Feasibility of introducing genetic services in the National Family Welfare Programme in India.
Abstract: Background & objective: Genetic factors could play an important role in the outcome of pregnancy. This study was carried out to identify risk factors that result in adverse pregnancy outcome and to develop a system of screening and referral to a tertiary hospital equipped with facilities for diagnosis and management of such high risk pregnancies.

Methods: District level hospitals close to the participating centers eg. All India Institute of Medical Sciences, New Delhi, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, BJ Medical College, Pune, St. John Medical College, Bangalore and Genetic Research Center, (ICMR), Mumbai, were selected. Pregnant women < 28 wk gestation attending antenatal OPD of selected district hospitals were included. All eligible women who gave consent for participation in the study, were screened using a predesigned proforma based on family history, past pregnancy history, history of genetic disease/ congenital malformation in previous child and history of present pregnancy. Pregnancy outcome was noted.

Results: There was statistically significant difference in the outcome of pregnancy in the following groups: (i) past pregnancy history of 3 or more spontaneous abortions (RR= 3.9; CI=1.17-9.02); (ii) still birth (RR= 2.5; CI= 1.41-4.48); (iii) previous child with neurol tube defect (NTD) (RR=2.3; CI= 1.22- 4.60); and (iv) previous child with congenital malformation (RR=2.2; CI = 1.11- 4.35).

Interpretation & conclusion: A sample questionnaire may be used for screening of pregnant women at risk of having and adverse outcome. Also screening of pregnant women for thalassaemia carrier state and maternal serum a-foetoprotein (AFP) for NTD may be useful.

Key words Genetic services--India--National Family Welfare Programme--pregnancy
Article Type: Clinical report
Subject: Pregnant women (Health aspects)
Birth defects (Care and treatment)
Birth defects (Risk factors)
Abortion (Risk factors)
Medical colleges
Pub Date: 10/01/2009
Publication: Name: Indian Journal of Medical Research Publisher: Indian Council of Medical Research Audience: Academic Format: Magazine/Journal Subject: Biological sciences; Health Copyright: COPYRIGHT 2009 Indian Council of Medical Research ISSN: 0971-5916
Issue: Date: Oct, 2009 Source Volume: 130 Source Issue: 4
Geographic: Geographic Scope: India Geographic Code: 9INDI India
Accession Number: 229721082
Full Text: The primary focus of antenatal care has been health of the mother during pregnancy and safe delivery of the child. Foetal medicine is now emerging as an equally important component of the antenatal care (1). For this purpose not only the scope of antenatal care needs to be enlarged to include foetal health but also to add the concept of preconceptional clinic with genetic counselling.

Adverse pregnancy outcomes comprise foetal loss (abortions and still birth), perinatal death, birth defects and a child born with genetic disorders. While state of mother's health and nutrition are important in determining birth weight and perinatal mortality, genetic factors play a major role in the causation of birth defects and foetal loss. Current estimates indicate that about 15-20 per cent of clinically recognized pregnancies end up in spontaneous abortion prior to 20 wk of gestation, while another 70 per cent of fertilized ova do not get implanted (2). The major cause of spontaneous abortion and foetal loss is chromosomal anomaly and genetic defects; 40-60 per cent of first trimester abortuses and 10 per cent of second trimester abortuses have chromosomal anomaly while 5 per cent of perinatal deaths are due to chromosomal and other genetic disorders (2). In developed countries with low infant mortality rates, this load is considerably higher (2,3).

Congenital malformations are present in 2-3 per cent of live births and in 10 per cent of still births (4,5). Those who survive with malformations place a heavy burden on the society and affected families. Among malformations, neural tube defect (NTD) is a major malformation in the Indian subcontinent (3) which has become highly amenable to primary and secondary prevention (5-10). Its prevalence is high in northern India, northern China, Egypt and Lebanon (11). Anencephaly and spina bifida comprising a vast majority of NTD are common congenital abnormalities, which contribute substantially to morbidity and mortality in infancy and childhood. One out of four affected foetuses is stillborn and one out of two results in spontaneous abortion (12,13). The risk of recurrence of NTD after birth of an affected child is 3-5 per cent which is 10 times higher than that of general population (14). Other disorders need careful diagnosis and genetic counselling. There is paucity of information on women attending antenatal outpatient department of district hospitals who are at risk of having adverse outcome of pregnancy. This study was undertaken to determine the relative frequency of genetic risk factors which may result in adverse pregnancy outcome and to develop a system of screening and referral to a hospital equipped with management of such high risk pregnancies to improve pregnancy outcome.

