What Makes Babies Retarded if They Drink It
J Inj Violence Res. 2012 Jan; 4(i): 10–19.
A study of the gamble of mental retardation amid children of pregnant women who accept attempted suicide past ways of a drug overdose
Dora Petik
a Foundation for the Customs Control of Hereditary Diseases, Budapest, Hungary.
Barbara Czeizel
a Foundation for the Community Control of Hereditary Diseases, Budapest, Republic of hungary.
Ferenc Bánhidy
b 2d Department of Obstetrics and Gynecology, Semmelweis Academy, School of Medicine, Budapest, Hungary.
Andrew E. Czeizel
a Foundation for the Community Control of Hereditary Diseases, Budapest, Republic of hungary.
Received 2010 May 25; Accepted 2010 Jul 15.
Abstract:
Background:
The aim of the study was to estimate the effect on the fetal development of high doses of prescription drugs taken as a suicide attempt during pregnancy.
Methods:
Meaning women were identified among self-poisoned females in the toxicological inpatient dispensary in Budapest between 1960 and 1993. Congenital abnormalities, intrauterine evolution based on nascence weight and mail service-conceptional age, mental retardation, cognitive-behavioral status were compared in exposed children born to mothers who had attempted suicide by means of a drug overdose during pregnancy with their siblings, born either before or later on the afflicted pregnancy, as sib controls.
Results:
Of a full of one 044 pregnant women, 74 used the combination of amobarbital, glutethimide and promethazine (Tardyl®, ane of the most pop drugs for handling of insomnia in Republic of hungary) for suicide attempt. Of these 74 women, 27 delivered live-born babies. The hateful dose of Tardyl® used for suicide attempts was 24 times the usually prescribed clinical dose. The rate of built abnormalities and intrauterine retardation was non higher in exposed children than in their sib controls. Even so, of the 27 exposed children, eight (29.6%) were mentally retarded (Χ)=79.7, p= Sig) while mental retardation did not occur amidst 46 sib controls. These exposed children were born to mothers who attempted suicide with Tardyl® between the 14th and 20th post-conceptional weeks. The components of Tardyl® used separately for a suicide try during pregnancy were not associated with a higher run a risk of mental retardation. Therefore the loftier doses of Tardyl® associated with the high risk for mental retardation may be due to the interaction of its 3 drug components.
Conclusions:
The findings of the report showed that the high doses of a drug containing iii components may be associated with a significantly increased risk for mental retardation without whatsoever structural defects, whereas each of these three component drugs taken lonely was not associated with this adverse upshot.
Introduction
Suicide and self-inflicted injury are classified as intentional causes of death or diseases.1-fourHungary led the globe in suicide mortality with the rates of about 45 per 100 000 persons in the 1970s and 1980s, later there was a decrease in this rate but it has remained high in an international perspective. In add-on, the rate of suicide attempts past ways of prescription drugs has increased significantly worldwide.3,4Suicide attempts past means of drugs and other chemicals have been termed self-poisoning.half-dozenThe recent cocky-poisoning epidemic has produced a major socio-medical trouble, generally amid young females.7Such suicide attempts also occur amid pregnant women.8,ixIt is of interest that the number of pregnant survivors of suicides has increased significantly as a result of more effective medical intervention. Nonetheless, survival may be associated with a greater risk of congenital abnormalities and/or mental retardation in the fetuses/children.
Nosotros have evaluated the potential to estimate the teratogenic/fetotoxic risk of these prescription drugs10Clinical trials conducted before approval and marketing of a drug generally do not include pregnant women. Thus, it is necessary to base the potential for human being teratogenic/fetotoxic risk on the results of experimental animal investigations. Ideally, screening tests in laboratory animals would place the doses of drugs that tin exist human being reproductive or developmental toxicants/teratogens. However, current screening systems are imperfect, and multiple factors prevent direct extrapolation of results on pregnant women. Thus, the harsh reality is that humans are the ultimate test model for detection of drugs and specially the doses of drugs that are establish to be homo teratogens.
2 types of post-marketing data of drugs have been used to estimate their human teratogenic potential. The commencement blazon of data ready is obtained through case reports, clinical instance series, and randomized controlled trials. However, instance reports have serious selection bias, clinical instance series ordinarily do non accept appropriate controls, and there are serious upstanding barriers to performing randomized controlled trials on significant women. The second type of data prepare is associated with analytical epidemiological studies and/or registry/surveillance/monitoring systems.11However, identifying a possible association between the low clinical doses of drugs and structural nativity defects, i.e. congenital abnormalities are confounded by the remember bias of mothers with afflicted children compared to mothers with healthy babies, and there is usually an inability to gauge a dose-response human relationship. Although such postal service-marketing data can exist useful in predicting man teratogenic gamble of drug exposures, medical practitioners must consider the accuracy of these predictions with circumspection.
Thus the self-poisoning model of pregnant women based on the Budapest Registry of Cocky-poisoned Patients12offers a unique approach for studying the potential teratogenic and fetotoxic-neurotoxic effects of drugs on the fetuses. Of one 044 self-poisoned significant women, 411 delivered live-built-in infants between 1960 and 1993, and of these 411 children, 367 (89.3%) were evaluated for health status, in item congenital abnormalities, nativity weight and post-conceptional age, cognitive status as well as behavioral evolution.10
This paper summarizes the data of 27 children who were born to mothers who used the combination of amobarbital, glutethimide and promethazine (Tardyl®) for a suicide attempt during pregnancy. This medicinal production is one of the nigh pop prescription drugs for the treatment of indisposition in Hungary. Of these 27 children, eight (29.6%) were mentally retarded.
