Skip to main content
  • Research article
  • Open access
  • Published:

Obstetric prognosis in sisters of preeclamptic women – implications for genetic linkage studies



To investigate obstetric prognosis in sisters of preeclamptic women.


We identified consecutive 635 sib pairs from the Birth Registry data of Kuopio University Hospital who had their first delivery between January 1989 and December 1999 in our institution. Of these, in 530 pairs both sisters had non-preeclamptic pregnancies (the reference group), in 63 pairs one of the sisters had preeclampsia and the unaffected sisters were studied (study group I). In 42 pairs both sister's first delivery was affected (study group II). Pregnancy outcome measures in these groups were compared.


Unaffected sisters of the index patients had uncompromised fetal growth in their pregnancies, and overall, as good obstetric outcomes as in the reference group. The data on affected sisters of the index patients showed an increased prematurity rate, and increased incidences of low birth weight and small-for-gestational age infants, as expected.


Unaffected sisters of the index patients had no signs of utero-placental insufficiency and they were at low risk with regard to adverse obstetric outcome, whereas affected sisters were high-risk. Clinically, affected versus unaffected status appears to be clear-cut in first-degree relatives regardless of their genetic susceptibility and unaffected sisters do not need special antepartum surveillance.

Peer Review reports


Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality[1] and the disease carries a tendency towards familial clustering [26]. Although the pattern of inheritance is not yet resolved, investigations into the genetic etiology of preeclampsia have yielded intriguing results implying that genes are responsible for the disease rather than shared environment [7]. Current concepts favor the hypothesis, that preeclampsia results from interplay of multiple genes and the environment, the disease being a polygenic trait with a strong maternal contribution [8]. First-degree relatives are known to have a fivefold increased risk of developing the disease compared with women with no family history of preeclampsia. Women above a certain threshold of this trait manifest the disease, whereas those below the threshold have a normal phenotype [9]. As far as we are aware of, studies looking at the obstetric outcome in unaffected sisters are still lacking. This study was undertaken to evaluate pregnancy outcome in unaffected sisters of preeclamptic women, to find out whether their genetic susceptibility is associated with adverse outcome. Such data is useful not only for scientific but also for counselling purposes.


The study was approved by the Research-Ethics Committee of Kuopio University Hospital.

The total number of deliveries during the study period was 23 772, and of those, 9576 women were primiparous and 14 196 women were multiparous. The study material comprised consecutive 635 sib pairs, both of whom had their first delivery in the Department of Obstetrics and Gynecology, Kuopio University Hospital, between January 1989 and December 1999. The data for this study were prospectively collected, and the case records were retrospectively analyzed. In 530 pairs both sisters had normotensive pregnancy and one sister of each sib pair (the one who gave birth later) was included in the analysis to constitute the reference group. In 63 sib pairs, one of the sisters had preeclampsia in her first pregnancy and study group I was derived from the unaffected sisters. In 42 pairs, both sisters had preeclampsia and one sister of each sib pair was incorporated (the one who gave birth later) to form study group II. All pregnant women were monitored in an identical manner as outpatients until the development of preeclampsia or another pregnancy complication requiring hospitalization. Basic clinical data were collected at prenatal visits and at delivery for all the target population by the team that took care of treatment.

Hypertensive complications of pregnancy were classified as advocated by the U.S. National Institute of Health Working Group on Hypertension in Pregnancy [10]. Preeclampsia wss defined as the development of hypertension and new-onset proteinuria (greater than 300 mg of urinary protein in 24 h) in women with no proteinuria at baseline. For those with a baseline diastolic pressure of 90 mmHg, hypertension was defined as a rise of at least 25 mmHg, measured on two consecutive occasions at least 24 h apart. For those with an initial diastolic pressure of 90 mmHg or above, an increament of at least 15 mmHg was required [11].

