- Email: [email protected]
Association between maternal bleeding during gestation and congenital anomalies in the offspring
Association between maternal bleeding during gestation and congenital anomalies in the offs~~ng ASHER SAM
ORNOY BENADY
REUVEN ALEX
KOHEN-RAZ. RUSSELL
The incidence of maternal bleeding complicating the jwegnancies of 324 childrett examined at the Jer~sa~m Gommun~t~ Center for Ghild and Farnil? ~eue~o~n~ is surveyed. A histo? of bleeding during ~e~u~~ was more frequent in ~h~~dre~ with congenital anomalies of th central nervous system, (and/or psychomotor retardation) (33 per cent) and in children zoith congenital anomalies of other systems (29 per cent) than in control ~hi~r~n (12 per cent). The ~rnpL~~a~io~ of these~~~ngs are demised in re~t~o~ to placental pathophys~olo~ a.& the pathogen& of threatened abortion.
HYPOXIA is known to influence fetal development sufficiently to induce anomalies in various animal species. 7, lo Human intrauterine growth retardation in the later months of gestation5 has been attributed to hypoxia but no strong evidence has emerged that it is teratogenic. Various investigators have reported prospective and retrospective studies in which they attempted to establish a correlation between pregnancy bleeding and poor fetal outcome.*~ 14*Is, I73 la, *I In most of the prospective studies no such direct relation could be demonstrated, possibly because of the low total number of anomalies. Where larger numbers were involved, as in the 8,000 pregnancies followed up from the first trimester by Rougette and associates,*a a greater incidence of genital bleeding during the first trimester was reported by mothers of children born with defects (24 per cent) than by the mothers of control infants (14 per cent). The retrospective studies have usually yielded a greater frequency of anomalies, and most investigators
have agreed there is a positive relation between the complications of pregnancy, including bleeding, and congenital anomalies or small and premature infants.” 14, 21 Most of these studies were based on data obtained retrospectively from routine hospital or clinic files and the incidence of bleeding was undoubtedly underestimated. The same reservation may well apply to the recorded incidence of anomalies, since the figures were based mainly upon neonatal records. so that. many anomalies probably remained undiagnosed. This would be particularly true for mentaf retardation, so that, not unexpectedly, the literature on the possible relation between complications of pregnancy and mental retardation is sparse.4* Ii In the Jerusalem Community Center for Child and Family Development, children from the age of 1 month with or suspected of having congenital abnormality or psychomotor retardation undergo separate comprehensive examinations by a psychologist and a developmental pediatrician. Before these examinations, each mother is interviewed and a detailed questionnaire about various aspects of her pregnancy and previous obstetric history is completed. We report below our findings with reference to gestational bleeding in mothers of 326 children examined during the last 3 years in our Center.
From the Je~ulem Child and Family ~evelapmen~ Center, and The fervent of Avatar and ~rn~o~o~, Hebrm University Hadassah Medical School. Receivedfor publkation Januq 14, 197.5. Revised Accepted
~e~~~
25,1975.
March
3, 1975.
fdlstsr@s
and methods
A total of 326 children between the ages of 6 months and 5 years who underwent comprehensive interdisciplinary assessment at our Center between 1971 and
Reprint requests: Dr. A. Omoy, ~e~~~n~ of A~tomy and ~rn~o~~, Hebrew Un~~~s~ Hadassah Ned&al School, Jerudem, Iwad. 474
Volume Number
Maternal bleeding during gestation and congenital anomalies
124 5
Table I. Occurrence
of maternal
bleeding
during
pregnancy
Total No. of infants
63
Percentage *No
statistically
si&icant
congenital anom&esand
Withut bleeding
examined*
Congenital CNS anomalies including chromosornal defects
Congenital anomalies excluding
in 326 infants
GNS With b~eding
45 71 difference between controls: p < 0.01.
