Drug-Induced Microbiome Changes: Considerations in Pregnancy

Abstract

During pregnancy, the maternal microbiome is associated with both the health of the mother as well as the developing fetus. Several classes of drugs are known to influence the microbiome and their use in pregnancy may impact maternal/fetal outcomes and long-term health of offspring. The drug-microbiome interactions of antibiotics, proton pump inhibitors, laxatives, metformin, and probiotics will be described, along with considerations for use of these agents in pregnancy.

“Clinicians need to be aware that drugs outside the antibiotic class are capable of modulating the microbiome and may ultimately lead to impaired health.”

Recent advances in technology have greatly increased our understanding of the composition and function of the human microbiome. The term “microbiome” refers to the entirety of microorganisms that reside in the tissues and organs of an individual and include archaea, bacteria, fungi, and viruses. ¹ The human microbiome has a major impact on health through a number of suggested benefits on the host including participation in the development and maintenance of metabolic, biochemical, and immunological processes. ² During pregnancy, the maternal microbiome is associated with both the health of the mother as well as the developing fetus.^2-4 Recent studies now suggest the microbiome may play a role in gestational diabetes, gestational obesity (weight gain during pregnancy which exceeds the expected norms), and preeclampsia, as well as digestive tract and autoimmune diseases in the mother. ³ The microbiome is also thought to have a significant impact on the immune system and neurodevelopment of the fetus. Associations have been made between dysiosis of the gut microbiome early in life and cognitive ability, obesity, asthma, and allergy conditions later in life.^5,6 The mechanism by which the microbiome mediates these effects is unclear but may be related to vertical transmission and/or microbiota-derived metabolite signaling/transmission. ²

During pregnancy, the maternal microbiome undergoes significant changes which can be attributed to a number of modifiable factors including maternal diet, stress, infections, and antibiotic use. ⁴ Regulating the maternal microbiome may serve as an important approach for improving pregnancy outcomes as well as fetal development and long-term health. The following will explore drug-induced microbiome changes and describe the observed and potential impact of these changes on maternal and fetal health.

Drug-Induced Microbiome Changes

Various human studies have reported associations between the use of medications and the make-up and function of the microbiome.^7-9 Antibiotics, proton pump inhibitors (PPIs), metformin, laxatives, and probiotics are among the most influential classes of drugs on the microbiome. Each class will be discussed in further detail below.

Antibiotics

Antibiotics have long been recognized as modulators of the microbiome through the inhibition of growth of certain bacteria. Antibiotics are administered in about 25% of pregnancies and account for nearly 80% of all medications prescribed for pregnant women. ¹⁰ Antibiotics are used during pregnancy to treat infections and prevent pre-term birth. Intrapartum antibiotic prophylaxis (IAP) is also common to prevent maternal infection after cesarean section and to prevent Group B streptococcus diseases in neonates.

Several studies demonstrate that IAP alters the neonatal gut microbiome and reduces bacterial diversity compared to healthy controls.^11-15 While some of these studies found the effect diminished within 30 days of antibiotic exposure, a study of IAP due to cesarean section demonstrated persistent alterations.^11,12,15 Human epidemiologic data demonstrate an increased risk of asthma, atopic dermatitis, food allergy, and inflammatory bowel disease in children with exposure to antibiotics during pregnancy suggesting dysbiosis early in life may lead to diseases later on.^16-18

Proton-Pump Inhibitors, Laxatives, and Metformin

Other non-antibiotic medications have recently been linked to dysbiosis. ⁷ The non-antibiotic drug classes with the strongest associations with the microbiome include PPIs, laxatives, and metformin. ⁷ PPIs are thought to induce alterations to the microbiome through their reduction in gastric acidity which enables oral bacteria to colonize in the gut. ¹⁹ It appears to be a class-effect of PPIs and may be contributing to decreased colonization-resistance to enteric infections like Clostridium difficile which have been observed in PPI users.^7,20 Although PPI use in pregnancy is not associated with birth defects at the time of delivery, use in childhood has been linked to obesity later in life which may be mediated through changes in the developing gut microbiome.^21,22

The effect of the use of laxatives on the microbiome is complicated by the impact laxatives have on intestinal transit time and stool consistency. Polyethylene glycol use is associated with an increased abundance of Bacteroides in mice; however, an increase in Bacteroides species is also observed in individuals with rapid intestinal transit time, independent of laxative use. ²³ Therefore, the microbiome changes associated with laxative use may be an indirect effect of a change in the gut osmolality rather than the direct effect of the drug itself.

