In many populations worldwide over 50% of women have a body mass index above 25. Therefore, an increasing number of women enter pregnancy overweight or obese. This increases the risk for pregnancy complications such as Gestational Diabetes Mellitus (GDM). Placental function is often affected in obese and GDM pregnancies, which affects fetal growth and development. Recent years have implicated placental extracellular vesicles (EV) in fetal-maternal communication, with their microRNA (miRNA) content affecting maternal metabolism and potentially the fetus. Overall, it is well-established that obese and glucose-intolerant pregnancies have short- and long-term health consequences for mother and child. Women with GDM are therefore treated to control maternal glycaemia and thereby prevent effects on the fetus caused by excessive glucose exposure. In many countries metformin (an oral glucose-lowering agent) is now the first line pharmacological treatment for GDM as it can control maternal glycaemia and reduce gestational weight gain. However, metformin can cross the placenta and thereby directly affect the fetus. A few studies in humans and in animal models have reported increased adiposity in offspring exposed to metformin during pregnancy. However, information regarding the immediate actions of metformin on the placenta and fetus is limited. This thesis therefore aimed to assess the impact of metformin treatment of an obese and glucose-intolerant pregnancy in a mouse model on (i) the mother (described in chapter 3), (ii) fetal growth and placental structure (described in chapter 4) and (iii) on the placental lipidome and transcriptome (described in chapter 5). A last aim of this thesis was (iv) the establishment of isolation of placental EVs and characterisation of their miRNA content in an obese and glucose-intolerant pregnancy (described in chapter 6). In this thesis it is shown (chapter 3) that feeding mice a diet high in sugar and fat prior to and throughout pregnancy increased maternal fat mass and impaired glucose tolerance. Additionally, a preeclampsia-like phenotype with impaired uterine artery compliance and increased serum sFlt levels was induced. All these parameters were improved by treatment of the dams with metformin at clinically relevant doses prior to mating and throughout pregnancy. These findings are consistent with metformin being beneficial for maternal metabolic health, as observed in human studies, including recent data highlighting the potential of metformin to prevent preeclampsia. Chapter 4 highlights that placentas from obese dams had calcium depositions and a reduced labyrinthine zone. Calcium deposits have been observed previously in pregnancies complicated by GDM and obesity, showing that our model resembles the human situation. The obesity-induced placental pathologies together with the reduced uterine artery supply likely led to the fetal growth restriction observed. Metformin treatment did not rescue any of these obesity-induced changes in the fetus and the placenta. Metformin crossed the placenta and entered the fetal circulation at levels equivalent to maternal concentrations and was also taken up into fetal tissues. Metformin can therefore exert direct effects on the placenta and/or the fetus that may explain why fetal growth restriction and placental impairments are not rescued by metformin despite the improvement in uterine artery compliance. Reduced body weight in babies exposed to metformin in utero has previously been shown in human studies. Metformin did not affect placental AMPK and mTOR signalling as previously reported, but increased apoptosis markers in the male placenta. As the placenta accumulated substantial levels of metformin and is the key interface between mother and fetus we investigated in chapter 5 effects of metformin on the lipidome and transcriptome by comparing obese untreated and obese metformin-treated placentas. Metformin reduced triglycerides with low carbon numbers and free carnitine. A reduction of carnitine has previously been linked to preterm birth. Additionally, phosphatidylserines (PS) and sphingosine (18:0) were increased in the male placenta and lyso-phosphatidylcholine was reduced in the female placenta upon metformin treatment. A few human studies reported previously increased rates of preterm births in pregnancies exposed to metformin, thereby the reduced carnitine levels together with increased PS levels that could be linked to apoptosis in the male placenta warrant further investigation. Placental transcriptome analysis identified no major changes in mRNA expression upon metformin exposure but highlighted overall sex differences within the placenta that were consistent with increased in utero vulnerability of male fetuses to maternal obesity. Lastly, chapter 6 of this thesis shows the feasibility of extracting placental EVs released from placental explants. In a pilot study EVs and their miRNA cargo from male control placentas were compared to those from male obese placentas. miRNAs previously identified as playing a role in IGF2 signalling, mitochondrial dysfunction and preeclampsia were altered in obese placental EVs. Therefore, further follow-up could identify the role of placental EVs in matching maternal supply and fetal demand via modulating IGF2 signalling and could add evidence for their use as biomarkers to identify impaired placental function and preeclampsia. Overall, this thesis shows beneficial effects of metformin on maternal metabolic health and adds evidence to the current discussion of metformin as a preeclampsia treatment. However, it also highlights that metformin can have direct effects on the fetus and the placenta, with some evidence that at least some of these effects are sexually dimorphic. The use of metformin in pregnancy is complex and might be good for some women where beneficial effects of metformin in pregnancy might outweigh potential short-and long-term effects on the offspring. However, this might not be the case in other women. Therefore identifying treatment strategies/metformin formulations that retain maternal benefits whilst reducing fetal exposure should be the important goal of future studies.