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Laura Maintz, Verena Schwarzer, Thomas Bieber, Katrin van der Ven, Natalija Novak, Effects of histamine and diamine oxidase activities on pregnancy: a critical review, Human Reproduction Update, Volume 14, Issue 5, September-October 2008, Pages 485–495, https://doi.org/10.1093/humupd/dmn014
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Abstract
Histamine has been assumed to contribute to embryo–uterine interactions due to its vasoactive, differentiation and growth-promoting properties. However, its exact functions in pregnancy are unclear. The histamine-degrading enzyme diamine oxidase (DAO) is produced in high amounts by the placenta and has been supposed to act as a metabolic barrier to prevent excessive entry of bioactive histamine from the placenta into the maternal or fetal circulation.
The literature available on PubMed published in English between 1910 and 2008 has been searched using the isolated and combined key words histamine, diamine oxidase, pregnancy, placenta, endometrium, miscarriage, implantation, pre-eclampsia, intrauterine growth retardation, diabetes and embryonic histamine-releasing factor (EHRF).
High expression of the histamine-producing enzyme histidine decarboxylase in the placenta, histamine receptors at the feto–maternal interface and the existence of an EHRF suggest a physiological role of histamine during gestation. The balance between histamine and DAO seems to be crucial for an uncomplicated course of pregnancy. Reduced DAO activities have been found in multiple heterogeneous complications of pregnancy such as diabetes, threatened and missed abortion and trophoblastic disorders. Whether women with histamine intolerance suffer from more complicated pregnancies and higher abortion rates due to impaired DAO activities and if low DAO levels or genetic modifications in the DAO gene might therefore represent a prognostic factor for a higher risk of abortion, has not been investigated yet.
Low activities of the histamine-degrading enzyme DAO might indicate high-risk pregnancies, although high intra- and interindividual variations limit its value as a screening tool.
Introduction
The biogenic amine histamine (2-[4-imidazolyl]ethylamine) was discovered in 1910 by Dale (Dale and Laidlaw, 1910) and acts as a key mediator of allergic and pseudoallergic reactions. Histamine has various roles in allergic and inflammatory processes and neuro-endocrinological actions in the central nervous system. In addition, a contribution to the menstrual cycle and pregnancy has been described, which is most likely based on an interplay between histamine and female steroids and its vasoactive, cell growth- and differentiation promoting properties (Pap, 2004).
Histamine exerts multiple effects via binding to its four histamine receptors
Histamine is synthesized by the pyridoxal phosphate containing L-histidine decarboxylase (HDC) from the amino acid histidine. It is produced mainly by mast cells, basophils, platelets, histaminergic neurons and enterochromaffine cells, where it is stored intracellularly in vesicles and released upon stimulation.
Histamine exerts its effects by binding to its four receptors [histamine 1 receptor (H1R), H2R, H3R and H4R] on target cells in various tissues. It causes smooth muscle cell contraction (H1R), vasodilatation (H1R, H2R), increased vascular permeability (H1R, H2R) and mucus secretion (H1R), tachycardia, arrhythmias (H1R, H2R), alterations of blood pressure (H1R, H2R) and stimulates gastric acid secretion (H2R) as well as nociceptive nerve fibres (H1R) (Maintz and Novak, 2007).
Histamine enhances Th1-type response by triggering H1R, whereas both Th1- and Th2-type responses are negatively regulated by H2R through the activation of different biochemical intracellular signals (Jutel et al., 2001). H3Rs are predominantly involved in the functions of the central nervous system as presynaptic autoreceptors influencing neuronal histamine release and thus various biological responses such as arousal, circadian rhythm, food intake, cognitive and memory processes (Igaz and Hegyesi, 2004). The most recently described histamine receptor, H4R, contributes to chemotaxis, cytokine and chemokine production and release in various types of immune cells including mast cells, eosinophils, dendritic cells and T cells. H4R antagonists have been shown to have anti-inflammatory properties and efficacy in a number of disease models, such as those for asthma and colitis in vivo (Zhang et al., 2006, 2007).
Extracellular histamine is catabolized by DAO, whereas intracellular histamine is metabolized by HNMT
Histamine can be metabolized by two alternative ways: oxidative deamination by DAO (former name: histaminase) or ring methylation by histamine-N-methyltransferase (HNMT) (Schwelberger, 2004). Whether histamine is catabolized by DAO or HNMT, is supposed to depend on the localization of histamine. The DAO protein is stored in plasma membrane-associated vesicular structures in epithelial cells of kidney and intestine and is secreted into the circulation upon stimulation (Schwelberger and Bodner, 1997; Schwelberger et al., 1998).
Therefore it has been proposed that DAO might be responsible for scavenging extracellular histamine after mediator release. Conversely, HNMT, the second important enzyme inactivating histamine, is a cytosolic protein (Brown et al., 1959), which can convert histamine only in the intracellular space of cells (Kufner et al., 2001; Klocker et al., 2005).
DAO also catabolizes other polyamines such as putrescine and spermidine. The highest expression of DAO has been observed in the intestine (Bieganski, 1983, Bieganski et al., 1983; Raithel et al., 1999), kidney and placenta (Schwelberger et al., 1998; Klocker et al., 2005).
A decreased activity of DAO has been discussed as a potential indicator of intestinal mucosa damage in inflammatory and neoplastic diseases (Schmidt et al., 1990; Raithel et al., 1998; Backhaus et al., 2005) or after chemotherapy (Tsujikawa et al., 1999).
How is histamine and its metabolism actually linked to pregnancy?
The balance between histamine and the histamine-degrading enzyme DAO seems to be crucial for an uncomplicated course of pregnancy (Brew and Sullivan, 2001). Reduced or precipitously falling DAO activities have been found in high-risk pregnancies (Fig. 1), whereas maternal plasma enzyme titres within the normal range have been mostly associated with a favourable fetal prognosis. DAO at the feto–maternal interface has therefore been supposed to act as a metabolic barrier to prevent excessive entry of bioactive histamine from the placenta into the maternal or fetal circulation.
High amounts of both the histamine synthesizing enzyme histidine decarboxylase (HDC) and the histamine-degrading enzyme diamine oxidase (DAO) are produced by the placenta.Persistently low or falling DAO plasma curves have been shown in pregnancy disorders, trophoblast diseases and premature rupture of membranes. Therefore DAO has been suggested to serve as a screening tool for complicated pregnancies.
In this review, we provide an overview of histamine and its metabolism during uncomplicated and pathological pregnancies and discuss the question whether reduced maternal plasma DAO activities serve as a reliable marker for pregnancy disorders.
Materials and Methods
The literature available on PubMed published in English between 1910 and 2008 has been searched using the isolated and combined key words histamine, diamine oxidase, pregnancy, placenta, endometrium, miscarriage, implantation, pre-eclampsia, intrauterine growth retardation, diabetes and EHRF. A total of 16 observational and various experimental studies and reviews concerning histamine and histamine metabolism, especially during pregnancy have been evaluated following the MOOSE guidelines for systematic reviews of observational studies. The current data regarding this topic using standardized assays for measurement of DAO activity is limited. In an effort to include all available studies investigating DAO activity during gestation, also heterogeneous studies have been included.