Metformin appears to exert some of its therapeutic effect through alterations in the gut microbiome. ²⁴ This effect is thought to be mediated primarily through an increase in short-chain fatty acid production. ⁷ Metformin has been used in pregnancy to treat gestational obesity, polycystic ovarian syndrome (PCOS), and gestational diabetes. ²⁵ The long-term effects of offspring exposed to metformin during pregnancy are not fully understood. Human studies suggest benefits to female offspring at risk for PCOS (reduced anti-mullerian hormone levels), but risks including increased bodyweight and metabolic derangements (higher glucose levels, elevated blood pressure) have also been observed.^26-30

Probiotics

Probiotics are live microbes delivered via diet or by supplementation to restore physiologic balance of the gut microbiota. During the perinatal period and infancy, the microbiome of offspring is closely related to that of the mother. A study by Ferretti et al., found that the maternal microbiome of the gut, vagina, oral cavity, and skin determine 22.1%, 16.3%, 7.2%, and 5.0% of the infant gut microbiome, respectively. ²⁷ Use of probiotics in pregnancy is a strategy being explored to modulate the maternal microbiome in an effort to colonize the infant gut with beneficial microbiota species to improve offspring health.

Within the last several years, various reviews and meta-analysis attempt to summarize the burgeoning body of research evaluating the effect of probiotic supplementation during pregnancy.^3,31-41 There is consistent evidence that maternally derived probiotic bacteria is transferred to the fetus. How long these supplemented strains persist in the offspring microbiome is less clear. While overall findings are conflicting, meta-analyses of randomized controlled trials report probiotic supplementation is associated with a significant improvements in glycemic control, blood lipid profiles, and inflammation and oxidatative stress in mothers with gestational diabetes, as well as a decrease atopic eczema, eczema, prolonged gestational age, risk of death, and incidence of necrotizing enterocolitis in the offspring.^36,41 Most of the reviews cited above suggest interpreting results with caution. Administration protocols, species-specific benefits, the window of susceptibility, and time to effect are all important questions which require further investigation.

Microbiome-Related Considerations for Drug Use in Pregnancy

Our understanding of the impact of the microbiome on maternal and fetal health during pregnancy is rapidly expanding. We are also just beginning to identify drug-microbiome interactions and their effect on the host. There is consistent evidence that antibiotic use during pregnancy can impact both the maternal and offspring microbiome with significant health consequences. Therefore, it is important to weigh the risk vs benefit of antibiotic use in pregnancy.

Clinicians need to be aware that drugs outside the antibiotic class are capable of modulating the microbiome and may ultimately lead to impaired health. The impact of the use of PPIs, laxatives and metformin on the microbiome in pregnancy should be further explored, especially as it relates to long-term health in offspring. Because PPIs and laxatives are available without a prescription and (some drugs within the class) are generally considered safe in pregnancy, expectant mothers should be counseled on the microbiome altering potential of these agents in order to make an informed decision about their use.

Studies evaluating the impact of probiotic supplementation during pregnancy are promising, but inconclusive, and require further investigation. Randomized controlled trial data seem to suggest that probiotic supplementation during pregnancy may have beneficial effects for both the mother and the baby.

Much of the data described above comes from relevance studies. Further mechanistic and interventional trials are needed to better understand the relationship between drug-induced changes on the microbiome in pregnancy and the effect on maternal and offspring health.