Original cartoon by Alex Martin
Source: Original cartoon by Alex Martin

Problems with high blood pressure (hypertension) afflict many pregnancies, counting alongside abortion and hemorrhage as a major cause of maternal death. Worldwide, more than 18% of pregnancies are affected, roughly half involving pre-eclampsia  —  a syndrome marked by excess protein in the urine and swollen limbs (oedema). This typically arises after mid-pregnancy and increases in severity until birth, which is the only effective remedy. In some cases, especially if untreated, the condition develops into full-blown, life-threatening eclampsia with seizures and even coma. Roughly one in ten pre-eclampsia cases develop into the more serious condition of eclampsia. (That word, derived from a Greek root meaning “shine forth”, refers to characteristic visual flashes experienced by sufferers.)

Global causes of maternal death — 1997-2007
Source: Adapted from a figure provided by UNICEF’s ChildInfo website (http://www.childinfo.org/facts_1038.htm)

Women older than 35 are at greater risk of pre-eclampsia, as are those with obesity, diabetes or previous high blood pressure. It is also more common with first pregnancies and multiple births. Well-designed prenatal care programmes include routine screening for pre-eclampsia.

Basic facts about pre-eclampsia

Although overt symptoms typically emerge after mid-pregnancy, pre-eclampsia is seemingly triggered very early. A 2005 paper by Hai‐Tao Yuan and colleagues aptly describes it as a 2‐stage disease: symptomless early processes in the placenta followed several months later by diagnosable pre-eclampsia. Several factors have been implicated, but it is widely accepted that inadequate development of blood vessels in the early placenta plays a major part, often limiting fetal growth in due course. In fact, significant changes in the womb begin once the egg leaves the ovary. Arteries in the womb’s internal lining lengthen, forming distinctive spirals. The human placenta is very invasive and maternal blood soon surrounds tree-like outgrowths from the outer fetal membrane, permitting direct interchange with blood vessels of the fetus. Maternal white blood cells also abound in the placenta during the first third of pregnancy, reflecting active engagement of the mother’s immune response.

Adapted from illustration in Anatomy of the Human Body (Henry Gray. 1918) by Henry Vandyke Carter, via Wikimedia Commons.
Scheme of human placental circulation
Source: Adapted from illustration in Anatomy of the Human Body (Henry Gray. 1918) by Henry Vandyke Carter, via Wikimedia Commons.

While traveling down the oviduct towards the womb, the fertilized egg develops into a hollow, two-layered ball of cells. The outer layer directly contacts and invades the womb lining, while the inner cell mass develops into the embryo, membranes and blood vessels. In particular, outer layer cells distend and weaken the walls of spiral arteries, such that maternal blood flows unhindered into the space surrounding fetal membrane outgrowths. This crucial modification is diminished in pre-eclampsia and the characteristic blood pressure rise is apparently a mechanism, probably triggered by the fetus, to augment blood flow through the placenta. A thoughtful 1993 review of mother:fetus conflicts during pregnancy by David Haig suggested that pre-eclampsia may amount to an attempt by the fetus to counter insufficiency of the placenta and increase nutrient supply.

Scarce knowledge about the condition in other placental mammals hampers our understanding of the causes of pre-eclampsia in women. Isolated cases have been reported for non-human primates: five great apes and four Old World monkeys. However, a 1979 paper by Amos Palmer and colleagues reported pre-eclampsia, characterized by limb swelling, raised blood pressure and excess urinary protein in six out of 98 pregnancies in a laboratory breeding colony of patas monkeys. As in women, the incidence was also higher with first-time pregnancies. Careful monitoring is needed to recognize symptoms, so the frequency of pre-eclampsia in other primates has probably been underestimated. But perhaps the patas monkey provides an unusual example of late-onset pre-eclampsia among non-human primates. Either way, the lack of any follow-up is regrettable.

Pre-eclampsia and maternal immunity

Proteins of paternal origin in the fetus and placenta challenge a pregnant woman's immune system. Significantly, pre-eclampsia is clearly a “disease of first pregnancy”, being at least twice as frequent with first-time mothers as in subsequent pregnancies. This suggests that a woman’s immune system slowly adapts to proteins from a specific male partner.

Incidence of pre-eclampsia according to type of pregnancy
Source: Adapted from a figure provided by MacGillivray (1958)

Supporting this are several reports that high blood pressure in pregnancy becomes less frequent with increasing duration of a couple’s sexual co-habitation. Pierre-Yves Robillard, who co-authored a landmark 1994 paper based on prospective study of over 1,000 pregnant women in Guadeloupe, has championed this interpretation. Cases of raised blood pressure in pregnancy were examined in relation to the mother’s period of cohabitation with the father before conception. High blood pressure occurred in 12% of first-time mothers but only 5% of mothers with previous pregnancies with the same father. Strikingly, a highly significant decrease in occurrence of high blood pressure accompanied increasing duration of sexual cohabitation before conception, falling from a staggering 40% at 4 months or less to around 5% beyond a year. But the incidence was 24% in women who conceived with a new partner after previous births. Robillard and colleagues concluded that high blood pressure in pregnancy may be more a problem of first fatherhood than of first pregnancy.

Adapted from a figure provided by Robillard et al. (2014)
Incidence of pre-eclampsia according to period of sexual cohabitation.
Source: Adapted from a figure provided by Robillard et al. (2014)

There was no real follow-up until 2002. But then Rolv Skjaerven and colleagues reported that the risk of pre-eclampsia may depend on the interval between pregnancies rather than on length of cohabitation. A longer gap between births is likely to follow any partner change. Analysis of data for almost 1,500,000 pregnancies confirmed previous findings: pre-eclampsia occurred in almost 4% percent of first pregnancies, but less than 2% of second and third pregnancies. But it also revealed that the risk of pre-eclampsia rises with time elapsed since the previous birth, regardless of partner change. However, long birth intervals may be linked to less frequent coitus, so sexual priming could still be a key factor.