18 29 non-CNS
Total I10 and CNS
1973 were referred from various clinics and newborn departments in the city of Jerusalem because of diagnosed or suspected congenital abnormality or psychomotor retardation. Examination showed many of them to be normal and we therefore decided to use the normal children as controls for this study. Before the children were examined, each mother was interviewed by a developmental nurse and a social worker, members of our interdisciplinary subunits, and the answers were recorded on a standard form. Various details of the pregnancy and previous obstetric and medical history were recorded, with special reference to potential teratogenic factors such as bleeding, drug ingestion, or irradiation during pregnancy. The children then underwent a developmental examination by a clinical psychologist using the Bayley’ Scales of Mental and Motor Development, standardized for Israeli ~pulat~ons by Kohen-Raz.l’* ” For the purpose of a more refined clinical diagnosis the original Bayley Scales were broken down into subscales of mental and motor functions based on a Scalogram Analysis” such as Mental Scales of Manipulation, Eye-Hand Coordination, Object Relation, Imitation, Comprehension, and Active Social Contact, Verbalization, as well as Motor Scales of Static Coordination, Body Coordination, Arm Coordination, Fine Coordination, and Walking. Following this a full neurologic and pediatric examination was completed. Most of the children were so examined on at least two occasions. A small number found to be normal on initial examination were not examined a second time. For the purpose of this study the children were divided into three groups: (1) 153 children (control subjects) with normal development and without congenital abnormalities; (2) 63 children with congenital anomalies (excluding children with central nervous system anomalies) but with normal mental development; (3) 110 children with congenital abnormalities of the central nervous system (CNS) or with psychomotor retardation (including 14 cases of Down’s syndrome and
Without bl-eeding 74 67 congenital
475
Controls (no anomalies, noun& development) With bhedisg 36 33
anomalies.
Total
153
Without bleeding 134 88
With bleeding 19 12
Highly significant difference between
8 cases of CNS anomalies without mental retardation). CNS damage and significant motor retardation on the Bayley Scales was qualitatively manifest in conspicuous retardation of Fine Motor Coordination, poor Eye-Hand Coordination, and lack of Object Relation as well as in a lon~tudinal decrease of developmental quotients, indicating tendencies of stagnation and inhibited growth.i3 Quantitatively, psychomotor retardation and suspect CNS damage was operationally defined as a score equal to or less than 70 on the mental scales on two consecutive tests, or a score of 50 or less in one examination when the infant was over the age of 1 year. We wish to report here our findings on the incidence of vaginal bleeding during the pregnancies with those infants. The mothers were asked whether bleeding or spotting occurred during gestation, if so, how long after the last menstrual period it first appeared, and its duration and intensity. Women with spotting only were considered “positive.” Known cases of placenta previa were omitted. The placentas were not examined.
Results The mothers from the three groups were of similar socioeconomic class, ethnic origin, and age. A significantly increased incidence of bleeding was found in both congenital anomaly groups (Table I). In both these groups the incidence of bleeding was over 2% times that in the control group (P < 0.01). There was, however, no significant difference between groups of CNS anomalies vs. non-CNS congenital anomalies, and there was no difference in the incidence of bleeding between the sexes. Table II shows the incidence of bleeding in the groups with congenital anomalies when 21 cases of known hereditary etiology (10 from the group of congenital CNS anomalies and 11 from the group of non-CNS congenital anomalies (Table III) were excluded. In both groups the incidence of bleeding rose to more than one third of the total cases, being almost three times the incidence of bleeding in the control group.
476
Omoy et al.
March
1. 1976
Am. 1. Obstet. Gynecol.
Cl
b)
a) CNS Gong. Anomalies
eon-CNS Anomalies
tong.
Conlrols
Number Of cases 10
0
12
3
4
55+ Months
Fig. 1. Distribution
0
12 of
3
4
55+
0
12
3
4
55+
Gestation
of maternal bleeding according to month of gestation.
NUMBER OF CASES
CNS
Anomalies
IO
6
132
OII
I02
300
5 03
4
Fig. 2. Duration and nature of bleeding starting in the first trimester (57 cases). “Like period”: Regular bleeding at the time of expected period described by the patient as such.
Fig. 1 represents a breakdown of the incidence of bleeding according to the month of gestation when bleeding first appeared. It will be seen that most examples of bleeding started in the first trimester of pregnancy (gestational age recorded according to the date of the last menstrua1 period); in a minority of cases bleeding started after the fifth month; no instance of bleeding was found to have started during the fourth and fifth months. Fig. 2 describes the duration and nature of vaginal bleeding starting in the first trimester. There were five cases with spots only and five cases with bleeding at the time of the expected period. In 16 of 29 cases of CNS anomalies, duration of bleeding was 1 to 4 days. Table IV indicates the percentage incidence of bleeding in the first trimester in all groups and Table V lists the conditions associated with first-trimester bleeding. When diseases of known hereditary etiology are
again excluded (Table VI), the incidence of bleeding starting in the first trimester rises to 25 per cent in the group with congenital non-CNS anomalies and to 28 per cent in the group with CNS anomalies or mental and psychomotor retardation, as opposed to only 10 per cent in the controls (Table IV).
