ReviewThe links between maternal histamine levels and complications of human pregnancy
Introduction
Shortly after it was shown histamine is a pharmacologically active component of contaminated ergot (Barger and Dale, 1910, Kutscher, 1910), Dale and Laidlaw (1910) observed that subcutaneous injection of histamine into cats in late pregnancy results in strong periodic uterine contractions of the tonic type with no expulsive value but strong enough to cause premature placental separation and intrauterine death of litters. This classic in vivo study initiated the interest in the links between histamine and pregnancy that continue more than 90 years later. Available evidence suggests that changes in the concentration of maternal blood histamine may be involved in a number of complications of pregnancy. Some investigations have concentrated on determining levels of histamine in maternal blood in normal and complicated pregnancies, attempting to correlate changes in histamine levels with pathology. Alternatively, comparisons have been made between pathological symptoms and the known effects of histamine in non-pregnant humans, or in animal models, to identify similarities that may implicate histamine.
Histamine levels are dependent on the overall balance between the rates of biosynthesis by histidine decarboxylase (HDC), and the rate of enzymatic and chemical metabolism (Fig. 1). Diamine oxidase (DAO) is the main metabolic pathway for blood histamine, but other mechanisms may be involved (Buffoni, 1966, Beaven, 1982, Haddock et al., 1990). Finally, the effects of histamine are mediated through cell-surface receptors and changes in the levels or localisation of these receptors may contribute to altered effects of histamine in any tissue. These general mechanisms apply to normal and complicated human pregnancy. This review will concentrate on histamine levels during pregnancy. A subsequent review will consider mechanistic aspects, including the synthetic and metabolic tissues of pregnancy, and how changes in their activity may be controlled, but the key components are outlined in Fig. 1. There is little information on histamine receptors in human pregnancy, and this will be summarised briefly in the second review.
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The effects of histamine in animal pregnancy
In experimental models, injection and infusion of histamine or inhibition of histamine metabolism (Table 1) in early pregnancy revealed specific effects on pregnancy outcome. The effects seemingly are dose- and time-dependent and include observations of spontaneous abortion, intrauterine death, skeletal ossification abnormalities, fetal resorption and fetal weight loss (Table 1). Some of the experimental observations are similar to clinical findings associated with certain adverse maternal
The determination of normal histamine levels
An accurate assessment of histamine levels is essential if comparative levels during pregnancy are to be studied. Histamine is a small, unstable molecule, and the determination of circulating levels in plasma or whole blood has proved to be a technical challenge. Total blood histamine levels in normal humans are in the range 50–60 ng/ml (Haimart et al., 1985), whereas plasma levels are considered to be 0.3–0.4 ng/ml (Kimura et al., 1999); early reports suggested higher plasma levels of 0.6–0.7
Blood histamine levels and clinical symptoms
Blood or plasma histamine levels above which histamine causes pathological effects are not clearly defined. In pathological conditions such as hyperchlorhydia, chronic myelocytic leukaemia, and sepsis, plasma histamine rises significantly to 8 ng/ml or more (Horakova et al., 1977, Neugebauer et al., 1996). In addition, elevation of plasma histamine to more than 1 ng/ml (9.09 nmol/l) is persistently associated with pathological symptoms, including increased gastric acid secretion, itching,
Levels of maternal blood histamine in normal pregnancy
Blood histamine (BH) levels during first trimester pregnancy are not well characterised but one paper (Dubois et al., 1977) suggests that, in normal pregnancy, BH levels may be highest during the first trimester (Table 2). The high histamine levels during gestational weeks 8–12 may be related to increased histamine production, coupled to no change in plasma DAO activity until week 8 of pregnancy (Dubois et al., 1977, Holinka and Gurpide, 1984), after which histamine levels would
Blood histamine and preeclampsia
Preeclampsia has been linked to maternal endothelial damage and increased oxidative stress (Poston and Chappell, 2001, Sacks et al., 1998). Endothelial damage and oxidative stress are both linked to histamine production (Sahnoun et al., 1998), so a further link between histamine and preeclampsia could be expected. In preeclampsia, mean BH levels increase with the severity of the disease (Kapeller-Adler, 1941, Achari et al., 1971, Sharma et al., 1984), with the levels at gestational weeks 28–40
Hyperemesis gravidarum and histamine
Nausea and vomiting in pregnancy (NVP), a mild form of hyperemesis gravidarum (HG), is a common problem affecting about 80% of all pregnancies within the first 7–12 weeks of gestation, and is characterised by episodic vomiting that is more pronounced in the morning (morning sickness). Approximately 9% of patients exhibit symptoms beyond week 20 of pregnancy (Weigel and Weigel, 1989). Between 0.3 and 2% develop HG, which is characterised by intractable nausea and vomiting, hypotension, rapid
Blood histamine in preterm labour
Labour at all gestational ages has been described as an inflammatory process, with increased production of prostaglandins and cytokines within the pregnant uterus (Kelly, 1996), so changes in histamine production would be expected as part of the inflammatory changes. Available evidence strongly links maternal blood histamine levels to preterm labour, but most of the data are indirect evidence involving pregnancies complicated by specific clinical conditions with known raised blood histamine (
Blood histamine in antenatal haemorrhage and spontaneous abortion
Two papers have investigated the relationship between maternal histamine levels and abruptio placentae (Clemetson and Cafaro, 1981, Sharma et al., 1985). Both studies showed that histamine levels in women with abruptio placentae were similar to or lower than those reported in normal pregnancy (25–35 ng/ml of blood, compare with Table 2), while there was a closer link with maternal ascorbate levels. Mean levels of ascorbate in normal pregnancy were ∼1 mg/ml, while women with level of 0.4–0.7 mg
Conclusion
Levels of histamine in whole blood and plasma during pregnancy have been investigated, and the normal ranges for whole blood established with confidence (Table 2), showing that histamine levels reach a minimum during the second trimester and increase towards term. Many of the complications of pregnancy, including preeclampsia, preterm labour, spontaneous abortion and hyperemesis gravidarum, are associated with increased levels of maternal blood histamine (maternal hyper-histaminemia). The net
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