregnancy                                                Normal                                            Marginal                                             Deficient                                            deficient

                      6                                  66.7                           (2)                                       0                                  33.3                        (1)                     33.3                            (1)
                   7-12                                  40.0                         (16)                   17.5                           (7)                     42.5                      (17)                       60.0                        (24)
                  13-18                                  42.9                         (18)                       7.1                        (3)                     50.0                      (21)                       57.1                        (24)
              19-24                                      39.2                         (20)                    7.8                           (4)                     52.9                      (27)                       60.8                        (31)
              25-30                                      45.7                         (32)                   11.4                           (8)                     42.9                      (30)                       54.3                        (38)
              31-36                                      53.5                         (76)                    7.8                         (11)                      38.7                      (55)                       46.5                        (66)
              37-42                                      58.2                         (64)                    4.6                           (5)                      37.3                     (41)                       41.8                        (46)
1342                                                                                                        HELLER                      ET          AL.

 TABLE                 4
 Percentage                     of cases ineach                 ciEGOT               range of women                           grouped               according                   to length             of pregnancy

                                                                                                     Percent             (number)                   of cas es in eachiEGOT
                                                                                                                                                                    c                                     range

               Week             of                                                                                                                                                                                                Marginal                 +

               delivery                                           Normal                                                Marginal                                                Deficient                                            deficient

                      30                                 28.6                           (4)                      14.3                        (2)                     57.1                        (8)                      71.4                          (10)
                31-36                                    52.4                        (11)                                          0                                 47.6                      (10)                       47.6                          (10)
                37-38                                    48.6                        (17)                         5.7                      (2)                          45.7                   (16)                       51.4                          (18)
                39-40                                    43.7                        (45)                        10.7                    (11)                        45.6                      (47)                       56.3                          (58)
                41-42                                    47.7                        (72)                         8.0                    (12)                        44.4                      (67)                       52.3                          (79)
                   >43                                   50.0                        (19)                         5.3                     (2)                        44.7                      (17)                       50.0                          (19)

                                cases                                                                                                  conversion                          to       pyridoxal-5’-phosphate                                        seem              un-

                                             Ij:L]IjU                                                                                  likely               as          high      cord       levels                                       of          pyridoxal-5’-

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                       60                                                                                                              phosphate                       and   pyridoxamine-5’-phosphate                                                     were