Material & Methods

Selection of centres: The study was carried out at five tertiary level hospitals having genetic centres, namely the All India Institute of Medical Sciences (AIIMS), New Delhi, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow, BJ Medical College, Pune, St. John Medical College, Bangalore and Genetic Research Centre (ICMR), Mumbai. Each centre selected a district level or equivalent peripheral hospital, with active obstetric service. All pregnant women below 28 wk of gestation enrolled for antenatal care at these hospitals during the year 1995-1996 were taken up for the study. Mumbai centre selected the Thane Civil Hospital, and five primary health centres in the Thane district for the study. Bangalore centre selected one of the City Corporation Hospitals, which was, located 7 kilometers away from the St. John's Medical College. AIIMS selected the Faridabad Hospital, and the Lucknow centre selected the Mahila Hospital, Golaganj, which is a Government District Hospital. Approval of the study protocol by the Institutional Ethics Committee of all the participating institutions was obtained prior to initiation of the study.

[ILLUSTRATION OMITTED]

Inclusion criteria: All women up to 28th wk of gestation, attending Obstetrics OPD of the chosen hospital for the first time were included in the study. Informed consent was obtained from those who agreed to participate in the study after being briefed about the purpose of the study. After consent, a pre-designed screening proforma was filled up (Annexure). Information was collected on age of women, family history of genetic disease, history of still birth, 3 or more spontaneous abortion in the past, 2 or more neonatal deaths, history of genetic disease in previous births (e.g., NTD, Down syndrome, congenital malformation, mental or physical retardation, thalassaemia, bleeding diathesis or other genetic syndrome, etc.) and history of systemic illnesses/history of infection/exposure to radiation and drug intake in the first trimester during the current pregnancy.

Blood samples (2 ml of EDTA blood from NESTROF test and 3 ml of non-ox lood for MSAFP) were collected from a subgroup of women with known last menstrual period (LMP) between 13-16 wk of gestation for estimation of maternal serum alpha-foetoprotein (MSAFP) and NESTROFT test (Naked Eye Single Tube Osmotic Fragility Test) along with routine haemogram. MSAFP was estimated by ELISA technique using modification of the method of McDonald and Kelly (15) to assess the risk of neural tube defect and chromosomal abnormality (Down Syndrome). Those having MSAFP value of 2 or more multiples of median value (MOM) for the given gestational age were advised to have an ultrasound evaluation done to rule out presence of neural tube defect. Those having MSAFP <0.8 times the median value were counselled for the risk of having Down syndrome and were offered antenatal diagnosis. NESTROFT was done to screen carrier status for beta thalassaemia, which was later confirmed by [HbA.sub.2] estimation by column chromatography method (16). If a woman was found to be a carrier for beta thalassaemia, her husband was also screened. If the husband was also a carrier, the couple was considered at a risk of having a foetus with thalassaemia major. The couple was then offered antenatal diagnosis by chorionic villous sampling.

[ILLUSTRATION OMITTED]

Exclusion criteria: Women who enrolled for delivery beyond 28 wk of pregnancy or who came as an emergency to the labour room were excluded from the study.

Women enrolled in the study were followed up till delivery to record the pregnancy outcome. They were advised to come for delivery in the same hospital where they were enrolled and those having risk factors on screening were given genetic counselling and referred to tertiary hospitals for delivery. In case of non availability of primary outcome, reply paid cards were sent, and home visits were made by social workers to collect information on outcome of pregnancy. Outcome of pregnancy and condition of newborn among live-born babies was noted.

Women having one or more risk factors on screening were considered at increased risk for genetic disease and those who did not have any risk factor were considered low risk. When the outcome of pregnancy was spontaneous abortion, still birth, induced abortion for NTD, Down syndrome, or thalassaemia, or the newborn was found to have congenital malformation/genetic syndrome, the outcome was considered as abnormal.

