Prenatal diagnosis of neural tube defects

Prenatal diagnosis of neural tube defects VIII. The importance of serum alpha-fetoprotein diabetic pregnant women AUBREY

MILUNSKY,

ELLIOT

ALPERT,

JOHN M.

M.B.,

L.

DONNA

M.R.C.P.,

D.C.H.

M.D.*

KITZMILLER,

RAYMOND

B.CH.,

screening in

M.D.

YOUNGER, K. NEFF,

M.D. Sc.D.

Ho\ton, Illa.\.\cichu.vett.s Maternal serum alpha-f&protein (AFP) screening of routine pregnancy is a valuable tool for the prenatal detection of neural tube defects (NTDs). Against our background experience with >24,900 screened pregnancies, we have studied 411 pregnant insulin-dependent diabetic women. More than a tenfold increase (19.5/1,000) in the frequency of Nl’Ds was observed in the offspring of these diabetic patients (p < 0.009901). Serum AFP values were lower in diabetic than in nondfabetic women. Our data indicate that the normal standard of care for diabetic pregnancy shoufd include serum AFP screening. (AM. J. OBSTET. GYNECOL. 142:1030, 1982.)

MATERNAL SERUM alpha-fetoprotein (AFP) screening has been used extensively in the United Kingdom and to a lesser extent elsewhere’, 2 for the prenatal detection of neural tube defects (NTDs). About nine of 10 children born with NTDs are delivered of women without a history of a previously affected child.Y The ability to detect 79% to 88%’ or more’ NTDs in routine pregnancies through AFP screening (optimally between 16 and 18 weeks’ gestation) has been the basis for initiating these programs. Now that the Food and Drug From the Departments of Pediatrics, Mediciw, and 0bstetric.s and Gynecology, Hanrard Medical School; Genetics Division, Eunice Kenwdy Shtiver Center-; Brigham and Women i Hospital; Joslin Clinic; the Health Sciences Computing Facility and the Department vf Biostnt&cs, Haruard School of Public Health. Support&

Grants

in part by United States Public No. HDo5515 and No. NSl6186.

Received for

publication

Rev&d

September

Accepted

hiovember

May

Health

Service

11, 1981.

29, 1981. 11, 1981.

Reprint requests: Dr. Aubrey Human Genetics, B.U.S.M., Massachusetts 02 I 18.

Milunsky, Center for 80 E. Concord St., Boston,

“Current addwss: Gastrwnterology Divi&n, Department of Mdicin~, Baylor College of Medicine, TaxaT Medicul Center, Houston, Texas 77030.

1030

Administration has published its proposed rules and regulations for such screening programs in the United States,” we would call attention to the importance of screening diabetic women in pregnancy. Since 1975, we have screened more than 24,000 routine pregnancies for AFP by radioimmunoassay, as has been previously described.* As a part of our we identified all 311 pregnant screening program, women with diabetes mellitus who received obstetric care at the Joslin Clinic and the Boston Hospital for Women since 1975. Samples of serum AFP from 322 of these insulin-dependent diabetic women were studied and the results were compared to our previously puhlished ranges for normal pregnancy.4 None of the 322 women had gestational diabetes. Gestational age was assessed in routine pregnancies by menstrual dates and by ultrasound only when uncertainty existed or when abnormality was suspected. In the diabetic women, gestational age was confirmed by ultrasound at 16 to 20 weeks. Results The range of serum AFP in diabetic pregnancy from 14 to 21 weeks is shown in Fig. 1, against the background of our established normal range (0.4 and 2.5 X median for normal pregnancies). The distinctly 0002-9378/82/081030+03$00.30/0~

1982 The C. \‘. Mosby Co.

Volume Number

142 8

lower values for diabetic women is striking. When the curve of medians is smoothed by simple curvilinear regression (Fig. 1), the correlation coefficient between observed AFP in diabetic pregnancy with smoothed AFP is 0.93. When the curve of medians for the normal women is compared to that of diabetic women, we see a very consistent and clear P-week shift, with diabetic women having the same AFP values as the nondiabetic women, only 2 weeks later. Among the progeny of the 411 diabetic women were eight infants born with neural tube defects (NTDs) (seven with anencephaly and one with spina bifida), a rate of 19.5/1,000. This rate compared to the approximately 1 to 2/ 1,000’ NTDs in routine pregnancies in the United States yields a P value <0.0000016 when the rate of 19.5/1,000 is compared to 211,000. Of the 322 diabetic women studied, sera from only three (of the eight) who had of’fspring with NTDs were obtained (all three had high AFP values). Among 11,000 completed nondiabetic pregnancies, we detected 11 NTDs (seven anencephaly and four spina bifida).

