Case Studies from the Wisconsin
Stillbirth Service Program - #1

Richard M. Pauli, M.D., Ph.D.

Beginning with this issue we have decided that we will occasionally present case studies that we think are instructive and illustrative. As with those presented in this issue, some will focus on a particular topic, while in other instances two or three interesting but utterly unrelated examples will be explored. The series of cases presented here center on issues related to neural tube defects.

Let us know whether you think these case synopses are or are not of value to you.

All of the evaluations, therefore, confirmed that this baby had isolated, typical anencephaly. Mildly unusual facial features are almost uniformly seen as well — ear anomalies because of abnormal innervation to the auricularis

muscles, prominent globes because of anomalous development of the calvarial base and so forth.

Figure 1 - Anencephaly

Family history was disconcerting. One close relative had had a baby with anencephaly born within a year of this birth. There were, in addition, two less well documented instances of neural tube defects within the family.

Comment: Anencephaly is one of the birth defects which arises early in gestation secondary to failure of closure of the neural tube. Such neural tube defects also include abnormalities of closure along the entire dorsal axis, including various forms of meningomyelocele (spina bifida). Neural tube defects are known to have a multifactorial origin (effects of large number of small, additive genes and certain environmental triggers). It is not terribly surprising, although relatively unusual, that the family history included other individuals with neural tube defects (because of the genetic determinants that contribute to the susceptibility for these birth defects). Likewise, these genetic determinants are why subsequent pregnancies would have a substantially increased risk for babies either with anencephaly or spina bifida — a risk in the vicinity of 3-5%.

Recently it has been demonstrated that folate deficiency is one powerful environmental trigger which predisposes to the development of neural tube defects. On this basis it is recommended that any woman who has given birth to one baby with either anencephaly or spina bifida be supplemented preconceptually with high dose folate. Preconceptual initiation of the supplementation is necessary since neural tube closure is normally complete prior to the time in pregnancy when a woman will recognize that the pregnancy exists. Such preconceptual supple-mentation (continued throughout the first trimester) seems to reduce the risk for recurrence by 50-70%. The currently generally accepted recommendation is for supplementation with 4 mg of folate daily under these circumstances (in contrast to the usual recommendation of 0.4 mg of additional folate daily in those without such a history).

Case 2:
A female infant was stillborn at 20 weeks gestation. Three prior prenatal visits were routine and with no unusual findings. At the time of presentation results of maternal serum alphafetoprotein testing were not yet available. Absence of fetal movement precipitated ultrasound assessment which confirmed absence of fetal cardiac activity and, in addition, showed an abnormal fetal head, features of which were thought to be entirely compatible with anencephaly. Following delivery, very limited assessment was elected, apparently because of the obvious anencephaly, including only limited post mortem evaluation and attempted chromosome assessment. Tissues for chromosome evaluation were contaminated and therefore karyotypic analysis was not possible. The examining pathologist reported the presence of ‘typical’ anencephaly. In addition, however, there were "maldeveloped fourth and fifth fingers [of the right hand] and maldeveloped second and third fingers [of the left]". No photos or radiographs were obtained. Cursory internal examination showed only maceration. The placenta was not assessed for integrity of the amnion.

Comment: Deciding how to counsel this family is problematic because of the assumption that the infant had ‘obvious’ anencephaly. One of the most common imitators of anencephaly is Early Amnion Disruption, in which rupture of the amniotic sac can result in adhesions to the early developing calvarium, resulting in an anencephalic-like picture, but in which amniotic strands can also result in amputations or syndactyly of the fingers. Clearly distinguishing anencephaly and Early Amnion Disruption is germane to counseling a family. Unlike the multifactorial origin of anencephaly described above, Early Amnion Disruption is sporadic with no implied risk for recurrence (and for which folate supplementation would be of no relevance).

Making assumptions about diagnoses based on superficial assessments is a risky business. Things that look alike may have diverse causes.

Case 3:
This female infant was delivered at 30 weeks gestation. The pregnancy was uncomplicated until there was acute development of oligohydramnios. Ultrasound at that stage was ambiguous, in part because of the severe polyhydramnios and in part because of difficulty

Figure 2 - Iniencephaly

assessing the orientation of the fetus. Labor developed spontaneously and the infant was liveborn but died within the first hour after delivery. Initial examination showed obvious malformations. Clinical examination after her death showed limitation of movement of the fingers, a short trunk, a short neck and a markedly hyperextended head as well as a cleft palate. Photographs also demonstrated low set ears and an exceedingly small mandible. Radiographs showed 90° of retroflexion of the neck and cervical vertebral fusions, while internal postmortem assessment did not demonstrate additional abnormalities.

Comment: All of the baby’s features are utterly typical for a disorder termed iniencephaly. This is a rare process for which considerable controversy persists regarding how it develops. A consensus seems to be developing that the primary abnormality is, in fact, a cervical neural tube defect. Can all of this baby’s features be explained? The external physical features (retroflexion, short neck, facial features) are typical for iniencephaly. Cleft palate is a common accompaniment of all craniad neural defects. Severe central nervous system malformations can non-specifically result in limitations of joint movement (central nervous system forms of arthrogryposis multiplex congenita).

As different as this baby seems from that shown in case 1, both derive from an exceedingly similar embryopathologic process. Both are neural tube defects. Both are multifactorial genetic processes. Recurrence in both likely can be minimized with folate supplementation.

Final comments:
Folate and Birth Defects. The recognition that folate deficiency contributes to the risk of neural tube defects has revolutionized the way we think about these anomalies. Not only can we reduce the risk for recurrence through high dose folate supplementation, but, in addition, the primary occurrence of neural tube defects can be reduced substantially (at least by half). Most of you are likely familiar with the folate campaign carried on throughout our State last year. Many of you may know as well that now fortified flours are supplemented with folate as a public health policy.

Not only has the recognition that folic acid deficiency is one of the environmental ‘triggers’ of a common birth defect affected our thinking about that defect, it has profoundly altered the way many of us view birth defects in general. It implies that, if the right triggers can be identified then many, common malformations can be truly prevented in a primary sense.

Stillbirths and Neural Tube Defects. These three cases, I hope, drive home some simple points: 1. any stillborn should be assessed carefully and should have a full evaluation done (see case 2); 2. things that look alike (e.g. cases 1 and 2) may not be the same and may have very different implications for families; 3. things that look very different (e.g. cases 1 and 3) may have the same underlying embryopathogenetic cause.

Further Reading*
Holmes L, Harris J, Oakley GP, Friedman JM (1998) Teratology Society consensus statement on use of folic acid to reduce the risk of birth defects. Teratology 55:381.

Butterworth CE, Bendich A (1996) Folic acid and the prevention of birth defects. Annual rev nutrit 16:73-97.

Morocz I, Szeifert GT, Molnar P, Toth Z, Csesei K, Papp Z (1986) Prenatal diagnosis and pathoanatomy of iniencephaly. Clin genet 30:81-86.

*Copies of these and other relevant articles are available for personal use by request from WiSSP.

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