Methods
Budapest and the surrounding area have a population of about three million people. All cocky-poisoned patients in this area were admitted to the Section of Toxicological Internal Medicine, Korányi Hospital, Budapest.12The objective of the study was to identify pregnant women amongst self-poisoned females and to evaluate the effect of large doses of drugs on their exposed children. Gestational historic period was calculated from the kickoff day of the last menstrual period, however, we used the term post-conceptional pregnancy age, estimated from the first day of the 3rd calendar week of the first lunar (28 twenty-four hour period) pregnancy month, i.e., from the speculative day of formulation. Thus the usual duration of pregnancy was 266 days and 38 pregnancy weeks.
The study included iii steps. Commencement, self-poisoned pregnant women were identified amongst female person patients in the Department of Toxicological Internal Medicine, Korányi Hospital, and their pregnancies were confirmed by gynecological examination. Each cocky-poisoned significant adult female had a personal carte du jour including personal, medical, lifestyle data likewise as all data regarding the self-poisoning in the written report pregnancy. Doses and acute effects of the drugs used for self-poisoning were based on data obtained from 3 sources: (i) data obtained from the pregnant women; (ii) drug levels present in their claret and (iii) the clinical picture show of intoxication. Clinical intoxication was defined equally mild (not asleep at or afterward admission), moderate (asleep or unconscious at or subsequently admission), severe (unconsciousness longer than ane mean solar day afterward admission and/or need for artificial respiration), very severe (life-threatening, i.e., unconsciousness more than than two days with astringent complications such equally uremia or multi-organ failure) and fatal. However, significant women whose suicides had had a fatal outcome were excluded from the written report considering their fetuses could not be evaluated.
The report protocol was evaluated first by the Institutional Ethical Review Board, but considering this methodological arroyo was unusual, it was forwarded to the Central Upstanding Commission of Ministry building of Health. This committee finally approved the report protocol with iii criteria: (i) Cocky-poisoned pregnant women had to sign a consent form regarding their voluntary participation in the report and granting permission for follow-upwardly habitation visits and test of their children. (ii) Self-poisoning pregnant women had a right to refuse the collaboration at any fourth dimension during the study. (iii) Nosotros had to organize a special high standard prenatal care and delivery service for cocky-poisoned pregnant women who decided to continue their pregnancies.
Secondly, all surviving cocky-poisoned meaning women were visited at dwelling afterwards the expected 24-hour interval of their deliveries to elucidate their pregnancy outcomes. Data regarding their miscarriages and still- and live-births (including birth weight and gestational age) were medically recorded in their discharge summaries because all deliveries and clinically recognized miscarriages took place in inpatient obstetric clinics and the birth attendants were obstetricians at the fourth dimension of the written report menstruum. In addition, the mothers with their live-born children were invited for a thorough medical and psychometric test at our institute.
Thirdly, all exposed children and their sibs/siblings were examined by a pediatrician, medical geneticist and psychologist according to the protocol of the study. The aim of detailed medical examination was the detection of built abnormalities (i.due east. structural birth defects) and small anomalies (unusual morphologic variants without serious medical consequences to the children). Chromosome evaluation (karyotyping) was undertaken for children with multiple defects and/or mental retardation. The diagnosis of fetal alcohol syndrome (FAS) was based on a semi-quantitative score.13Autopsy records were available for the evaluation of deceased children. The cognitive development of children was measured by the help of the Hungarian Developmental Testfourteenused routinely in Republic of hungary. Children were classified into 4 groups according to their intelligence caliber (IQ): 1) above mean (110-120 IQ), 2) mean (ninety-109 IQ), 3) under mean (70-89 IQ) and four) mental retardation (less than 70 IQ). There were two diagnostic criteria of mental retardation: (i) less than 70 IQ , and (ii) children were not able to attend normal chief school.15All exposed children with suspected mental retardation were followed until schoolhouse age, when they were examined by official experts and they were referred to special schools for retarded students. The behavioral condition of children was estimated by the psychologist using the Behavioral Style Questionnaire.xvi
Mothers, who could not visit our constitute, were visited at dwelling by the pediatrician and psychologist to examine exposed children and their sibs according the study protocol. Visits of families to our plant and the visits to the home of exposed children were used to check and to complete personal and lifestyle data of mothers that were collected on hospital records. Socioeconomic status of mothers was estimated based on employment status and educational level, and they were classified into 3 classes: high, medium and depression. Smoking was classified according to the number of cigarettes smoked daily. Drinking habits were estimated on the information provided by the mothers and classified as abstinent, occasional (less than ane beverage per week), regular (from one potable per week to one beverage/day) and hard (more than ane drink/twenty-four hour period) drinkers. If the quantity of drinking inverse during the study pregnancy, we recorded the maximum.