Prenatal

-zF it6100 f680* 220

of NTDs.

VIII

1031

0

210

10 Anencephrly)

l’

160

140

120-

60-

40

20

0’

1 14

Comment The occurrence of NTDs in the children of these diabetic women is equivalent to a frequency of almost 20 per thousand births. This would represent at least a tenfold increase in the frequency of NTDs over that in nondiabetic women. Clearly, there is no explanation other than the diabetes for this striking excess of NTDs. Other investigators have reported a specific and striking increase in the frequency of NTDs in the progeny of diabetic women.‘. 8 All eight NTDs occurred in the progeny of women who were being cared for since their first trimester, with none of these women having been referred in because of suspected or known abnormality. Only one of the eight women had had a previous child with a NTD. It is possible that in general, patients referred to the Joslin Clinic have more severe diabetes associated with a higher frequency of KTDs. This would be consistent with other data which we have that show a definitive association between poor diabetic control in early pregnancy and an increased risk of major congenital anomalies.!’ The frequency of 19.3 1,000 for NTDs that we observed almost certainly represents somr selection bias, but, nevertheless, serves to emphasize an undoubted significant increase in NrDs in diabetic pregnant\ A twofold to fourfi,ld increase in the frequency of congenital malformations in the offspring of diabetic women is well established.“’ Any of these defects which leak (e.g., omphalocele) would also be detectable through serum screening. Our observations of low serum AFP in diabetic preg-

diagnosis

15

16

17

1 I6

I 19

I

I

20

21

WEEKS GESTATION Fig. 1. Maternal concentrations of sewn1 AFP between 14 and 21 weeks’ gestation. Shaded zone represents the upper (2.5 x median) and lower (0.4 X median) limits of normal. The bold curves represent the upper, median, and lower limits similarly derived

for

diabetic

pregnancy.

nancy confirm those originally made by Wald and associates.” Thev considered inaccurate menstrual dates to be an unlikely possibility and were unable IO marshal any supportive data that the fetus of a diabetic mother produced less AFP or transferred less to the maternal circulation than did the fetus of a normal mother. They did observe that AFP Gilues were normal in the third trimester of diabetic pregnancy when the typical macrosomia is evident. Perhaps relative intrauterine growth retardation of diabetic fetuses occurs consistently to the end of the second trimester and is associated with a diminished synthesis, secretion, excretion, or transport of AFP. Indeed, Pedersen and Molsted-Peder-sen,” in their ultrasound studies of first-trimester diabetic pregnancy, showed that the fetuses were, on the average, smaller than normal, whereas about a third had even more marked fetal growth retardation. ‘l‘he\~ also suggested that this latter subgroup had poorer- diabetic control and an increased frequencv of congenital anomalies. Notwithstanding any certain explanation of lower serum AFP values in diabetic women, it would be.judicious to use 2.0 or 2.5 x median as the upper limit of normal, but to refer to ;I diabetic pregnancy curve fol

1032

Milunsky

et al.

recommending a second sample of serum for AFP assay. If second-rrimester serum AFP values for diabetic pregnanq are not available, an upper-limit cutoff at 2.0 or 2.3 x median could be used on a normal pregnant!

control group of only 100 who had had Imrmal pwgen?. The soundness of this conclusion can be quesConed on methodologic grounds and. indeed. ih contrary

to

curve,

‘The

carefully

controlled

and,

point.

hut

increased

at a point

equivalent

to ‘L weeks

frequency

of congenital

earlier.