Results
Histamine in pregnancy
Maternal blood histamine levels are comparable to non-pregnant values in the first trimester and decrease during the second and third trimester of normal pregnancies
Maternal total blood histamine (TBH) levels are highest during the first trimester (mean ca 60 ng/ml) (Dubois et al., 1977) and do not differ significantly from normal non-pregnancy values (range TBH 50–60 ng/ml (Haimart et al., 1985), plasma histamine levels 0.3–0.7 ng/ml (Lorenz et al., 1972; Kimura et al., 1999; Brew and Sullivan, 2006). TBH levels decrease during the second (week 13–24: 9–48 ng/ml; Dubois et al., 1977; Clemetson and Cafaro, 1981) and third trimester (week 25–40: 30–54.7 ng/ml; Kapeller-Adler, 1949; Gunther and Glick, 1967; Achari et al., 1971; Dubois et al., 1977; Sharma et al., 1984) of normal pregnancy showing a nadir in the second trimester (Brew and Sullivan, 2006). Study results on puerperial blood histamine are contradictory and limited (Brew and Sullivan, 2006), varying between a rapid decrease (Brew and Sullivan, 2006) and increase (Sharma, 1982) of maternal TBH after delivery (Brew and Sullivan, 2006).
The human endometrium and myometrium features high amounts of mast cells which are thought to be the main source of uterine histamine (Massey et al., 1991; Pap, 2004). Functional mast cells have also been demonstrated in the placenta itself (Purcell and Hanahoe, 1991). However, also decidual cells have been shown to release histamine upon stimulation of the IgE receptor in vitro (Schrey et al., 1995).
High expression of the histamine-producing enzyme HDC in the placenta, histamine receptors at the feto–maternal interface and the existence of an EHRF suggest a physiological role of histamine during gestation
Histamine has been supposed to contribute to embryo–uterine interactions during implantation. In the placenta, the expression of the histamine-producing enzyme HDC is about 1000 times higher than in other organs (Pap, 2004). This might be explained by the finding that HDC gene transcription is regulated by progesterone (Paria et al., 1998) which increases during pregnancy. Moreover, HDC transcription correlates with endometrial differentiation for blastocyst implantation (Paria et al., 1998). Inhibition of HDC has been shown to induce delayed implantation in the rabbit (Dey, 1981). Murine preimplantation blastocysts have been found to express H2R (Zhao et al., 2000). Conversely, histamine seems to promote cytotrophoblast invasiveness specifically through activation of H1R in humans (Liu et al., 2004). In humans, H1Rs are expressed in syncytiotrophoblasts of placental villi, which play important roles in the exchange of substances between maternal and fetal blood and in the secretion of many hormones [e.g. human chorionic gonadotropin (HCG), estrogen etc.] (Matsuyama et al., 2004). H1R (Fukui et al., 1994), and H2R are expressed in both decidual and placental components (human amnion, chorion, decidua, villous cytotrophoblast and stromal cells) of the feto–maternal interface (Fukui et al., 1994; Brew and Sullivan, 2001), suggesting a role of histamine at the feto–maternal interface after implantation (Brew and Sullivan, 2001; Pap, 2004).
Histamine has been shown to modulate vascular resistance during gestation in human (Maguire et al., 1985) and animal models (Berhe et al., 1988). Via H1R, histamine has been shown to mediate vasoconstriction in the fetal circulation of the guinea pig placenta (Berhe et al., 1988), guinea pig umbilical arteries (Nair and Dyer, 1974) and of human umbilical arteries and veins (Altura et al., 1972). Conversely, histamine has been observed to cause a dose-dependent dilatation of the fetal circulation via H2Rs in the dually perfused human placental cotyledon under low PO2 conditions, when tone is already elevated with angiotensin II (Maguire et al., 1985). This effect might be beneficial in hypoxia. Histamine has also been shown to increase permeability of guinea pig placentas to macromolecules (Berhe et al., 1988).
Implantation of the placenta depends on the complex process of trophoblast differentiation which goes along with the expression of various adhesion molecules (Szewczyk et al., 2006). The invasive trophoblast becomes α6-β4 integrin negative and α5-β1, α1-β1 and αν-β3 integrin positive (Aplin, 1993). In vitro, stimulation with histamine has been shown to enhance the physiological αν-β3 integrin expression (Szewczyk et al., 2008).
The embryo is thought to contribute to the release of histamine in mast and endometrial cells by an EHRF (Pap, 2004; Cocchiara et al., 1987a; 1987b; 1988). Pre-embryos growing in vitro produce an EHRF from the 2-cell to the 8-cell stage in humans (Cocchiara et al., 1987a, b, 1988) and from the 2-cell to the blastocyst in rats (Cocchiara et al., 1992, 1996) which has been shown to release histamine in human basophils and rat uterine mast cells (Cocchiara et al., 1992). Whereas administration of anti-histamines (Hoos and Hoffman, 1983) and indomethacin (Saksena et al., 1976; Hoos and Hoffman, 1983) have been shown to inhibit implantation in rabbits (Hoos and Hoffman, 1983) and mice (Saksena et al., 1976), this effect could be partially compensated in mice by an injection of histamine and reversed completely by administration of histamine and prostaglandin (PGF2α) (Saksena et al., 1976). However, mice do not feature the human hemochorial placentation. Therefore transfers from the murine to the human model have to be regarded critically.
Anyhow, in view of all these findings, histamine has been implicated as a paracrine signal during endometrial decidualization and embryo implantation (Noskova et al., 2006).
Histamine functions as a paracrine oxytocic directly on gestational myometrium and indirectly by an increased production of the unterotonic PGF2α
Histamine has been shown to stimulate arachidonate release and PGF2α production in human decidual cells in vitro (Schrey et al., 1995). An increased PG production by the uterine decidua is thought to play a key role in the initiation and maintenance of normal labour (Casey and MacDonald, 1988; Schrey et al., 1995). PGs have also been implicated as mediators of preterm labour associated with intrauterine infection (Lopez et al., 1989; Schrey et al., 1995). Elevated histamine plasma levels have been shown in women during preterm compared with term labour (Caldwell et al., 1988). Hence, histamine might stimulate both preterm and term labour in an indirect and direct way. Histamine may function directly as a paracrine oxytocic due to its potent positive ionotropic action on gestational myometrium (Cruz et al., 1989; Schrey et al., 1995). Moreover, PGF2α and histamine are able to potentiate each others contractile effects (Rudolph et al., 1992).
Excessive histamine levels had fatal effects on pregnancy in animal models
Elevated histamine concentrations in pregnancy due to histamine injection (Dale and Laidlaw, 1910; Woods et al., 1976) or DAO inhibition with aminoguanidine (Roberts, 1954; Nava and Fraile, 1988) had fatal effects in various animal models (Brew and Sullivan, 2006). Histamine injection resulted in uterine contraction and spontaneous abortion in cats (Dale and Laidlaw, 1910), fetal ductus arteriosus constriction in lambs (Woods et al., 1976), whereas inhibition of DAO led to liver, lung and head haematomas in fetuses from treated rats (Nava and Fraile, 1988), abnormal fetal cranial skeletal ossification (Nava and Fraile, 1988) and spontaneous abortion (Roberts, 1954) in pregnant rats. These observations stress the impact of a sufficient histamine degradation during pregnancy.
DAO is synthesized by decidual and trophoblast cells, leading to high DAO levels during pregnancy
It has long been observed that maternal plasma DAO activity levels rise (Ahlmark, 1944) exponentially during the first 20 weeks of gestation to levels which are about 1000 times higher than before pregnancy (Southren et al., 1966b; Carrington et al., 1972), leading to a decline of circulating maternal histamine levels (Dubois et al., 1977; Brew and Sullivan, 2001; Brew et al., 2007).
