March 1999, Volume 49, Issue 3

Student's Corner

Intrauterine Growth Restriction: A Perspective for Pakistan

Aliya Shamim  ( Fourth Year Medical Students, The Aga Khan University Hospital, Karachi. )
Hammad O. Khan  ( Fourth Year Medical Students, The Aga Khan University Hospital, Karachi. )
Jamal S. Rana  ( Fourth Year Medical Students, The Aga Khan University Hospital, Karachi. )
Kaashif Aqeeb Ahmed  ( Fourth Year Medical Students, The Aga Khan University Hospital, Karachi. )

Pathophysiology (in relation to maternal malnutrition)
As previously discussed, nutrition sets the growth trajectory. Once the trajectory is set, environmental factors determine whether the fetus will meet the full potential of the trajectory or will fall short. In Pakistan, maternal malnutrition is of great importance, so the answer to the following question shall occupy us: what are the required nutrients of the maternal blood, and how does a deficit of these nutrients biochemically affect the fetus?
Three major substrates must be available for placental transfer - oxygen, glucose, and amino acids. Severe oxygen deficit is generally independent of nutrition, but rather on any co-morbids such as chronic lung disease or severe anemia - though mild nutritional anemia is common in Pakistan. In fact, it is the other two substrates that more directly concern us; these are glucose and amino acids.
Glucose crosses the placenta by facilitated diffusion, while amino acids are actively transported across the placenta, causing higher fetal amino acid levels. Maternal nutrition will affect both the amount of glucose as well as amino acids that are available for transfer. The signals eliciting alterations in the fetal growth pattern in response to a compromised maternal supply have not been elucidated in detail yet, although details are slowly emerging.
Current theories
An IUGR fetus is sometimes hypoinsulinemic due to hypoglycemia in utero, and the low insulin levels will slow the growth rate in insulin-sensitive tissues such as skeletal muscle and liver, whereas brain growth is relatively spared. Recently, concentration has been given to the insulin like growth factors (IGF) because the IGFs seem to play a crucial role in fetal growth. They have been found to cause stimulation of fetal cell proliferation and anabolism. They have also been found to have a capacity to direct nutrients from the placenta towards the fetus36. Direct correlation between umbilical cord serum IGF-l levels with birth weight have repeatedly been reported37,38,39. Evidence of the role of 1GFs in fetal growth have been found in mice -in whom targeted mutagenesis of the genes encoding IGF-l and IGF-II have produced profound embryonic, fetal, and postnatal growth retardation in mice40,41. In humans, a patient with severe IUGR due to the deletion of IGF-l has been recently described as well42. It has been postulated that the growth-promoting machinery of the fetus - an integral link of which are the IGFs is frozen in IUGR fetuses to minimize energy expenditure for growth and to favor survival and development of vital organs43.
Another area currently being actively explored is the role of amino acids in IUGR, how the concentrations change throughout pregnancy, and how specific amino acids contribute to the growth of various organ systems. The information in this area is not yet as advanced as that for the IGFs. Experiments have mostly been done on animals, including rats and cats. An important example is taurine - deficiency of taurine in cats has been found to be directly linked to IUGR44, suggesting that taurine plays a role in regulating fetal growth. In human fetuses, taurine is an essential amino acid45,46. It has been found recently that IUGR is associated with a reduced activity of placental taurine transporters, both in the microvillous membrane and the basement membrane47. Correlating this with the role that it is thought to play in animals, it has been recently postulated that this could be yet another link in the pathophysiology of some forms of IUGR.
Identification and Surveillance of an IUGR fetus
A thorough clinical assessment and appropriate laboratory investigations are the two broad-based tools available. Regarding the clinical assessment, a detailed history should be focused at the identification of risk factors. Wennergren48 classified the risk factors into 5 broad categories:
1) Low maternal pre-pregnancy weight and height. and low weight gain during pregnancy,
2) Poor prior obstetric history (high parity, previous LBW, stillbirth/NND).
3) Pregnancy complications (hypertension, bleeding etc.).
4) Maternal medical diseases (vascular, renal diseases etc.).
5) Environmental factors (malnutrition, low socioeconomic status etc.).
The environmental factors seem to be most relevant to the broader context of our population.
The physical examination should be directed to assess the general medical condition of the mother as well as the measurement of symphysis-fundal height which if found to have a discrepancy of more than 3 cm has a very high sensitivity and specificity for IUGR detection. The identification of risk factors together with Small Fetal Height measurement may screen out positively up to 85% of fetuses who have a higher probability of being growth-restricted49.
From a primary care setting, these cases can then be referred to secondary or tertiary care centers where more expertise and sophisticated techniques should be at hand for further management.
The tools of investigation available are TORCH titers, U/S biometry, biophysical profile, non-stress test, fetal doppler U/S and then certain invasive techniques such as amniocentesis, chorionic villus sampling and cordocentes is.
TORCH titers and invasive procedures are important to find out the etiology of a symmetrical growth restriction, if present.
1. Ultrasound for gestational age should be done no later than 20th week with 8-13 weeks being the most appropriate time50. Fetal weight should measured to see if it is less than 10th percentile and Abdominal Circumference is less than 2.5th percentile. It is important to select the appropriate percentiles depending on the sensitivity required for a particular population or center.