Comment There is insufficient information concerning the possible deleterious effects of early vaginal bleeding upon the human fetus. We can presume that bleeding originating in the placental area may be associated with partial separation of the placenta9 which can be manifested at a later stage of pregnancy in the form of partial or complete abruptio placentae. This type of disturbance could undoubtedly interfere with some placenta1 function, possibly to the extent of leading to fetal hypoxia and/or malnutrition.3. 5
Volume Number
Maternal bleeding during gestation and congenital anomalies
124 5
Table II. Occurrence of maternal bleeding infants with congenital anomalies excluding disorders with known hereditary pattern
Total
No. of patients Percentage
52
Table V. Diagnoses of 42 infants with congenital anomalies associated with bleeding in the first trimester
in 152
No.
Conge~‘tal aisles non-CNS
Without bleeding
CNS
With
bleeding Total
34
18
66
34
100
ano~l~s
Without bleeding
With
bleeding
65
35
65
35
Table III. Diagnoses of 21 infants with congenital anomalies of known hereditary pattern -
I ~‘~h~~t-t~rnest~
Cleidocranial
No.
bleeding:
1
dysostosis ( + PMR)
Withoutfirst-trimester
bbeding:
Marinescu-Sjogren syndrome Von Gierke’s disease Riley-Day syndrome Von R~kiinghausen’s disease Tay-Sachs disease Ellis-van Creveld syndrome Weidermann Beckwith syndrome Thalassemia Achondroplasia Windmill syndrome Albinism FamiliaI dwarfism FamihaI deafness Familial cataracts
z I
63
13 21
110
29 26
Psychomotor retardation Psychomotor retardation associated with non-CNS anomaly CNS anomaly without psychomotor retardation Mongolism Non-CNS anomalies: Congenital heart disease Renal anomalies (polycystic kidney, renal dysostosis) Hare lip + cleft palate Hernia Polydactyly Hypospadias, cryptorchidism, club foot - Congenital cirrhosis
: 1 1 1 : 1 2 2 1
6 2 1 1 1 1 1
~
Total number of infants Percentage
153
20 3 (hernia f CDH) (harelip + cleft palate) (cleidocranial dysostosis) 2 (petit mal, meningomyelocele) 4
Table VI. Occurrence of maternal bleeding in the first trimester of pregnancy in 152 infants with congenital anomalies, excluding disorders with known hereditary pattern*
Table IV. Occurrence of maternal bleeding in first trimester of pregnancy in 326 infants examined*
No. of infants Percentage
477
15 10
*No statistically significant differences between non-CNS and CNS congenital anomalies. Highly significant difference between congenital anomalies and controls: P < 0.01. In the collaborative perinatal study of the National Institute of Neurological Diseases and Strokels attention was given to the problem of vaginal bleeding during pregnancy. The authors found not only that bleeding increases the risk of fetal and neonatal death or of low birth weight, but that neurologic impairment at 1 year of age was found in a higher percentage in infants whose mothers had bleeding during the second trimester than in control infants. In cases of partial
52
13 25
100
28 28
*The difference between the groups is not statisticahy significant. abruptio placentae, very similar results were found regarding birth weight, neonatal death, and neurologic impairment at 1 year of age. It is not clear, however, whether placental injury earlier in gestation can be responsible for congenital anomalies. One of the first placental functions to be affected by placental damage is oxygen transfer21 and fetal nutrition.3. 5 Severe hypoxia and/or malnutrition will result in fetal death, and less severe damage may interfere with fetal growth, but, during the period of organogenesis, one can only speculate upon such teratogenic effects of hypoxia or malnutrition8 Certainly there is abundant evidence that gestational hypoxia is teratogenic in some species.‘, lo Although direct evidence is lacking, our results may suggest a similar effect upon the human embryo. In favor of the hypothesis that bleeding early in pregnancy is a cause rather than a mere accompaniment might be the fact that in the group of anomalies
478
Omoy et al.