DAO has been identified as the main enzyme for histamine catabolism at the feto–maternal interface (Kapeller-Adler, 1944; Lindberg et al., 1963; Brew and Sullivan, 2001). DAO is located predominately in the cytosol (Weisburger et al., 1978) and intercellular space (Lin et al., 1978) of decidual cells (Swanberg, 1950a, b; Southren et al., 1965; Gunther and Glick, 1967; Bell, 1986) and has been regarded for a long time as an exclusively maternal but not fetal product in this tissue (Weisburger et al., 1978). Negative immunofluorescent staining of DAO has been reported for syncytio- and cytotrophoblast of the chorionic villi (Lin et al., 1978). However, the expression of mRNA for DAO has also been shown in the villous trophoblast besides decidual cells (Brew and Sullivan, 2001). During pregnancy, maximal DAO activity has been found in the retroplacental decidua (Weingold and Southren, 1968), followed by fetal membranes, placental cross sections, amniotic fluid, maternal plasma, cord and fetal plasma (Weingold and Southren, 1968). The amniotic fluid has been reported to possess approximately a 2- to 3-fold enzyme activity over an equivalent amount of maternal plasma (Weingold and Southren, 1968). Fetal plasma DAO levels have been found to be ∼50-fold lower than maternal plasma DAO levels at parturition following uncomplicated pregnancies (Southren et al., 1964). Decidual DAO activity increased from 6 to 17 weeks of pregnancy (Holinka and Gurpide, 1984). The course of maternal DAO plasma activities has been studied during normal (Table I) and pathological pregnancies with various demographic and medical complications (Table II) ( Bradshaw and Jessop, 1955; Southren et al., 1964, 1966a, b; 1968; Resnik and Levine, 1969; Southren and Weingold, 1970; Torok et al., 1970; Carrington et al., 1972; Beaven et al., 1975; Jones and Kelly 1976; Dubois et al., 1977; Legge and Duff, 1981; Gahl et al., 1982a, b).
Plasma DAO activity in normal pregnancies.
| n . | DAO range . | Unit . | Week of gestation . | Complications . | Fetal outcome . | References . |
|---|---|---|---|---|---|---|
| 70 | 0.1–0.9 | nm/ml/min | 4–40 | no | n.s. | Dubois et al. (1977) |
| 83 | 0.5–4.9 | µg/h | 14–40 | no | n.s. | Bradshaw and Jessop (1955)a |
| 110 | 5–500 | mµM/ml | 8–40 | no | Term infants | Resnik and Levine (1969) |
| 15 | 1–460 | U/ml | 4–40 | no | n.s. | Southren et al. (1964) |
| 6 | 120–2300 | 8–40 | no | n.s. | Southren et al. (1966a) | |
| 34 | 0–2200 | 8–40 | no | Full-term | Southren et al. (1966b) | |
| 89 | 12–1940 | 8–40 | no | n.s. | Jones and Kelly (1976) | |
| 66 | 7–1800 | 0–39 | no | n.s. | Carrington et al. (1972) | |
| 66 | 0.9–2.5 | 10−3 DAO (U/ml)a | 8 | n.s. | Live births | Gahl et al. (1982a, b)a |
| 261 | 2.8–7.6 | 12 | ||||
| 261b | 0–29 | 8-34 | no | 8 twins, 11 infants with minor defects |
| n . | DAO range . | Unit . | Week of gestation . | Complications . | Fetal outcome . | References . |
|---|---|---|---|---|---|---|
| 70 | 0.1–0.9 | nm/ml/min | 4–40 | no | n.s. | Dubois et al. (1977) |
| 83 | 0.5–4.9 | µg/h | 14–40 | no | n.s. | Bradshaw and Jessop (1955)a |
| 110 | 5–500 | mµM/ml | 8–40 | no | Term infants | Resnik and Levine (1969) |
| 15 | 1–460 | U/ml | 4–40 | no | n.s. | Southren et al. (1964) |
| 6 | 120–2300 | 8–40 | no | n.s. | Southren et al. (1966a) | |
| 34 | 0–2200 | 8–40 | no | Full-term | Southren et al. (1966b) | |
| 89 | 12–1940 | 8–40 | no | n.s. | Jones and Kelly (1976) | |
| 66 | 7–1800 | 0–39 | no | n.s. | Carrington et al. (1972) | |
| 66 | 0.9–2.5 | 10−3 DAO (U/ml)a | 8 | n.s. | Live births | Gahl et al. (1982a, b)a |
| 261 | 2.8–7.6 | 12 | ||||
| 261b | 0–29 | 8-34 | no | 8 twins, 11 infants with minor defects |
Values were mostly read from figures and might therefore deviate from the measured values which were often not exactly given in the manuscripts. aSerum DAO activity is measured whereas the other studies use plasma DAO activity; bnumber of subjects varies between n = 20 and n = 261 at different gestational age periods. n, number of patients; n.s., not specified.
Plasma DAO activity in normal pregnancies.
| n . | DAO range . | Unit . | Week of gestation . | Complications . | Fetal outcome . | References . |
|---|---|---|---|---|---|---|
| 70 | 0.1–0.9 | nm/ml/min | 4–40 | no | n.s. | Dubois et al. (1977) |
| 83 | 0.5–4.9 | µg/h | 14–40 | no | n.s. | Bradshaw and Jessop (1955)a |
| 110 | 5–500 | mµM/ml | 8–40 | no | Term infants | Resnik and Levine (1969) |
| 15 | 1–460 | U/ml | 4–40 | no | n.s. | Southren et al. (1964) |
| 6 | 120–2300 | 8–40 | no | n.s. | Southren et al. (1966a) | |
| 34 | 0–2200 | 8–40 | no | Full-term | Southren et al. (1966b) | |
| 89 | 12–1940 | 8–40 | no | n.s. | Jones and Kelly (1976) | |
| 66 | 7–1800 | 0–39 | no | n.s. | Carrington et al. (1972) | |
| 66 | 0.9–2.5 | 10−3 DAO (U/ml)a | 8 | n.s. | Live births | Gahl et al. (1982a, b)a |
| 261 | 2.8–7.6 | 12 | ||||
| 261b | 0–29 | 8-34 | no | 8 twins, 11 infants with minor defects |
| n . | DAO range . | Unit . | Week of gestation . | Complications . | Fetal outcome . | References . |
|---|---|---|---|---|---|---|
| 70 | 0.1–0.9 | nm/ml/min | 4–40 | no | n.s. | Dubois et al. (1977) |
| 83 | 0.5–4.9 | µg/h | 14–40 | no | n.s. | Bradshaw and Jessop (1955)a |
| 110 | 5–500 | mµM/ml | 8–40 | no | Term infants | Resnik and Levine (1969) |
| 15 | 1–460 | U/ml | 4–40 | no | n.s. | Southren et al. (1964) |
| 6 | 120–2300 | 8–40 | no | n.s. | Southren et al. (1966a) | |
| 34 | 0–2200 | 8–40 | no | Full-term | Southren et al. (1966b) | |
| 89 | 12–1940 | 8–40 | no | n.s. | Jones and Kelly (1976) | |
| 66 | 7–1800 | 0–39 | no | n.s. | Carrington et al. (1972) | |
| 66 | 0.9–2.5 | 10−3 DAO (U/ml)a | 8 | n.s. | Live births | Gahl et al. (1982a, b)a |
| 261 | 2.8–7.6 | 12 | ||||
| 261b | 0–29 | 8-34 | no | 8 twins, 11 infants with minor defects |
Values were mostly read from figures and might therefore deviate from the measured values which were often not exactly given in the manuscripts. aSerum DAO activity is measured whereas the other studies use plasma DAO activity; bnumber of subjects varies between n = 20 and n = 261 at different gestational age periods. n, number of patients; n.s., not specified.
