Hum. Genet. 32,349--352 (1976) © b y Springer-Verlag 1976
Clinical Case Reports Prenatal Diagnosis of Congenital Anomalies in an Intrauterine Growth Retarded Fetus ~ i t c h e l l S. G o l b u s , B r y a n D. H a l l , a n d R o b e r t K . C r e a s y Departments of Obstetrics and Gynecology and of Pediatrics and the Cardiovascular Research Institute, University of California School of Medicine, San Francisco l~eceived November 5, 1975 / F e b r u a r y 3, 1976
Summary. Chromosome analysis of amniotic fluid cells and amniotic fluid alpha-fetoprotein determinations were used to investigate a fetus with severe intrauterine growth retardation in the third trimester. The karyotype was 4 7 , X Y , 1 8 ~ and increased alpha-fetoprotein levels indicated the presence of congenital malformations. We suggest t h a t when severe fetal growth retardation is detected early in the a n t e p a r t u m course, amniotic fluid alpha-fetoprotein and amniotic fluid cell chromosome studies be done to determine if congenital anomalies may be an etiological factor. Introduction Infants with a chromosomM trisomy syndrome usually have a low birth weight (Smith, 1970). This is frequently reflected as fetal growth retardation of a severe degree which is detected unusually early in the antepartum course. Chromosome analysis of the amniotie fluid cells during the late second, or early third, trimester may provide pertinent information that will assist in guiding the obstetrician faced with alternate modes of management during late pregnancy or parturition. Additional studies of the amniotic fluid, usually used for prenatal diagnosis of genetic defects, may provide additional information. An example of such a case is presented.
Case Report S. S. was a 17-year-old Arabic primagravida with a LMP of May 10th giving her an EDC of F e b r u a r y 15th. W h e n she missed her J u n e menstrual period she was given hormone pills of a n undisclosed type to "bring on her period" b u t there was no withdrawal bleeding. The prenatal course was further complicated by a consistently small-for-dates uterus first detected at 16 menstrual weeks and felt to represent either intrauterine growth retardation or incorrect dates, and b y a hemorrhagic cystitis treated with sulfisoxozole when she was 30 weeks pregnant. A sonogram at 30 weeks revealed an abnormally thick posterior placenta, hydramnios, a biparietal diameter of 7.9 cm which verified the menstrual dating of the pregnancy and a chest diameter of 4.9 cm. Repeat sonogram at 32 weeks confirmed b o t h the hydramnios and the disproportion of the cranio-thoracic diameters (they should be approximately equal) with the biparietal diameter being 8.2 cm and the chest diameter 5.0 cm. A t 34 weeks the sonogram gave a biparietM diameter of 9.0 cm and a chest diameter unchanged a t 5.0 cm. An amniogram was done replacing 50 cm s of straw colored amniotic fluid with 50 cm 3 of Renografin-60. The amniogram demonstrated an abnormal left arm with radial aplasia, a malformed ulna, and
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Fig. 1. The fetus at birth demonstrating a large omphalocele and numerous other congenital anomalies (see text for details)
only two recognizable rays in the hand. There was no dye in the gastrointestinal tract on the 24-hour follow-up film. The amniotie fluid cells were cultured and the karyotype (available 3 weeks later) was 47,X¥,18-~. The amniotic fluid alpha-fetoprotein was 2.01 and 3.28 mg% (N ~ 0 - - 0.7 rag%) in two different laboratories (Milunsky and Macri, 1975). Spontaneous rupture of membranes occurred 10 days after the amniogram and on admission to the hospital no fetal heart beat was detectable. An intravenous pitoein induction was begun and after a 19-hour first stage and a 10-minute second stage a stillborn male infant was delivered. At birth the infant weighed 1700 g and was 40 cm long. Positive physical findings (Fig. i) included low set "windswept" ears with a prominent antihelix, a left cleft lip, a cleft palate, a webbed neck, a short sternum, an omphalocele, left radial aplasia, absent distant flexion creases of the fingers of the left hand, bilateral syndactyly of the 2nd and 3rd toes, and "rocker bottom" feet. These findings are compatible with a trisomy 18 syndrome.