Statistical analysis: Data were analyzed using software EPI--info version 5 and SPSS version 12.0 Chicago, Illinois, USA. Univariate analysis was performed for all the variables considered as risk factors for screening. Z--test was used for comparing the outcome in the two groups viz., the increased risk vs non risk group. All variables that achieved significance on univariate analysis were identified, and subjected to step-wise logistic regression analysis to determine independent risk factors associated with adverse outcome of pregnancy.

Results

Demographic and obstetric profile: A total of 8,331 women were enrolled for the study at the five centres. Mean [+ or -] SD age of the women was 23.5[+ or -] 3.8 yr. Seventy four (0.8 %) women were below 18 yr of age and 39 (0.5%) above 35 yr. Majority (83.2%) of the women enrolled in the study were Hindus at all the centres; only at Bangalore centre about half (46.4%) of women enrolled were Muslims. Mean gestational age at the time of enrollment was 19.8 [+ or -] 5.1 wk (range 18.5 [+ or -] 5.8 to 20.8 [+ or -] 4.6 wk) at various centres. Frequency of consanguinity varied from centre to centre. It was high in Bangalore (41.6%) and Pune (27.5%) centres, while at Mumbai, Lucknow and Delhi centres it was 14.2, 5.8 and 0.7 per cent only.

Increased risk for genetic disease: Based on history, a total of 1167(14.0%) women were found to be at increased risk for genetic disease/abnormal outcome of pregnancy, while 7164 (86.0%) women did not have any of the listed risk factors. Proportion of women with one or more risk factors varied from 10.3 per cent in Lucknow to 23.0 per cent in Mumbai. In Delhi, Bangalore and Pune these percentages were 11.3, 12.6, and 19.4, respectively. Majority of the women (10.5%) had single risk factor, while 3.5 per cent had 2 or more risk factors (Table I).

Pregnancy outcome: Information on outcome of pregnancy was available for a total of 4041 (48.5%) women enrolled; others were lost to follow up. Of these, 794 (19.6%) cases were enrolled at Delhi, 878 (21.7%) at Mumbai, 459 (11.4%) at Pune, 443 (11.0%) at Bangalore and 1467 (36.3%) at Lucknow. In order to test whether loss to follow up could have introduced any bias, two groups viz., those with and without information on outcome were compared for the prevalence of risk factors. There was no statistically significant difference in the two groups indicating that loss to follow up was not selective. Of the 4041 women on whom outcome information was available, 570 (14.1%) had one or more risk factors on screening and 3471 (85.9 %) did not have any risk factor.

Laboratory investigations NESTROFT followed by HB A2 estimation and MSAFP were carried out in 2548 cases. Of the 1526 couples screened, 17 (1.1%) were at a risk of having a foetus positive for beta thalassaemia major. On maternal serum alpha foetoprotein assay, 221 (8.7%) women were found to have MSAFP value < 0.8 MOM; and 170 (6.7%) had MSAFP >2 MOM indicating risk for neural tube defect.

Outcome of pregnancy in increased risk and low risk groups is given in Table II. Abnormal outcome of pregnancy was observed in 11.2 per cent (64/570) cases in increased risk group and in 4.9 per cent (171/3471) in low risk group, the difference was statistically significant (RR=2.3, CI 1.73-3.0). The occurrence of spontaneous abortion, induced abortion and still birth were 2.8, 3.5, 3.0 per cent respectively in high risk group and 0.7, 1.1 and 1.8 per cent respectively in low risk group. All the differences were statistically significant (P<0.05) except for still birth. Abnormal condition in foetus/newborn (presence of Down syndrome, congenital malformation and neural tube defect) was observed in a total of 54 cases, 17 (3.0%) in increased risk group and 37(1.1%) in low risk group. The differences in the outcome in the newborn in both groups were statistically significant (RR = 2.9, CI 1.65-5.14) (Table III).