Plasma DAO activity in complicated pregnancies.
| n . | Range of plasma DAO activity . | Unit . | Gestational week . | Complications of pregnancy . | Fetal outcome . | References . |
|---|---|---|---|---|---|---|
| 25 | 40–1300 | U/ml | 0–37 | 19 normal, 6 anovulatory with HCG | 24 term, 1 abortion | Beaven et al. (1975) |
| 9 | 10–2400 | 4–42 | Age <15 years (n = 9), toxaemia (n = 2) | 1 late abortion, 1 premature | Southren and Weingold (1970) | |
| 23 | 75–1300 | 10–40 | Age 15–19 Toxaemia (n = 13), poor obstetric history (n = 5), diabetes (n = 4), antepartum bleeding (n = 3), anaemia (n = 2), pyelonephritis (n = 6), Obesity or anorexia (n = 21) | 1 abortion, 3 stillbirths, 9 premature infants, 1 congenital anomaly | ||
| 79 | 0–2100 | 6–42 | Age 15–19, uncomplicated | |||
| 23 | 400–1400 | 14–41 | Patients age ≥40 years Toxaemia (n = 7), excessive weight gain (n = 5), anaemia (n = 2), poor obstetric history (n = 1) | 1 abortion, 3 premature, 1 anomaly, 1 neonatal death | ||
| 44 | 200–1050 | U/ml | 12–42 | Underweight ≤99 pounds (n = 44), poor obstetric history (n = 5), toxaemia (n = 6), excessive weight gain (n = 3), anaemia (n = 3) | 1 abortion, 1ectopic pregnancy, 1 congenital anomaly, 3 neonatal deaths, 9 premature births | |
| 30 | 350–1650 | 11–40 | Obesity (≥200 pounds) (n = 30); Toxaemia (n = 18), excessive weight gain (n = 10), diabetes (n = 7), poor obstetric history (n = 3), anaemia (n = 1) | 3 premature, 2 neonatal deaths, 1 abortion, 4 weight ≥10 pounds | ||
| 208 | 10–2200 | 8–42 | Normal and complicated pregnancies 17% toxaemia, 6.2% diabetes | 25 premature, 9 perinatal death | ||
| 6 | 50–3174 | 10–32 | Threatened abortion | n.s., pregnancies continued >20 week | Southren et al. (1966a, b) | |
| 3 | 10–400 | 8–20 | Threatened abortion, treatment with progestational agents | Unsuccessful termination of pregnancy | ||
| 3 | 25–120 | 8–24 | Missed abortion | Abortion >16 week | ||
| 5 | 10–800 | 8–40 | History of habitual abortion | Live infants | ||
| 4 | 100–1950 | 12–34 | Incompetent os syndrome | 4 premature, 1 neonatal death | ||
| 3 | 100–900 | U/ml | 16–36 | Incompetent os syndrome | Live, term | |
| 5 | 80–1700 | 12–36 | Poor obstetrical historya | Premature, 1 antepartum death, 1 neonatal death | ||
| 5 | 0–1800 | 8–38 | Poor obstetrical history | term | ||
| 68 | 20–2085 | 10–40 | Diabetes mellitus | 4 stillbirths | Southren et al. (1968) | |
| 44 | 0–0.5 | 10−3 DAO (U/ml)a | 8 | n.s. | Early deaths <21st week | Gahl et al. (1982a, b)b |
| 29 | 0.5–2.9 | 12 | n.s. | |||
| 29 | 0.8–4.8 | 12 | n.s. | Late deaths >21st week | ||
| 23 | ‘normal’ | IU/l | >8 | Antepartum bleeding at ≤20 weeks of gestation | 47.83% (n = 11) continued pregnancies, 52.17% (n = 12) aborted | Legge and Duff (1981) |
| 31 | ‘below normal’ | 19.35% (n = 6) pregnancies continued, 80.65% (n = 25) aborted | ||||
| 4 | Normal (>8) | ≤8 | 3 aborted | |||
| 8 | Low (≤8) | 4 aborted, 4 pregnancies continued | ||||
| 120 | 10–510 | nM/0.6 ml | 8–40 | no | n.s. | Torok et al. (1970)b |
| 110 | 5–500 | mµM/ml | 8–40 | No | Term infants | Resnik and Levine(1969) |
| 6 | 60–300 | 12–34 | No | Premature, >2500 g | ||
| 25 | 20–450 | 18–40 | ‘high-risk’ i.e. toxaemia, diabetes, anaemia, erythroblastosis, dysmaturity | Term infants | ||
| 5 | 0–225 | 24–39 | ‘high-risk’: toxaemic, anaemic, alcoholic | premature |
| n . | Range of plasma DAO activity . | Unit . | Gestational week . | Complications of pregnancy . | Fetal outcome . | References . |
|---|---|---|---|---|---|---|
| 25 | 40–1300 | U/ml | 0–37 | 19 normal, 6 anovulatory with HCG | 24 term, 1 abortion | Beaven et al. (1975) |
| 9 | 10–2400 | 4–42 | Age <15 years (n = 9), toxaemia (n = 2) | 1 late abortion, 1 premature | Southren and Weingold (1970) | |
| 23 | 75–1300 | 10–40 | Age 15–19 Toxaemia (n = 13), poor obstetric history (n = 5), diabetes (n = 4), antepartum bleeding (n = 3), anaemia (n = 2), pyelonephritis (n = 6), Obesity or anorexia (n = 21) | 1 abortion, 3 stillbirths, 9 premature infants, 1 congenital anomaly | ||
| 79 | 0–2100 | 6–42 | Age 15–19, uncomplicated | |||
| 23 | 400–1400 | 14–41 | Patients age ≥40 years Toxaemia (n = 7), excessive weight gain (n = 5), anaemia (n = 2), poor obstetric history (n = 1) | 1 abortion, 3 premature, 1 anomaly, 1 neonatal death | ||
| 44 | 200–1050 | U/ml | 12–42 | Underweight ≤99 pounds (n = 44), poor obstetric history (n = 5), toxaemia (n = 6), excessive weight gain (n = 3), anaemia (n = 3) | 1 abortion, 1ectopic pregnancy, 1 congenital anomaly, 3 neonatal deaths, 9 premature births | |
| 30 | 350–1650 | 11–40 | Obesity (≥200 pounds) (n = 30); Toxaemia (n = 18), excessive weight gain (n = 10), diabetes (n = 7), poor obstetric history (n = 3), anaemia (n = 1) | 3 premature, 2 neonatal deaths, 1 abortion, 4 weight ≥10 pounds | ||
| 208 | 10–2200 | 8–42 | Normal and complicated pregnancies 17% toxaemia, 6.2% diabetes | 25 premature, 9 perinatal death | ||
| 6 | 50–3174 | 10–32 | Threatened abortion | n.s., pregnancies continued >20 week | Southren et al. (1966a, b) | |
| 3 | 10–400 | 8–20 | Threatened abortion, treatment with progestational agents | Unsuccessful termination of pregnancy | ||
| 3 | 25–120 | 8–24 | Missed abortion | Abortion >16 week | ||
| 5 | 10–800 | 8–40 | History of habitual abortion | Live infants | ||
| 4 | 100–1950 | 12–34 | Incompetent os syndrome | 4 premature, 1 neonatal death | ||
| 3 | 100–900 | U/ml | 16–36 | Incompetent os syndrome | Live, term | |
| 5 | 80–1700 | 12–36 | Poor obstetrical historya | Premature, 1 antepartum death, 1 neonatal death | ||
| 5 | 0–1800 | 8–38 | Poor obstetrical history | term | ||
| 68 | 20–2085 | 10–40 | Diabetes mellitus | 4 stillbirths | Southren et al. (1968) | |
| 44 | 0–0.5 | 10−3 DAO (U/ml)a | 8 | n.s. | Early deaths <21st week | Gahl et al. (1982a, b)b |
| 29 | 0.5–2.9 | 12 | n.s. | |||