with a known hereditary pattern the incidence of bleeding was very low (one case in a total of 21 patients-Table III). On the other hand, in our series of Down’s syndrome, four out of 14 mothers had genital bleeding. In these cases the bleeding is clearly not the cause of the defect and this finding may point to an association of chromosomal aberration to pregnancy bleeding, although the numbers are too small to be conclusive. Similarly, Rougette and associateslg found a high incidence of gestational bleeding in genetically determined anomalies. The possibility cannot be excluded that an association similar to that found between genetically determined anomalies and bleeding, which cannot be related on the basis of cause and effect, may occur in other anomalies. Although in many cases the causes for vaginal bleeding during gestation (threatened abortion) are unknown, sometimes abnormal placentation, uterine anomalies, or infections are encountered as possible causes.3 Of particular importance are inflammatory lesions of the decidua or placenta. During the rubella epidemic in Israel in 1972, fetuses and placentas from women whose pregnancies were interrupted due to gestational rubella were studied. It was found that in 50 per cent the placentas showed various inflammatory lesions.16 From eight infants with the congenital rubella syndrome examined in our Developmental Center (not included in this study), there was a positive history of genital bleeding in three. Although direct evidence is lacking, we might suspect that intrauterine infection
March 1, 1976 Am. J. Obstet. Gynecol.
can be responsible for a significant proportion of the gestational bleeding in our cases. Our study, like all retrospective studies, is open to the criticism that mothers with abnormal children are more likely to recall abnormalities in pregnancy.20 It is worth stressing, however, that all children reached our Center because of suspected congenital abnormality or psychomotor retardation, and that the interview in each case was carried out before the outcome of the examination was known; we therefore believe that this factor was insignificant in our cases. The population examined was, of course, highly selected, and the numbers are too small for definite conclusions to be drawn in favor of the teratogenic effect of bleeding in early pregnancy, but the high percentage of bleeding in mothers whose infants suffered from congenital anomalies is impressive and clearly significant of at least an association between the two. Extensive prospective studies are required to establish the incidence of congenital abnormality OI psychomotor retardation following threatened abortion, which may be important for the question of intensive treatment of threatened abortion. A proper experimental model for the study of the effects of gestational bleeding upon fetal development is lacking. Reduction of oxygen tension7’ 3 or clamping of uterine arterie? in pregnant animals are far from being the appropriate comparative experimental models.
REFERENCES 1. Asanti, R., and Vesanto, T.: Acta Obstet. Gynecol. Stand. 42: 107, 1963. 2. Bayley, N.: Child Devel. 36: 379, 1965. 3. Benirschke, K., and Driscoll, S. G.: The Pathology of the Human Placenta, Berlin, 1967, Springer Verlag, pp. 216-234, 306-340. 4. Bishop, E.H., Israel, S. L., and Briscoe, C. C.: Obstet. Gynecol. 26: 628, 1965. 5. Brent, R. L., and Jensh, R. P.: Adv. Teratol. 2: 140, 1967. 6. Fehlhaber, C., Friedel, B., Lempp, R., Rocher, D., and Wacher, H.: Arch. Kinderheilk. 176: 134, 1967. 7. Grabowski, C. T.: Adv. Teratol. 4: 125, 1970. 8. Gruenwald, P.: Biol. Neonatol. 5: 215, 1963. 9. Hollstein, K.: Zentralbl. Gynaekol. 80: 16, 1958. 10. Ingalls, T. H.: J. A. M. A. 161: 1047, 1956. 11. Kohen-Raz, R.: Genet. Psychol. Monogr. 76: 3, 1967. R.: Child Devel. 39: 489, 1968. 12. Kohen-Raz, 13. Kohen-Raz, R., Ornoy, A., and Russell, A.: Ment. Health Sot. 2: 1975. In press.
14. Lilienfeld, A. M., and Pasamanick, B.: J. A. M. A. 155: 719, 1953. 15. Niswander, K. R., and Gordon, M.: The Women and their Pregnancies: The Collaborative Studv of the National I&titute of Neurological Diseases aid Stroke, Philadelphia, 1972, W. B. Saunders Company, pp. 398404, 409-415. 16. Ornoy, A., Segal, S., Nishmi, M., Simcha, A., and Polishuk, W. Z.: AM. J. OBSTET. GYNECOL. 116: 349, 1973. 17. Pasamanick, B., and Lilienfeld, A. M.: Jo A. M. A. 159: 155, 1955. 18. Peckham, C. H.: Obstet. Gynecol. 35: 937, 1970. 19. Rougette, C., Etienne, C., and Gougard, J.: In Proc. of the 2nd European Congress of Perinatal Medicine, Base], 1970, S. Karger AG. pp. 300-301. 20. Smithells, R.-W.: Adv-. -Teratol. 1: 251, 1966. 21. Turnbull, E. P. N., and Walker, J.: J. Obstet. Gynaecol. Br. Emp. 63: 553, 1956.