Family history of any disease affecting multiple members, congenital malformation, mental retardation, treatment for sub fertility/infertility, history of previous child with mental retardation, bleeding diathesis, muscular dystrophy, transfusion dependant anaemia, other genetic diseases, significant maternal illnesses (diabetes, epilepsy, thyroid disease, heart disease, TB, fever, rashes lymphadenopathy, etc.), drug intake and exposure to radiation was not found to be risk factors for adverse outcome of pregnancy in this study probably due to small numbers in each category. Multivariate logistic regression analysis was applied for identifying risk factors for adverse pregnancy outcome. The risk factors identified for abnormal outcome of pregnancy were past history of 3 or more spontaneous abortion (RR= 3.9; CI=1.17-9.02), still birth (RR= 2.5; CI= 1.41-4.48), previous child with NTD (RR=2.3; CI= 1.224.60), previous child with congenital malformation (RR=2.2; CI = 1.11- 4.35) (Table IV). MSAFP level >2 (RR 7.1, CI 2.63-19.35) was also found to be independent risk factor for adverse outcome in the live births.

Discussion

It was observed that out of 8331 pregnant women attending OPD of five district hospitals screened, 1167(14.0 %) were at risk of having adverse pregnancy outcome. Genetic factors play a major role in adverse pregnancy outcome like foetal wastage and congenital malformations. Of the 42 variables used for screening for increased risk in pregnant women, past history of spontaneous abortion, still birth, previous child with NTD/congenital malformation were found to be risk factors for adverse outcome of pregnancy. Adverse outcome in the previous pregnancy has also been observed as most serious risk factor in other studies (17-20). In a community based prospective study where 6275 deliveries (6084 live births, 167 neonatal deaths and 150 still births were followed up for a period of 3 yr, adverse outcome in the previous pregnancy was observed as most serious risk factor (18). In a case control study based on the record of the epidemiological surveillance system of neural tube defect association between history of maternal reproductive loss and the risk of anencephaly was evaluated in three Mexican States. Mothers of 157 cases of anencephaly and 151 controls were interviewed about their reproductive history and other additional factors. After adjusting for confounders, women with a history of miscarriage in previous pregnancies were 4.58 times more at risk of having a child with anencephaly than those who did not have such a history (OR = 4.58, 95% CI 1.22-17.23)19.

NTD is the most common congenital malformation of CNS. Its prevalence in US and worldwide is 1 in 100011. Primary prevention of genetic diseases is emerging as an important area to improve quality of life and prevent disease burden. It requires targeting of preventive measures to entire population or to individuals with increased risk, if the increased risk individuals could be identified by suitable screening strategies. Screening for genetic diseases otherwise is very expensive if it is applied to whole population. Moreover, screening facilities are not always available or there is a lack of trained manpower to carry out the tests. In this study around half of women screened were not available for follow up inspite of maximum possible efforts made to obtain traceable address at the time of registration. It remained a major challenge to reach them through post, or even by personal visit to obtain the details of the pregnancy outcome.

Initially it was planned that during the first year both screening, and genetic counselling cum intervention if any, will be done by the Genetic team at the district/ peripheral hospital itself. In the second year it was proposed to continue screening at the selected hospital by the Genetic team but to refer the at risk women to the attached tertiary care hospital for counselling intervention if any. In the third year it was envisaged that screening will also be carried out by the local hospitals' obstetric team. In order to achieve the goal, creation of awareness and training of the local team was carried out systematically from the very beginning. But the experience proved to the contrary. During the second year a number of referred at risk patients did not reach the tertiary care hospitals, and in the third year local hospitals obstetric team did not continue with screening because of excess workload of routine hospital services. In the end, the genetic team continued to provide both the screening and counselling-cum-intervention services throughout the study period.

The study establishes both the need and utility of introduction of preventive genetic services in the National Family Welfare Programme. At present, it has remained as an add on vertical programme. The reasons for failure of integration are multiple, primary reason being lack of motivation of both pregnant women and medical practitioner to accept and adopt the programme in routine obstetric practice. Besides, motivation, lack of appropriate infrastructure at the participating hospitals and logistics of travel to the tertiary centres and its response also came in the way. In case of thalassaemia screening, tracing the husbands, their counselling and acceptance to be tested were also major hurdles.