Discussion T h i s p a t i e n t was r e f e r r e d to t h e " h i g h r i s k " clinic w i t h a d i a g n o s i s of possible f e t a l i n t r a u t e r i n e g r o w t h r e t a r d a t i o n . T h e h y d r a m n i o s a n d t h e d i s c r e p a n c y bet w e e n t h e b i p a r i e t a l a n d c h e s t d i a m e t e r s also s u g g e s t e d t h e p o s s i b i l i t y o f g e n e t i c d e f e c t s a n d led to t h e a m n i o t i c fluid s t u d i e s a n d a m n i o g r a m . I f r e p a i r a b l e defects c o u l d be d e m o n s t r a t e d it w o u l d be a d v i s a b l e t o h a v e b o t h a p e d i a t r i c i a n a n d a p e d i a t r i c s u r g e o n a v a i l a b l e a t p a r t u r i t i o n , a n d if t h e defects w e r e s e v e r e e n o u g h it
Intrauterine Growth Retardation
351
might influence obstetrical decisions such as whether or not to do a Cesarean section for fetal distress indications. I n the case reported here the hydramnios, the radial aplasia, the lack of fetal swallowing, and the abnormal amniotic fluid alphafetoprotein findings indicated multiple congenital abnormalities, but the etiology (trisomy 18) was not demonstrated until after the fetal demise. An elevated amniotic fluid alpha-fetoprotein level has been associated with the presence of a fetus with severe neural tube defects (Brock and Sutcliffe, 1972 ; Allan et al., 1973; Milunsky et al., 1974). That this test is not specific has been suggested by reports of increased amniotie fluid alpha-fetoprotein levels in association with a fetus with esophageal atresia (Seppala, 1973), congenital nephrosis (Kjessler et al., 1975), omphaloeele (DeBruijn andHuisjes, 1975), or sacrocoeeygeal teratoma (Schmid and Muhlethaler, 1975). The alpha-fetoprotein level has not been raised in association with trisomie fetuses, per se (Macri et al.). The elevated level in this ease is presumed to be related to the presence of the omphalocele. The fact there are now two reported cases of omphalocele associated with an increased amniotie fluid alpha-fetoprotein level suggests that the prenatal diagnosis of the Wiedemann-Beckwith syndrome might be possible. This genetic defect which may be inherited in an autosomal recessive fashion often presents with an omphalocele as one of its components (Smith, 1970). There is some uncertainty how a normal amniotie fluid alpha-fetoprotein level would be interpreted since two fetuses with omphalocele and normal alpha-fetoprotein levels have been reported (Brock et al., 1975). Since isolated omphalocele appears to be of sporadic occurrence there would be no value in determining alpha-fetoprotein levels in future pregnancies of families who have had a previous child with an isolated omphalocele.
There have been a number of recent reports (Nora and Nora, 1973; Janerich et al., 1974; 2kTora and Nora, 1975) suggesting associations between the ingestion of steroid hormones early in pregnancy and subsequent fetal congenital defects. Since there was no evidence of chromosomal mosaicism in our fetus, the nondisjunction had occurred either during gamete meiosis or very early zygote mitosis. This was prior to the hormone medication being prescribed and the medication should not be implicated as an etiological factor. Supported in part by grants from The National Foundation-March of Dimes (CRBS-321) and The National Institute of General Medical Services (GM-19527).