ORNOY BENADY
REUVEN ALEX
KOHEN-RAZ. RUSSELL
The incidence of maternal bleeding complicating the jwegnancies of 324 childrett examined at the Jer~sa~m Gommun~t~ Center for Ghild and Farnil? ~eue~o~n~ is surveyed. A histo? of bleeding during ~e~u~~ was more frequent in ~h~~dre~ with congenital anomalies of th central nervous system, (and/or psychomotor retardation) (33 per cent) and in children zoith congenital anomalies of other systems (29 per cent) than in control ~hi~r~n (12 per cent). The ~rnpL~~a~io~ of these~~~ngs are demised in re~t~o~ to placental pathophys~olo~ a.& the pathogen& of threatened abortion.
HYPOXIA is known to influence fetal development sufficiently to induce anomalies in various animal species. 7, lo Human intrauterine growth retardation in the later months of gestation5 has been attributed to hypoxia but no strong evidence has emerged that it is teratogenic. Various investigators have reported prospective and retrospective studies in which they attempted to establish a correlation between pregnancy bleeding and poor fetal outcome.*~ 14*Is, I73 la, *I In most of the prospective studies no such direct relation could be demonstrated, possibly because of the low total number of anomalies. Where larger numbers were involved, as in the 8,000 pregnancies followed up from the first trimester by Rougette and associates,*a a greater incidence of genital bleeding during the first trimester was reported by mothers of children born with defects (24 per cent) than by the mothers of control infants (14 per cent). The retrospective studies have usually yielded a greater frequency of anomalies, and most investigators
have agreed there is a positive relation between the complications of pregnancy, including bleeding, and congenital anomalies or small and premature infants.” 14, 21 Most of these studies were based on data obtained retrospectively from routine hospital or clinic files and the incidence of bleeding was undoubtedly underestimated. The same reservation may well apply to the recorded incidence of anomalies, since the figures were based mainly upon neonatal records. so that. many anomalies probably remained undiagnosed. This would be particularly true for mentaf retardation, so that, not unexpectedly, the literature on the possible relation between complications of pregnancy and mental retardation is sparse.4* Ii In the Jerusalem Community Center for Child and Family Development, children from the age of 1 month with or suspected of having congenital abnormality or psychomotor retardation undergo separate comprehensive examinations by a psychologist and a developmental pediatrician. Before these examinations, each mother is interviewed and a detailed questionnaire about various aspects of her pregnancy and previous obstetric history is completed. We report below our findings with reference to gestational bleeding in mothers of 326 children examined during the last 3 years in our Center.
From the Je~ulem Child and Family ~evelapmen~ Center, and The fervent of Avatar and ~rn~o~o~, Hebrm University Hadassah Medical School. Receivedfor publkation Januq 14, 197.5. Revised Accepted
~e~~~
25,1975.
March
3, 1975.
fdlstsr@s
and methods
A total of 326 children between the ages of 6 months and 5 years who underwent comprehensive interdisciplinary assessment at our Center between 1971 and
Reprint requests: Dr. A. Omoy, ~e~~~n~ of A~tomy and ~rn~o~~, Hebrew Un~~~s~ Hadassah Ned&al School, Jerudem, Iwad. 474
Volume Number
Maternal bleeding during gestation and congenital anomalies
124 5
Table I. Occurrence
of maternal
bleeding
during
pregnancy
Total No. of infants
63
Percentage *No
statistically
si&icant
congenital anom&esand
Withut bleeding
examined*
Congenital CNS anomalies including chromosornal defects
Congenital anomalies excluding
in 326 infants
GNS With b~eding
45 71 difference between controls: p < 0.01.