The major methodological challenge was to find advisable controls for exposed children, and finally we used familial and population controls. The familial controls comprised of the previous and subsequent unexposed kid(ren) of self-poisoned significant women and they were called sib controls for comparison with the exposed kid. (If meaning women repeated suicide attempts during the study period, their live-born babies were evaluated as exposed children, only these exposed children were non evaluated as sibs.) The medical condition, including nascency defects and mental retardation, in add-on to the cognitive status and behavioral scale of the sib controls were examined and diagnosed at the same time and place (our found or their dwelling house) as of exposed children past the same protocol and past the aforementioned experts.
Population controls included 38 151 newborns without nativity defects in the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996,17they were used as a reference sample (representing 1.viii% of all Hungarian births) for the comparing of exposed children.
Details of these materials and methods, in addition to the characteristics of self-poisoned pregnant women were described previously.10,9
The meaning women evaluated in this paper attempted suicide with Tardyl® alone or in combination with other drugs. Tardyl® (EGIS) contains 125 mg amobarbital, 125 mg glutethimide, and seven.v mg promethazine in ane tablet, and virtually of these significant women used it as a hypnotic drug.
At the statistical analysis of information, the SAS version eight.02 statistical software parcel was used (SAS Plant, Cary, NC). Quantitative variables of pregnant women and their children were evaluated by the Educatee t test and categorical variables by the chi foursquare test. The prevalence at nascence of built abnormalities and mental retardation in exposed children was compared with their unexposed sib controls, and odds ratios (OR) with 95% confidence interval (CI) were calculated by an unconditional multiple logistic regression model.
Results
Of 1044 cocky-poisoned significant women in the full sample, 74 (7.1%) used Tardyl® for their suicide attempt. Of these 74 meaning women, ane had a fake address and i refused to participate, 27 decided to terminate their pregnancy (based upon socioeconomic reasons affecting their unplanned and unwanted pregnancies; in addition to the suspected teratogenic furnishings of the drugs used for their suicide attempts), xviii pregnancies ended in fetal death (very early loss: 12; miscarriage: 6) and 27 pregnant women delivered live-born babies. Thus, of 367 live-born and evaluated exposed children, 27 (7.4%) belonged to the Tardyl® sample.
The characteristics of the 27 pregnant women who attempted suicide with Tardyl® and delivered live-born babies were compared to the Hungarian reference pregnant sample (Tabular array 1). The mean age is lower among mothers who attempted suicide because of a larger proportion of the youngest (19 years or less) historic period group (37.0% vs. 8.6%), though their mean nascence club was not significantly lower. The lower proportion of married women and college proportion of low socioeconomic status were likewise characteristic for pregnant women who attempted suicide. In that location was a 2.8- and 18.5-fold higher rate of smokers and regular/difficult drinkers, respectively, among self-poisoned pregnant women. Built abnormalities and mentally retardation did not occur among the self-poisoned significant women (the latter determination is based on their schooling and personal communication with united states of america), i.eastward. the mothers of exposed children.
Table i: Principal variables of 27 significant women who attempted suicide during pregnancy with Tardyl® (amobarbital 125 mg, glutethimide 125 mg, promethazine vii.v mg in one tablet) lone or with other drugs and delivered live-built-in babies, and a reference sample of Hungarian pregnant women who delivered newborns without birth defects in the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-199617
The number of Tardyl® tablets taken by the 27 cocky-poisoned pregnant women ranged from 10 to sixty tablets with a mean of 24.one + eleven.5 tablets. Of these 27 pregnant women, viii combined Tardyl® with other drugs, mainly benzodiazepines, for their suicide attempt. The drug intoxication was classified as very severe in 3, severe in xix, moderate in two and balmy in iii pregnant women.
Of 27 exposed newborns, xiv (51.9%) were male. The data of nativity outcomes of the 27 exposed children and their 46 unexposed sibs are shown in Table 2. These information were bachelor for all exposed children and unexposed sibs. Ii exposed children (7.four%) had built abnormalities, namely undescended left testicle and a multiple defect diagnosed every bit FAS by us. The mother of the male child affected with the undescended testis attempted suicide using twoscore tablets of Tardyl® in the 20th pregnancy calendar week (Figure 1), however, the critical catamenia of undescended testis is during the last months of pregnancy. The exposed boy with FAS had a mild microcephaly (his commencement twelvemonth head circumference was 40 cm) and three minor anomalies (flat occiput, polish philtrum, thin upper lip) and his IQ was 65 and 70 in two different measurements. His hard drinker female parent had a panic disorder, and she attempted suicide with xx tablets of Tardyl® and 10 tablets of glutethimide (2,500 mg) on the 16th postal service-conceptional week.