For data analysis, the following were used as evidence of fetal compromise: intrauterine death, admission to a neonatal intensive care unit, small-for-gestational -age delivery, low birth weight, prematurity, low Apgar scores at 1 and 5 min, and fetal acidosis at birth. Reference material values for the birth weight percentiles were obtained from own records [12].

Differences between study subjects and the reference group were tested for significance by using X2 statistics or Fisher's exact tests, as appropriate. Student's t-test was used to analyze continuous variables. Differences were considered to be significant when P < 0.05.


The mean maternal age in study group I (± SD) was 24.3 years (± 4.7 years) and it was 25.5 years (± 4.5 years) in the reference group (P = 0.04). In study group II, the mean maternal age was 24.3 years (± 3.4 years) (P = 0.04). Characteristics of women in study groups I and II, who gave birth at our hospital, during the 10-year period are compared against those of the reference group in Table 1. Apart from maternal age, the demographic data investigated in this study were comparable in the three groups.

Table 1 Maternal Risk Factors

Table 2. summarizes the frequencies of various pregnancy and delivery characteristics in the two study groups and in the control group. Preeclamptic women whose sisters also had preeclampsia in their first pregnancy underwent cesarean deliveries more often than the control women. However, the rate of vaginal operative deliveries did not differ between the groups. 1.59% of the women in study group I and 0.57% in the reference group had pregnancy-induced hypertension. Otherwise, the pregnancy characteristics were similar in these groups.

Table 2 Pregnancy and Delivery Characteristics

The mean birth weight (± SD) among those delivering at term (after 37 gestational weeks) was 3530 g (± 444 g) in the reference group, 3471 g (± 378 g) in study group I (P = 0.33) and 3398 g (± 494 g) in study group II (P = 0.12). Table 3. shows the pregnancy outcome measures in the reference and study groups. As expected, the incidence of prematurity (P < 0.001), low birth weight (P < 0.001) and small-for-gestational age infants (P = 0.06) was increased in sisters affected by preeclampsia (group II), whereas there was no difference in the rate of fetal death between the groups. Obstetric outcomes in study group I were comparable with those in the reference group.

Table 3 Obstetric Outcomes


The main finding of this study was, that unaffected sisters of preeclamptic index patients had normal outcomes in their first pregnancy, the course of pregnancy being comparable to that in the general obstetric population. Basically, no differences were noted in the reproductive risk factors of the groups studied. Among affected sisters, the rate of prematurity, low birth weight, and small-for-gestational age infants were increased, as expected [13]. Although a trial of this size cannot reliably detect differences in rare complications, such as neonatal death ascribable to familial risk, the number of cases in the present study is sufficient to make statistically valid comparisons with regard to commonly used outcome variables. However, it is not known whether similar changes are present in unaffected first-degree relatives during pregnancy because of their genetic susceptibility to preeclampsia which in turn would adversely affect their pregnancies. Any adverse effect was undetectable in the present study, since only one (1.59%) of the unaffected women with a first-degree relative with preeclampsia developed pregnancy-induced hypertension and there were no signs of chronic utero-placental insufficiency.

Caruso et al. demonstrated in their study of pregnant women that preeclampsia, but not gestational hypertension, was characterized by atherogenic metabolic features similar to those of patients with insulin resistance syndrome, such as lower insulin sensitivity, and higher levels of triglycerides and nonesterified fatty acids [14]. Thus, the clinical definition seems appropiate, and in clinical work, preeclampsia phenotypes defined by other criteria such as glomerular endotheliosis are too difficult to assess routinely [15].