malformations,

specifically. NT& in the offspring of diabetic women soundly supports routine diagnostic ultrasound studies in these patknts. A good case could be made, also, on the

same

basis

for

offering

amniocentesis,

MY assay. in these pregnancies, elevated serum AFP. ‘I‘here are data which show overt

diabetes

CLII~~S

children yion birth

who

have

have a significantly \virh

was based to children

congenital on studies with

at least

fat

even after- only one that

without diabetic glucose tolerance increased risk of bearing

malfbrmations.“’ of ?&I

women

malformations

women

This who

conclu-

had

given

T‘he

been

’ and that

pregnanq tween

IS

retain

the

We

and

have

Kingdom’. indicate

the and

negative

now wish program Kathy

ohservation~.”

studies

effectiveness

screening

should

carlier

are value

clearly

the

of

18 weeks’

right

States.‘,

gestation.

to voluntarilv

become

the

’ Out-

this AFP

L’nitetl

data

IIO\\

of care for diabetic AFP screeniy? be1.1~

opt

a standard

xt'rm~

in both

rhe normal standard should include serunl

and

to c1aril.F

maternal

shown

rnited

Fttrthci-

required

for

plttient

should

or decline

\vhat

lecomm~ildation.

to thank Jill C;orvoy @-al, who and collected the data, and Harris who pl-ovided technical

coordinated I,eo Seman assisr:uncc.

and a matched

REFERENCES

1. L.nited Kingdom Collaborative Study on Alpha-Fetoprotein in Relation to Neural-Tube Defects: Maternal serumalpha-fetoprotein measurement in antenatal screening for anencephalp and spina bifida in early pregnancy, Lancet 1:13”7 -I. 1975. 2. hlilrmskv, .\.. editor: Genetic Disorders and the Fetus: Diagnosis, Prevention, and Treatment, New York, 1979. Plenum Press. 3 Laurence, K. >I.: Fetal malformations and abnormalities, I.ancet 2939. 1974. :. Milunsk\, A., Alpert, E., Neff, R. K., and Frigoletto, D.: Prenatal diagnosis of neural tube defects. IV. Maternal serum alpha-fetoprotein screening, Obstet. Gynecol. 55: 60, 19x0. 3. Part 11. :\lpha-fetoprotein test kits; proposed restrictions and proposed additional quality control and testing requirements Fed. Reg. 45:74158, 1980. 6. Goldstein, A .: Biostatistics: An lntroductorl Text, New York, 1964, The Macmillan Co. 7. Kucera, J.: Rate and type of congenital anomalies among offspring of diabetic women, J. Reprod. Med. 7:61, 197 1. 8. 51ills. J. LA., Baker, L.., and Goldman, A. S.: Malformations

9.

in infants of diabetic mothers occur before the seventh gestational week. Implications for treatment, Diabetes 28:292, 1979. Miller, E., Hare, J. W., Clohert), J. P., Dunn, P. J., Gleason. R. E.. Soeldner. I. S.. and Kitzmiller. 1. L.: Elevated maternal HbA,, in early pregnancy and major congenital anomalies in infants of diabetic mothers. N. Engl. J. Med. 304:1331, 1981. Bennet, P. H., Webner, C., and Miller. .tI.: Congenital anomalies and the diabetic pregnancy, in Pregnant) Metabolism, Diabetes and the Fetus (Ciba Foundation Symposium 63). Amsterdam, 1979, Excerpta Medica. Wald, N. I., Cuckle. H., Boreham, I., Stirrat. G. M.. and Turnbull:A. C.: Maternal serum ilpha-fetoprotein and diabetes mellitus, Br. J. Obstet. Gynaecol. 8&101, 1979. Pedersen. I. F.. and M&ted-Pedersen. L.: Early prowth retardation in diabetic preanancv, Br. tied. 1. l:iXf1979. Navarrete, V. N ., Roja;, CYE.. Aiger, C. K.. &d Paniagua, H. E.: Subsequent diabetes in mothers delivered of a malformed infant, Lancer 2:993, 1970. Comess, L. J., Bennett, P. H., Man, M. B.. Burch, T. A., and Miller, M.: Congenital anomalies and diabetes in the Pima Indians of i\rizona, Diabetes l&47 1, 1969. .J

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