2. Crown-Rump Length (5-l2weeks), Biparietal Diameter (12-18 weeks)5’ and Femur Length (>1 5weeks)50, are very accurate in determination of gestational age. Abdominal Circumference has >95% sensitivity for IUGR detection51 whereas HC/AC has >70% sensitivity for the detection of asymmetric IUGR52.
3. Biophysical profile has a sensitivity of 65-100% for the identification of acidemia53. Doppler ultrasound of fetal circulation is still in the experimental stage54 even in western countries and its utility lies in identifying a compromised fetus55 and then intervening at a step where the degree of damage to the fetus is not irreversible.
4. Non-stress test is also an important tool for assessment of fetal well-being but has the disadvantage of missing the intermittent stage of partial decompensation which could be the appropriate time for intervention.
A rank-ordering for abnormalities of fetal assessments in a progressively deteriorating IUGR fetus has been developed56. Abnormal fetal umbilical artery waveforms precede the changes in fetal rest-activity cycle. Subsequently, late decelerations and poor variability appear on NST, followed by a low score on biophysical profile. Growth changes (as measured by AC) occur in between.
A Perspective for Pakistan
Every year out of the 30 million newborns born with IUGR, 75% are born in Asia-mainly in south-centraE Asia8. Whereas 30% of Africa’s children are underweight; the corresponding figure for South Asia is over 50%57.
Virtually half of the world’s malnourished children are to be found in just three countries, namely Bangladesh, India and Pakistan. The fact that the problem is more in this area as compared to sub-Saharan African region indicates that the underlying problem is beyond the more obvious poverty, agricultural performance and social inequalities.
Ramalingaswami pointed out that the key to this deadlock is the woman of a country57. Imagine women as Soil’ nourishing the seed of every new generation. So it becomes important that our very foundation should be healthy. According to The State of the World Children 1998, enrollment ratio of females in schools in Pakistan, as a percent of males was around 50% and 81% of the births are not attended by any health personnel. Around 60% of females in South Asia have iron deficiency, anemia, compared to 40% in Sub-Saharan region58. The pregnancy weight gain should be ten kilos where as in South Asia it is five kilos". And this is only the tip of the iceberg.
All this comes to prove that the girls in South Asia are less well regarded and less cared for. And it is a fatal mistake on our part for not seriously realizing this issue. According to a community-based study in Karachi, the incidence of term intrauterine growth restriction was 24.4% among 738-singleton births9. The major risk factors, with an attributable risk of 20% or more were, low maternal weight, grand multiparity, low level of education, consanguinity and short birth-to-conception interval. A comparable study in Ahmedabad, India, showed similar results59. Risk factors suggested were, low mean height and booking weight, low paternal height and weight, anemia (mean Hb 8.lg/dl) and malnutrition (54% consumed less than 1500cal/day). Still another study in India concluded maternal malnutrition as a risk factor for IUGR with an attributable risk of 42%60. These facts further reinforce the notion of inequality of women in a society.
According to M de Onis, IUGR is a major public health problem worldwide, which contributes to closing the intergenerational cycle of poverty, disease and malnutrition8, A prevalence of IUGR in access of 20% has been recommended as the cutoff point for triggering public health action61. The prevalence in Pakistan is around 25%8,9. So a dire need for an immediate intervention is imperative.
While evaluating prevention strategies we have to keep in mind the concept of inter generation cycle of growth failure. In this viscous cycle a low birth weight baby grows up to be a small adult woman, who eventually with early pregnancies in turn bears small children. Studies have shown that a woman’s birth weight influence the birth weight of the offspring62,63. So the challenge is to reach women well before they become pregnant. This will help adolescent girls to achieve the best nutrition status possible, before they enter the reproductive years.
Intrauterine growth restriction is a problem with a multi factorial cause. A macroscopic view of the situation points out the roots of the problem to be based in our political, cultural, social and economic infrastructure. With basic contributing determinants being family and community resources, information, and education. Personal communication with Bhutta revealed that the underlying determinants like inadequate food, hygiene, sanitation and health services are all interconnected with disease and low birth weight.
This calls for a synergistic approach to reduce multicausal outcome like IUGR8. A review of 126 randomized control trials pointed out interventions like balanced protein/energy supplements, anti malarial chemoprophylaxis and smoking cessation64. More than this it is a matter of political will. The age-old notion of’agenda of welfare’ is to be changed to ‘agenda of rights’. The ‘key of keys’ is the education of girls57. Health services should be affordable, of adequate quality, and reasonable distance from home. Women should be given better status in the family. Women empowerment will give her more decision making power. Especially in the rural setting community awareness and understanding is the basic platform, from which goal oriented targets can be achieved.
Strategies to reduce IUGR in the present generation of infants are for the benefit of the generations to come64. A lot of responsibility lies with the doctors and health care workers, it is us who have to make these problems known to the government and the media. We have to sensitize communities to organize themselves. It is the same ‘good will’, which Dante spoke of in Paradise of his Divine Comedy, which is required today. Otherwise Intrauterine Growth Restriction will remain a testimony to the regression of a civil society.
 

