Introduction

Top Abstract Introduction Subjects and methods Results Discussion References

Pre-eclampsia is a life threatening complication of pregnancy characterised by high blood pressure and proteinuria¹; 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

Top Abstract Introduction Subjects and methods Results Discussion References

The Medical Birth Registry of Norway comprises all births in Norway since 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.

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.

	Results

Top Abstract Introduction Subjects and methods Results Discussion References

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<0.001).

Mothers who had pre-eclampsia in the first pregnancy also had a high risk in their next pregnancy. The risk was 13.1% if she had her second pregnancy with the same partner but dropped to 11.8% if she changed the partner (P =0.12 for difference) (table 2). Mothers without pre-eclampsia in the first pregnancy had a slightly increased risk in the second if they changed partner (1.6% v 1.3%, P=0.03). Mothers had a substantially increased risk in their second pregnancy (2.9%) if they became pregnant by a man who had fathered a pre-eclamptic first pregnancy in another woman. This risk was nearly as high as the average risk among first pregnancies.

These absolute risks may also be expressed as relative risks. Mothers with pre-eclampsia in their first pregnancy were nearly 12 times more likely than other mothers to have pre-eclampsia in their second pregnancy (odds ratio 11.8; 95% confidence interval 11.1 to 12.6). If these women changed partners for their second pregnancy their risk of recurrence was reduced but still substantial (8.2; 5.9 to 11.3), although not significant (P=0.18). Some risk of recurrence was, however, transmitted by the father. Men who fathered one pre-eclamptic pregnancy were nearly twice as likely to father a pre-eclamptic pregnancy in a different woman (1.8; 1.2 to 2.6; after adjustment for parity), regardless of whether she had already had a pre-eclamptic pregnancy or not.

Maternal age, calendar time, and time between pregnancies may confound these risks of recurrence so we used logistic regression models to adjust for these factors. The risk of pre-eclampsia in a second pregnancy increased with maternal age (1.3 per 5 years of increased age; P<0.0001) and with interval between pregnancies (1.5 per 5 years of increased interval between first and second pregnancy; P<0.0001). Calendar time had no significant effect. The estimated risks of recurrence for mothers with the same partners and mothers with different partners were, however, only marginally affected by the adjustment (11.7 and 9.0, respectively). A change in residential municipality was also entered into this model but had no effect on risks of recurrence of pre-eclampsia (P=0.91).

A similar model was used to adjust for maternal age and calendar year when we compared pairs of pregnancies of same mother with different fathers and pregnancies of different mothers with the same father. Maternal age had a similar effect in this analysis, and calendar year of the birth was insignificant. Again, the odds ratios of recurrence were only marginally affected by the adjustment (8.8 for pregnancies of same mother with different fathers and 2.0 for pregnancies of different mothers with same father).

Finally, we estimated the association of risks between pairs of mothers who were either full sisters, half sisters with same mother but different fathers (maternal half sisters), or half sisters with same father but different mothers (paternal half sisters) (table 3). The estimated odds ratio was highest for full sisters and lowest for maternal half sisters (2.2 v 1.6). For paternal half sisters the odds ratio was 1.8. None of the differences between these odds ratios reached significance.

	Discussion

Top Abstract Introduction Subjects and methods Results Discussion References

This study shows a high risk of recurrence of pre-eclampsia among women who had pre-eclampsia in an earlier pregnancy, confirming estimates provided by previous studies.⁹ Our data, however, also strongly suggest that paternal genes (as expressed in the fetus) contribute to the mother's risk of pre-eclampsia. Mothers who were pregnant by a partner who fathered a pre-eclamptic pregnancy in another woman had nearly twice the risk in their own pregnancy. Alternative but less likely explanations are persistent environmental exposures or infections transmitted by the man.

Contribution of fetal genes
The total effect of genes in the fetus on mother's risk of pre-eclampsia is probably larger than the effect of genes from the father because maternal genes in the fetus may also contribute. Genomic imprinting or specific immunological mechanisms that distinguish between maternal and paternal influence may result in maternal genes in the fetus having a different effect from paternal genes.

Contribution of father's genes
Our results are compatible with a recently published model in mice showing that both renin genes from the father and angiotensinogen II genes in the mother may contribute to the risk of hypertension during pregnancy.¹⁹

Contribution of mitochondrial genes
Structural and genetic changes in mitochondria have been reported in patients with pre-eclampsia. ^{15 20} If maternal susceptibility was entirely attributable to mitochondrial genes, women who have same father but different mothers (paternal half sisters) should share no risk because their mitochondrial DNA is unrelated. Our data indicate that there is still some shared risk among paternal half sisters. This is consistent with a smaller study from Iceland,¹¹ which found that the association between risk of pre-eclampsia in grandmothers and granddaughters was independent of whether the connection was through the grandmother's son or daughter. This evidence makes it unlikely that inherited mitochondrial genes play a major part in the aetiology of pre-eclampsia.

Possible biases and confounding
Our data covered all births occurring in Norway between 1967 and 1992. There was no effect of year of birth that could confound our results nor any effect of change in residence. The absence of an effect on risk of change in residence suggests that estimates of risk of pre-eclampsia are neither strongly affected by environmental factors nor by regional differences in diagnosis and reporting.¹⁷ We used well accepted criteria of pre-eclampsia, and apparently the reporting was consistent throughout the whole period. Even though we adjusted for maternal age there is still potential for confounding and bias by other factors. Different unknown social and biological factors may act in families of half siblings and other families.