                                                                                                                                       found              in         the          fetus           (20)           without                       any             increase             in
                                                                                                                                       maternal                   urinary       excretion                                  of         4-pyridoxic                            acid
                                                                                                                                       or    the               non-phosphorylated                                      forms             of the                     vita-
                                                                                                                                       mm.          Also,             rapid             phosphorylation                           occurred                        after
                                                                                                                                       administration                                   of     pyridoxine;                            maximum                         pyri-
                                                                                                                                       doxal-5’-phosphate                                      levels     were                       attained                      10 mm
                                                                                                                                       after          intravenous                            and          2 hr          after              oral        administra-
                                  0-30           31-36     37-38          39-40        41-42       )43
                                                                weeks                                                                  tion.
                                      I     deficient                               marginal                                                   It      has             been                  reported                      (43)                 that               in        early
                                                                                                                                       pregnancy        the excretion                                             of       xanthurenic                               acid           is
       FIG.      3. Percentage                        w
                                                     of omen                  in each          ciEGOT              range,              much      higher        for     a                                      given          plasma                              pyridoxal
grouped              according                   to length              of pregnancy.                                                  phosphate         level     than                                  it       is        for                nonpregnant
                                                                                                                                       women                   with               the        samel              level           of         coenzyme.                         This
                                                                                                                                       indicates                 that             the        abnormal                     excretion                        of trypto-
 (Pearson)                      for        the       vitamin                    B6          status           and          various
                                                                                                                                       phan           metabolites                            in       pregnancy        is unlikely        to                                    be
 clinical   findings        during                                       pregnancy.                          In         all        cases
                                                                                                                                       solely          due      to                 vitamin               B6 deficiency.           Studies                                        in
 the degree       of correlation                                          is negligible.
                                                                                                                                       pregnant                      women                    (3-6,                9,          11,             18,         43,       1)44)
                                                                                                                                       during                  the              different                     phases                 of         the             menstrual
                                                                                                                                       cycle      (45),   2)      in     women                                                  taking                     estrogen-
        Various                      mechanisms                         have               been           proposed                     as
                                                                                                                                       containing        oral       contraceptive                                                  agents                    (46-52),
the    cause     of the                           maternal       vitamin         B6                            deficiency              3) in       postmenopausal              women                                                        administered
during       pregnancy.                                 Impaired        intestinal                                   absorp- synthetic                                 estrogen                       (53),               4)              in women                           with
tion           of dietary                    pyridoxine                       is unlikely                       in view carcinoma
                                                                                                                              of                                           of       the        breast                     5
                                                                                                                                                                                                                       (45, 4),           and   with  5)
the           maintained                      urinary                   excretion         of                 its metabo- comparisons                                              with           tryptophan                          metabolism          in
lite          4-pyridoxic                         acid           (20,               36).          Fetal           sequestra-           the          male             (45, 55-57)                    suggest                     that    there      is an
 tion           is     supported                          by            the          more                 than            twofold estrogen-mediated                                            in crease                         in t ryptophan
higher               concentration                             of pyridoxine                              in cord
                                                                                                      in pregnancy.                thanmetabolism
in        maternal                        blood                (15,             20,
                                                                                 the The       37-40)
                                                                                                mechanism                and
                                                                                                                         by      which        estrogen           (and
higher       aminotransferase               activity     (37, , 42).
                                                            41          It       certain       progestogens,               the    metabolites           of which
is     probably             a major          cause      during       the        last
                                                                                have      estrogenic           activity)         stimulates         the     trypto-
trimester;            the    mechanism           may      be active       trans-phan-nicotinic               acid        ribonucleotide          pathway
port       across          the     placenta          or    increased          fetal
                                                                                appears          to     be       by       the      induction          of      hepatic
binding         sites     (37).     Impairment          of phosphoryla-          tryptophan             oxygenase                   (P.C.
tion           of          the            vitamin                to           its      active              form               or       the -tryptophan:oxygen
                                                                                                                                        L                                                            oxidoreductase                                   (trypto-
oxidation                        to        4-pyridoxic                              acid          rather                than           phan
                                                                                                                                        its                 pyrrolase),                              which                  catalyzes                             the         first
                                                                             ViTAMIN                     B6       STATUS                IN         PREGNANCY                                                                                 1343

TABLE      S
Comparison                 of vitamin B6                    status             of      mothers             with       two        and>          three            previous              pregnancies”

                                                        Two                 previous             pregnancies                                                          >Three               previ ous       pregnancies

   Week     of                                                                                                      Marginal        +                                                                                           Marginal          +

  pregnancy                         Normal               Marginal                          Deficient                 deficient                     Normal                         Marginal            Deficient                  deficient

            6                  66.7    (2)                         0                     33.3    (1)                 33.3         (1)
         7-12                  40.0(12)                  13.3                (4)           46.7(14)                  60.0(18)                 40.0              (4)          30.0(3)                  30.0         (3)           60.0           (6)
        13-18                  45.5(15)                   9.1                (3)         45.5(15)                    54.6(18)                 33.3              (3)                  0                66.7         (6)           66.7           (6)
        19-24                  44.1(15)                   8.8                (3)           47.1(16)                  55.9(19)                 29.4              (5)               5.9(1)              64.7(11)                   70.6(12)
        25-30                  47.3(26)                  12.7                (7)           40.0(22)                  52.7(29)                 40.0              (6)               6.7(1)              3.3      (8)               60.0     (9)
        31-36                  52.5(64)                     8.2(10)                        39.3(48)                  47.5(58)                  60.0(12)                           5.0(1)              35.0         (7)           40.0           (8)
        37-42                  59.3(54)                      3.3             (3)            37.4(34)                 40.7(37)                  52.6(10)                      10.5(2)                  36.8          (7)          47.4           (9)

    0    Percent         ( number)                f
                                                  o mothers                        in each ciEGOT.