References Allan, L. D., Ferguson-Smith, M. A., Donald, I., et al. : Amniotic-fluid alpha-fetoprotein in the antenatal diagnosis of spina bifida. Lancet 1973 II, 522--525 Brock, D. J. H., Scrimgeour, B., Nelson, M. M.: Amniotic fluid alpha-fetoprotein measurements in the early prenatal diagnosis of central nervous system disorders. Clin. Genet. 7, 163 169 (1975) Brock, D. J. H., Sutcliffe, R. G. : Alpha-fetoprotein in the antenatal diagnosis of aneneephaly and spina bifida. Lancet 1972 II, 197--199 De Bruijn, H. W. A., Huisjes, H. J. : Omphalocele and raised alpha-fetoprotein in amniotic fluid. Lancet 1975 I, 525 526 Janerieh, D. T., Piper, J. M., Glebatis, D. M.. Oral contraceptives and congenital limb-reduetion defects. New Engl. J. Med. 291, 697--700 (1974)
352
M.S. Golbus et al.
Kjessler, B., Johannsson, S. G. D., Sherman, M., et al. : Alpha-fetoprotein in antenatal diagnosis of congenital nephrosis. Lancet 197~ I, 432--433 Macri, J. N., Weiss, P~. R., Golbus, M. S. : Unpublished data Milunsky, A., Alpert, E., Charles, D. : Amniotic fluid alpha-fetoprotein in anencephaly. Obstet. and Gynec. 4], 592--594 (1974) Milunsky, A., Macri, J. : Each provided alpha-fetoprotein data Nora, A. H., Nora, J. J. : A syndrome of multiple congenital anomalies associated with teratogenie exposure. J. Amer. Med. Ass. ]0, 17--21 (1975) Nora, J. J., Nora, A. H. : Birth defects and oral contraceptives. Lancet 197] I, 941--942 Schmid, W., Muhlethaler, J. P. : High ~mniotie fluid alpha-l-fetoprotein in ~ case of fetal saeroeoecygeal teratoma. Hum~ngenetik 26, 353--354 (1975) Seppala, M. S. : Increased alpha fetoprotein in amniotic fluid associated with a congenital esophageal atresi~ of the fetus. Obstet. and Gynec. 42, 613--614 (1973) Smith, D. W. : Recognizable patterns of human malformations. Philadelphia: Saunders 1970 Mitchell S. Golbus, M.D. Department of Obstetrics and Gynecology University of California Medical Center San Francisco, California 94143, USA
Clinical Case Reports Prenatal Diagnosis of Congenital Anomalies in an Intrauterine Growth Retarded Fetus ~ i t c h e l l S. G o l b u s , B r y a n D. H a l l , a n d R o b e r t K . C r e a s y Departments of Obstetrics and Gynecology and of Pediatrics and the Cardiovascular Research Institute, University of California School of Medicine, San Francisco l~eceived November 5, 1975 / F e b r u a r y 3, 1976
Summary. Chromosome analysis of amniotic fluid cells and amniotic fluid alpha-fetoprotein determinations were used to investigate a fetus with severe intrauterine growth retardation in the third trimester. The karyotype was 4 7 , X Y , 1 8 ~ and increased alpha-fetoprotein levels indicated the presence of congenital malformations. We suggest t h a t when severe fetal growth retardation is detected early in the a n t e p a r t u m course, amniotic fluid alpha-fetoprotein and amniotic fluid cell chromosome studies be done to determine if congenital anomalies may be an etiological factor. Introduction Infants with a chromosomM trisomy syndrome usually have a low birth weight (Smith, 1970). This is frequently reflected as fetal growth retardation of a severe degree which is detected unusually early in the antepartum course. Chromosome analysis of the amniotie fluid cells during the late second, or early third, trimester may provide pertinent information that will assist in guiding the obstetrician faced with alternate modes of management during late pregnancy or parturition. Additional studies of the amniotic fluid, usually used for prenatal diagnosis of genetic defects, may provide additional information. An example of such a case is presented.