Table 2: Comparison of birth outcomes in exposed children born to pregnant women who attempted suicide with Tardyl® during pregnancy and in their unexposed sibs
| Variables | Exposed children(N=27) | Unexposed sibs(N=46) | Comparing | |||
|---|---|---|---|---|---|---|
| Categorical | No. | % | No. | % | OR | 95% CI |
| Congenital abnormalities | ii | vii.4 | 2 | four.4 | ane.viii | 0.ii – 13.9 |
| Mental retardation | 8 | 29.6 | 0 | 0.0 | Χ | p<0.0001 |
| Depression nascence weight (less than 2500 grand) | 4 | xiv.8 | vii | 15.two | i.0 | 0.3 – 3.8 |
| Preterm nativity (less than 35th week) | half dozen | 22.2 | viii | 17.4 | 1.half-dozen | 0.half-dozen – five.five |
| Quantitative | Mean | Southward.D. | Mean | S.D. | t = | p = |
| Birth weight (g) | 2,883 | 55 | 2,895 | 67 | 0.x | 0.94 |
| Pregnancy age (wk) | 36.four | 2.8 | 36.viii | two.9 | 0.08 | 0.79 |
Six pregnant women used loftier doses of Tardyl® for their suicide endeavor betwixt the tertiary and 8th postal service-conceptional weeks, i.e., the critical catamenia for virtually major congenital abnormalities; all the same, these six exposed children did not have any defect.
Of 46 sibs, two (iv.4%) were afflicted with defects: oesophageal atresia with tracheal fistula and FAS (he was the sib of the previously mentioned exposed kid with FAS). Thus, the prevalence at birth of congenital abnormalities was non higher in exposed children than in their unexposed sibs (Table 2).
Mean nascency weight was similar in exposed children and their sibs (Table 2)although both had lower values than the hateful nascency weight of the reference Hungarian newborns (3,276 + 511 gram). Pregnancy age at delivery too did not show a significant difference betwixt exposed children and their sibs, which was likewise shorter than the Hungarian population figure (37.four + ii.0 calendar week). Thus, the pregnancy week specific birth weights did not signal whatever intrauterine fetal growth retardation. The rate of low birth weight and preterm nascency was too similar in exposed children and in their sibs.
Of 27 exposed children, eight (29.six%) had the diagnosis of mental retardation and they attended a special schoolhouse for mentally retarded children. In general their IQs were measured twice or more with almost like findings. Just two exposed children: a boy with FAS (who was mentioned previously) and a girl had once 65 IQ and on some other measurement 70 IQ. The master data of these 8 exposed children are shown in Table 3. Of their eight mothers, 6 used only Tardyl® for their suicide attempt, three took 20 tablets. (One box of Tardyl® contains 20 tablets) Of these viii pregnant women, 1 was classified as hard and five as regular drinkers, but we were able to diagnose FAS simply in one exposed child (and his sib) of a difficult-drinker mother. Of these viii exposed children, half dozen had normal karyotypes; the other two children were without whatever visible defects just were housed in a special establishment and thus chromosome examination was not allowed. Other syndromes were also not identified in these exposed children.
Table 3: Data of exposed children with mental retardation and moderate behavioral deviation
| Period/Number | Suicide endeavour | Exposed children | IQ | Mental retardation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Tardyl (tbl) | Other drugs | Pregnancy Age (wk) | Sex activity | Birth weight(g) | Pregnancy historic period (wk) | Defect (Small-scale anomaly) | Karyo-type | Age of diag-nosis(yr) | Estimated etiology | ||
| I/41 | 30 | Yes* | 20 | Grand | 2,650 | 39 | 0 (0) | 65 | 46,XY | 15 | Tardyl phenobarbital |
| I/86 | xl | 0 | 20 | Grand | two,000 | 33 | Undescended testicles (0) | 60 | 46,XY | thirteen | Tardyl® |
| II/29 | 20 | AA | xviii | F | 2,850 | 35 | 0 (NE) | 65 | NE | 6 | Tardyl® |
| Ii/81 | 30 | AA | 18 | M | two,550 | 36 | 0 (NE) | 55 | NE | 6 | Tardyl® |
| Ii/107 | 40 | 0 | 14 | F | two,750 | 37 | 0 (NE) | 65,70 | NE | six | Tardyl® |
| Three/107 | 20 | AA | 17 | F | 2,550 | 37 | 0 (enamel hypoplasia) | 55 | 46,XX | 6 | Tardyl® |
| 3/572 | 20 | Aye* | sixteen | M | ii,500 | 38 | FAS | 65,70 | 46,XY | half dozen | Tardyl®+Glutethimide/booze |
| 3/603 | 20 | AA | 16 | F | 1,500 | thirty | 0 (low broad nasal span, umbilical hernia) | threescore | 46,Xx | half-dozen | Tardyl® |
| Moderate behavioral deviation | |||||||||||
| II/91 | 20 | 0 | 21 | F | 2,400 | 31 | 0 (NE) | 85 | NE | 6 | Tardyl® |
| Iii/185 | xx | AA | 28 | F | 3,450 | 39 | 0 (low wide nasal bridge, enamel hypoplasia) | 85 | 46,20 | half-dozen | Tardyl® |
Continue table 3: Information of exposed children with mental retardation and moderate behavioral deviation
| Behavioral departure | Female parent | Remarks *** | |||
|---|---|---|---|---|---|
| Age(yr) | Drinking | Smoking (cig/d) | Health | ||
| Astringent | 21 | 0 | 40 | Repeated suicide | vi sibs: one of them I/86**,some other sib: 115 IQ |
| NE | 24 | 0 | 40 | Repeated suicide | 6 sibs: i of them I/41**,another sib: 115 IQ |
| Severe | 19 | Regular | 20 | - | EC in foster home,1 sib |
| Severe | xix | Regular | 20 | - | EC in foster home,no sib |
| Balmy | 28 | 0 | 0 | - | 2 sibs,i: 100 IQ |
| Severe | 18 | Regular | thirty | Repeated suicide | 1 sib |
| Moderate | 25 | Difficult | xx | Panic disorder | 2 sibs: 100 IQ,85 IQ |
| Severe | 22 | Regular | 10 | - | 2 sibs |
| Moderate | 24 | 0 | 20 | - | 2 sibs: 100 IQ;85 IQ |
| Moderate | 22 | Regular | 0 | - | 2 sibs,one: 100 IQ |
Eight mentally retarded exposed children had twenty sibs, but two were excluded as exposed children considering their mothers attempted suicide in two different pregnancies (Effigy 1). The female parent of these ii exposed children was non a drinker, but was a heavy smoker and her children showed an association between the maternal suicide attempt with Tardyl® during pregnancy and some neurotoxic effects of the loftier doses of Tardyl®. Of her five unexposed children, four had normal cognitive status, and the IQ was measured as 115 in the 5th kid, i.e. her son. Nevertheless, the two exposed children were mentally retarded, and i of them had been placed in a immature offenders institution for repeated offences by the time he was 15 years old.
