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NIRMAN
Maternal Metabolic Disorders

Maternal Metabolic Disorders and their effect on fetus

Dr. Anil B. Jalan
M.D. , D.C.H. , M.C.P.S.

Maternal metabolic and endocrinal disorders :-

1 ) Maternal diabetes mellitus .
2 ) Maternal hypothyroidism or hyperthyroidism
3 ) Maternal adrenal gland dysfunction.
4 ) Maternal calcium metabolsim dysfunctions .
5 ) Trace mineral metabolsim e.g . Zinc, Copper , Lead , Mercury etc.
6 ) Inborn Errors of Metabolism -

a. Phenylketonuria
b. Homocystinuria
c. Histidinemia
d. Tyrosinemia II
e. Hyper trypto phnemia
f. Hyper ornithinemia
g. Hyper lysinemia
h. Arginosuccinic acidemia
i. Hyper prolinemia type
j. Hydroxy prolinemia
k. Isovaleric acidemia
l. Hartnup disease
m. Imino glycinuria
n. Galactosemia
o. Refsum disease
p. Porphyria
q. Wilson ?disease
r. Dubin Johnson Syndrome

1 ] PHENYLKETONURIA :- This is an Autosomal Recessive ( A. R.) disorder, with a general population frequency of approx .1 in 15,000 to 1 in 20,000 . Approximately 9 variants are known . Hall mark of the disease is elevated blood phenylalanine levels. Routinely Phenylalanine level in blood is < 2.0 mgm / dL .

Elevated maternal Sr. Phenylalanine level through out the pregnancy is associated with

1 . Mental retardation and microcephaly in the baby .
2 . Intra uterine growth retardation and L . B . W . baby .
3 . Convulsions in the baby .
4 . Typical phenotype .
5 . May be associated with congenital heart defects .

Mothers with PKU have a high incidence of recurrent spontaneous abortions ( Stevenson and Huntley ,1967 ). The fetal damage is due to prenatal exposure to high concentrations of phenylalanine and its metabolities in the maternal serum .

1. Mental Retardation Denniston & Coldwell , 1966
2. Growth retardation & Microcephaly Stevenson & Huntley , 1969
3. Congenital Heart defects Frankenburg et.al. , 1968
4. Recurrent spontaneous abortions Stevenson & huntley et.al. , 1967
5. Abnormal fetuses in PKU mothers with normal Intelligence Fisch et. al. , 1969

The levels of PHE > 20 mgm % are harmful to the fetus .

1. Mental retardation 92 %
2. Microcephaly 73 %
3. Cardiac defects 10 %
4. I . U . G . R . 40 %
Treatment of mother :- Low PHA diet to maintain Sr .PHA level < 10 mgm % . throughout pregnancy .

Prevention :- screening of mother before pregency especially in women with h/o recurrent spontaneous abortions .

2 ] Homocystinuria :- This is an Autosomal Recessive disorder , with general population frequency reported to be 1 in 1-2 lac. But recently the neonatal screening data , especially from India gives a higher figure .This is a Methionine metabolism disorder .

Clinical features :-

1. Mental retardation & microcephaly
2. Dislocated lenses , myopia , optic atrophy .
3. Cerebro vascular accidents .
4. Skeletal anomalies .
5. Failure to thrive .
6. Developmental delay .
7. Marfanoid features .
8. Patient may have normal intelligence .

More than 5 different varieties are known .

38 pregnancies in 14 homocystinuria patients are known . The details are as follows :-

Of the 20 untreated pregnancies -

a. 16 Fetal losses
b. 1 M.T.P.
c. 1 Hydrocephalic stillbirth
d. 2 Normal babies

Of 17 treated with pryridoxin -

a. 15 Normal offsprings
b. 1 Unrelated brain damage
c. 1 Trisomy 21 .

Unresponsive to pyridoxin 1 patient - Normal child .

Children of men with homocystinuria have no abnormality.

