Clinical Pharmacology Unit, Aberdeen Royal Infirmary, Aberdeen, UK
Correspondence to Professor John Webster, Clinical Pharmacology Unit, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, UK. E-mail: firstname.lastname@example.org
During pregnancy, substantial physiological changes occur to facilitate the growth of the foetus and the adaptive changes in the mother necessary to accommodate the enlarging uterus, and in preparation for parturition and lactation. Cardiac output may double; plasma volume and glomerular filtration rate increase by 50%; the placenta provides a major source of new and existing hormones; blood viscosity decreases; lung function changes in a complex fashion; and the musculoskeletal system alters to cope with the usual weight gain of 15 kg and the pelvic changes necessary for delivery.
Most pregnancies are uncomplicated and, though not necessarily uneventful, proceed without any need to agonize about pathophysiology. Nonetheless, understanding the complex changes that evolve over a 40-week gestation is fundamental to good obstetric practice. Furthermore, pregnancy may act as a barometer of disease in later life, and by providing a short-term ‘stress test’ may reveal underlying problems that had been previously unrecognized, such as hypertension, glucose intolerance, a variety of cardiac abnormalities, and thrombophilia. Thus, understanding the mechanisms and potential variations in these changes may yet throw light on the early origins of chronic disease processes.
Even in ‘developed’ countries, maternal mortality remains a significant problem. In the UK, it has remained at approximately six per 100 000 maternities since 1985 . Cardiovascular disorders remain an important cause of maternal morbidity and mortality and of adverse foetal outcomes. Hypertensive disorders account for a significant proportion of this group of pregnancy-associated complications, and preeclampsia, especially, remains in the top three direct causes of maternal mortality, along with sepsis and haemorrhage. Among indirect causes, cardiac disorders are by far the largest contributor. Understanding the derangement of haemodynamics and vascular function that underlie these disorders continues to exercise clinicians and researchers. Determining the ‘cause’ of preeclampsia, in particular, in which changes in blood pressure are such an important feature, has been one of the holy grails of obstetric research for many decades. That continues to prove elusive, though much has been done to increase understanding of the changes that underlie this condition. The study by Mahendru et al. may add to that understanding, and supplements a previous study by these authors on the same subject . In their first study, they reported on haemodynamic changes from preconception to shortly after first positive pregnancy test (at about 6 weeks’ gestation). In the current study, they extend these observations to a longitudinal follow-up throughout pregnancy and in to the postpartum period.
It has long been recognized that normal pregnancy is accompanied by small but important changes in blood pressure. In very general terms, blood pressure falls slightly towards mid-pregnancy and by term has increased again to levels recorded in early pregnancy. By early pregnancy, we mostly refer to the patient's first ‘booking’ visit, which, in most developed health services, will be at or around 12 weeks’ gestation. What has not heretofore been recognized is just how early some of these cardiovascular changes occur, largely for the very obvious reason that women tend to announce their pregnancy a few months after conception.
Trophoblastic cells in the embryo and placenta produce a variety of hormones. One of the earliest to appear is the glycoprotein beta-human chorionic gonadotrophin (β-hCG). Messenger RNA for β-hCG is detectable in the blastomere of early embryos at a few days of age, though only reliably detectable in maternal serum [4,5] and urine  after implantation – usually about 10 days after conception. The beta core fragment becomes the predominant form at about 5 weeks after conception, its concentration rising exponentially during this interval, at which time the hyperglycosylated form in the maternal urine forms the basis for most current pregnancy testing kits. Thus, even before a woman recognizes that she is pregnant, significant hormonal changes have begun, and it would not be at all surprising if these may already be having an effect on maternal cardiovascular function.
Until recently, most of the information available to us about haemodynamic changes in normal pregnancy relate to changes that occur some time after pregnancy has been confirmed. Most women suspect their pregnancy at around 6 weeks’ gestation, when pregnancy testing becomes reliably accurate, but, at least in the UK, seldom present to maternity/medical services before about 10–12 weeks when a ‘booking’ visit may be scheduled. The great proportion of our knowledge about blood pressure and other cardiovascular changes start from this point. Three recent studies reported in this Journal are typical, where the gestational age at ‘baseline’ was from 8 to 15 weeks [7–9].
The most interesting feature of the present study and its predecessor is the identification of women for study before they became pregnant. Noninvasive, well standardized and validated measurements of brachial blood pressure (Omron – M7), cardiac output (Innocor – inert gas rebreathing technique) and pulse wave analysis (Sphygmocor) were performed in a group of 54 women who were planning to become pregnant. Pregnancy testing was undertaken after the luteinizing hormone (LH) surge of each cycle until a positive result was obtained. Haemodynamic measurements were performed before conception and then as soon as possible after pregnancy was confirmed by urine testing for β-hCG – on average at 6 weeks’ gestation. Further measurements were made at 23 and 33 weeks and at 16 weeks postpartum. The main novel observation is that many of the changes in haemodynamics, though previously recognized, can be observed within a few weeks of conception. These include an increase in heart rate, a fall in blood pressure and a fall in total peripheral resistance.
The undeniable conclusion of this very carefully conducted study is that significant changes in cardiovascular parameters, even though modest in magnitude, can be observed almost as soon as implantation has been established. These observations have a number of important consequences. First, they put into perspective many preceding studies about cardiovascular change in normal pregnancy. That is in no way to invalidate these previous studies, but these now need to be seen and interpreted in the context that some changes have preceded those previously reported. Second, they raise interesting questions about the possible mechanisms underlying such early changes. Third, they raise questions about generalizability. This was a tightly controlled study in a relatively homogeneous group of healthy English women. Would similar patterns of change be observed in other groups and in other populations? Do similar changes occur in pregnancies that subsequently turn out to be complicated by hypertensive disorders, such as gestational hypertension, preeclampsia and intrauterine growth retardation?
At the very early stages of gestation, cytotrophoblasts infiltrate the myometrium and begin to express vascular phenotypes that facilitate endovascular invasion and establishment of a functioning placenta. There is evidence to suggest that failure of this early placentation phase may predispose to some of the later hypertensive disorders of pregnancy. It would certainly be of interest to know if variations in this phenomenon of placentation are reflected in the very early maternal haemodynamic changes reported by Mahendru et al. Now that really might be useful.
Conflicts of interest
There are no conflicts of interest.
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