Of the unexposed 46 sibs, none had mental retardation (Table 2); all sibs attended normal chief schools.
The cerebral condition and behavioral scale measurements were planned for all exposed children and their unexposed sibs, but IQ could only exist tested in 22 exposed children and 20 unexposed sibs, while the behavioral scale was measured in 16 exposed children and 16 unexposed sibs (Table 4). The calculated mean IQ was lower in exposed children than in their unexposed sibs. The timing of suicide attempts showed that the high doses of Tardyl® were associated with a high chance for mental retardation when exposure occurred betwixt the 14th and 20th post-conceptional weeks, i.east. in the second trimester of pregnancy (Table 5).
Table 4: Comparing of cognitive condition and behavioral scale in exposed children built-in to pregnant women who attempted suicide with Tardyl® during pregnancy and in their unexposed sibs
| Cognitive status (IQ) | Exposed children(N=22) | Unexposed sibs(N=xx) | Behavioral scale | Exposed children(N=16) | Unexposed sibs(N=16) |
|---|---|---|---|---|---|
| To a higher place mean (110-120) | 3 | four | Normal | 4 | 9 |
| Mean (90-109) | 7 | 12 | Mild | four | 6 |
| Under mean (lxx-89) | 4 | four | Moderate | 3 | ane |
| Mental retardation (less than lxx) | 8 | 0 | Astringent | 5 | 0 |
| Mean ± S.D. | 82.2 ± 20.0(t=3.8) | 100.0 ± nine.7(p=0.04) | Distribution | χ | p=0.03 |
Table 5: Association betwixt the occurrence of different categories of cerebral status in exposed children and the time of suicide attempts with Tardyl® co-ordinate to pregnancy age periods, in addition distribution of dissimilar categories of cognitive status in exposed children and their sibs co-ordinate to the drinking habit of cocky-poisoned pregnant women
In addition, we evaluated the cognitive condition of the exposed children and their sibs according to the drinking habits of cocky-poisoned pregnant women (Tabular array 5). Exposed children and their sibs who were born to mothers without a drinking habit had a higher mean IQ than exposed children and their sibs built-in to alcohol drinking mothers. However, a lower hateful IQ was also found in exposed children compared to their unexposed sibs who were built-in to the same non-drinker mothers and this suggests that there may be a neurotoxic effect of Tardyl®.
Behavioral scales also showed some differences between exposed children and unexposed sibs (Table 4). Of eight mentally retarded exposed children, 5 had astringent and i had moderate behavioral departure (it was non possible to estimate behavioral condition in another mentally retarded boy). In addition two other exposed children had moderate behavioral deviation. On the other hand, of 16 sibs, none had severe and only 1 had a moderate behavioral deviation.
Thus, of 27 exposed children, 8 were mentally retarded (29.6%) while of 46 sibs, none were mentally retarded (Χ)=79.7, p<0.0001). Furthermore, moderate behavioral deviations occurred in 2 other exposed children and in ane command sib. If nosotros evaluate these 10 exposed children together, the per centum figure is 37.0% in the group of exposed children, while the similar effigy was two.ane% in the total group of unexposed sibs based on one kid with moderate behavior deviation (OR with 95% CI: 27.6, 3.iii-232.4).
Finally we make a comparing of exposed children born to mothers who attempted suicide with Tardyl® and with the components of Tardyl® separately (Table 6). There was no mentally retarded exposed child in the group exposed to amobarbital or glutethimide; ane exposed child in the group exposed to promethazine was mentally retarded but the boy had a genetic X -linked fragile X chromosome.Table 7 shows the maternal characteristics in these report groups. The drinking and smoking habits during the report pregnancy were not significantly dissimilar in the three components of Tardyl® separately and together in Tardyl®. The mean maternal age and birth lodge did also not differ significantly among pregnant women who used these drugs and Tardyl® for their suicide try.
