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In-utero exposure to metformin for type 2 diabetes or polycystic ovary syndrome: A prospective comparative observational study
Accepted Manuscript Title: In-utero exposure to metformin for type 2 diabetes or polycystic ovary syndrome: a prospective comparative observational study Authors: Orna Diav-Citrin, Salit Steinmetz-Shoob, Svetlana Shechtman, Asher Ornoy PII: DOI: Reference:
S0890-6238(18)30047-9 https://doi.org/10.1016/j.reprotox.2018.05.007 RTX 7673
To appear in:
Reproductive Toxicology
Received date: Revised date: Accepted date:
13-2-2018 14-5-2018 26-5-2018
Please cite this article as: Diav-Citrin Orna, Steinmetz-Shoob Salit, Shechtman Svetlana, Ornoy Asher.In-utero exposure to metformin for type 2 diabetes or polycystic ovary syndrome: a prospective comparative observational study.Reproductive Toxicology (2018), https://doi.org/10.1016/j.reprotox.2018.05.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
In-utero exposure to metformin for type 2 diabetes or polycystic ovary syndrome: a prospective comparative observational study
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Running Heading: Metformin for type 2 diabetes or PCOS in pregnancy
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Orna Diav-Citrin1,2**, MD, Salit Steinmetz-Shoob1,3, PharmD*, Svetlana Shechtman1, PhD, and Asher Ornoy2, MD.
The Israeli Teratology Information Service, Israel Ministry of Health, Jerusalem.
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The Hebrew University Hadassah Medical School, Jerusalem, Israel.
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The Division of Clinical Pharmacy, the Hebrew University of Jerusalem, Israel.
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Previous presentation at the 2nd international ENTIS (European Network of Teratology Information Services) and OTIS (Organization of Teratology Information Specialists) joint meeting, Toronto, Canada, September 19th-21st, 2014 **
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Corresponding author: Orna Diav-Citrin, MD The Israeli Teratology Information Service, Israel Ministry of Health, P.O. Box 1176 Jerusalem, 9446724, Israel, Tel: 972-2-5080441, Fax: 972-2-6474822 e-mail address: [email protected]
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Highlights:
The present study is a prospective comparative observational cohort
Metformin first trimester exposure per se is not associated with a teratogenic
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risk The pattern of anomalies in the groups with diabetes may be hyperglycemia-
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related
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Abstract
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Objective: To evaluate the rate of major anomalies after first trimester (T1)-
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metformin exposure. Design: Comparative, observational cohort study done at the
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Israeli Teratology Information Service between 2000 and 2013. Results: 170 T1-
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metformin-exposed pregnancies [119 for diabetes and 51 for polycystic ovary syndrome (PCOS)] were prospectively followed-up and compared with 93 pregnancies of T1-insulin treated women and 530 non-teratogenic exposed (NTE)
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pregnancies. The differences in the rate of major anomalies excluding
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genetic/cytogenetic, and spontaneously resolved cardiovascular anomalies were not significant [4.4% (2/45) - metformin-PCOS, 1.1% (1/90) - metformin-diabetes, 2.5%
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(2/80) - insulin, and 1.7% (9/519) - NTE; ORadj metformin /NTE 1.77; 95% CI 0.45-7.01; ORadj insulin /NTE 1.69; 95% CI 0.35-8.11]. The rate of Cesarean section was higher in both the metformin-diabetes 51/90 (56.7%) and insulin 45/79 (57.0%) compared with the NTE group [138/503 (27.4%)]. Conclusion: Metformin-T1-exposure per se is not associated with an increased risk of major anomalies. 2
Keywords: metformin, diabetes mellitus, polycystic ovary syndrome, pregnancy,
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congenital anomalies.