Concluded!

Acknowledgements

We would like to extend our gratitude to Dr. Thomas Martin, Professor and Chairman, Department of Obstetrics and Gynecology and Dr. Zulfiqar A. Bhutta, Professor, Department of Pediatrics,The Aga Khan University Hospital, for their guidance and support in this project.

References

1. Wolfe, H.M., Gross,TL.. Increased risk to the growth retarded fetus. Pill. in Gross TM, Sokol RJ (eds); Intrauterine Growth Retardation. Year Book Medical Publishers Chicago, 1989.
2. Barker, Di., Gluckman, PD., Robinson, iS.. Conference report: fetal origins of adult disease-report of the First International Study Group, Sydney, 29-30 Oct.1994 Placenta. 1995, 1 6(3):3 17-20.
3. Barker, DiP., Clark, PM.. Fetal under nutrition and disease in later life. Rev- Reprod. 1997,22: 105- 12.
4. Barker, DJP.. In utero programming ofchronic disease. Clin-Sci-Colch. 1998; 95:115-28.
5. Spinillo, A., Stronati, M., Otnetto, A., et al. Infant iieurodevelopmental outcome in pregnancies complicated by gestational hypertension and intrauterine growth retardation . J-Perinat-Med . 1993;21 : 195-203.
6. Low, JA., Handley-Derry, MH., Burke, S. . Association of intrauterine fetal growth retardation and learning deficits at age 9 to 11yrs. . An-J-Obstet­ Gynecol. 1992;167: 499.505.
7. Wollmann, HA.. Intrauterine growth restriction:definition and etiology. Horm Res 1998;49(Suppl 2): 1-6.
8. Onis, M., Blossner., Villar, J. . Levels and patterns of intrauterine growth retardation in developing countries. Euro-J-Clin-Nutr., 1998; 52:S 1-3.
9. Fikree, F., Berendes, RW.. Risk factors for term intrauterine growth retardation: a corniiiunity based study in Karachi . Bull-World-Health-Organ. 1994; 72(4):360-62.
10. On, W..Consideratioiis in neonates with intrauterine growth retardation. In Frigoiette FD (ed): Clinical Obstetrics and Gynecology. Harper & Raw. Hagerstown, MD. R77, 1994; p.989.
11. Godfrey, KM., Barker, DJ.. Maternal nutrition in relation to fetal and placental growth. Eur-J-Obstet-Gynecol-Reprod-Biol . 1995:61 : 15-22.
12. Barker, DJ,. Outcome of low birth weight. Horm-Res. 1 994;42(4-5):223-30.
13. Barker, DJ. Fetal nutrition and cardiovascular disease in later life. Br-Med­ Bull. 1997;53:96-108.
14. Godfrey, KM.. Maternal regulation of fetal development and health in adult life. Euro-J-Obstet-Gynecol-Reprod-Biol. 19981,78: 141.150.
15. Barker, DJP.. Maternal and fetal origins of coronary heart disease. J-R-ColI­ Physicians-Lond. 1994;28:544-51.
16. Barker, DIP.. Intrauterine programming of coronary heart disease and stroke. Acta-Paediatr-Suppl. 1997;423:178-82
17. Stein, CE., Fall, CH., Kumaran, K., et al. Fetal growth and coronary heart disease in South India. Lancet. 1996:348:1269-73.
18. Eriksson, JG., Forscn, T., Barker, DJP., et al. Catch-tip growth in childhood and death from coronary heart disease:longitudinal study. BMJ 1999; 318:427-31.
19. Hales, CN.. Fetal and infant growth and impaired glucose tolerance in adulthood: the ‘thrifty phenotype” hypothesis revisited. Acta-Paediatr­Suppl.l 997;422:73-77.
20. Fall, CH., Barker, DIP.. The fetal origins of coronary heart disease and non­insulin dependent diabetes in India. lndian-Pediatr. 1997;34:5-8.
21. Hales, CN., Barker, DJP., Clark PMS. et al, Fetal and infant growth and impaired glucose tolerance at ages 64. Br Med J 1991; 303: 1019-22,