18 29 non-CNS
Total I10 and CNS
1973 were referred from various clinics and newborn departments in the city of Jerusalem because of diagnosed or suspected congenital abnormality or psychomotor retardation. Examination showed many of them to be normal and we therefore decided to use the normal children as controls for this study. Before the children were examined, each mother was interviewed by a developmental nurse and a social worker, members of our interdisciplinary subunits, and the answers were recorded on a standard form. Various details of the pregnancy and previous obstetric and medical history were recorded, with special reference to potential teratogenic factors such as bleeding, drug ingestion, or irradiation during pregnancy. The children then underwent a developmental examination by a clinical psychologist using the Bayley’ Scales of Mental and Motor Development, standardized for Israeli ~pulat~ons by Kohen-Raz.l’* ” For the purpose of a more refined clinical diagnosis the original Bayley Scales were broken down into subscales of mental and motor functions based on a Scalogram Analysis” such as Mental Scales of Manipulation, Eye-Hand Coordination, Object Relation, Imitation, Comprehension, and Active Social Contact, Verbalization, as well as Motor Scales of Static Coordination, Body Coordination, Arm Coordination, Fine Coordination, and Walking. Following this a full neurologic and pediatric examination was completed. Most of the children were so examined on at least two occasions. A small number found to be normal on initial examination were not examined a second time. For the purpose of this study the children were divided into three groups: (1) 153 children (control subjects) with normal development and without congenital abnormalities; (2) 63 children with congenital anomalies (excluding children with central nervous system anomalies) but with normal mental development; (3) 110 children with congenital abnormalities of the central nervous system (CNS) or with psychomotor retardation (including 14 cases of Down’s syndrome and
Without bl-eeding 74 67 congenital
475
Controls (no anomalies, noun& development) With bhedisg 36 33
anomalies.
Total
153
Without bleeding 134 88
With bleeding 19 12
Highly significant difference between
8 cases of CNS anomalies without mental retardation). CNS damage and significant motor retardation on the Bayley Scales was qualitatively manifest in conspicuous retardation of Fine Motor Coordination, poor Eye-Hand Coordination, and lack of Object Relation as well as in a lon~tudinal decrease of developmental quotients, indicating tendencies of stagnation and inhibited growth.i3 Quantitatively, psychomotor retardation and suspect CNS damage was operationally defined as a score equal to or less than 70 on the mental scales on two consecutive tests, or a score of 50 or less in one examination when the infant was over the age of 1 year. We wish to report here our findings on the incidence of vaginal bleeding during the pregnancies with those infants. The mothers were asked whether bleeding or spotting occurred during gestation, if so, how long after the last menstrual period it first appeared, and its duration and intensity. Women with spotting only were considered “positive.” Known cases of placenta previa were omitted. The placentas were not examined.
Results The mothers from the three groups were of similar socioeconomic class, ethnic origin, and age. A significantly increased incidence of bleeding was found in both congenital anomaly groups (Table I). In both these groups the incidence of bleeding was over 2% times that in the control group (P < 0.01). There was, however, no significant difference between groups of CNS anomalies vs. non-CNS congenital anomalies, and there was no difference in the incidence of bleeding between the sexes. Table II shows the incidence of bleeding in the groups with congenital anomalies when 21 cases of known hereditary etiology (10 from the group of congenital CNS anomalies and 11 from the group of non-CNS congenital anomalies (Table III) were excluded. In both groups the incidence of bleeding rose to more than one third of the total cases, being almost three times the incidence of bleeding in the control group.
476
Omoy et al.
March
1. 1976
Am. 1. Obstet. Gynecol.
Cl
b)
a) CNS Gong. Anomalies
eon-CNS Anomalies
tong.
Conlrols
Number Of cases 10
0
12
3
4
55+ Months
Fig. 1. Distribution
0
12 of
3
4
55+
0
12
3
4
55+
Gestation
of maternal bleeding according to month of gestation.
NUMBER OF CASES
CNS
Anomalies
IO
6
132
OII
I02
300
5 03
4
Fig. 2. Duration and nature of bleeding starting in the first trimester (57 cases). “Like period”: Regular bleeding at the time of expected period described by the patient as such.
Fig. 1 represents a breakdown of the incidence of bleeding according to the month of gestation when bleeding first appeared. It will be seen that most examples of bleeding started in the first trimester of pregnancy (gestational age recorded according to the date of the last menstrua1 period); in a minority of cases bleeding started after the fifth month; no instance of bleeding was found to have started during the fourth and fifth months. Fig. 2 describes the duration and nature of vaginal bleeding starting in the first trimester. There were five cases with spots only and five cases with bleeding at the time of the expected period. In 16 of 29 cases of CNS anomalies, duration of bleeding was 1 to 4 days. Table IV indicates the percentage incidence of bleeding in the first trimester in all groups and Table V lists the conditions associated with first-trimester bleeding. When diseases of known hereditary etiology are
again excluded (Table VI), the incidence of bleeding starting in the first trimester rises to 25 per cent in the group with congenital non-CNS anomalies and to 28 per cent in the group with CNS anomalies or mental and psychomotor retardation, as opposed to only 10 per cent in the controls (Table IV).
