This is a new series of articles that will explain what changes in a pregnant womans’ body, what is needed to be taken into consideration when prescribing medicines and the complications that could occur.
The first article discusses the general aspects related to pregnancy and explains how and why these changes take place during gestation.
Birth rates vary considerably around the world, from 8 to 10 live births per 1,000 population per year in developed countries, to over 40 births per 1,000 population in the developing world. In the UK, there has been a decrease in both maternal and perinatal mortality in the UK, suggesting improved antenatal care.
Pregnancy is the period of foetal development. It lasts around 40 weeks, measured from the first day of the last menstrual period. It is typically divided into three trimesters:
- The first starts with conception and runs to week 12;
- the second spans weeks 13 to 28;
- the third from week 29 to term; historically defined as any time from week 37 to 42.
Each of these trimesters are characterised by distinct periods of foetal development and growth, all of which are vulnerable to disruption or harm following drug exposure.
Organogenesis of the foetus, or the formation of organs and their systems, occurs in the first trimester from fertilisation to week eight (the embryonic period). By week four, the placenta and umbilicus are in place and continue to develop until the end of the third month, in order to provide a source of nutrition and oxygen to the foetus. The embryonic period is followed by the foetal period, during which time the organs formed over the previous eight weeks grow to resemble their final forms.
The need for drug therapy during pregnancy may arise from pre-existing medical conditions or as a result of pregnancy-related complications such as diabetes, pre-eclampsia and venous thromboembolism (VTE). As all drugs have the potential to cause harm in pregnancy, any decisions to use medication are made on a balance of risk versus benefit to the mother and the unborn foetus, with the mother, where possible, actively involved in making a fully informed choice.
During pregnancy, physiological changes in all body systems occur to meet foetal requirements for growth and development, and later to prepare for delivery. These changes can impact on both the pharmacokinetic and pharmacodynamic effects of any medicine, potentially impacting both efficacy and toxicity.
Cardiovascular changes are present from conception, with vascular resistance decreasing by up to 40%. This leads to a decline in blood pressure until about 24 weeks’ gestation, before gradually returning to pre-pregnancy levels at term. In compensation, there is a gradual increase in heart rate and stroke volume, leading to an overall increase in cardiac output that plateaus at the end of the second trimester and increases during labour. Cardiac output declines rapidly at birth and has normalised by 24 weeks postpartum.
Haematological changes during pregnancy include an increase in plasma volume by approximately 40–50%, along with a smaller increase of 15–20% in red cell volume, leading to a reduction in overall blood viscosity. Changes in the coagulation cascade also occur during pregnancy, which lead to an increase in coagulation factors (e.g. VII, VIII, IX, X and XII, fibrinogen and von Willibrand factor) and decrease in fibrinolysis through increased levels of plasminogen activator inhibitors, in order to minimise blood loss at the time of delivery. This leads to an increased risk of VTE.
Respiratory changes are mediated, likely through progesterone, in order to meet increased maternal and foetal oxygen demand. There is a significant increase in oxygen consumption and a 40% increase in ventilation, which is caused by a rise in tidal volume rather than respiratory rate. The increase in tidal volume reduces the partial pressure of carbon dioxide (PCO2) in the mother to half that of the foetus to aid with gas exchange. At the same time, progesterone acts to loosen the ligaments between ribs, enabling the chest to flare and thereby compensating the loss in chest volume as the uterus expands upwards.
Renal changes (caused by increased blood volume) lead to an increase in renal blood flow of 35–60% and glomerular filtration rate of 40–50% by the end of the first trimester. Renally cleared drugs have the potential to be excreted more rapidly. There are also changes to the renin-angiotensin system leading to fluid and sodium retention, likely triggered to compensate for the reduction in vascular resistance. Glucose loss through the kidneys is increased during pregnancy, leading to an increase in the risk of urinary tract infections and making urinalysis a less reliable indicator for gestational diabetes (see below).
Hepatic changes during pregnancy include a decrease in serum albumin levels and altered activity of hepatic enzymes involved in drug metabolism. By the time of the delivery, albumin levels have reduced to 70–80% of normal levels, which can impact on drug levels of highly protein-bound drugs, although in clinical practice this is more likely an issue with drugs that are extensively metabolised by the liver. When monitoring blood levels of highly protein-bound drugs, they should be adjusted for low albumin levels.
Gastrointestinal changes are related to the smooth muscle effects of progesterone and increased pressure from the expanding uterus, which leads to decreased lower oesophageal sphincter muscle pressure and gastrointestinal motility. As a result, pregnant women are more prone to bloating, constipation and oesophageal reflux. There is also a theoretical risk of altered absorption as a result of changes in gastric pH and motility, although there is no evidence of this in clinical practice.
In the next articles we will write about important aspects that should be taken into consideration when prescribing medicines for a pregnant woman and about the complications that can occur during the 9 months of pregnancy or post-partum.
Ps1: If you welcomed a baby or know someone who is preparing for this moment, don’t hesitate to share this article! Stay close for the next articles from this series!
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