Table vi: Occurrence of mental retardation, in addition to the distribution of cerebral condition with mean IQ and behavioral scale in exposed children born to mothers who attempted suicide during pregnancy with amobarbital, glutethimide, promethazine and Tardyl® (including these three drugs)
| Variables | Amobarbital (North=14) | Glutethimide (N=16) | Promethazine(N=32) | Tardyl®(Due north=27) | |||||
|---|---|---|---|---|---|---|---|---|---|
| No. | % | No. | % | No. | % | No. | % | ||
| Mental retardation (instead of MR) | 0 | 0.0 | 0 | 0.0 | i* | 3.ane | viii | 29.half dozen | |
| Cognitive condition | |||||||||
| To a higher place mean | 0 | 0.0 | 1 | 7.7 | v | 20.0 | three | 13.half-dozen | |
| Mean | 9 | 81.8 | ten | 76.9 | 13 | 52.0 | 7 | 31.8 | |
| Under mean | ii | 18.two | 2 | 15.4 | 6 | 24.0 | iv | 18.ii | |
| MR | 0 | 0.0 | 0 | 0.0 | 1* | 4.0 | viii | 36.4 | |
| Subtotal | 11 | 100.0 | 13 | 100.0 | 25 | 100.0 | 22 | 100.0 | |
| IQ, mean ± S.D. | 96.4 ± 8.4 | 100.iv ± 10.8 | 98.4 ± 11.2 | 82.ii ± 20.0 | |||||
| Behavioral scale | |||||||||
| Normal | five | 62.5 | 8 | 72.7 | 11 | 55.0 | 4 | 25.0 | |
| Mild | 2 | 25.0 | two | eighteen.2 | 9 | 45.0 | 4 | 25.0 | |
| Moderate | 0 | 0.0 | 1 | 9.1 | 0 | 0.0 | 5 | 31.3 | |
| Severe | 1 | 12.5 | 0 | 0.0 | 0 | 0.0 | five | 31.3 | |
| Subtotal | viii | 100.0 | eleven | 100.0 | 20 | 100.0 | 16 | 100.1 | |
Table 7: Comparing of maternal characteristics of pregnant women who attempted suicide with amobarbital, glutethimide and promethazine (i.due east. the components of Tardyl®) separately, and Tardyl®
| Variables | Amobarbital(Northward=14) | Glutethimide(N=16) | Promethazine(N=32) | Tardyl®(N=27) | ||||
|---|---|---|---|---|---|---|---|---|
| Age, yr (mean, Southward.D.) | 22.8 | 6.1 | 26.ane | seven.v | 22.9 | five.3 | 22.4 | 5.4 |
| Birth order (mean, S.D.) | i.5 | 0.8 | two.0 | 1.3 | i.ix | 1.2 | ane.vi | 0.9 |
| Married (%) | 50.0 | 50.0 | 53.one | 63.0 | ||||
| Socioeconomic status (%) | ||||||||
| High | seven.1 | 12.5 | 9.4 | 7.4 | ||||
| Medium | 35.7 | 37.5 | 37.5 | 22.ii | ||||
| Depression | 57.1 | 50.0 | 53.i | 70.4 | ||||
| Smoker (%) | 57.1 | 43.viii | 62.5 | 51.9 | ||||
| Regular/hard drinker (%) | 21.4 | 31.3 | 8.8 | 29.6 | ||||
Discussion
Pregnant women who attempted suicide with Tardyl® showed the general characteristics of self-poisoned meaning women, i.due east. many of them were young, unmarried and had depression socioeconomic status, besides as ofttimes being smokers and/or drinkers.ten
Our data did not indicate the "classical" human teratogenic effect of the loftier doses of Tardyl® (its mean dose was 24-folds higher than the usual clinical dose) considering in that location was no difference in the prevalence at birth of congenital abnormalities between exposed children and their unexposed sibs. The intrauterine fetal evolution based on pregnancy anile specific nativity weight also did not show a significant departure betwixt exposed children and their sibs.
However, of 27 exposed children, 8 (29.half dozen%) were diagnosed as mentally retarded and they attended special schools. Mental retardation did non occur among 46 unexposed sibs born to the same mothers. The recorded incidence of mental retardation in schoolhouse-age (vi-18 years) children is nigh three percent in Hungary,18thus the occurrence of mental retardation was about 10-fold higher in exposed children born to the mothers who had attempted suicide with Tardyl®.
Of 7 mentally retarded children who were evaluated for behavioral development,5 had severe and ane moderate behavioral divergence. In add-on, ii other exposed children showed moderate behavioral deviation. Thus, of 27 exposed children, ten (37.0%) showed mental retardation and/or severe/moderate behavioral divergence and these findings suggest a possible neurotoxic effect of Tardyl® (i.e., the combination of amobarbital, glutethimide and promethazine).
These results of our written report were supported by the lack of familial occurrence of mental retardation in these families. Neither the mothers nor the 46 unexposed sibs of these eight exposed children suffered from any mental retardation. The fathers of exposed children were not examined, only the mothers stated that they did not endure from mental retardation.
Several environmental agents induce congenital aberration syndromes (such as FAS, fetal rubella, varicella, hydantoin, valproate, methylmercury upshot, iodine deficiency, etc) and these syndromes include both structural defects and mental retardation. In this study we did not find structural defects in the eight exposed children who were mentally retarded. Exposed children and their sibs were examined thoroughly in the report but just FAS was diagnosed: in 1 exposed boy and one sib, the brother of this exposed boy.
