In Depth

Fetal Deaths At Less Than 20 Weeks Gestation

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

Introduction. Most intrauterine deaths occur during the first trimester. Far fewer are miscarried in the 13-20 week span of early mid-gestation. Each of these circumstances, as well as stillbirth per se (death at 20 weeks or more gestation), have different underlying causes and, hence, demand different methods of evaluation. This In Depth tackles the issue of how intrauterine deaths prior to twenty weeks should be assessed.

Pre-early losses. Recent studies, using sensitive methods to detect exceedingly early hormonal changes, have allowed estimation of the proportion of pregnancies which are spontaneously aborted prior to implantation (and prior to the time when pregnancy is normally detected). These studies suggest that about 20-25% of all pregnancies normally go unrecognized and are aborted in the first three weeks after conception. Little information is available on the causes of these subclinical pregnancy losses. Such losses, when recurrent, are frequently misinterpreted as being difficulties in conceiving. Probably many of these recurrent losses arise from intrinsic abnormalities of the early embryo and sometimes this may be secondary to chromosomal aberration. It is for that reason that cytogenetic studies are appropriate in couples with apparent subfertility of long duration.

Early losses. Spontaneous abortion of recognized pregnancies has been far better studied. Intrauterine death between the time of pregnancy recognition and twelve gestational weeks are usually classed together. In addition to the pre-early losses, epidemiological studies have demonstrated that about 20-25% of all recognized pregnancies are miscarried in the first trimester. Studies of cause have demonstrated that between 50 and 75% of such embryos have demonstrable cytogenetic abnormalities. Most of these arise from accidental, nondisjunctional processes in egg or sperm formation. The most common resulting abnormalities are various trisomies (with the most common being trisomy 16 which is never seen in liveborns) and monosomy X. Triploidy, which results from simultaneous fertilization by two sperm, is also very common in this group.

What evaluation is justifiable following such an early loss? Given that more than a quarter of recognized pregnancies end in miscarriage, extensive assessment is probably not warranted. Morphological evaluation appears to be of little benefit in assessing possibilities for recurrence. One could argue that cytogenetic evaluation of the products of conception (only) can provide information helpful to the family. About 50-60% of the time a cytogenetic abnormality without any risk for recurrence will be demonstrated. And, paradoxically, empiric recurrence risks are less in next pregnancies when such a cytogenetic aberration is demonstrated (presumably because these chromosome problems are truly chance events while other causes — genetic or maternal — may imply greater risk for a similar outcome in subsequent pregnancies.) Rarely, a translocational aberration will be discovered which implies very high risks in next pregnancies. While justifiable, routine cytogenetic testing in these circumstances has not become a usual standard of care.

Only when three or more first trimester spontaneous abortions have occurred do most physicians feel that comprehensive assessment is justified. This justification is principally numerical. That is, if spontaneous abortions arise once in every 4 pregnancies, then the probability of occurrence in anyone is: 1/4 for one miscarriage; 1/16 for two miscarriages; 1/64 for three (consecutive) miscarriages. Thus, after three miscarriages the 2% probability of this arising purely by chance is low enough that specific causes should be sought. Such assessments usually include chromosomal evaluation of both parents, hormonal, endocrinologic and immune assessment of the mother, consideration of structural uterine studies etc.

Late losses (stillbirth). As we have summarized elsewhere, comprehensive, nonselective and intensive search for fetal causes is justifiable in those babies who die in utero at 20 weeks and beyond. Through thorough assessment about 40% will be found to have a specific identifiable cause, of which around 60% of those causes (25% overall) will be of fetal origin.

Because WiSSP is fundamentally a service program we have accepted assessments done on fetuses of less than 20 weeks gestation. However, we have not previously critically assessed whether a different protocol is appropriate under those circumstances.

Intrauterine Deaths between 13 and 20 Weeks. Relatively few studies have examined the causes of fetal deaths during this gestational period (see, for example Gaillard et al. Arch pathol lab med 117:1022, 1993). For lack of study the causes of abortion during this period are not nearly so well defined.

Those studies which have been completed suggest that the underlying causes of such intrauterine deaths are distinguishable both from those causing early miscarriage and from those resulting in stillbirth. Furthermore, two groups or classes of causes seem to be present and seem to be distinguishable based upon the length of retention (that is, the degree of maceration) following intrauterine death. Infections seem to be exceedingly frequent, probably accounting for around 40-70% of these losses. Furthermore, chorioamnionitis most often appears to precipitate labor very shortly after death of the fetus. Therefore non-macerated (and minimally macerated) fetuses who are miscarried at this gestational age are very likely to either have an infectious cause or to have no demonstrable cause regardless of how thorough an assessment is completed. In contrast, fetal causes of all sorts most often do not result in early expulsion. Therefore, finding fetal causes which could be of relevance with respect to subsequent recurrences is far more likely in the significantly macerated fetus. Furthermore, it is in just such macerated fetuses that morphological concomitants of fetal processes are most difficult to recognize.

Finally, one must decide how aggressively specific agents of infectious causes should be sought. Data are scanty concerning this question. Most often, post-delivery cultures will demonstrate Mycoplasma/ureaplasma, Streptococcus type B, E. Coli, and a variety of other potential pathogens. Culture information may be of some benefit in maternal management and, primarily for this purpose is justifiable. There is no evidence that routine viral culturing is cost effective.

On the basis of this information, we suggest that a protocol for evaluation of fetuses dying at 13 through 19 weeks have a primary branch point based upon severity of maceration (length of retention). A suggested protocol is shown on the previous page.

Further Reading*
Cowchock FS, Gibas Z, Jackson LG (1993) Chromosome errors as a cause of spontaneous abortion: the relative importance of maternal age and obstetric history. Fertil steril 59:1011-1014.

Gaillard DA, Paradis P, Lallemand AV, Vernet VM, Carquin JS, Chippaux CG, Visseaux-Coletto BJ (1993) Spontaneous abortions during the second trimester of gestation. Arch pathol lab med 117:1022-1026.

Goldenberg RL, Mayberry SK, Copper RL, Dubard MB, Hauth JC (1993) Pregnancy outcome following a second-trimester loss. Obstet gynecol 81:444-446.

Hakim RB, Gray RH, Zacur H (1995) Infertility and early pregnancy loss. Am j obstet gynecol 172:1510-1517.

Kalousek DK, Pantzar T, Tsai M, Paradice B (1993) Early spontaneous abortion: Morphological and karyotypic findings in 3,912 cases. Birth defects OAS 29[1]:53-61.

Pauli RM, Reiser CA, Lebovitz R, Kirkpatrick SJ (1994) Wisconsin stillbirth service program: I. Establishment and assessment of a community-based program for etiologic investigation of intrauterine deaths. Am j med genet 50:116-134.

Pauli RM, Reiser CA (1994) Wisconsin stillbirth service program: II. Analysis of diagnoses and diagnostic categories in the first 1,000 referrals. Am j med genet 50:135-153.