In spite of these limitations, around 14.0 per cent women who were at risk of having adverse pregnancy outcome were identified in this study using a simple questionnaire for screening women for genetic diseases during pregnancy. Thus this study highlights the need and benefit of screening women during pregnancy for genetic diseases. In view of the fact that around 80 per cent of our population live in the rural area , this calls for evolving and implementing a national programme with emphasis on screening of all pregnant women for genetic diseases. First step could be to develop appropriate information, education and communication (IEC) materials, combined with genetic centres/ preconception clinics preferably with community extension activities.

Acknowledgment

This study was funded as a National Task Force study by the ICMR, New Delhi. Authors thank Smt. I. Kambo and Smt. S. Datey for data analysis and Ms. Saravjit and Ms Shashi for data cleaning, and acknowledge the contribution of Drs Madhulika Kabra and Shubha Phadke for reviewing the manuscript.

Received August 1, 2008

References

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(3.) Dubey S, Chowdhury MR, Prahlad B, Kumar V, Mathur R, Hamilton S, et al. Cytogenetic causes for recurrent spontaneous abortions--An experience of 742 couples (1484 cases). Indian J Hum Genet 2005; 11 : 94-8.

(4.) Verma IC, Mathews AR. Congenital malformations in India. In: Satyavati GV, editor. Peoples of India--some genetical aspects. New Delhi: Indian Council of Medical Research. 1983. p. 70-84.

(5.) Talukdar G, Sharma A. Genetic causes of congenital malformations in India. Int J Hum Genet 2006; 6 : 15-25.

(6.) Yaron Y, Hamby DD, O'Brian JE, Critchfield G, Lcon J, Ayoub M; et al. Combination of maternal scrum alpha-fetoprotein (MSAFP) an low estriol is highly predictive of anencephaly. Am J Med Genet 1998; 75 : 297-9.

(7.) Smithells RW, Shephard S, Schorah CJ, Seller MJ, Neyin NC, Hards R, et al. Possible prevention of neural tube defects by periconceptional vitamin supplementation. Lancet 1980; i : 339-40.

(8.) Laurence KM, James N, Miller MH, Tennant GB, Campbell N. Double-blind randomized controlled trial of folate treatment before conception to prevent recurrence of neural-tube defects. BMJ 1981; 282 : 1509-11.

(9.) Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study. Lancet 1991; 338 : 131-7.

(10.) Czeizel AE, Dudas I. Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation. N Engl J Med 1992; 327 : 1832-5.

(11.) Agarwal SS. Neural tube defect: A preventable congenital malformations. Indian Paediatr 1999; 36 : 643-58.

(12.) Centers for Disease Control: Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. JAMA 1993; 269 : 1233-8.

(13.) Whiteman D, Murphy M, Hey K, Donnell MO, Goldacre M. Reproductive factors, sub fertility and risk of neural tube defects: a case control study based on the Oxford record linkage study register. Am J Epidemiol 2000; 152 : 823-8.

(14.) Reingel S, Lahat E, Greenberg R, Bedovitch M. Awareness of folic acid for neural tube defect prevention among Israeli women. Teratology 1999; 60 : 29-32.

(15.) Gupta A, Verma IC, Arora NK, Kumar R, Bhargava VL, Ghai OP. Maternal serum alphafetoprotein assay using ELISA in normal pregnancy. Indian J Med Res 1982; 76 : 843-6.

(16.) Huisman THJ, Schroeder WA, Brodie AN, Mayson SM, Jakway J. Microchromatography of hemoglobins. III. A simplified procedure for the determination of hemoglobin A2. J Lab Clin Med 1975; 86 : 700-2.

(17.) Tolmis J. Neural tube defects and other congenital malformations of the central nervous system. In: Rimoin DL, Connor JM, Pyeritz RE, editors. Principle and practice of medical genetics, 3rd ed. New York: Churchill Livingstone; 1996. p. 2145-76.

(18.) Ibrahim SA, Babiker AG, Amin IK, Omer MI, Rushwan H. Factors associated with High risk of perinatal and neonatal mortality; an interim report on a prospective community based study in rural Sudan. Paediatr Perinatal Epidemiol 1994; 8 : 193-204.