22. Clark, PM., Hindmarsh, PC., Shell, AW,, et al. Size at birth and adrenocortical function in childhood. Clin Endocrinol 1996; 45: 72-26.
23. Phillips, DIW., Barker,DJP.. Association between low birth weight and high resting pulse in adult like: is the sympathetic nervous system involved in programming the insulin resistance syndrome. Diabetic Med 1997; 14: 673-7
24. Phillips, DIW., Barker, DIP., Fall, CHD., et al. Elevated plasma cortisol concentrations: a link between low birthweight and the insulin resistance syndrome?. J-CIin-Endocrinol-Metab, in press.
25. Vandenbosche, R., Kirchner, J.T. Intrauterine Growth Retardation. American Family Physician, 1998;58: 1384-1390.
26. Lechtig, A., Yarbrough, C., Delgado, H., et al. Effect of moderate maternal malnutrition on the placenta. Am I Obstet Gynecol 1975; 123:191.
27. Singer, I.E., Westphal, M., Niswander, K.. Relationship of maternal weight gain during pregnancy to birth weight and infant growth and development in the first year of life. Obstst Gynecol 1968;31:117.
28. Abrams, B.F., Laros, R.K.. Prepregnancy weight, weight gain and birth weight. Am J Obstet Gynecol 1986;154:503.
29. Walton, A., Hammond, J. The maternal effects on growth and confonnation in Shire horse - Shetland pony crosses. Proc Royal Soc Series B 1938;125:311-35.
30. Morton, N.E. The inheritance of human birthweight. Ann Hum Genet 1955;20:123-4.
31. Brooks, A.A., Johnson, MR., Steer, P.J., et al. Birthweight: nature or nurture? Early Human Devel 1995 ;42 :29-35.
32. Carr-Hill, R., Campbell, D.M., Hall, M.H., et al. Is birthweight determined genetically? Br Med J., 1987-295:687-9.
33. Harding, J.E., Liu, L., Evans, P., et al. Intrauterine feeding of the growth-retarded fetus: can we help? Early Human Devel., 1992;29:193-7.
34. Robinson, iS., Harnvich, KM., Walker, S.K., et al. Early influences on embryonic and placental growth. Acts Pacdiatr., 1997;423:159-63.
35. Rudolph, AM. The fetal circulation and its response to stress. J Devel Physiol., 1984;6:11-19.
36. Gluckinan, PD. The endocrine regulation offetal growth in late gestation: the role of insulin-like growth factors. J Clin Endocrinol Metab., 80:1047-1050.
37. Lassarre, C., Hardouin, S., Daffos, E, et al. Serum insulin-like growth factors and insulin—like growth factor binding proteins in the human fetus. Relationships with growth in nonnal subjects and in subjects with intrautenne growth retardation. Pediatr Res., 1991 ;29:219-225.
38. Ashton, I.K., Zapf, J., Ehischenk, I., et al. Insulin-like growth factor (IGF) I and II in human foetal plasma and relationship to gestational age and foetal size during mid-pregnancy. Acts Endocrinol., 1985;10:558-563.
39. Reece, E.A., Wiznitzer, A., Le, E., et sI. The relation between human fetal growth and fetal blood levels of insulin-like growth factors I and II, their binding proteins, and receptors. Obstet. Gynecol., 1994;84:88-95.
40. Liu, J-P., Baker, J., Perkins, AS., et al. Mice carrying null mutations of the genes encoding insulin-like growth factor-I (Igf-l) and type-I IGF receptor (Igflr)..Cell, 1993;75:59-72.
41. Baker, J., Liu, i-P., Robertson, E.i., et al. Role of insulin-like growth factors in embryonic and poslnatal growth. Cell, 1993;75:73-82.
