CORDIS - EU research results

A woman's reproductive experience: Long-term implications for chronic disease and death

Periodic Reporting for period 2 - HealthierWomen (A woman's reproductive experience: Long-term implications for chronic disease and death)

Reporting period: 2021-03-01 to 2022-08-31

Pregnancy complications are known to affect infant health, and in severe situations the child may die during delivery or shortly thereafter, or it may be born with serious handicaps. Sometimes pregnancy complications will also influence maternal health. In Europe, and especially the Nordic countries, few maternal deaths are observed in connection to delivery or in the first weeks after. However, several studies from the US report of increasing early maternal mortality. The WHO definition of maternal mortality is death within the first 42 days after delivery, while studies from the US include maternal deaths for the first year after delivery. We have recently submitted a paper using Norwegian data, covering more than 50 years of population based birth records. In our country, these first year maternal deaths are on its lowest during the last 10 years, opposite to the US trend.
However, there is another aspect of maternal death in relation to pregnancies. Especially during the last 20 years, studies have shown that women who had complications during pregnancies die earlier than other women, mostly due to cardiovascular causes (CVD). The most frequent complications are hypertensive disorders (especially preeclampsia), placental abruption, gestational diabetes, preterm delivery, stillbirths and growth retarded children. One of the first review papers on preeclampsia and its relation to cardiovascular disease (stroke and/or ischaemic heart disease) later in life was published by Bellamy et al (BMJ, 2007), although Chesley published a paper on this relation 40 years earlier (1976). Since this BMJ paper, there has been a long series of reviews covering the major complications. Most estimates vary between 1.5 and 2.5 (Hazard Ratios (HR) of deaths) both linked to stroke and ischaemic heart disease.
After reading the literature, I was surprised that there were few reports on recurrent events in successive pregnancies. My expectation would be that the effects on CVD disease and deaths would be stronger if the mother experienced repeated pregnancies with complications. However, a specific combinations of complications had strong focus – the combination of preeclampsia, preterm birth and a growth retarded fetus (SGA).
When focusing on recurrent events, I discovered another group of mothers with complications, a relatively small group of mothers, “one child mothers”. Also this group have had little attention. In Norway, 85% of women have two or more pregnancies. This means that 15% of women have only one lifetime pregnancy. We found that this group of mothers had a higher risk for early death, even without one of the complications listed above.
We chose to study preeclampsia. Also, we added the effects of preterm delivery. The effects were much stronger than we had expected. We also found that ‘one-child’ interacted strongly with the occurrence of preterm-preeclampsia onto early maternal CVD deaths. Preterm preeclampsia for one-child mothers gave us an almost 10-fold CVD risk (hazard ratio; HR=9.4) while on the other hand, term preeclampsia in women with two or more lifetime pregnancies provided a much lower risk (HR=1.5). Our study was published in BMJ in 2010. We found that ‘one-child’ interacted strongly with the occurrence of preterm-preeclampsia onto early maternal CVD deaths. We learned from that study that there are huge heterogeneities in CVD risk way beyond what is stated by the many review papers.
We followed up on this result, switching to stillbirths and perinatal death, and found a HR of 1.8 i.e. women with an early child loss had 80% higher risk for premature death due to CVD causes. Again we saw huge heterogeneity. Most women with stillbirths in first pregnancy will try for another pregnancy, and with ‘unaffected’, healthy children, the maternal mortality is largely reduced. (Halland et al 2016).
To us, these results suggest that studying only the outcome of first pregnancy is not capturing the dynamics between complete reproduction and maternal long term health.
Studies on complications in pregnancy usually focus one type of complication, and in case of recurrence, also recurrence would be relative to the same condition. Preeclampsia seems to be a complication that holds a strong recurrence risk. Another condition that also hold a strong recurrence is gestational diabetes (GDM).
For all pregnancy complications, the typical picture we have for recurrence of complications between two successive pregnancies is that ALL complications hold a stronger recurrence towards itself, rather than ‘cross-over’ to another complication. However, all the major complications that we have studied are linked to each other, both within one pregnancy and between two successive pregnancies to the mother.
Roberto Romero suggested in 2009 the Great Obstetric Syndrome (GOS). We have adapted this idea by including all 6 types of complications (mentioned earlier) in successive pregnancies, i.e. complete reproduction of women. Our data are unique, and with this we will change the understanding of complications in pregnancy and maternal longevity.
May be the most difficult topic we are addressing is the relation between preeclampsia and gestational diabetes (GDM). They are both conditions that ‘are cured’ by delivery, but at the same time we observe a strong effect onto premature CVD death. Preeclampsia and diabetes may be present in the same pregnancy. An interesting observation is that preeclampsia is strongly related to a fetus born small for gestational age, while a typic child for a GDM mother will be a large fetus given the gestational age. In a study some year ago, we published a paper titled “Is pre-eclampsia more than one disease?”
We concluded: Our results indicate that the heterogeneous expression of pre-eclampsia may represent separate pathogenetic entities, instead of being one fundamental process expressing varying degrees of clinical severity. Thus, placental dysfunction is likely to be the basis for pre-eclampsia associated with low birthweight, preterm delivery, and gestational diabetes. Pre-eclampsia at term, accompanied by offspring that appears unaffected by the condition, may represent a mixture of conditions, ranging from mild pre-eclampsia with moderate placental involvement to hypertensive conditions without placental dysfunction. (Vatten and Skjaerven; 2004).
Our main focus for these early years has been aspects of the link between pregnancy complications and maternal mortality caused by CVD. Worldwide the studies have been based on the complications in first pregnancies. The reason for that is lack of the possibility to link successive pregnancies in many countries.
Above, we have tried to describe the general pattern we see in the relation between complications and longevity for mothers. One child mothers have overall higher mortality than mothers with two or three pregnancies, as long as these latter women do not have complications in the later pregnancies. In fact, for term 1st pregnancies, even with complications, and if the women do not have complications later, their survival is the same as for women without complications in 1st pregnancy.
This type of heterogeneity is one of the main research focus in our project. The work-packages described in the ERC-AdG project are basically all linked to the ideas we developed with the BMJ paper (2012). All focus the relations between complications in pregnancies, and their complicated relation towards premature maternal CVD death. Our research strength lies in the possibilities to envisage a strong heterogeneity in CVD risk for women with complications in pregnancy, either in 1st pregnancy or even in last pregnancy. The costumed strategy to only rely on the first pregnancy and its complications is only the start of a complete reproductive process. Basically, all pregnancies to a woman will count.
We have recently submitted a paper that conclude that women’s last pregnancy holds a stronger effect of a specific complications than the effect the same complication when the complication was related to the first pregnancy. Again, we learn that later pregnancies matters.
Although we mostly focus CVD deaths, we plan to also study cancers. In a previous study we found that preeclampsia protected for Cancer (HR=0.8). We want to follow up on this, inspired by the heterogeneity ideas described above. Effects of smoking in pregnancies on both CVD, as well as Breast Cancer death, may be especially rewarding, since we know that preeclampsia is ‘protected’ among smoking mothers. On the other hand, we know that smoking increase risk for stillbirths, and stillbirth is again linked to preeclampsia.
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