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                        7-12           13-18          19-24            25-30 31-36               37-42                                                      7-12            13-18          19-24 25-30            31-36       37-42
                                                        weeks                                                                                                                                 weeks
                          U         deficient                          ::      margin            al                                                         U         deficient                          4:     margin     al

   FIG.            4.          Comparison                of     vitamin           B6                       status           of       FIG.             5.           Comparison                         of      vitamin               B6       status              of
mothers          with          2 and >3                previous       pregnancies,                                               mothers             with           normal              and         pathological                pregnancies.

TABLE              6
Comparison                     of     vitamin            status
                                                        B6                     of      mothers            with         normal           and         pathological                     pregnancies”

                                                              Normal                   pregnancies                                                                        Pathological                   pregnancies

    Week    of                                                                                                      Marginal        +                                                                                           Marginal          +
  pregnancy                         Normal               Marginal                          Deficient                 deficient                     Normal                         Marginal                   Deficient           deficient

             6                      66.7        (2)                0                     33.3            (1)            33.3        (1)                100.0(1)                     0                         0                          0
         7-12                        40.0(16)            17.5                (7)           42.5(17)                         60.0(24)               50.0(4)                          0                     50.0(4)                    50.0(4)
        13-18                        42.9(18)                7.1             (3)           50.0(21)                       57.1(24)                     0                           33.3(1)                   66.7(2)                         100.0(3)
        19-24                        39.2(20)             7.8     (4)                       52.9(27)                        60.8(31)               25.0(1)                          0                     75.0(3)                    75.0(3)
        25-30                        45.7(32)            11.4     (8)                       42.9(30)                        54.3(38)               60.0(3)                          0                     40.0(2)                    40.0(2)
        31-36                        53.5(76)             7.8(11)                           38.7(55)                        46.5(66)                     100.0(9)                   0                       0                            0
        37-42                        58.2(64)             4.6 (5)                        37.3(41)                    41.8(46)                      80.0(4)                          0                     20.0(l)                    20.0(1)

    0    Percent           (number)                   of mothers in each                          of     ciEGOT.

irreversible          step    of                      the       metabolic                        pathway                    (58,which                L-tryptophan                              is converted                      into        nicotinic
59);       this    is mediated                                  either                   indirectly                   via       acid
                                                                                                                              the                  ribonucleotide,                           and          several               of        the           side
hypothalamo-pituitary-adrenal                                                             axis       and               an         reactions                        along                the           main                pathway                      involve
increase              in             corticosteroids                 (60-66),          or     by                            a pyridoxal                           phosphate-dependent            enzyme                                               sys-
direct           effect                of      estrogen                 on    tryptophan                                       tems
                                                                                                                            oxy-        (see                     Fig. 6). More        tryptophan        enters                                           this
genase             (44,               46).       The               metabolic         pathway,                                  pathway,
                                                                                                                               by                            overloads                        the       later        steps,            and        causes         a
1344                                                                             HELLER                  ET            AL.
                                                                                                                                                -     -    -   -   -     Estrogens

                                                                                                             -   -           -   - - (enzyme              induction)
                                                   tryptophan                     oxygenase                                                    -Corticosteroids

                                  KYNURENINE                                 -                                                     -p               KYNURENIC                ACID
                                                                                      amino          trans              ferase

                                              I                          -
                                                                                                                                                    XANTHURENIC                ACID

                                                                                                                                                                                                      Downloaded from by guest on September 17, 2011
                         P-5’     -P               kynureninase