Comment There is insufficient information concerning the possible deleterious effects of early vaginal bleeding upon the human fetus. We can presume that bleeding originating in the placental area may be associated with partial separation of the placenta9 which can be manifested at a later stage of pregnancy in the form of partial or complete abruptio placentae. This type of disturbance could undoubtedly interfere with some placenta1 function, possibly to the extent of leading to fetal hypoxia and/or malnutrition.3. 5
Volume Number
Maternal bleeding during gestation and congenital anomalies
124 5
Table II. Occurrence of maternal bleeding infants with congenital anomalies excluding disorders with known hereditary pattern
Total
No. of patients Percentage
52
Table V. Diagnoses of 42 infants with congenital anomalies associated with bleeding in the first trimester
in 152
No.
Conge~‘tal aisles non-CNS
Without bleeding
CNS
With
bleeding Total
34
18
66
34
100
ano~l~s
Without bleeding
With
bleeding
65
35
65
35
Table III. Diagnoses of 21 infants with congenital anomalies of known hereditary pattern -
I ~‘~h~~t-t~rnest~
Cleidocranial
No.
bleeding:
1
dysostosis ( + PMR)
Withoutfirst-trimester
bbeding:
Marinescu-Sjogren syndrome Von Gierke’s disease Riley-Day syndrome Von R~kiinghausen’s disease Tay-Sachs disease Ellis-van Creveld syndrome Weidermann Beckwith syndrome Thalassemia Achondroplasia Windmill syndrome Albinism FamiliaI dwarfism FamihaI deafness Familial cataracts
z I
63
13 21
110
29 26
Psychomotor retardation Psychomotor retardation associated with non-CNS anomaly CNS anomaly without psychomotor retardation Mongolism Non-CNS anomalies: Congenital heart disease Renal anomalies (polycystic kidney, renal dysostosis) Hare lip + cleft palate Hernia Polydactyly Hypospadias, cryptorchidism, club foot - Congenital cirrhosis
: 1 1 1 : 1 2 2 1
6 2 1 1 1 1 1
~
Total number of infants Percentage
153
20 3 (hernia f CDH) (harelip + cleft palate) (cleidocranial dysostosis) 2 (petit mal, meningomyelocele) 4
Table VI. Occurrence of maternal bleeding in the first trimester of pregnancy in 152 infants with congenital anomalies, excluding disorders with known hereditary pattern*
Table IV. Occurrence of maternal bleeding in first trimester of pregnancy in 326 infants examined*
No. of infants Percentage
477
15 10
*No statistically significant differences between non-CNS and CNS congenital anomalies. Highly significant difference between congenital anomalies and controls: P < 0.01. In the collaborative perinatal study of the National Institute of Neurological Diseases and Strokels attention was given to the problem of vaginal bleeding during pregnancy. The authors found not only that bleeding increases the risk of fetal and neonatal death or of low birth weight, but that neurologic impairment at 1 year of age was found in a higher percentage in infants whose mothers had bleeding during the second trimester than in control infants. In cases of partial
52
13 25
100
28 28
*The difference between the groups is not statisticahy significant. abruptio placentae, very similar results were found regarding birth weight, neonatal death, and neurologic impairment at 1 year of age. It is not clear, however, whether placental injury earlier in gestation can be responsible for congenital anomalies. One of the first placental functions to be affected by placental damage is oxygen transfer21 and fetal nutrition.3. 5 Severe hypoxia and/or malnutrition will result in fetal death, and less severe damage may interfere with fetal growth, but, during the period of organogenesis, one can only speculate upon such teratogenic effects of hypoxia or malnutrition8 Certainly there is abundant evidence that gestational hypoxia is teratogenic in some species.‘, lo Although direct evidence is lacking, our results may suggest a similar effect upon the human embryo. In favor of the hypothesis that bleeding early in pregnancy is a cause rather than a mere accompaniment might be the fact that in the group of anomalies
478
Omoy et al.