Evidence for sexual priming

In 1983, Jillian Need and colleagues reported an analysis of almost 600 cases of artificial insemination with semen from unfamiliar donors. The overall incidence of pre-eclampsia was two to three times higher than in the general population. And no difference was seen between first-time and subsequent pregnancies. Reinforcing the interpretation that a reaction to unfamiliar proteins is involved, similar findings have been reported for infertility treatment using egg donation. Women who become pregnant with donated eggs are at greater risk of high blood pressure, especially pre-eclampsia. At a conference held in 2014, Hélène Letur-Koenirsch and colleagues reported results from almost 600 pregnancies including over 200 with egg donation. Compared to controls, the risk of high blood pressure was more than three times greater in pregnancies with donated eggs, and previous pregnancy had no significant effect.

Moreover, a 2003 paper by Jon Einarsson and colleagues examined the relationship between frequency of pre-eclampsia and previous exposure to a partner’s semen. Over a hundred women with pre-eclampsia were compared with twice as many matched controls with normal blood pressure. For first-time pregnancies, the risk of pre-eclampsia was significantly higher for women using semen-blocking contraception who had cohabited with their sexual partners less than 4 months than for women who cohabited for over a year before conception.

The relationship between contraceptives and pre-eclampsia is interesting in itself. In a 1977 paper Jean-Jacques Marti and Uli Herrman examined the incidence of pre-eclampsia in women using oral contraceptives. They found that episodes of unprotected sexual intercourse for women in a control group were three times more common than in women with pre-eclampsia, supporting the interpretation that contact with semen has a protective effect. In 1989, Hillary Klonoff-Cohen and colleagues reported on a case-control study designed to test whether barrier methods that block exposure to semen are associated with an increased risk of pre-eclampsia during subsequent pregnancy. Over a hundred women who experienced pre-eclampsia during first-time pregnancies were compared with as many pregnant women without raised blood pressure. The risk of pre-eclampsia was more than twice as high in users of barrier contraception and increased with decreasing exposure to semen.

Yet more evidence for a priming effect of semen came from a 2000 paper by Carin Koelman and colleagues. They discovered that a low incidence of pre-eclampsia was associated with oral sex, especially if semen was swallowed. They proposed a crucial rôle for induction of maternal tolerance to paternal antigens that they identified in seminal plasma.

So a woman may need exposure to semen from a particular male partner for several months to develop adequate immunological tolerance of the fetus in her womb. Without such priming, the mother’s immune system reacts negatively to the fetus and compromises development of blood vessels in the placenta. The resulting increase in blood pressure is a counter-measure that boosts maternal blood flow to offset deficiencies of the spiral arteries. This throws entirely new light on the significance of lengthy courtship and strong pair bonding in humans.

References

Einarsson, J.I., Sangi-Haghpeykar, H. & Gardner, M.O. (2003) Sperm exposure and development of pre-eclampsia. American Journal of Obstetrics & Gynecology 188:1241-1243.

Haig, D. (1993) Genetic conflicts in human pregnancy. Quarterly Review of Biology 68:495-532.

Klonoff-Cohen, H.S., Savitz, D.A., Cefalo, R.C. & McCann, M.F. (1989) An epidemiologic study of contraception and preeclampsia. Journal of the American Medical Association 262:3143-3147.

Koelman, C.A., Coumans, A.B., Nijman, H.W., Doxiadis, I.I. & Dekker, G.A. (2000) Correlation between oral sex and a low incidence of pre-eclampsia: A role for soluble HLA in seminal plasma. Journal of Reproductive Immunology 46:155-166.

Letur-Koenirsch, H., Peigne, M., Ohl, J., Cedrin, I., d'Argent, E.M., Scheffler, F., Gzregorczyk-Martin, V. & de Mouzon, J. (2014) Pregnancies issued from egg donation are associated to a higher risk of hypertensive pathologies then control ART pregnancies. Results of a large comparative cohort study. Human Reproduction 29, Supplement 1:68-69.

Marti, J.-J. & Herrmann, U. (1977) Immunogenetics: A new etiologic concept of "essential" EPH gestosis, with special consideration of the primigravida patient. American Journal of Obstetrics & Gynecology 128:489-493.

MacGillivray, I. (1958) Some observations on the incidence of preeclampsia. Journal of Obstetrics & Gynaecology of the British Empire 65:536-539.

Need, J.A., Bell, B., Meffin, E. & Jones, W.R. (1983) Pre-eclampsia in pregnancies from donor inseminations. Journal of Reproductive Immunology 5:329-338.

Palmer, A.E., London, W.T., Sly, D.L. & Rice, J.M. (1979) Spontaneous preeclamptic toxemia of pregnancy in the patas monkey (Erythrocebus patas). Laboratory Animal Science 29:102-106.

Robillard, P.-Y., Hulsey, T.C., Perianin, J., Janky, E., Miri, E.H. & Papiernik, E. (1994) Association of pregnancy-induced hypertension with duration of sexual cohabitation before conception. Lancet 344:973-975.

Skjaerven, R., Wilcox, A.J. & Lie, R.T. (2002) The interval between pregnancies and the risk of preeclampsia. New England Journal of Medicine 346:33-38.

Yuan, H.T., Haig, D. & Ananth Karumanchi, S. (2005) Angiogenic factors in the pathogenesis of preeclampsia. Current Topics in Developmental Biology 71:297-312.

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