Treatment :-

1. Pyridoxine 200 - 1000 mgm / day
2. Folic acid 5 mgm / day
3. Betain ( trimethyl glycine ) 6 Gm / day .
4. Methionine restricted diet .

Anti-coagulant therapy to pregnant women is must with Aspirin & Dipyridamol. Avoid smoking and O.C. Pills . The degree of enzyme deficiency is intermediate , so are the levels of toxic metabolites . It will be quite clear that even carrier mothers may have certain degree of effect on the fetus and on herself e.g. mild mental retardation , microcephaly , recurrent spontaneous abortions etc. Many more studies and population screenings are requiered to really understand the I.E.M. and its effects on fetus .

3 ] Maternal Histidinemia :- Histidinemia is an inborn error of Histidine metabolism caused by reduced activity of Histidase enzyme , an enzyme that catalyzes the conversion of Histidine to uroconic acid . The biochemical phenotype of Histidinemia includes increased Histidine in blood , Urine , and other fluids and the excretion of imidazole metabolites of Histidine. Histidinemia is probably a benign disorder . A low Histidine diet will controll the biochemical abnormalities of Histidinemia and has been used in a few patients. ( Synderman et. al. 1979 ) .

Maternal Histidinemia in humans , doesnot seem to produce fetal harm. 25 offsprings from untreated pregnancies in Histidinemic women have been reported ( Bruckman et.al. 1971 ).

No congenital anomalies , microcephaly or mental retardation has been found in these children . No offspring are known to have ataxia or other imbalance as observed in the offsprings of Histidinemic mice .

4 ] Maternal Tyrosinemia II :- Tyrosinemia type II ( Richner Hanhart Syndrome ) is an inborn error of Tyrosine metabolism in which cytosolic tyrosine aminotransferase is deficient . Observed biochemical abnormalities include increased tyrosine and the urinary excretion of tyrosine metabolites such as p - hydroxy-phenylpyruvate , p - hydroxy-phenylacetate , and p - hydroxy-phenyllactate . The clinical phenotype is a characteristic triad of palmo plantar hyperkeratosis , keratitis and / or conjunctival lesions and mental retardation . Dietary therapy with phenylalanine and tyrosine restriction controls the somatic features and , if begun in infancy , may prevent the mental retardation .

Maternal tyrosinemia II has been recorded in one women ( Garibaldi and Durand , 1980 ) . The normotyrosinemic offspring from an untreated pregnancy was mentally retarded and had seizures . This suggests that maternal tyrosinemia II may ptoduce a fetal effect similar to that of maternal P.K.U. If so , this would be surprising given the biochemical similarities of tyrosinemia II and P.K.U.

5 ] Maternal Hypertryptophenmia :-Hypertryptophanemia is a metabolic disorder associated with increased tryptophan and the urinary excretion of tryptophan metabolites such as indolepyruvate , indolelactate and indoleacetate . The enzymatic defect has not been defined , but the metabolic block seems to limit oxidation of tryptophan to Kyneurenine ( Snedden , Mellor and Martin et. al. 1983 ) . Two affected adult siblings were mentally subnormal and had severe emotional liability , but one other adult was normal , as were three infants ( Sardharwala & Fowler 1980 ) .

Treatment with a low tryptophan diet controls the biochemical abnormalities .

Maternal hypertryptophanemia has been observed in one women ( Sardaharwala & Fowler 1980 ) . She has had three untreated pregnancies - one ending in a spontaneous abortion , and two producing normal offspring .

6 ] Maternal Ornithinemia :- Choreo-retinal degeneration with an ophthalmologic picture known as gyrate atrophy of the choroid and retina is associated with hyper-ornithinemia secondary to a deficiency of ornithine ketoacid transaminase activity . This is a pyridoxine dependent enzyme and ,. as in homocystinuria , there is a pyridoxine - responsive and a pyridoxine non responsive form of the disorder ( Shih et.al. 1978 ) . Night blindness and loss of peripheral vision develop in adolescence with continued constriction of the visual fields , leading to blindness in middle age .