                   3-HYDROXYANTHRANILIC                         ACID

                                              I          ACID

               NICOTINIC               ACID       RIBONUCLEOTIDE

                                         FIG.      6. Tryptophan-nicotinic                          acid             ribonucleotide            pathway.

secondary           functional                deficiency            of           pyridoxine.                 nine        aminotransferase,                             and   especially   kynureni-
Furthermore,            induction                   of        aminotransferase                               nase.
enzymes,           also     subsequent                     to    elevatedplasma      The      result           of these          disturbances              of pyri-
glucocorticoid            levels,     increases          the availability        doxine       metabolism                is an increased              appearance
of pyridoxal           phosphate-binding                   sites   that      mayof intermediate                   tryptophan            metabolites             in the
result       in partial         removal         of coenzyme                 fromurine,         i.e.,         elevated           urinary           excretion            of
vitamin        B6 -requiring          enzymes             in the        trypto- kynurenine,                3 -hydroxykynurenine              (HK),          xan-
phan-niacin            pathway           (44,       59).        In addition, thurenic               acid        (XA) (9,       67-69),           and       an in-
there        is interference            by      estrogen          conjugates creased              HK/HA               (3-hydroxyanthraniic               acid)
with      the binding           of pyridoxal             phosphate           (48,ratio      (70).            There         may        be      a     further         and
49)       to    two of         the      vitamin            -dependent
                                                           B6                    unrecognized                 vitamin         B6-dependent                 step,     as
enzymes         of tryptophan                 metabolism,             kynure- increased              excretion           of HA        (48)     and      quinolinic
                                                                        VITAMIN                 B6       STATUS             IN         PREGNANCY                                                                                       1345

TABLE                  7
 Comparison                    of the       vitamin              B6 status           in mothers            with       abnormal               pregnancies                     or gravidity
                                                                                                                                                                                  > 3

                                                                                                                                                                                                              Marginal            +
                                                                            Normal                               Marginal                                 Deficient                                               deficient

          Non-stillbirth                         (-)                    46.8           (162)                   7.8            (27)                  45.4                     (157)                          53.2                 (184)
          Stillbirth                               (+)              100.0                 (3)                           0                                         0                                                     0

          Non-diabetic                           (-)                    48.3           (215)                   8.3              (37)                43.4                     (193)                          51.7                 (230)
          Diabetes                                (+)               100.0                 (2)                           0                                         0                                                     0

          Non-pre-eclamptic                      (-)                    48.3           (214)                   8.4            (37)                  43.3                   (192)                            51.7                 (229)
          Pre-eclampsia                           (+)                   75.0              (3)                          0                            25.0                         (1)                        25.0                       (1)

          Gravidity            2                                        51.1           (188)                   8.1          (30)                    40.8                   (150)                            48.9                 (180)
          Gravidity            >3                                       44.4             (40)                  8.9            (8)                   46.7                     (42)                           55.6                   (50)

          “Percent             (number)                of     mothers          in each         ciEGOT.