(19.) Blanco- Munoz J, Lacasana M, Borja--Aburto VH. Maternal miscarriage history and risk of anencephaly. Paediatr Perinatal Epidemiol 2006; 20 : 210-8.

(20.) A National Collaborative Study of Identification of High Risk Families, Mothers and Outcome of their offsprings with Particular Reference to the Problem of Maternal Nutrition. Low birth weight, perinatal and infant morbidity and mortality in rural and urban slum communities--ICMR Task Force Study. New Delhi: Indian Council of Medical Research; 1990.

Reprint requests: Dr Reeta Rasaily, Scientist E, Division of RHN, Indian Council of Medical Research, Ansari Nagar, New Delhi 110 029, India e-mail: rasailyr@icmr.org.in

Indian Council of Medical Research (ICMR) Collaborating Centers & *Central Technical Coordinating Un ICMR, New Delhi, India

Collaborating Centers: [In alphabetical order of city giving address of the Department, Principal investigator(s), Co-investigators/Research staff of the collaborating center]. (i) Bangalore: Division of Human Genetics, Department of Anatomy, St. Jone's Medical College: I.M. Thomas, S. Hegde. (ii) Lucknow: Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences; S.S. Agarwal, S.Phadke. (iii) Mumbai: ICMR Genetic Research Center, Institution of Research in Reproduction Building; Z.M. Patel, R. Adhia. (iv) New Delhi: Genetics Unit, Department of Paediatrics, All India Institute of Medical Sciences; I.C. Verma, A. Gulati.

(v) Pune: Department of Paediatrics, B.J. Medical College; M. Phadke, P.S. Gambhir.

* Central Technical Coordinating Unit, ICMR Headquarters, New Delhi: R. Rasaily, A. Mathur, M.P. Singh, A.N. Kapoor, N.C. Saxena and B.N. Saxena.
Table I. Centre-wise distribution of women having risk factor on
basis of history

Centre                     No. of risk factors

                        1            2          3

Delhi (n=2029)      190 (9.4)    39 (1.9)    0 (0.0)
Mumbai (n=902)      136 (15.1)   58 (6.4)   14 (1.6)
Pune(n=1612)        215 (13.3)   64 (4.0)   22 (1.4)
Bangalore (n=1130)  109 (9.6)    27 (2.4)    5 (0.4)
Lucknow (n=2658)    223 (8.4)    45 (1.7)    5 (0.2)
Total (n=8331)      873 (10.5)  233 (2.8)   46 (0.6)

Centre                   No. of risk      Total risk
                           factors          factor

                      [greater than
                      or equal to] 4

Delhi (n=2029)                 0 (0.0)    229 (11.3)

Mumbai (n=902)                 0 (0.0)    208 (23.0)
Pune(n=1612)                  12 (0.7)    313 (19.4)
Bangalore (n=1130)             2 (0.2)    143 (12.6)
Lucknow (n=2658)               1 (0.0)    274 (10.3)
Total (n=8331)                11 (0.1)   1167 (14.0)

Values in parentheses are percentages

Table II. Distribution of risk factors in relation to outcome
of pregnancy

Variables                          Status        Total
                                   of risk      (n=4041)
                                   factors

Consanguinity                         A       3505 (86.7)
                                      P        536 (13.3)

I. Family history:
Any disease affecting                 A       4030 (99.7)
multiple members                      P         11 (0.3)
Congenital malformation               A       4017 (99.4)
                                      P         24 (0.6)
Mental retardation                    A       4016 (99.4)
                                      P         25 (0.6)

II. Past pregnancy history:           A       4002 (99.2)
3 or more spontaneous abortions        P        39 (1.0)
(<28 wk)
Still birth                           A       3934 (97.4)
                                      B        107 (2.6)
2 or more neonatal death              A       4005 (99.1)
                                      P         36 (0.9)
Treatment for subfertility/           A       4022 (95.5)
  infertility                         P         19 (0.5)