Maternal hyper-ornithinemia seems to produce no adverse fetal effect. Five affected women have had six normal offspring ( Takki & Simell 1974 ). None of the offspring had ornithinemia .

7 ] Maternal Lysinemia :- Hyperlysinemia is an inborn error of lysine metabolism in which two enzymes in the lysine degradation pathway , Lysine ketoglutarate reductase and saccharopine dehydrogenase , are defective ( Dancis et.al. 1979 ) . Affected individuals have increased concentrations of lysine in blood and urine . Most of them have been clinically normal with or without diaetary therapy . One woman with hyperlysinemia is known to have given birth , the offspring was normal ( Dancis et. al. 1983 )

8 ] Maternal Arginosuccinic Acidemia :- Arginosuccinic acidmeia is an inborn error of metabolism involving urea cycle . The defect is at the argininosuccinate lyase catalysed step ., the penultimate reaction in the urea cycle responsible for the cleavage of argininosuccinate with large amounts excreted in the urine , mild hyper-citrullinemia with episodic hyper ammonemic crisis and mental retardation . Treatment with arginine supplementation and a low protein diet control the hyperammonemia and may prevent the mental retardation .

One woman with argininosuccinic acidemia is known to have given birth ( Lamon et. al. 1981 ) . Her untreated pregnancy was uncomplicated and resulted in an offspring without argininosuccinic acidemia who was normal when evaluated at age 18 months .

9 Maternal Hyperprolinemia - I
10 Maternal Hydroxyprolinemia
11 Maternal Isovaleric acidemia
12 Maternal Hartnup disease
13 Maternal Iminoglycinuria *

The conditions mentioned above from 9 to 13 have not known to be associated with any fetal effect including I.U.G.R. , M.R. etc.

14 Maternal Galactosemia
15 Maternal Refsum disease
16 Maternal Porphyria
17 Maternal Wilson?disease

The discussion for the above condtions is beyond the scope of this article and the readers are requested to go through the classical text book by Charles Scriver - Genetic and Metabolic Disease in Paediatrics .

At present the consensus is to control maternal Galactosemia with restriction of Lactose in her diet and maintain Sr. galactose 1 phosphate levels in the normal range . It is knwon to prevent the mental retardation in offsprings and gonadal failures in female babies .

Thyroid function abnormalities in mother and its effect on fetus .

Clinical profile :-

Sub clinical Hypothyroidism
Hyperthyroidism
Clinically Overt Hypothyroidism
Hyperthyroidism

Decreased conception rate and repeated fetal losses are associated with only overt hypothyroidism or hyperthyroidism .

Subclinical thyroid dysfunction is less likely to produce above features , however the latest thinking is that the maternal thyroid antibodies are related to some congenital anomalies , mental retardation and even Down? syndrome .

Iodine :-Endemeic cretinism :- ( Iodine deficiency goiter ) products -

Goiter

a. Mental deficiency
b. Hearing and speech defect .
c. Stance and gait abnormality .
d. Severe growth retardation .

Treatment :- Correction of Iodine deficiency state in the population .

During the pregnancy , demand for Iodine increases due to :-

1. Increased renal clearance .
2. Mother?expanded plasma volume
3. Fetal requierments .

Supplementation of maternal diet with 150 umg / day of potassium Iodine .

Excess amount of Iodine will lead to :-

1. Inhibition of fetal thyroid-function
2. Goiter
3. Compromise tracheal patency
4. After birth severe respiratory distress


Maternal drugs which cross placenta and has effect on fetal Thy. Function

1. Propyl thiouracil Inhibit fetal thyroid function .
2. Methimazole Inhibit fetal thyroid function .
3. Carbimazole Inhibit fetal thyroid function .
4. Thioamides Inhibit fetal thyroid function .
5. Beta blockers
6. Glucocorticoids
7. Lithium
8. Iodine
9. Amiodarone Inhibit fetal thyroid function .
10. Methadone Transient increase in T3 , T4 .
11. Cigarette smoking Increases fetal thyroid function .