| 29 | 0.8–4.8 | 12 | n.s. | Late deaths >21st week | ||
| 23 | ‘normal’ | IU/l | >8 | Antepartum bleeding at ≤20 weeks of gestation | 47.83% (n = 11) continued pregnancies, 52.17% (n = 12) aborted | Legge and Duff (1981) |
| 31 | ‘below normal’ | 19.35% (n = 6) pregnancies continued, 80.65% (n = 25) aborted | ||||
| 4 | Normal (>8) | ≤8 | 3 aborted | |||
| 8 | Low (≤8) | 4 aborted, 4 pregnancies continued | ||||
| 120 | 10–510 | nM/0.6 ml | 8–40 | no | n.s. | Torok et al. (1970)b |
| 110 | 5–500 | mµM/ml | 8–40 | No | Term infants | Resnik and Levine(1969) |
| 6 | 60–300 | 12–34 | No | Premature, >2500 g | ||
| 25 | 20–450 | 18–40 | ‘high-risk’ i.e. toxaemia, diabetes, anaemia, erythroblastosis, dysmaturity | Term infants | ||
| 5 | 0–225 | 24–39 | ‘high-risk’: toxaemic, anaemic, alcoholic | premature |
Values were mostly read from figures and might therefore slightly deviate from the measured values which were often not given numerically in the manuscripts. aPoor obstetrical history was defined by the authors as a history of recurrent abortions, premature deliveries and stillbirths mixed with infrequent successful pregnancies (Southren et al., 1966a, b); bserum DAO activity is measured whereas the other studies use plasma DAO activity. n, number of patients; n.s., not specified.
Plasma DAO activity in complicated pregnancies.
| n . | Range of plasma DAO activity . | Unit . | Gestational week . | Complications of pregnancy . | Fetal outcome . | References . |
|---|---|---|---|---|---|---|
| 25 | 40–1300 | U/ml | 0–37 | 19 normal, 6 anovulatory with HCG | 24 term, 1 abortion | Beaven et al. (1975) |
| 9 | 10–2400 | 4–42 | Age <15 years (n = 9), toxaemia (n = 2) | 1 late abortion, 1 premature | Southren and Weingold (1970) | |
| 23 | 75–1300 | 10–40 | Age 15–19 Toxaemia (n = 13), poor obstetric history (n = 5), diabetes (n = 4), antepartum bleeding (n = 3), anaemia (n = 2), pyelonephritis (n = 6), Obesity or anorexia (n = 21) | 1 abortion, 3 stillbirths, 9 premature infants, 1 congenital anomaly | ||
| 79 | 0–2100 | 6–42 | Age 15–19, uncomplicated | |||
| 23 | 400–1400 | 14–41 | Patients age ≥40 years Toxaemia (n = 7), excessive weight gain (n = 5), anaemia (n = 2), poor obstetric history (n = 1) | 1 abortion, 3 premature, 1 anomaly, 1 neonatal death | ||
| 44 | 200–1050 | U/ml | 12–42 | Underweight ≤99 pounds (n = 44), poor obstetric history (n = 5), toxaemia (n = 6), excessive weight gain (n = 3), anaemia (n = 3) | 1 abortion, 1ectopic pregnancy, 1 congenital anomaly, 3 neonatal deaths, 9 premature births | |
| 30 | 350–1650 | 11–40 | Obesity (≥200 pounds) (n = 30); Toxaemia (n = 18), excessive weight gain (n = 10), diabetes (n = 7), poor obstetric history (n = 3), anaemia (n = 1) | 3 premature, 2 neonatal deaths, 1 abortion, 4 weight ≥10 pounds | ||
| 208 | 10–2200 | 8–42 | Normal and complicated pregnancies 17% toxaemia, 6.2% diabetes | 25 premature, 9 perinatal death | ||
| 6 | 50–3174 | 10–32 | Threatened abortion | n.s., pregnancies continued >20 week | Southren et al. (1966a, b) | |
| 3 | 10–400 | 8–20 | Threatened abortion, treatment with progestational agents | Unsuccessful termination of pregnancy | ||
| 3 | 25–120 | 8–24 | Missed abortion | Abortion >16 week | ||
| 5 | 10–800 | 8–40 | History of habitual abortion | Live infants | ||
| 4 | 100–1950 | 12–34 | Incompetent os syndrome | 4 premature, 1 neonatal death | ||
| 3 | 100–900 | U/ml | 16–36 | Incompetent os syndrome | Live, term | |
| 5 | 80–1700 | 12–36 | Poor obstetrical historya | Premature, 1 antepartum death, 1 neonatal death | ||
| 5 | 0–1800 | 8–38 | Poor obstetrical history | term | ||
| 68 | 20–2085 | 10–40 | Diabetes mellitus | 4 stillbirths | Southren et al. (1968) | |
| 44 | 0–0.5 | 10−3 DAO (U/ml)a | 8 | n.s. | Early deaths <21st week | Gahl et al. (1982a, b)b |
| 29 | 0.5–2.9 | 12 | n.s. | |||
| 29 | 0.8–4.8 | 12 | n.s. | Late deaths >21st week | ||
| 23 | ‘normal’ | IU/l | >8 | Antepartum bleeding at ≤20 weeks of gestation | 47.83% (n = 11) continued pregnancies, 52.17% (n = 12) aborted | Legge and Duff (1981) |
| 31 | ‘below normal’ | 19.35% (n = 6) pregnancies continued, 80.65% (n = 25) aborted | ||||
| 4 | Normal (>8) | ≤8 | 3 aborted | |||
| 8 | Low (≤8) | 4 aborted, 4 pregnancies continued | ||||
| 120 | 10–510 | nM/0.6 ml | 8–40 | no | n.s. | Torok et al. (1970)b |
| 110 | 5–500 | mµM/ml | 8–40 | No | Term infants | Resnik and Levine(1969) |
| 6 | 60–300 | 12–34 | No | Premature, >2500 g | ||
| 25 | 20–450 | 18–40 | ‘high-risk’ i.e. toxaemia, diabetes, anaemia, erythroblastosis, dysmaturity | Term infants | ||
| 5 | 0–225 | 24–39 | ‘high-risk’: toxaemic, anaemic, alcoholic | premature |
| n . | Range of plasma DAO activity . | Unit . | Gestational week . | Complications of pregnancy . | Fetal outcome . | References . |
|---|---|---|---|---|---|---|
| 25 | 40–1300 | U/ml | 0–37 | 19 normal, 6 anovulatory with HCG | 24 term, 1 abortion | Beaven et al. (1975) |
| 9 | 10–2400 | 4–42 | Age <15 years (n = 9), toxaemia (n = 2) | 1 late abortion, 1 premature | Southren and Weingold (1970) | |
| 23 | 75–1300 | 10–40 | Age 15–19 Toxaemia (n = 13), poor obstetric history (n = 5), diabetes (n = 4), antepartum bleeding (n = 3), anaemia (n = 2), pyelonephritis (n = 6), Obesity or anorexia (n = 21) | 1 abortion, 3 stillbirths, 9 premature infants, 1 congenital anomaly | ||
| 79 | 0–2100 | 6–42 | Age 15–19, uncomplicated | |||
| 23 | 400–1400 | 14–41 | Patients age ≥40 years Toxaemia (n = 7), excessive weight gain (n = 5), anaemia (n = 2), poor obstetric history (n = 1) | 1 abortion, 3 premature, 1 anomaly, 1 neonatal death | ||
| 44 | 200–1050 | U/ml | 12–42 | Underweight ≤99 pounds (n = 44), poor obstetric history (n = 5), toxaemia (n = 6), excessive weight gain (n = 3), anaemia (n = 3) | 1 abortion, 1ectopic pregnancy, 1 congenital anomaly, 3 neonatal deaths, 9 premature births | |