Case Report S. S. was a 17-year-old Arabic primagravida with a LMP of May 10th giving her an EDC of F e b r u a r y 15th. W h e n she missed her J u n e menstrual period she was given hormone pills of a n undisclosed type to "bring on her period" b u t there was no withdrawal bleeding. The prenatal course was further complicated by a consistently small-for-dates uterus first detected at 16 menstrual weeks and felt to represent either intrauterine growth retardation or incorrect dates, and b y a hemorrhagic cystitis treated with sulfisoxozole when she was 30 weeks pregnant. A sonogram at 30 weeks revealed an abnormally thick posterior placenta, hydramnios, a biparietal diameter of 7.9 cm which verified the menstrual dating of the pregnancy and a chest diameter of 4.9 cm. Repeat sonogram at 32 weeks confirmed b o t h the hydramnios and the disproportion of the cranio-thoracic diameters (they should be approximately equal) with the biparietal diameter being 8.2 cm and the chest diameter 5.0 cm. A t 34 weeks the sonogram gave a biparietM diameter of 9.0 cm and a chest diameter unchanged a t 5.0 cm. An amniogram was done replacing 50 cm s of straw colored amniotic fluid with 50 cm 3 of Renografin-60. The amniogram demonstrated an abnormal left arm with radial aplasia, a malformed ulna, and
350
~I. S. Golbus et al.
Fig. 1. The fetus at birth demonstrating a large omphalocele and numerous other congenital anomalies (see text for details)
only two recognizable rays in the hand. There was no dye in the gastrointestinal tract on the 24-hour follow-up film. The amniotie fluid cells were cultured and the karyotype (available 3 weeks later) was 47,X¥,18-~. The amniotic fluid alpha-fetoprotein was 2.01 and 3.28 mg% (N ~ 0 - - 0.7 rag%) in two different laboratories (Milunsky and Macri, 1975). Spontaneous rupture of membranes occurred 10 days after the amniogram and on admission to the hospital no fetal heart beat was detectable. An intravenous pitoein induction was begun and after a 19-hour first stage and a 10-minute second stage a stillborn male infant was delivered. At birth the infant weighed 1700 g and was 40 cm long. Positive physical findings (Fig. i) included low set "windswept" ears with a prominent antihelix, a left cleft lip, a cleft palate, a webbed neck, a short sternum, an omphalocele, left radial aplasia, absent distant flexion creases of the fingers of the left hand, bilateral syndactyly of the 2nd and 3rd toes, and "rocker bottom" feet. These findings are compatible with a trisomy 18 syndrome.
Discussion T h i s p a t i e n t was r e f e r r e d to t h e " h i g h r i s k " clinic w i t h a d i a g n o s i s of possible f e t a l i n t r a u t e r i n e g r o w t h r e t a r d a t i o n . T h e h y d r a m n i o s a n d t h e d i s c r e p a n c y bet w e e n t h e b i p a r i e t a l a n d c h e s t d i a m e t e r s also s u g g e s t e d t h e p o s s i b i l i t y o f g e n e t i c d e f e c t s a n d led to t h e a m n i o t i c fluid s t u d i e s a n d a m n i o g r a m . I f r e p a i r a b l e defects c o u l d be d e m o n s t r a t e d it w o u l d be a d v i s a b l e t o h a v e b o t h a p e d i a t r i c i a n a n d a p e d i a t r i c s u r g e o n a v a i l a b l e a t p a r t u r i t i o n , a n d if t h e defects w e r e s e v e r e e n o u g h it
Intrauterine Growth Retardation
351
might influence obstetrical decisions such as whether or not to do a Cesarean section for fetal distress indications. I n the case reported here the hydramnios, the radial aplasia, the lack of fetal swallowing, and the abnormal amniotic fluid alphafetoprotein findings indicated multiple congenital abnormalities, but the etiology (trisomy 18) was not demonstrated until after the fetal demise. An elevated amniotic fluid alpha-fetoprotein level has been associated with the presence of a fetus with severe neural tube defects (Brock and Sutcliffe, 1972 ; Allan et al., 1973; Milunsky et al., 1974). That this test is not specific has been suggested by reports of increased amniotie fluid alpha-fetoprotein levels in association with a fetus with esophageal atresia (Seppala, 1973), congenital nephrosis (Kjessler et al., 1975), omphaloeele (DeBruijn andHuisjes, 1975), or sacrocoeeygeal teratoma (Schmid and Muhlethaler, 1975). The alpha-fetoprotein level has not been raised in association with trisomie fetuses, per se (Macri et al.). The elevated level in this ease is presumed to be related to the presence of the omphalocele. The fact there are now two reported cases of omphalocele associated with an increased amniotie fluid alpha-fetoprotein level suggests that the prenatal diagnosis of the Wiedemann-Beckwith syndrome might be possible. This genetic defect which may be inherited in an autosomal recessive fashion often presents with an omphalocele as one of its components (Smith, 1970). There is some uncertainty how a normal amniotie fluid alpha-fetoprotein level would be interpreted since two fetuses with omphalocele and normal alpha-fetoprotein levels have been reported (Brock et al., 1975). Since isolated omphalocele appears to be of sporadic occurrence there would be no value in determining alpha-fetoprotein levels in future pregnancies of families who have had a previous child with an isolated omphalocele.