42. Woods, K.A., Camaeho-Hubner, C., Savage, M.O. et sI. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N EngI I Med., 1996;335:1363-1367.
43. Cianfarani, S., Gcnnani, Ut., Rossi, P., at aI. Intrauterine Growth Retardalion: Evidence for the Activation ofthe Insulin-Like Growth Factor (IGF)-Related Growth-Promoting Machinery and the Presence ofa Cation-Independent IGF Binding Protein-3 Proteolytie Activily by Two Months of Life. Pediatr Res., 1998;44:374-380.
44. Sturman, iA., Gargano, AD., Messing, J.M., et al. Feline matemal deficiency: effect on mother and offspring. J. NuIr., 1986;1 16:665-67.
45. Siurman, J.A.. Taurine in development. J Nutr 1988;118:1169-76.
46 Hayes, K.C., Sturman, J.A.. Taurine in metabolism. Annu Rev Metabol 1981;1:401-425.
47. Norberg, S., Powell, T.L., iansson, T.. tntrauterine Growth Restrielion is 238.
48. Wennergren, M. Antenatal screening and risk factors for IUGR. Int. J.Technol. Assess Health Care, 1992; S:(Suppl I) 147.
49. Gasiano, E. Antenatal Ultrasound and Fetal Doppler, Diagnosis and outcome in IUGR.Clinics in Perinatology,mar 1995,22:121-137.
50. Campbell, B. Utilizing sonography to follow fetal growth. Obstetrics And Gynaecology Clinics of North America , 1998.22:,597-607.
51. Hadloek F., Deter R., Harvist, R. et al:Fetal Biparietal Diameter:A critical re­evaluation of relation to menstrual age by means of real-time ultrasonography. J.Ultrasound Med., 1982; 1 : 191.
52. Brown Ft., Miller J,M., Gabert H,A.,et al: Ultrasound recognition ofthe small for gestational age fetus. Obstet Gynaecol.,1987;69:631-35.
53. Snijders, R., Hyett, J. Fetal testing in intra-uterine growth retardation. Curr.Opin.Obstet.Gynaecol., 1997; 9:91-95.
54. Peleg, D., Kennedy, C., Hunter, S., et al Intrauterine Growth Restriction: Identification and Management. Am J. Fain . Physicians., 1998;.58 :453-60.
55. Craigo, S.,Beaeh, M., Harvey, K. et al.Ultrasound predictors of neonatal outcome in intrauterine growth restriction. Am J Perinatology 1996;36:465.
56. Visser, G. Fetal Health Assess. Cuff Opin Obatet.Gynecol., 199 1;3:242.
57. Ramalingaswami, V., Jonsson, U., Rohed, J. The Asian Enigma, In: UNICEF, The Progress of Nations, New York, United Nations Children’s Fund, 1997, pp.11-17.
58. Intemational Institute for Population Sciences, ‘National Family Health Survey, India, 1992-93: Bombay., 1995,
59. Chabbra, S., Bhandare, v. Some medico-socio-demographic factors and Intrauterine growth retardation. J. Indian. Med. Assoc., 1996; 94:127-30.
60. Mavalankar D, Gay H. Risk factors for small gestational age birth in Ahmedabad, India. J.Trop.Pediatr., 1994:40:2 85-90.
61. Report of a WHO Expert Committee. Physical status: the use of and interpretation of anthropometry, Technical Report Series No. 854. Geneva, WHO., pp. 121-60.
62. Klebanoff MA, Meirik 0, Berendes HW. Second generation consequences of small-for-dates birth. Pediatrics, 1989;84 :343-47.
63. Emanuel I, Filakti H, Alberman E, et al. Inter—generational studies of human birth weight from 1958 birth cohort. Evidence fora multi-generational effect. Br.J.Obstet.Gynaecol., 1992;99:67-74.
64. Gulmezogln M, de Onis M, villar J. Effectiveness of intervention to prevent and treat impaired fetal growth. Obstet. Gynaecol. Surv., 1997;52:139-49.

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