| 30 | 350–1650 | 11–40 | Obesity (≥200 pounds) (n = 30); Toxaemia (n = 18), excessive weight gain (n = 10), diabetes (n = 7), poor obstetric history (n = 3), anaemia (n = 1) | 3 premature, 2 neonatal deaths, 1 abortion, 4 weight ≥10 pounds | ||
| 208 | 10–2200 | 8–42 | Normal and complicated pregnancies 17% toxaemia, 6.2% diabetes | 25 premature, 9 perinatal death | ||
| 6 | 50–3174 | 10–32 | Threatened abortion | n.s., pregnancies continued >20 week | Southren et al. (1966a, b) | |
| 3 | 10–400 | 8–20 | Threatened abortion, treatment with progestational agents | Unsuccessful termination of pregnancy | ||
| 3 | 25–120 | 8–24 | Missed abortion | Abortion >16 week | ||
| 5 | 10–800 | 8–40 | History of habitual abortion | Live infants | ||
| 4 | 100–1950 | 12–34 | Incompetent os syndrome | 4 premature, 1 neonatal death | ||
| 3 | 100–900 | U/ml | 16–36 | Incompetent os syndrome | Live, term | |
| 5 | 80–1700 | 12–36 | Poor obstetrical historya | Premature, 1 antepartum death, 1 neonatal death | ||
| 5 | 0–1800 | 8–38 | Poor obstetrical history | term | ||
| 68 | 20–2085 | 10–40 | Diabetes mellitus | 4 stillbirths | Southren et al. (1968) | |
| 44 | 0–0.5 | 10−3 DAO (U/ml)a | 8 | n.s. | Early deaths <21st week | Gahl et al. (1982a, b)b |
| 29 | 0.5–2.9 | 12 | n.s. | |||
| 29 | 0.8–4.8 | 12 | n.s. | Late deaths >21st week | ||
| 23 | ‘normal’ | IU/l | >8 | Antepartum bleeding at ≤20 weeks of gestation | 47.83% (n = 11) continued pregnancies, 52.17% (n = 12) aborted | Legge and Duff (1981) |
| 31 | ‘below normal’ | 19.35% (n = 6) pregnancies continued, 80.65% (n = 25) aborted | ||||
| 4 | Normal (>8) | ≤8 | 3 aborted | |||
| 8 | Low (≤8) | 4 aborted, 4 pregnancies continued | ||||
| 120 | 10–510 | nM/0.6 ml | 8–40 | no | n.s. | Torok et al. (1970)b |
| 110 | 5–500 | mµM/ml | 8–40 | No | Term infants | Resnik and Levine(1969) |
| 6 | 60–300 | 12–34 | No | Premature, >2500 g | ||
| 25 | 20–450 | 18–40 | ‘high-risk’ i.e. toxaemia, diabetes, anaemia, erythroblastosis, dysmaturity | Term infants | ||
| 5 | 0–225 | 24–39 | ‘high-risk’: toxaemic, anaemic, alcoholic | premature |
Values were mostly read from figures and might therefore slightly deviate from the measured values which were often not given numerically in the manuscripts. aPoor obstetrical history was defined by the authors as a history of recurrent abortions, premature deliveries and stillbirths mixed with infrequent successful pregnancies (Southren et al., 1966a, b); bserum DAO activity is measured whereas the other studies use plasma DAO activity. n, number of patients; n.s., not specified.
A sharp increase of DAO levels during the first trimester (Southren et al., 1964; Dubois et al., 1977) with a following plateau phase during the second and third trimester has been described in normal pregnancies (Southren et al., 1964; Dubois et al., 1977). In conception cycles, plasma DAO activity has been shown to increase between 9 to 28 days following ovulation and to rise exponentially with a doubling time of 4–5 days during the first 10 weeks of pregnancy (Beaven et al., 1975). In humans, implantation is thought to occur on Day 7 to 8 post-ovulation (Beaven et al., 1975). The initiation of the rise has been reported to depend on non-pregnant DAO levels. An earlier rise (beginning 8–19 days following ovulation) has been described in patients with lower non-pregnant DAO levels compared with patients with higher non-pregnant values (Beaven et al., 1975). DAO peak activities seem to be reached between 12 (Southren et al., 1964) and 24 weeks (Dubois et al., 1977) of gestation. Beyond the 20th week, DAO levels of of ≥500 U/ml have been regarded as normal (Southren and Weingold, 1970; Carrington et al., 1972) (Fig. 2). After delivery, maternal enzyme titres decline to normal non-pregnancy levels in ∼10–15 days (Southren et al., 1964) with a half-live of DAO of ∼24 h (Carrington et al., 1972).
Plasma DAO activities of 66 women with uncomplicated pregnancies. Means and standard deviations are given.Data are taken and figure is adapted from (Carrington et al., 1972).
The various different studies conducted on histamine metabolism during pregnancy show the same tendency, but values are only roughly comparable, as different techniques have been used to determine DAO activity (Okuyama and Kobayashi, 1961; Tufvesson and Tryding, 1969). Clearly defined, homogenous study populations are rare and various study designs with diverse (normal and multiple heterogeneous pathological pregnancies) at different ages of gestation complicate comparability.
In general, it has been proposed that the high decidual DAO activity acts as a counter-regulation to elevated histamine concentrations in pregnancy (Kahlson, 1962; Southren et al., 1965) due to the high placental HDC activity and the EHRF. This is assumed to be an adaptive response designed to protect both the pregnant woman and the fetus against the exposure of excessive amounts of histamine (Carrington et al., 1972).
Histamine intolerance
Histamine intolerance (HIT) results from a disequilibrium of accumulated histamine and the capacity for histamine degradation. Ingestion of histamine-rich food (Sattler et al., 1988), alcohol (Wantke et al., 1994, 1996; Zimatkin and Anichtchik, 1999) or drugs (Sattler et al., 1987; Sattler and Lorenz, 1990; Wantke et al., 2001; Jarisch R et al., 2004) releasing histamine or blocking DAO may provoke diarrhoea, headache, in particular premenstrual headache (Jarisch and Wantke, 1996), congestion of the nose, asthmatoid wheezing (Sattler et al., 1988; Wantke et al., 1996; Wohrl et al., 2004), hypotension, arrhythmia, urticaria (Schmidt et al., 1990; Pollock et al., 1991), pruritus, flushing, dysmenorrhoea and others in these patients (Maintz and Novak, 2007). Symptoms can be reduced by a histamine-free diet or be eliminated by anti-histamines, mast cell stabilizers or substitution of DAO.