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Introduction
Metformin is a biguanide oral antihyperglycemic agent. It is a first line drug in the treatment of type 2 diabetes mellitus [1]. Additionally, it is commonly used in
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polycystic ovary syndrome (PCOS) [2-3]. Its mechanism of action is primarily by inhibiting hepatic gluconeogenesis and by increasing the action of insulin in certain
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peripheral tissues [4]. Studies suggest that metformin could also affect pituitary
gonadotropin secreting cells [5]. According to the American Diabetes Association [6], insulin is the preferred agent for management of pre-gestational type 1 diabetes and
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type 2 diabetes that are not adequately controlled with diet, exercise and metformin.
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In contrast to insulin, human placental transfer of metformin has been documented
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[7]. Animal reproductive studies have been inconsistent. Metformin has not been
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teratogenic in rats and rabbits at doses up to 600mg/kg/d [8]; however, in some rat
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studies neural tube defects and anophthalmia were observed in less than 0.5% of the fetuses [9]. Studies on the use of metformin for gestational diabetes often deal with late exposure beyond the period of organogenesis. Human first trimester pregnancy
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experience with metformin has been reassuring but limited [10-25], especially for pregestational diabetes. The data have been summarized in several published meta-
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analyses [26-30]. All support lack of increased risk for major anomalies and show
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some benefits for metformin treatment. In the meta-analysis published by Cassina et al [28] the rate of major anomalies was 3/351 among pregnancies of women treated with metformin during the first trimester for PCOS with an OR of 0.86 (95% CI 0.184.08). The overall rate of major anomalies was 0.6% in the group of 517 women who discontinued the therapy upon pregnancy confirmation and 0.5% in the sample of 634 4
who were treated with metformin throughout the first trimester, after inclusion of uncontrolled PCOS studies reported in the literature. The number of pregnancies among women treated with metformin in the first trimester for type 2 diabetes was too small to perform a meta-analysis. Even in the various meta-analyses the data regarding congenital anomalies after early pregnancy exposure to metformin are
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relatively scant, and for the indication of pre-gestational diabetes are even more
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limited.
The primary objective of the present study was to evaluate the rate of major anomalies after first trimester (T1) metformin exposure among women with pre-gestational
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diabetes or PCOS compared with two groups: 1) women with pre-gestational diabetes
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treated with insulin, and 2) women counseled for non-teratogenic exposure.
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Secondary objectives were to compare the rate of pregnancy outcome (i.e. live-birth,
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miscarriage, elective termination of pregnancy, stillbirth), mode of delivery, birth
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weight, rate of preterm delivery, and neonatal effects between the groups.
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Materials and Methods
Pregnant women counseled by the Israeli Teratology Information Service (TIS), Jerusalem, in regard to metformin between the years 2000 and 2013 were enrolled in the present prospective comparative observational study. The metformin group was
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divided by indication to those receiving the medication for diabetes (metformin DM) or PCOS (metformin PCOS). In the case of known diagnosis of diabetes in the
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presence of PCOS the woman was assigned to the metformin DM group. Outcome
was compared with two comparison groups consisting of: 1) pregnant women with
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pre-gestational diabetes treated with insulin (insulin) at a convenience sample of
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approximately a hundred, and 2) women counseled for non-teratogenic exposure
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(NTE) at a ratio of 1:3 in a similar time frame. The NTE group was randomly selected
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from the Israeli TIS database and included women counseled during pregnancy in regard to exposures known to be non-teratogenic or fetal toxic such as analgesics
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(paracetamol or dipyrone), low dose diagnostic radiation, topical preparations with negligible systemic exposure, antibiotics (penicillins or cephalosporins), oral contraceptives taken no longer than the 5th week of pregnancy, hair dye or house-
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cleaning agents. Pregnancies of women, who have chronic diseases, including pre-
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gestational diabetes, were not included in the NTE group. Details of exposure were collected at the initial contact with the TIS during pregnancy and before pregnancy