with a known hereditary pattern the incidence of bleeding was very low (one case in a total of 21 patients-Table III). On the other hand, in our series of Down’s syndrome, four out of 14 mothers had genital bleeding. In these cases the bleeding is clearly not the cause of the defect and this finding may point to an association of chromosomal aberration to pregnancy bleeding, although the numbers are too small to be conclusive. Similarly, Rougette and associateslg found a high incidence of gestational bleeding in genetically determined anomalies. The possibility cannot be excluded that an association similar to that found between genetically determined anomalies and bleeding, which cannot be related on the basis of cause and effect, may occur in other anomalies. Although in many cases the causes for vaginal bleeding during gestation (threatened abortion) are unknown, sometimes abnormal placentation, uterine anomalies, or infections are encountered as possible causes.3 Of particular importance are inflammatory lesions of the decidua or placenta. During the rubella epidemic in Israel in 1972, fetuses and placentas from women whose pregnancies were interrupted due to gestational rubella were studied. It was found that in 50 per cent the placentas showed various inflammatory lesions.16 From eight infants with the congenital rubella syndrome examined in our Developmental Center (not included in this study), there was a positive history of genital bleeding in three. Although direct evidence is lacking, we might suspect that intrauterine infection
March 1, 1976 Am. J. Obstet. Gynecol.
can be responsible for a significant proportion of the gestational bleeding in our cases. Our study, like all retrospective studies, is open to the criticism that mothers with abnormal children are more likely to recall abnormalities in pregnancy.20 It is worth stressing, however, that all children reached our Center because of suspected congenital abnormality or psychomotor retardation, and that the interview in each case was carried out before the outcome of the examination was known; we therefore believe that this factor was insignificant in our cases. The population examined was, of course, highly selected, and the numbers are too small for definite conclusions to be drawn in favor of the teratogenic effect of bleeding in early pregnancy, but the high percentage of bleeding in mothers whose infants suffered from congenital anomalies is impressive and clearly significant of at least an association between the two. Extensive prospective studies are required to establish the incidence of congenital abnormality OI psychomotor retardation following threatened abortion, which may be important for the question of intensive treatment of threatened abortion. A proper experimental model for the study of the effects of gestational bleeding upon fetal development is lacking. Reduction of oxygen tension7’ 3 or clamping of uterine arterie? in pregnant animals are far from being the appropriate comparative experimental models.
REFERENCES 1. Asanti, R., and Vesanto, T.: Acta Obstet. Gynecol. Stand. 42: 107, 1963. 2. Bayley, N.: Child Devel. 36: 379, 1965. 3. Benirschke, K., and Driscoll, S. G.: The Pathology of the Human Placenta, Berlin, 1967, Springer Verlag, pp. 216-234, 306-340. 4. Bishop, E.H., Israel, S. L., and Briscoe, C. C.: Obstet. Gynecol. 26: 628, 1965. 5. Brent, R. L., and Jensh, R. P.: Adv. Teratol. 2: 140, 1967. 6. Fehlhaber, C., Friedel, B., Lempp, R., Rocher, D., and Wacher, H.: Arch. Kinderheilk. 176: 134, 1967. 7. Grabowski, C. T.: Adv. Teratol. 4: 125, 1970. 8. Gruenwald, P.: Biol. Neonatol. 5: 215, 1963. 9. Hollstein, K.: Zentralbl. Gynaekol. 80: 16, 1958. 10. Ingalls, T. H.: J. A. M. A. 161: 1047, 1956. 11. Kohen-Raz, R.: Genet. Psychol. Monogr. 76: 3, 1967. R.: Child Devel. 39: 489, 1968. 12. Kohen-Raz, 13. Kohen-Raz, R., Ornoy, A., and Russell, A.: Ment. Health Sot. 2: 1975. In press.
14. Lilienfeld, A. M., and Pasamanick, B.: J. A. M. A. 155: 719, 1953. 15. Niswander, K. R., and Gordon, M.: The Women and their Pregnancies: The Collaborative Studv of the National I&titute of Neurological Diseases aid Stroke, Philadelphia, 1972, W. B. Saunders Company, pp. 398404, 409-415. 16. Ornoy, A., Segal, S., Nishmi, M., Simcha, A., and Polishuk, W. Z.: AM. J. OBSTET. GYNECOL. 116: 349, 1973. 17. Pasamanick, B., and Lilienfeld, A. M.: Jo A. M. A. 159: 155, 1955. 18. Peckham, C. H.: Obstet. Gynecol. 35: 937, 1970. 19. Rougette, C., Etienne, C., and Gougard, J.: In Proc. of the 2nd European Congress of Perinatal Medicine, Base], 1970, S. Karger AG. pp. 300-301. 20. Smithells, R.-W.: Adv-. -Teratol. 1: 251, 1966. 21. Turnbull, E. P. N., and Walker, J.: J. Obstet. Gynaecol. Br. Emp. 63: 553, 1956.