Approximately 1% of the population suffer from HIT. Most of them are middle-aged females (Missbichler, 2004). Due to the multifaceted symptoms, the existence of HIT is frequently underestimated or its symptoms misinterpreted. Whether women with HIT suffer from more complicated pregnancies and higher abortion rates due to impaired DAO activities and if low DAO levels might therefore represent a prognostic factor for a higher risk of abortion, has not been investigated yet.
DAO measurement avails diagnosis of PROM
Due to the presence of DAO in amniotic fluid, but absence in vaginal secretions, measurement of DAO in vaginal secretions has been suggested as a method for the diagnosis of premature rupture of membranes (PROM) (Gahl et al., 1982a, b). In patients with suspected PROM, a higher sensitivity (90.9%) and specificity (100%) has been observed for the measurement of DAO activity compared with vaginal fluid pH (Amnicator) (81.81; 83.33%) (Gaucherand et al., 1995; De Meeus et al., 1997). However, currently, the detection of insulin-like growth factor binding protein-1 in cervicovaginal secretions is regarded as the most accurate diagnostic test and predictor of latency in patients with suspected PROM (Erdemoglu and Mungan, 2004).
Low DAO activities as a screening tool for trophoblast diseases
In patients with trophoblast diseases mimicking pregnancy such as hydatid mole (Torok et al., 1970) and choriocarcinoma (Southren et al., 1964; Weingold and Southren, 1968; Torok et al., 1970; Beaven et al., 1975), low DAO activities have been observed despite high titres of HCG (Weingold and Southren, 1968). In molar pregnancies, DAO values have been shown to be comparable to normal pregnancies during the first trimester, but fall after the 15th week of gestation (Weingold and Southren, 1968). In contrast, no DAO activity has been found in patients with choriocarcinoma associated with molar pregnancy and most of the patients with choriocarcinoma of other than molar origin (Torok et al., 1970). Similar to the absence of estriol in these neoplasias, it has been concluded that the presence of the fetus seems to be necessary to induce DAO production (Weingold and Southren, 1968). Therefore the measurement of DAO has been proposed as a differential test between normal pregnancy and trophoblastic diseases (Southren et al., 1964).
Are high maternal histamine levels or reduced plasma DAO activities a reliable marker for pregnancy disorders?
Elevated maternal histamine levels in pre-eclampsia, hyperemesis gravidarum, spontaneous and threatened abortion, but a decreased placental number of mast cells and histamine concentration in intrauterine growth retardation
Pregnancies lacking an increase of DAO activity (Dubois et al., 1977) lead to elevated plasma and urine histamine concentrations (Beaven et al., 1975). These pregnancies are at increased risk for pre-eclampsia, hyperemesis gravidarum, spontaneous and threatened abortion (Kapeller-Adler, 1941a; Ahlmark, 1944; Beaven et al., 1975; Dubois et al., 1977; Clemetson and Cafaro, 1981; Brew and Sullivan, 2006).
In pre-eclampsia, mean TBH levels seem to increase with the severity of the disease (Kapeller-Adler, 1941b; Achari et al., 1971; Sharma et al., 1984) with TBH levels at gestational weeks 28–40 ranging between 63 and 87 ng/ml (Achari et al., 1971; Sharma et al., 1984) compared with 49–55 ng/ml (Sharma et al., 1984) for the same gestational age in normal pregnancies (Brew and Sullivan, 2006). An increased number of mast cells (Szukiewicz et al.,1999a) and elevated histamine concentrations in pre-eclamptic compared with normal placentae have been shown in most (Kapeller-Adler, 1952; Southren et al., 1966b; Szukiewicz et al., 1999a; Szewczyk et al., 2005), but not all (Brew et al., 2007) studies. Plasma levels of the histamine precursor histidine are similar in both normal and pre-eclamptic pregnancies (Page et al., 1955; Glew et al., 2004; Brew and Sullivan, 2006). Conversely, production of histamine by HDC is higher in pre-eclamptic placentae than in control tissues (Brew et al., 2007). A direct relationship between maternal TBH levels and maternal hypertension has been observed (Achari et al., 1971), which were inversely correlated with serum DAO levels (Achari et al., 1971; Brew and Sullivan, 2006). Therefore, higher maternal TBH levels in pre-eclamptic women might derive both from an increased placental HDC activity and from an impaired DAO activity in these patients (Brew et al., 2007).
Moreover, trophoblast cells in pre-eclampsia show an altered response to histamine (Szewczyk et al., 2008). An impaired trophoblast invasion mirrored by a decreased expression of the adhesion molecule αν-β3 integrin is thought to be a major reason for the pathogenesis of pre-eclampsia (Szewczyk et al., 2008). In vitro, stimulation with histamine has been shown to enhance the physiological αν-β3 integrin expression in trophoblast cell cultures derived from normal placentae via H1R (Szewczyk et al., 2006), but not from pre-eclamptic placentae (Szewczyk et al., 2008).
Furthermore, placental extracts from women with pre-eclampsia have been observed to exacerbate histamine-induced vasoconstriction in porcine carotid artery compared with extracts from normotensive women (Thomson et al., 2000).
The resemblance of some symptoms of pre-eclampsia such as hypertension, proteinuria, oedema, nausea and headaches to those of hyperhistaminemia might insinuate a causation by high levels of histamine, probably due to its vasomodulating capacities (Brew et al., 2007).
Increased blood, plasma and urine histamine levels and a reduced DAO activity have also been shown in hyperemesis gravidarum (Kapeller-Adler, 1944; Uuspaa and Jarvinen, 1955; Brew and Sullivan, 2006).
Conversely, a decreased number of mast cells and histamine concentration has been observed in placentae of intrauterine growth retarded pregnancies compared with placentae obtained from gestationally matched preterm controls (Szukiewicz et al., 1999b). Ischaemia due to placental insufficiency has been regarded as a main pathological factor associated with intrauterine growth retardation (Szukiewicz et al., 1999b). It has been speculated that the decreased number of mast cells in intrauterine growth retarded pregnancies might lead to an impaired adaptive response to hypoxia due to a deficiency of angiogenic factors derived from mast cells (Szukiewicz et al., 1999b).
Precipitously falling or persistently low maternal plasma DAO activities in heterogenous pregnancy complications such as toxaemia, diabetes, threatened, habitual and missed abortions
Plasma DAO has been proposed to be of value as an indicator of fetoplacental integrity (Southren et al., 1966b; Weingold and Southren, 1968; Southren and Weingold, 1970). As a consequence, precipitously falling DAO curves have been regarded indicative for fetal distress or intrauterine death (Southren and Weingold, 1970).
Serial plasma enzyme titres within the normal range have been shown to indicate maintenance of pregnancy into the third trimester in the majority of the patients (Southren et al., 1966b). Persistently low or falling DAO plasma curves have been shown in various pregnancies complications such as toxaemia, diabetes, anaemia, threatened and missed abortion (Fig. 3) compared with normal pregnancies (Southren et al., 1966b; Weingold and Southren, 1968; Legge and Duff, 1981), especially during the last trimester (Southren et al., 1966b; Southren and Weingold, 1970; Legge and Duff, 1981).
Range of Plasma DAO activities during gestation.Normal DAO ranges (black lines, grey field) (n = 34) and DAO ranges of women with missed abortions (grey lines) as an example for high-risk pregnancies are given. Data are taken, and the figure is adapted from (Southren et al., 1966b).