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TABLE                  8                                                                                             towards                  term                in             the            degree                 of          pyridoxine
Correlation                of vitamin                   B6 status         and                                        deficiency                 and          in            the         percentage                       of        mothers                        in
clinical            findings           in 458          cases
                                                                                                                     the        deficient                range.              Our findings,                               however,                         did
                                                                                         Vitamin                     not         confirm                 this.              The  mean0EGOT                                declined
                                            EGOT activity                                B6 status                   slightly            towards                  term                 from            a peak               of        1 .68          at      I9
                                                                                                                     to 24           weeks             to      I .59 at                    37         to       42      weeks       (Table                          2
                                        Without                     With
                                                                                                                     and            Fig.             1).        Similarly,                                  the         percentage                                of
                                          P-S’-P                     P-5’-P
                                        (EGOT0)                    (EGOT)                 ciEGOT
                                                                                                                     mothers                 in    the    deficient                                     and      marginal                            range
                                                                                                                     declined                 from     61     to 42%                                      (Table        3                 and           Fig.
No.         of previous                   0.06          16               0.0759             0.0344                   2).        These      findings          could                                    not       be          explained                     by
                                                                                                                     the         premature          delivery                                    of          mothers              with                 defi-
No. of previous                         -0.0492                   -0.0531                      -0.0055
                                                                                                                     cient    aEGOT                      values;    the                         length                of         pregnancy
Hemoglobin                              -0.1112                     -0.0811                 0.0119                   appeared          to                be independent                                      of       the         vitamin 6
Proteinuria                               0.0467                    0.0021               -0.1233                     status     (Table                    4 and    Fig.                         3).         On        the         other     hand,
Glucosuria                                0.0286                    0.0345               -0.0044                     mothers                 with           three                 or       more                previous                  pregnan-
Acetonuria                              -0.0088                     -0.0042              -0.0076
                                                                                                                     cies       were,          in        general,                   more                deficient                  than          those
Birthweight                               0.1018                    0.0965               -0.0435
     of child                                                                                                        with              two          or      less                 previous                     pregnancies,                            both
Length              of child                0.0909                  0.0807               -0.0525                     groups              showing                       a         slight               improvement                               in          the
     at     birth                                                                                                    second     half of the pregnancy          (Table       5 and Fig.
                                                                                                                     4 and         Table    7).    Thus,   our      results      are  not
                                                                                                                     consistent        with  those    of Coppini        and Camurri
acid           (10)        has      also               been        found.          These            increases        (77)         who         showed                       that           urinary                   xanthurenic                           acid
in         urinary           tryptophan                         intermediate                    metabolites        excretion                   was     higher                             late  in pregnancy                                          than
are          found             after       a tryptophan                         load        (48,         49,      71)
                                                                                                                    early,   and               Hamfelt        and                          Hahn   (43) who                                found                   a
and,      in the                    case       of A,
                                                H       without     prior                            loading   rising                   xanthurenic                                acid                and             total              estrogen
(spontaneous                           excretion)          in women                              taking    oralexcretion                      and         a corresponding         fall                               in pyridoxal
contraceptive                           agents       (72,     73),   and                          in vitamin phosphate                               plasma         concentration                                     throughout
B6 deficiency                    (74);                 they            by the pregnancy.
                                                                  are correctable
prior               administration                         of     (9,
                                                                         11, 12, Sprince             et al. (3)        reported         that     patients        with
47-49,75,76).                                                                     pre-eclampsia             or eclampsia          excreted         abnormally
    In view          of this relationship            between          estrogen high        quantities           of     xanthurenic              acid      after        a
and        vitamin        B6, it might          be      expected            that tryptophan              load,      suggesting        a relationship               be-
during         pregnancy         the   rising       estrogen          synthesis tween        pyridoxine        deficiency         and toxemia;             these
in     the       placenta       and     greatly          elevated          plasma findings        have       been       considered           doubtful           (42).
levels         would         cause       a      progressive             increase Our results           (three      of four cases of pre-eclampsia
1346                                                                                              HELLER                ET       AL.

had         aEGOT                 values                    in      the              normal                 range)              the        influence                    of      various              amounts               of      pyridoxine
                                                                                                                                hydrochloride                            upon             the   abnormal                       tryptophan
unfortunately                    do           not        allow               us      to    draw            signifi-
                                                                                                                                load        test        in pregnant                       women. J. Lab.                   Clin.    Med.
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                                                                                                                           7.    MUSAJO,                    L.,         AND          C.         A.      BENASSI.                   Aspects               of
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       By        means                of         the        specific                EGOT-activation                             63,       1964.
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                                                                                            depletion             J.     M.,      R.    R.      BROWN           AND      N.     YESS.
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                                                               to                         45860%  Testing
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No        evidence          was        found          that          this        form          of BROWN,
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                                                                                             10. BROWN,               R.      R.,      N.      YESS,       J. M. PRICE,                H.
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