RE: "PARITY AND THE RISK OF DOWN’S SYNDROME"

Maurizio Clementi1, Sebastiano Bianca2 and Romano Tenconi1

1 Genetica Clinica ed Epidemiologica, Dipartimento di Pediatria, Padova, Italy
2 Registro ISMAC, Catania, Italy

Doria-Rose et al. (1) recently examined parity as a risk factor for Down’s syndrome and concluded that their data support an association between parity and Down’s syndrome at any age. However, as Chan (2) pointed out in the invited commentary that accompanied this Journal article, the Doria-Rose et al. paper suffers from some limitations, such as ascertainment of Down’s syndrome births and lack of data on prenatal diagnosis.

The association between parity and Down’s syndrome has been investigated in the past to identify an additional risk factor for trisomy 21. However, the results were contradictory, and it still remains unclear whether parity plays a role in determining trisomy 21. In general, major criticisms concerning studies on parity and Down’s syndrome have been related to the maternal age truncation effect, different rates of accessing the prenatal diagnosis of multiparous women, and inclusion of terminations of pregnancy in the analysis.

In 1999, we conducted a study (3) on this topic with data from two congenital malformation registries operating in northeast Italy (NEI) and Sicily (ISMAC), and we used the same methodology. All liveborns and stillborns affected by Down’s syndrome are registered within 7 days of birth, and, since 1988, terminations of pregnancy are registered in NEI. During the study period, an overall 716,939 consecutive liveborns and 114,726 consecutive stillborns were listed in the two registries. The study sample consisted of 1,088 consecutive newborns (1,063 (97.7 percent) liveborns and 25 (2.3 percent) stillborns) and 169 consecutive fetuses, all affected by Down’s syndrome; information regarding parity and maternal age was available for 1,052 (97 percent) and 159 (94 percent) cases, respectively.

To reduce the truncation effect, we analyzed our data by 2-year and 5-year intervals, and, depending on their size, the two samples were grouped into 13 and six age classes, respectively, to estimate the effects of parity independently of the mother’s age. Parity in both samples was grouped into three different classes: I (primiparous), II (multiparous; parity of two to four), and III (multiparous; parity of more than four). By definition, spontaneous abortions were not included.

To estimate birth prevalence, the number of terminations of pregnancy was multiplied by 0.74, that is, the probability that a Down’s syndrome fetus will survive to birth (4). Thus, the overall termination-adjusted birth prevalence of Down’s syndrome in this study was 1.46 per 1,000.

In both the NEI and ISMAC series, we found a significantly increased risk of having a Down’s syndrome child for multiparas 35 years of age or older. In the ISMAC sample only, a significantly reduced risk for primiparas was found at all ages.

Our data confirm a higher risk of a Down’s syndrome child limited to only those women with a parity of more than four. However, because this effect is evident for women only 35 years of age or older, its practical impact is null because these women are usually offered prenatal diagnosis in any case. However, understanding the mechanisms involved, if this association is true, is very intriguing and could stimulate scientific studies allowing better knowledge of the nondisjunction mechanisms.

REFERENCES

  1. Doria-Rose VP, Kim HS, Augustine ET, et al. Parity and the risk of Down’s syndrome. Am J Epidemiol 2003;158:503–8.[Abstract/Free Full Text]
  2. Chan A. Invited commentary: parity and the risk of Down’s syndrome—caution in interpretation. Am J Epidemiol 2003;158:509–11.[Free Full Text]
  3. Clementi M, Bianca S, Benedicenti F, et al. Down syndrome and parity. Community Genet 1999;2:18–22.[CrossRef][Medline]
  4. Hook EB, Topol BB, Cross PK. The natural history of cytogenetically abnormal fetuses detected at midtrimester amniocentesis which are not terminated electively: new data and estimates of the excess and relative risk of late fetal death associated with 47, +21 and some other abnormal karyotypes. Am J Hum Genet 1989;45:855–61.[ISI][Medline]