III. Previous child with genetic      A       4001 (99.0)
  disease:                            P         40 (1.0)
Down syndrome
Neural tube defect                    A       3964 (98.1)
                                      P         77 (1.9)
Bleeding diathesis                    A       4040 (100.0)
                                      P          1 (0.0)
Transfusion dependent anaemia         A       4028 (99.7)
                                      P         13 (0.3)
Muscular dystrophy                    A       4039 (99.9)
                                      P          2 (0.1)
Congenital malformation               A       3964 (98.1)
                                      P         77 (1.9)
Mental retardation                    A       4007 (99.2)
                                      P         34 (0.8)
Other genetic disease                 A       3986 (98.6)
                                      P         55 (1.4)

IV. Significant maternal illness
  in current pregnancy:
Diabetes                              A       4039 (99.5)
                                      P          2 (0.5)
Epilepsy                              A       4036 (99.9)
                                      P          5 (0.1)
Thyroid disease                       A       4040 (100.0)
                                      P          1 (0.0)
Heart disease                         A       4038 (99.9)
                                      P          3 (0.1)
Chronic lung disease                  A       4038 (99.9)
                                      P          3 (0.1)
Tuberculosis                          A       4031 (99.7)
                                      P         10 (0.3)
Cancer                                A       4039 (100.0)
                                      P          2 (0.0)

V. History in 1st trimester:
Fever                                 A       3951 (97.8)
                                      P         90 (2.2)
Rash                                  A       4025 (99.6)
                                      P         16 (0.4)
Lymphadenopathy                       A       4039 (100.0)
                                      P          2 (0.0)
Jaundice                              A       4030 (99.7)
                                      P         11 (0.3)
Genital ulcers                        A       4038 (99.9)
                                      P          3 (0.1)
Drug intake                           A       3988 (98.6)
                                      P         53 (1.4)
Unprotected exposure to X-rays        A       4038 (99.9)
                                      P          3 (0.1)

Variables                            Normal out-       Abnormal
                                         come           outcome
                                       (n=3806)         (n=235)

Consanguinity                        3300 (86.7)      205 (87.2)
                                      506 (13.3)       30 (12.8)

I. Family history:
Any disease affecting                3797 (99.8)      233 (99.1)
multiple members                        9 (0.2)         2 (0.9)
Congenital malformation              3783 (99.4)      234 (99.6)
                                       23 (0.6)         1 (0.4)
Mental retardation                   3784 (99.5)      232 (98.7)
                                       22 (0.5)         3 (1.3)

II. Past pregnancy history:          3776 (99.2)      226 (96.2)
3 or more spontaneous abortions         30 (0.8)        9 (3.8)
(<28 wk)
Still birth                          3717 (97.7)      217 (92.4)
                                       89 (2.3)        18 (7.6)
2 or more neonatal death             3774 (99.2)      231 (98.3)
                                       32 (0.8)         4 (1.7)
Treatment for subfertility/          3789 (99.6)      233 (99.1)
  infertility                          17 (0.4)         2 (0.9)

III. Previous child with genetic     3771 (99.1)      230 (97.9)
  disease:                             35 (0.9)         5 (2.1)
Down syndrome
Neural tube defect                   3743 (98.3)      221 (94.4)
                                       63 (1.7)        14 (6.0)
Bleeding diathesis                   3805 (99.9)      235 (100.0)
                                        1 (0.1)         0 (0.0)
Transfusion dependent anaemia        3794 (97.7)      234 (99.6)
                                       12 (0.3)         1 (0.4)
Muscular dystrophy                   3804 (99.9)      235 (100.0)
                                        2 (0.1)         0 (0.00)
Congenital malformation              3743 (98.3)      221 (94.0)
                                       63 (1.7)        14 (6.0)
Mental retardation                   3776 (99.2)      231 (98.3)
                                       30 (0.8)         4 (1.7)
Other genetic disease                3757 (98.7)      229 (97.4)
                                       49 (1.3)         6 (2.6)

IV. Significant maternal illness
  in current pregnancy:
Diabetes                             3805 (99.9)      234 (99.6)
                                        1 (0.1)         1 (0.4)
Epilepsy                             3801 (99.9)      235 (100.0)
                                        5 (0.1)         0 (0.0)
Thyroid disease                      3805 (99.9)      235 (100.0)
                                        1 (0.1)         0 (0.0)
Heart disease                        3805 (99.9)      235 (100.0)
                                        3 (0.1)         0 (0.0)
Chronic lung disease                 3803 (99.9)      235 (100.0)
                                        3 (0.1)         0 (0.0)
Tuberculosis                         3796 (99.7)      235 (100.0)
                                       10 (0.3)         0 (0.0)
Cancer                               3805 (99.9)      234 (99.6)
                                        1 (0.1)         1 (0.4)