Inborn Errors of Metabolism of thyroid function . :-

Autosomal recessive :-

1 . Infant with hypothyroidism and thyromegaly , elevated T.S.H. Dysmorphogenesis accounts for 20 % of neonatal cases .
2 . Familial congenital nongoitrous hypothyroidism .

Autosomal Dominant :-

Hypothyroidism with thyromegaly
Peripheral insensitivity to T3 , T 4 , T.S.H.
Refetoff Syndrome - Mc Cusick no. 27430

X Linked :-

Post receptor insensitivity to T.S.H
Infantile hypothyroidism .
Pseudo hypo para thyroidism type I a obesity , short stature , Brachydactyly Ectopic calcification .

Effect of thyroid disorder of mother on the fetus :-

Molecular effects :-

1 Two fold increase in renal clearance of Iodine .
2 Increased thyroidal Iodine uptake
3 Decreased plasma - inorganic Iodine.
4 Two fold increase in Sr. TBG level
5 Increased hepatic TBG production

Net effects :

1 . Goitre - due to

a Hyperplastic & Hypertrophic colloid filed follicles .
b Increased Vascularity .

2 Increased T3 , T4 , & rT3 .

3 Concentration of free T3 , T4 remains normal .

4 TSH remains same or decreases in the 1 st trimester during the 2 nd
& 3 rd trimester there is increase in TSH .

5 . Slight increase in thyroid hormone production .

6 . B.M.R. increases by 20 %

7 . Reduced T 4 binding albumin & prealbumin .

8 . Increased Iodine requirements during pregnancy due to
a Increased renal clearance
b Expanded plasma volume
c Fetal requirements

Per day requirements 150 mgm Potassium Iodide ( K 2 1 )

Incidence of various thyroid related disorders :-

i Nontoxic goitre up to 50 % pregnancy in certain areas .
ii Autoimmune thyroid disorders in mothers 3 - 6 %
iii Congenital hypothyroidism - 1 in 4000 live births .
iv 7.5 % infants with cong. Hypothy. Have major congenital anamolies .


Excessive Iodine intake :-

?nhibition of thyroid function
|
Goitre
|
Compromise tracheal patency
|
After birth severe respiratory distress .

Increased intake from :-

i Iodine containing proprietary formulas for Asthama / Cough etc.
ii Iodine herapy of maternal thyrotoxicosis .

iii Iodine containing contrast agents before or during pregnancy leads to
slow release of Iodine .
iv Topical application of Iodine containing antibacterial agents during :-

Pregnancy
Labour
Lactation

v In smoker mothers ? Hyper function of fetal thyroid glands
|
Increase T 4 & T.S.H.

vi TG IIG :- Thyroid Growth Inhibiting Immunoglobulin present in maternal
serum in :-

a Infants with dysgenetic thyroid glands
b Transient hypothyroidism .
c Goitrous hypothyroidism .

Maternal titres of TG IIG tend to decline over several years .


Metabolic Disorders affecting the fetus :-

1. Diabetes Mellitus
2. Hypothyroidism
3. Hyperthyroidism
4. Phenylketonuria
5. Tyrosinemia
6. Homocystinuria
7. Biotinidase deficiency
8. Galactosemia

Tests suggested for high risk couple :-

1. Maternal ( mother's ) tests

a. Fasting and post lunch blood sugar levels
b. Glycosylated Haemoglobin level
c. T 3, T 4, T.S.H., Thyroid antibody test , free T3 and free T4
d. Sr. Ammonia and Lactate levels
e. Biotinidase enzyme
f. GAL - 1 - PUT enzyme
g. Aminoacidogram on plasma and urine.
h. Sr. Phenylalanine , Homocysteine and GALT level by quantitative assay methods ( EIA or HPLC )