Low nativity weight and/or preterm birth is associated with a college rate of mental retardation and behavioral divergence.15Of eight exposed children with mental retardation, two (25.0%) had preterm nascency with low birth weight. Still, of their xviii sib controls, 5 (27.8%) had low birth weight. In improver there was no pregnant deviation in the rate of preterm birth and depression nascency weight between exposed children and sib controls, thus these confounder factors cannot explain the higher risk for mental retardation in exposed children.
In addition, we take to consider an obvious interaction between alcohol abuse and Tardyl®, because five out of the eight exposed children diagnosed with mental retardation were built-in to drinker mothers. However, the drinking habits may have been exaggerated in this study because pregnant women who attempted suicide with drugs ofttimes combined this course of action with concomitant alcohol abuse, and these meaning women were diagnosed every bit drinkers, though in general they were non hard or regular drinkers. In addition, the phenotypic features of these mentally retarded children did non fit the well-known design of FAS.13,19FAS was diagnosed only in 1 exposed boy and in his brother born to the same mother. Exposed children and their sibs were born to the same mothers in general with a similar drinking addiction in their pregnancies, withal the mean IQ was significantly lower in exposed children than in their unexposed sib controls built-in to both the aforementioned drinker or non-drinker mothers. On the other paw some interaction between the effect of Tardyl® and alcohol seems to be plausible, just the mental retardation inducing effect of this medicinal product cannot exist explained only by the concurrent outcome of alcohol.
Nosotros did not discover a college rate of mental retardation in exposed children born to mothers who attempted suicide with either amobarbital,20 glutethimide21or promethazine22taken separately, compared with the information of their sibs in the previous studies of these drugs. Thus merely the combination of the three drugs in Tardyl® produced a high hazard for mental retardation and very low IQ. We hypothesized that the 3 components of Tardyl® may result in additive or potentiated drug interactions.23,24Glutethimide can stimulate hepatic microsomal enzyme product, thus self-induction of its own metabolites, and has frequent interactions with other drugs (due east.m., oral anticoagulants) and alcohol.25
Some other important argument for the potential neurotoxic consequence of Tardyl® is that its association with mental retardation in the exposed children occurred when significant women attempted suicide with Tardyl® between the 14th and 20th postal service-conceptional weeks of pregnancy. Otaka and Schull26studied the disquisitional menses of mental retardation amid i 600 children exposed to radiation from the atomic bomb attack on Nippon and found it to be between 8th to 15th post-conceptional weeks. This menstruation corresponds to the fourth dimension when major proliferation of neuroblasts occurs in the brain of human being fetuses.
Thus the final conclusion of this study is that maternal exposure to high doses of Tardyl®, due to the interaction of its component drugs, may induce mental retardation. As far as we know drug induced mental retardation without structural defects has not been described until now.27,28
There are many strengths of the self-poisoning model, due east.g., there is the potential to gauge a dose-response relationship; i can establish the absence of birth defects after high doses of a drug used during the disquisitional period of embryonic development; there is a potential to examine the neurotoxic effect of drugs following fetal exposure. A further strength of this project is that stresses the clinical and social importance of the self-poisoned pregnant women.9
Amid the limitations of the study nosotros tin mention hither that Tardyl® is a popular hypnotic drug in Hungary and some other Central-Eastern European countries, only non in the Western part of Europe. However, the recognition of the potential for a drug effect on the origin of mental retardation appears to be important from both clinical and theoretical points of view.
In conclusion, the results of this study did not bear witness the classical teratogenic, i.east. congenital abnormality inducing effect of loftier doses of a combination of amobarbital, glutethimide and promethazine (a popular hypnotic drug, Tardyl® in Hungary) in children born to mothers who attempted suicide with this drug during pregnancy. There was no intrauterine growth retardation in children after the suicide effort of their mothers with high doses of Tardyl®. However, the findings of the study showed a statistically meaning association betwixt a higher risk for mental retardation and high doses of Tardyl® when exposure was during the 2nd trimester of pregnancy.
Acknowledgements
The project was supported past IARC, Lyon and the work of Erzsébet H Puhó regarding mathematical calculations of our information prepare was sponsored by Richter Gedeon Pharmaceutical Ltd, Budapest, Hungary. We thank the contribution for our previous co-workers: P Bácskai, A Glauber, A Lendvay, G Molnár, I Szekeres, I Szentesi, L Tímár, and 1000 Tomcsik. We also very much appreciated the editorial assistance of A. Bendich.
Footnotes
Funding:None
Competing interests:None declared
Ethical approval:Primal Ethical Committee, Hungarian Ministry of Health.