V. History in 1st trimester:
Fever                                3724 (97.8)      227 (99.6)
                                        82 (2.2)        8 (3.4)
Rash                                 3791 (99.6)      234 (99.6)
                                       15 (0.4)         1 (0.4)
Lymphadenopathy                      3804 (99.9)      235 (100.0)
                                        2 (0.1)         0 (0.0)
Jaundice                             3796 (99.7)      234 (99.6)
                                       10 (0.3)         1 (0.4)
Genital ulcers                       3804 (99.9)      234 (99.6)
                                        2 (0.1)         1 (0.4)
Drug intake                          3753 (98.6)      235 (100.0)
                                       53 (1.4)         0 (0.0)
Unprotected exposure to X-rays       3803 (99.9)      235 (100.0)
                                        3 (0.1)         0 (0.0)

Variables                           P value & 95%
                                      Confidence
                                    Interval (CI)

Consanguinity                            0.89

I. Family history:
Any disease affecting                    0.26
multiple members
Congenital malformation                  1.00

Mental retardation                       0.17

II. Past pregnancy history:            RR=4.86
3 or more spontaneous abortions     (CI 2.33-11.11)
(<28 wk)
Still birth                            RR=3.26
                                     (2.01-5.34)
2 or more neonatal death                 0.15

Treatment for subfertility/              0.30
  infertility

III. Previous child with genetic         0.13
  disease:
Down syndrome
Neural tube defect                     RR=3.60
                                     (2.05-6.33)
Bleeding diathesis                       1.0

Transfusion dependent anaemia            0.54

Muscular dystrophy                      >0.05

Congenital malformation                RR=3.60
                                     (2.05-6.33)
Mental retardation                       0.26

Other genetic disease                    0.18

IV. Significant maternal illness
  in current pregnancy:
Diabetes                               RR 16.2
                                   (CI 1.02-258.13)
Epilepsy                                >0.05

Thyroid disease                         >0.05

Heart disease                           >0.05

Chronic lung disease                    >0.05

Tuberculosis                            >0.05

Cancer                                  RR 6.2
                                   (CI 1.02-258.13)

V. History in 1st trimester:
Fever                                    0.30

Rash                                     0.61

Lymphadenopathy                         >0.05

Jaundice                                 0.48

Genital ulcers                           0.16

Drug intake                             >0.05

Unprotected exposure to X-rays          >0.05

A, absence of risk factor; P, presence of risk factor
Values in parentheses denote percentages

Table III. Distribution of outcome of pregnancy in relation to the
risk factors

                             Increased    Low risk (%)   Total
                             risk (%)
                             N=570        N=3471         N=4041
Outcome of pregnancy:
Live birth *                 517 (90.7)   3346 (96.4)    3863 (95.6)
Still birth                  17 (3.0)     62 (1.8)       79 (2.0)
Spontaneous abortion *       16 (2.8)     26 (0.7)       42 (1.0)
Induced abortion *           20 (3.5)     37(1.1)        57 (1.4)
Outcome in newborn/foetus:
NTD/DS/ other malformation   17(3.0)      37(1.1)        54 (1.3)
  (foetus/newborn) *

* Statistically significant difference P<0.05

Table IV. Results of multiple logistic regression : risk factor for
adverse outcome of pregnancy (n=4041, 235 high risk and 3806
non risk)

Variable/ risk factor       Relative risk   95% CI

[greater than or equal to]  3.9             1.77-9.02
  3 spontaneous abortion
H/O still birth             2.5             1.41-4.48
Previous child with NTD     2.3             1.22-4.60
Previous child with
congenital malformation     2.2             1.11-4.35

(Adjusted for age, family history of disease affecting multiple
members, previous child with genetic disease, present maternal
illness, illnesses during first trimester of pregnancy)
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