Preeclampsia is a heterogeneous disorder, and women with various medical problems are at risk of developing the disease [1618]. Many of these conditions are known to be governed by some components which may have genetic origin, e.g. genetic risks associated with essential hypertension and diabetes mellitus, and mitochondrial abnormalities, which in turn, are characterized by microvascular disease [1921]. Our results may be useful in counselling patients and their first-degree relatives. Genetic susceptibility to preeclampsia has minor effects, if any, on pregnancy outcome in first-degree relatives of index patients, if they do not develop the disease. Basically, routine antenatal care in which blood pressure and urine dipstick are checked each visit is sufficient for women with an affected sister and there is no need to initiate special fetal monitoring in these pregnancies. Accordingly, the results may have implications in genetic linkage studies [22], since the phenotype in unaffected sisters of preeclamptic women can be considered normal in terms of clinical outcome measures. In other words, this observation provides justification to stratify pregnant women into the categories of affected and unaffected individuals which is the current practice in clinical work [23].


The sisters of preeclamptic women are at low risk with regard to adverse pregnancy outcome if they do not develop preeclampsia. They have pregnancy outcomes comparable to that of the general obstetric population, and routine antenatal follow-up and management is sufficient in these cases. Although the etiology and pathogenesis are as yet unresolved, the complexity of the disease phenotype supports the theory of a polygenic trait. Women belonging to the liability group could have considerable pathological changes in their placental tissue without developing the maternal syndrome, and this might explain, why such changes are occasionally observed in fetal growth retardation, which has also been called normotensive preeclampsia [24]. However, in the present study genetic liability in unaffected first-degree relatives of preeclamptic index patients was not associated with any clinical phenotype


  1. Kaunitz A, Hughes J, Grimes D, Smith J, Rochat R, Kafrissen M: Causes of maternal mortality in the United States. Obstet Gynecol. 1985, 65 (5): 605-612.

    CAS  PubMed  Google Scholar 

  2. Chesley L, Cosgrave R, Annitto L: Pregnancy in sisters and daughters of eclamptic women. Path Microbiol. 1961, 23: 662-666.

    Google Scholar 

  3. Chesley L, Annitto L, Cosgrave R: The familial factor in toxemia of pregnancy. Obstet Gynecol. 1968, 32: 303-311.

    CAS  PubMed  Google Scholar 

  4. Cooper D, Liston W: Genetic control of severe pre-eclampsia. J Med Genet. 1979, 16: 409-416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chesley L, Cooper D: Genetics of hypertension in pregnancy: Possibly single gene control of preeclampsia and eclampsia in decendants of eclamptic women. Br J Obstet Gynaecol. 1986, 93: 898-908.

    Article  CAS  PubMed  Google Scholar 

  6. Lie R, Rasmussen S, Brunborg H, Gjessing H, Lie-Nielsen E, Irgens L: Fetal and maternal contributions to risk of pre-eclampsia: population based study. BMJ. 1998, 1343-1347. 316

  7. Sibai BM: Prevention of preeclampsia. A big disappointment. Am J Obstet Gynecol. 1998, 179: 1275-1278.

    Article  CAS  PubMed  Google Scholar 

  8. Arngrimsson R, Björnsson H, Geirsson R: Analysis of different inheritance patterns in preeclampsia/eclampsia syndrome. Hypertens Pregnancy. 1995, 14: 27-38.

    Article  Google Scholar 

  9. Falconer D: The inheritance of liability to certain diseases, estimated from the incidence among relatives. Ann Hum Genet. 1965, 2: 51-76.

    Article  Google Scholar 

  10. National High Blood Pressure Education Program: Working Group report on high blood pressure in pregnancy: Consensus report:. Am J Obstet Gynecol. 1990, 163: 1691-1712.

    Article  Google Scholar 

  11. Brown M, de Swiet M: Classification of hypertension in pregnancy. Baillieres Clin Best Pract Obstet Gynaecol. 1999, 13 (1): 713-726.

    Google Scholar 

  12. Heinonen S, Taipale P, Saarikoski S: Weights of placentae from small-for-gestational age infants revisited. Placenta. 2001, 22 (5): 399-404. 10.1053/plac.2001.0630.