In patients with threatened (Legge and Duff, 1981) or missed abortion (Weingold and Southren, 1968), DAO levels within the normal range were associated with continuing pregnancies, whereas levels below the normal range were associated with subsequent abortion (Legge and Duff, 1981). A single period of antepartum bleeding accompanied by a rapid linear rise of plasma DAO titres in the first 20 weeks of gestation has been associated with a favourable prognosis (Southren et al., 1966b; Weingold and Southren, 1968). Conversely, cases of recurrent bleeding have been associated with a falling or flat plasma DAO curve and a poor prognosis (Southren et al., 1966b; Weingold and Southren, 1968). There is only very limited data available on the DAO activity in patients with habitual (≥3 consecutive) abortions. One study showed 5 patients with a history of habitual abortion who featured increasing DAO levels, although slowly rising and at the lower level of normal, which were associated with live infants in spite of their history (Southren et al., 1966b; Weingold and Southren, 1968).
Older mothers (age ≥40 years) have been shown to feature a higher percentage of abnormal DAO values than young (≤19 years) mothers (Southren and Weingold, 1970). Conversely, no significant differences have been observed between obese patients without other major health problems and normal weight patients whereas in maternal underweight (<99 pounds), a high incidence of prematurity was found in association with a low maternal plasma DAO curve (Southren and Weingold, 1970).
Although a falling or persistently low activity of plasma DAO in early pregnancy has been associated with significant fetal wastage (Southren et al., 1966b, 1968; Weingold and Southren, 1968; Beaven et al., 1975; Gahl et al., 1982a, b), some of these pregnancies have been shown to continue, some to successful term deliveries (Southren et al., 1966b). The different studies show comparable data in term of the course of DAO activity during normal pregnancies, but not all studies could confirm precipitously falling or persistently low DAO activities in high-risk pregnancies (Resnik and Levine, 1969; Carrington et al., 1972). Unfortunately, screening for chromosomal aberrations as a frequent reason for miscarriage is not indicated in the studies. The relative risk for fetal demise associated with a low DAO activity has been shown to increase from 3.7 at 8 weeks of gestation to 16.6 at 12 weeks of gestation (Gahl et al., 1982a, b). A reduction of placental growth caused by the death of the fetus with subsequently low DAO production has been discussed as a reason for the decrease of DAO activity (Gahl et al., 1982a, b). However, study results are discussed controversially regarding this parameter (Southren et al., 1966b; Southren and Weingold, 1970). Anyhow, the contractile effect of high amounts of insufficiently degraded histamine on the uterine musculature might contribute to a higher rate of abortion in patients with a low DAO activity.
Histamine competes with the other DAO substrates spermidine and putrescine for the enzyme (Holinka and Gurpide, 1984). However, the decreased DAO activity in complicated pregnancies seems to affect only the degradation of histamine and not of other polyamines (Kapeller-Adler, 1944; Kapeller-Adler, 1965a, b; Brew and Sullivan, 2001), as no significant differences have been found for the concentration of other polyamines of normal term placentae compared with placentae from growth retarded and pre-eclamptic pregnancies (Kumazawa et al., 1991; Sooranna and Das, 1995; Brew and Sullivan, 2001). DAO activities have therefore been suggested to act as an indicator of the fetal environment (Lin et al., 1978) and serial measurements have been proposed for the early detection of ‘high-risk’ pregnancies and trophoblast diseases (Southren et al., 1966b; Weingold, 1968; Weingold and Southren, 1968; Beaven et al., 1975; Lin et al., 1978). Due to low DAO activities in early pregnancy and the presence of DAO in the plasma of non-pregnant women, measurement of DAO as a prognostic marker has been recommended to be of value only from the 8th week of gestation (Legge and Duff, 1981).
Discussion
High expression of the histamine-producing enzyme HDC in the placenta, histamine receptors at the feto–maternal interface and the existence of an EHRF indicate a physiological role of histamine during implantation. Later in pregnancy, histamine functions as a paracrine oxytocic directly on gestational myometrium giving rise to contraction and indirectly by an increased production of the uterotonic PGF2α by the decidua. It might therefore contribute to both term and preterm labour.
Without the protective action of an increased DAO activity, an excess of histamine exerts pathological effects on the course of pregnancy. The presence of the HRs at the feto–maternal interface also support the view that prolonged exposure of feto–maternal interface tissues to high levels of histamine might have fundamental roles in the pathogenesis of pre-eclampsia (Szewczyk et al., 2005), spontaneous abortion and other pregnancy related diseases in which high levels of histamine have been demonstrated (Southren et al., 1966b; Beaven et al., 1975; Dubois et al., 1977; Brew and Sullivan, 2001). However, the techniques used for determination of histamine levels in the older studies are considered inaccurate by modern standards (Brew and Sullivan, 2006). Moreover, the instability, and wide inter- and intraindividual variations of histamine (Brew and Sullivan, 2006) complicate reliable comparisons of values between normal and complicated pregnancies.
DAO at the feto–maternal interface is supposed to serve as a metabolic barrier to prevent excessive entry of bioactive histamine into the maternal or fetal circulation as well as to impede prolonged exposure of decidual cells (Brew and Sullivan, 2001). Persistently low or falling DAO plasma curves have been shown in various pregnancies complications such as toxaemia, diabetes, anaemia, threatened and missed abortion compared with normal pregnancies (Southren et al., 1966b; Weingold and Southren, 1968; Legge and Duff, 1981), especially during the last trimester (Southren et al., 1966b; Southren and Weingold, 1970; Legge and Duff, 1981). Fetal organic and skeletal abnormalities (Nava and Fraile, 1988) as far as spontaneous abortion (Roberts, 1954) after DAO inhibition with aminoguanidine observed in pregnant rats (Nava and Fraile, 1988) stress the impact of a sufficient histamine degradation during pregnancy.
However, high intra- and interindividual variations have been found in both normal and pathological pregnancies which query the identification of reliable deviations from normal pregnancy levels (Southren et al., 1964; Resnik and Levine, 1969). Moreover, data of homogeneous study collectives and standardized serial measurements of DAO are limited and show intraindividual variations during pregnancy which did not necessarily have prognostic significance (Southren et al., 1966a; Resnik and Levine, 1969; Southren and Weingold, 1970). Together with the high financial costs of the DAO assay these might be the reasons why the measurement of DAO activity has not become accepted in daily clinical practice yet. More studies with standardized assay procedures and large well-defined and homogeneous study collectives are needed to allow a final statement regarding the prognostic value of DAO activities for the course of pregnancies. Anyhow, especially in conjunction with other tests, detection of an increased relative risk of fetal death with the help of DAO measurement might prompt certain obstetrical precautions late in pregnancy (Gahl et al., 1982a, b).
Whether patients with complicated pregnancies mirrored by low DAO values also suffer from HIT-like symptoms during this period or before pregnancy and whether they feature abnormal low DAO activities already in the non-pregnant-status, which might serve as diagnostic tool to identify women at risk for pregnancies complicated by insufficient histamine degradation, has not been investigated yet. Moreover, a substitution of DAO might present a therapeutical option for patients with high-risk pregnancy or women with yet-to be identified genetically predetermined defects in DAO activity in the future.
Funding
This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG NO454/1-4 and DFG NO454/2-3) and a BONFOR grant of the University of Bonn. N.N. is supported by a Heisenberg-Professorship of the DFG NO454/5-1. L.M. is supported by a Gerok/BONFOR grant of the University of Bonn.