There have been a number of recent reports (Nora and Nora, 1973; Janerich et al., 1974; 2kTora and Nora, 1975) suggesting associations between the ingestion of steroid hormones early in pregnancy and subsequent fetal congenital defects. Since there was no evidence of chromosomal mosaicism in our fetus, the nondisjunction had occurred either during gamete meiosis or very early zygote mitosis. This was prior to the hormone medication being prescribed and the medication should not be implicated as an etiological factor. Supported in part by grants from The National Foundation-March of Dimes (CRBS-321) and The National Institute of General Medical Services (GM-19527).
References Allan, L. D., Ferguson-Smith, M. A., Donald, I., et al. : Amniotic-fluid alpha-fetoprotein in the antenatal diagnosis of spina bifida. Lancet 1973 II, 522--525 Brock, D. J. H., Scrimgeour, B., Nelson, M. M.: Amniotic fluid alpha-fetoprotein measurements in the early prenatal diagnosis of central nervous system disorders. Clin. Genet. 7, 163 169 (1975) Brock, D. J. H., Sutcliffe, R. G. : Alpha-fetoprotein in the antenatal diagnosis of aneneephaly and spina bifida. Lancet 1972 II, 197--199 De Bruijn, H. W. A., Huisjes, H. J. : Omphalocele and raised alpha-fetoprotein in amniotic fluid. Lancet 1975 I, 525 526 Janerieh, D. T., Piper, J. M., Glebatis, D. M.. Oral contraceptives and congenital limb-reduetion defects. New Engl. J. Med. 291, 697--700 (1974)
352
M.S. Golbus et al.
Kjessler, B., Johannsson, S. G. D., Sherman, M., et al. : Alpha-fetoprotein in antenatal diagnosis of congenital nephrosis. Lancet 197~ I, 432--433 Macri, J. N., Weiss, P~. R., Golbus, M. S. : Unpublished data Milunsky, A., Alpert, E., Charles, D. : Amniotic fluid alpha-fetoprotein in anencephaly. Obstet. and Gynec. 4], 592--594 (1974) Milunsky, A., Macri, J. : Each provided alpha-fetoprotein data Nora, A. H., Nora, J. J. : A syndrome of multiple congenital anomalies associated with teratogenie exposure. J. Amer. Med. Ass. ]0, 17--21 (1975) Nora, J. J., Nora, A. H. : Birth defects and oral contraceptives. Lancet 197] I, 941--942 Schmid, W., Muhlethaler, J. P. : High ~mniotie fluid alpha-l-fetoprotein in ~ case of fetal saeroeoecygeal teratoma. Hum~ngenetik 26, 353--354 (1975) Seppala, M. S. : Increased alpha fetoprotein in amniotic fluid associated with a congenital esophageal atresi~ of the fetus. Obstet. and Gynec. 42, 613--614 (1973) Smith, D. W. : Recognizable patterns of human malformations. Philadelphia: Saunders 1970 Mitchell S. Golbus, M.D. Department of Obstetrics and Gynecology University of California Medical Center San Francisco, California 94143, USA