    Article  CAS  PubMed  Google Scholar 

  13. Mostello D, Catlin T, Roman L, Holcomb W, Leet T: Preeclampsia in the parous woman: who is at risk?. Am J Obstet Gynecol. 2002, 187 (2): 425-429. 10.1067/mob.2002.123608.

    Article  PubMed  Google Scholar 

  14. Caruso A, Ferrazzani S, De Carolis S, Lucchese A, Lanzone A, De Santis L, et al: Gestational hypertension but not preeclampsia is associated with insulin resistance syndrome characteristics. Hum Reprod. 1999, 14 (1): 219-223. 10.1093/humrep/14.1.219.

    Article  CAS  PubMed  Google Scholar 

  15. Fisher K, Luger A, Spargo , Lindheimer M: Hypertension in pregnancy: clinical-pathological correlations and remote prognosis. Medicine. 1981, 60 (4): 267-276.

    Article  CAS  PubMed  Google Scholar 

  16. Rasmussen S, Irgens L, Albrechtsen S, Dalaker K: Predicting preeclampsia in the second pregnancy from low birth weight in the first pregnancy. Obstet Gynecol. 2000, 96 (5 Pt): 696-700. 10.1016/S0029-7844(00)01008-5.

    CAS  PubMed  Google Scholar 

  17. Livingston J, Sibai B: Chronic hypertension in pregnancy. Obstet Gynecol Clin North Am. 2001, 28 (3): 447-463.

    Article  CAS  PubMed  Google Scholar 

  18. Taylor D: The epidemiology of hypertension during pregnancy. In: Handbook of Hypertension. Hypertension in Pregnancy. Edited by: Rubin PC. 1988, Amsterdam: Elsevier, 10: 223-240.

    Google Scholar 

  19. Thorbergsen T, Öian P, Mathiesen E, Borud O: Pre-eclampsia, a mitochondrial disease?. Acta Obstet Gynecol Scand. 1990, 68: 45-48.

    Google Scholar 

  20. Roberts J, Redman C: Pre-eclampsia: more than pregnancy-induced hypertension. Lancet. 1993, 341: 1447-1451. 10.1016/0140-6736(93)90889-O.

    Article  CAS  PubMed  Google Scholar 

  21. Arngrimsson R, Geirsson R: Analysis of different inheritance patterns in preeclampsia/eclampsia syndrome. Hypertens Pregnancy. 1995, 14 (1): 27-38.

    Article  Google Scholar 

  22. Arngrimsson R, Sigurardottir S, Frigge M, Bjarnadottir R, Jonsson T, Stefansson H, et al: A genome-wide scan reveals a maternal susceptibility locus for pre-eclampsia on chromosome 2p13. Hum Mol Genet. 1999, 8: 1799-1805. 10.1093/hmg/8.9.1799.

    Article  CAS  PubMed  Google Scholar 

  23. Moses E, Lade J, Guo G, Wilton A, Grehan M, Freed K, et al: A genome scan in families from Australia and New Zealand confirms the presence of a maternal susceptibility locus for pre-eclampsia, on chromosome 2. Am J Hum Genet. 2000, 67: 1581-1585. 10.1086/316888.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Brosens I, Dixon H, Robertson W: Fetal growth retardation and the arteries of the placental bed. Br J Obstet Gynaecol. 1977, 84: 656-663.

    Article  CAS  PubMed  Google Scholar 

Pre-publication history

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Nonna Heiskanen.

Additional information

Competing interests

None declared.

Authors' contributions

NHE participated in the design of the study and performed the statistical analysis and drafted the manuscript.

SHE participated in the design of the study, drafted the manuscript and coordination.

PKI conceived of the study and participated in its desingn and coordination.

All authors has read and approved the final manuscript.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Heiskanen, N., Heinonen, S. & Kirkinen, P. Obstetric prognosis in sisters of preeclamptic women – implications for genetic linkage studies. BMC Women's Health 3, 1 (2003).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: