Introduction

Pre-eclampsia is a life threatening complication of pregnancy characterised by high blood pressure and proteinuria[1]; it occurs in about 3% of all pregnancies.[2] The aetiology of pre-eclampsia is still obscure, despite many attempts to identify possible causes.

Theoretically, both mother and fetus may contribute to the risk Pre-eclampsia may reflect problems in the close biological interaction between the two subjects.[3] Early stages in the development of pre-eclampsia may be related to poor placental perfusion,[4] possibly due to incomplete invasion of fetal trophoblast cells into the uterus and maternal resistance against such invasion. Maternal symptoms like hypertension and proteinuria may reflect the later stages of fetal and maternal strategies to compensate for poor perfusion. Current knowledge on the epidemiology of pre-eclampsia, like the particularly high risk in first pregnancies, points primarily to an effect of maternal factors.[5 6]

An immunological model for pre-eclampsia has been suggested, and studies indicate that a previous pregnancy with the same father and a longer period of sexual cohabitation with the father before conception reduces the risk.[6 7] One interpretation is that a mother adapts to imprinted antigens from the father.

A substantial risk of recurrence and a tendency of familial clustering of pre-eclampsia is well documented.[8 9] Several models of inheritance have been proposed,[10-12] and specific candidate genes that may account for maternal susceptibility have been identified.[13 14] Recently it was suggested that genetic susceptibility to pre-eclampsia was partly due to maternal inheritance by mitochondrial genes.[15]

We hypothesised that pre-eclampsia is initiated in part by the fetus and in part by maternal susceptibility. Specifically we attempted to identify any contribution from paternal genes in the fetus. We used population based family data from the Medical Birth Registry of Norway and the Central Population Register of Norway to assess these contributions. We also attempted to quantify any contribution to susceptibility from mitochondrial genes, which are transmitted only through the mother.

Subjects and methods

The Medical Birth Registry of Norway comprises all births in Norway Ace 1967 with more than 16 weeks of completed gestation (about 60 000 births a year). Births up till 1992 were included in this study. For all births the national identification number was recorded for mother and child. Father's identification was missing for 8% of the births.

Pre-eclampsia is usually recorded by the registry as a specified diagnosis. The medical birth registration form may also hold information about specific symptoms of pre-eclampsia, such as hypertension, proteinuria, or oedema during pregnancy. Our case definition included all pregnancies with a specified diagnosis of pre-eclampsia and pregnancies recorded with both pregnancy related hypertension and proteinuria.

Record linkage

By internal record linkage with the national identification numbers of mothers and fathers in the birth registry we identified 363 758 pairs of first and second pregnancies when the two children had the same mother and father; 14 266 pairs of pregnancies when the children had the same mother but different fathers; and 26 152 pairs of pregnancies where the children had the same father but different mothers. The reported number of children with either same mother and different fathers or same father but different mothers may be too low because the father of one or both children may not have been recorded.

Firstly, we assessed the proposed immunological hypothesis that several pregnancies with the same father reduce the risk by comparing the risk in second pregnancies of mothers who had the same partner with risk in mothers who changed partner after their first pregnancy. We then studied the risk of recurrence of pre-eclampsia among mothers who had a second pregnancy with the same partner, mothers who had their second pregnancy with a new partner, and mothers whose second pregnancy was fathered by a man who had also fathered a pre-eclamptic pregnancy in another woman.

Analysis

The relative risk of recurrence of pre-eclampsia in a second pregnancy was used to measure the degree of association between pregnancies. These relative risks were estimated by odds ratios.[16] The statistical analyses were based on logistic regression techniques,[17] considering the risk of pre-eclampsia in the second pregnancies as the outcome and pre-eclampsia in the first pregnancy as a covariate, eliminating the effect of parity. We also adjusted for the potential confounding of mother's age and time interval between pregnancies and estimated the effect of calendar time to test for possible changes in diagnosis of pre-eclampsia over time.

Next, we linked the birth registry with the population register, which contains identification numbers of parents of everyone born in Norway after 1952. We used this linkage to identify pairs of mothers in the birth registry who were sisters. Only mothers whose first pregnancy was recorded by the registry were included. Altogether, 61 186 pairs of mothers had same parents. These full sisters served as the reference group. In total 3766 pairs of mothers were half sisters with same mother but different fathers (maternal half sisters) and 4290 pairs were half sisters with same father but different mothers (paternal half sisters).

The odds ratio was again used to measure the degree of association between the risk of the two sisters for pre-eclampsia. Instead of considering only pairs of first and second pregnancies, pairs of any first three pregnancies from two sisters were considered to increase the sample size. To compute a pooled odds ratio for this association we paired all pregnancies for a mother with all pregnancies of her sister. Thus, if a mother A had [a.sub.A] pregnancies with b, cases of pre-eclampsia and her sister B had [a.sub.B]pregnancies with [b.sub.B] cases of pre-eclampsia, this pair of sisters contributed ([a.sub.A] - [b.sub.A]) ([a.sub.B] - [b.sub.B]), ([a.sub.A] - [b.sub.A])[b.sub.B], [b.sub.A] ([a.sub.B]- [b.sub.B]), and [b.sub.A][b.sub.B] pairs of the types (0,0), (0,1), (1,0), and (1,1), respectively, to the computation of the pooled odds ratio. Here, 0 denotes a pregnancy without pre-eclampsia and 1 a pregnancy with pre-eclampsia. We then joined these [a.sub.A] [a.sub.B] pairs with the corresponding pairs from all sister units in a formula for the odds ratio that does not distinguish between pairs of the type (0, 1) and the type (1,0) as the sequence of the mothers A and B is arbitrary,[18] When we computed confidence intervals for the odds ratio we accounted for the statistical dependence between the [a.sub.A][a.sub.B] pairs arising from the same pair of mothers by using a Monte Carlo resampling technique. This strategy gives wider and more correct confidence limits compared with an analysis of all pairs of pregnancies that ignores the dependency.

Results

The strong effect of parity on risk of pre-eclampsia was confirmed in our data (table 1). In first pregnancies the risk was above 3%, slightly increasing with mother's age. The risk was 1.7% among second pregnancies in mothers who had their second pregnancy with the same partner and 1.9 % among second pregnancies in mothers who had changed their partner since the first pregnancy. This small tendency of increased risk in second pregnancy when the mother changed partner was highly significant, even after adjustment for maternal age and calendar year (P [is less than] 0.001).

Table 1 Total risk of pre-eclampsia in first aid second pregnancy for mothers who had two pregnancies with same father and mothers who had two pregnancies with different fathers. Data from Medical Birth Registry of Norway, 1967-92

                                           Mother's 1st pregnancy

                                                     Mean (SD) age
                                                       of mother
Detail               No of pregnancies    Risk (%)      (years),
Pregnancies with
 same father             363 758             3.4      24.0 (3.8)
Pregnancies with
 different fathers        14 266             3.0      21.7 (3.3)

                                Mother's 2nd pregnancy

                                        Mean (SD) age of mother
Detail                Risk (%)                  (years)
Pregnancies with
 same father            1.7                   27.2 (4.1)
Pregnancies with
 different fathers      1.9                   28.5 (4.7)