References
1. Scheidemann ES (eds): Suicidology, Contemporary Development. New York: Grune and Stratton, 1976. [Google Scholar]
2. Weckstein Fifty. Handbook of Suicidology. Principles, Problems and Practice.New York: Brunner-Mazel, 1980. [Google Scholar]
3. Hawton K, Van Heeringen 1000. The International Handbook of Suicide and Attempted Suicide. Chichester: Wiley, 2000. [Google Scholar]
4. Bertolote JM, Fleischmann A. Suicidal behaviour prevention: WHO perspectives on inquiry. Am J Med Genet C Semin Med Genet. 2005 Feb 15;133C(ane):viii–12. [PubMed] [Google Scholar]
5. Värnik P, Sisask G, Värnik A, Laido Z, Meise U, Ibelshäuser A, et al. Suicide registration in eight European countries: a qualitative analysis of procedures and practices. Forensic Sci Int. 2010 October;202(1):86–92. [PubMed] [Google Scholar]
6. Skegg Yard. Self-impairment. Lancet. 2005 Oct 22;366(9495):1471–83. [PubMed] [Google Scholar]
7. Male monarch RA, Apter A. Suicide in Children and Adolescents. Cambridge: Cambridge Univ Press, 2003. [Google Scholar]
8. Kleiner GJ, Greston WM (eds): Suicide in Pregnancy.Boston: John Wright, 1984. [Google Scholar]
10. Czeizel AE, Gidai J, Petik D, Timmermann Thou, Puhó EH. Cocky-poisoning during pregnancy as a model for teratogenic take a chance estimation of drugs. Toxicol Ind Health. 2008 February;24(i):11–28. [PubMed] [Google Scholar]
xi. Czeizel AE. The estimation of human teratogenic/fetotoxic risk of exposures to drugs on the basis of Hungarian experience:a critical evaluation of clinical and epidemiological models of human teratology. Skilful Opin Drug Saf. 2009 May;8(3):283–303. [PubMed] [Google Scholar]
12. Czeizel AE. Budapest Registry of Self-poisoned Patients. Mutat Res. 1994 April;312(2):157–63. [PubMed] [Google Scholar]
13. Vitéz M, Korányi M, Gönczy East, Rudas T, Czeizel A. A semiquantitative score organization for epidemiological studies of fetal alcohol syndrome. Am J Epidemiol. 1984 Mar;119(3):301–eight. [PubMed] [Google Scholar]
14. Szegal B. Diagnostic of psychomotor development. Hung Psychol. 1980;37:148–88. [Google Scholar]
15. Czeizel A, Lányi-Engelmayer A, Klujber Fifty, Métneki J, Tusnády Yard. Etiological written report of mental retardation in Budapest, Hungary. Am J Ment Defic. 1980 Sep;85(ii):120–eight. [PubMed] [Google Scholar]
sixteen. Lendvay A, Czeizel AE. A behavioural teratologic study on offspring of self-poisoned pregnant women. Acta Paediatr Hung. 1992;32(4):347–69. [PubMed] [Google Scholar]
17. Czeizel AE, Rockenbauer Chiliad, Siffel C, Varga E. Description and mission evaluation of the Hungarian case-control surveillance of congenital abnormalities, 1980-1996. Teratology. 2001 May;63(v):176–85. [PubMed] [Google Scholar]
18. Czeizel A, Sankaranarayanan K, Szondy Thou. The load of genetic and partially genetic diseases in man. III. Mental retardation. Mutat Res. 1990 Oct;232(2):291–303. [PubMed] [Google Scholar]
19. Jones KL, Smith DW, Ulleland CN, Streissguth P. Design of malformations in offspring of chronic alcoholic mothers. Lancet. 1973 Jun nine;1(7815):1267–71. [PubMed] [Google Scholar]
20. Petik D, Timmermann G, Czeizel AE, Acs Northward, Bánhidy F. A written report of the teratogenic and fetotoxic effects of large doses of amobarbital used for a suicide attempt by 14 pregnant women. Toxicol Ind Health. 2008 Feb;24(ane):79–85. [PubMed] [Google Scholar]
21. Petik D, Ács North, Bánhidy F, Czeizel AE. A study of the effects of large doses of glutethimide that were used for self-poisoning during pregnancy on human fetuses. Toxicol Ind Health. 2008 Feb;24(1):69–78. [PubMed] [Google Scholar]
22. Petik D, Ács N, Bánhidy F, Czeizel AE. A study of the potential teratogenic effect of big doses of promethazine used for a suicide attempt past 32 pregnant women. Toxicol Ind Wellness. 2008 Feb;24(1):87–96. [PubMed] [Google Scholar]
23. Hanstein PD. Drug Interactions, fifth ed. Philadelphia: Lea and Febiger, 1985. [Google Scholar]
24. Gorrod IW, Beckett AH (eds): Drug Metabolism in Man. London: Taylor and Francis, 1978. [Google Scholar]
25. Nicholson AN. The utilise of short- and long-acting hypnotics in clinical medicine. Br J Clin Pharmacol. 1981;11(1):61S–69S. [PMC gratuitous article] [PubMed] [Google Scholar]
26. Otake Chiliad, Schull WJ. In utero exposure to A-bomb radiation and mental retardation: a reassessment. Br J Radiol. 1984 May;57(677):409–fourteen. [PubMed] [Google Scholar]
27. Shepard Th, Lemire RJ. Itemize of Teratogenic Agents,11th ed. Baltimore: Johns Hopkins Univ. Press, 2004. [Google Scholar]
28. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation, seventh ed. Philadelphia: Lippincott Williams and Wilkins, 2005. [Google Scholar]
29. Czeizel AE, Petik D, Puhó E. Smoking and alcohol drinking during pregnancy:the reliability of retrospective maternal cocky-reported information. Centr Eur J Public Health. 2004 Dec;12(4):179–83. [PubMed] [Google Scholar]
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291287/
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