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outcome was known, using a structured questionnaire. Retrospective cases were not included in the study. Verbal consent to participate in the study was given by the woman. The study protocol was approved by the ethics committee of Hadassah Medical Centre in Jerusalem. In addition, the following information was recorded at the initial contact: maternal demographics, medical and obstetric histories, and 6
exposure details (dose, duration, and timing in pregnancy, additional exposures). Women with diabetes treated either with metformin or with insulin were asked for their glycosylated hemoglobin (HbA1C) test results performed in the first trimester of pregnancy. Poor glycemic control was defined in women with HbA1C≥8.5 or in women with reported unbalanced disease. Pregnancy outcome was actively sought
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after the expected date of delivery in the exposed and comparison groups. Follow-up was conducted by a telephone interview with the woman to obtain details on the
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pregnancy outcome, gestational age at delivery, birth weight, congenital anomalies, and neonatal complications. In cases of anomalies an attempt was made to obtain
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medical records. In addition, all exposures were ascertained. It was verified that the
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exposure/s the woman was counseled for indeed occurred during pregnancy. Details
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on dose modifications during pregnancy, exact timing and duration of treatment, and
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additional exposures during pregnancy were also ascertained. The vast majority of infants in Israel are delivered in hospitals. Each neonate in Israel undergoes at least
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two physical examinations before being discharged from the hospital. All neonates in the present study were delivered in hospitals. The interview was conducted after discharge from the nursery units. Data collection methods were similar in the exposed
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and comparison groups. Major anomalies were defined as structural abnormalities in
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the offspring that have serious medical, surgical or cosmetic consequences. The classification of anomalies was done by a certified pediatrician blinded to the
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exposure group using guidelines of two classification systems [31-32]. Genetic (e.g. Di George syndrome) or cytogenetic anomalies were excluded from the analysis. Children with minor anomalies or functional problems without any morphological changes (e.g. ankyloglossia, birth marks not requiring a medical intervention, systolic heart murmur with normal echocardiography) or infants with complications of 7
preterm delivery were not considered as having major anomalies. Children with neurodevelopmental disorders without structural abnormalities were not included in the comparison of major anomalies but are mentioned in the text. Cardiac septal defects are structural anomalies of the heart and were considered major anomalies in the initial analysis, but were not considered major anomalies at a later comparison, if
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spontaneously resolved within the first year of life. Anomalies such as developmental hip dysplasia requiring braces or casting, that often are not formed during the first
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trimester of pregnancy, were not considered major anomalies in the present study. Thus, the analysis of major congenital anomalies was performed among live-born
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infants, pregnancy losses with confirmed anomalies, and elective terminations of
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pregnancy due to prenatally diagnosed anomalies. In the metformin groups the rate of
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congenital anomalies was calculated only among pregnancies exposed to metformin
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in the period of organogenesis, from four completed weeks after the last menstrual period (LMP) till the end of the first trimester i.e. week 12 and 6 days post LMP. In
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the case of multiple births, each live-born offspring was included separately in the analysis. Gestational age was defined from LMP. Spontaneous pregnancy loss before or at 20 completed weeks was considered a miscarriage, whereas spontaneous
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pregnancy loss beyond 20 completed weeks was termed stillbirth. Preterm delivery
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was defined as birth before 37 completed weeks.
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Statistical Analysis Categorical data are expressed as ratios or percentages. Continuous data are presented using mean±SD or median with interquartile range (IQR). Hazard ratios (HR) and 95% confidence interval (CI) for miscarriages after various exposures were estimated using Cox proportional hazards modeling, while accounting for left truncation due to 8
varying time of gestation at enrollment. The analyses were adjusted for maternal age, gestational age at initial contact, and number of previous miscarriages. Linear regression analysis was used to evaluate the relative contribution of various predictors [i.e. exposure groups (metformin PCOS, metformin DM and insulin DM), maternal
and pregnancy complication] to the differences in birth weight.
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age, smoking, parity, multi-fetal gestation, maternal age, gestational age at delivery,
The associations between metformin exposure and the risk of major anomalies as well
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as other outcomes of pregnancy were evaluated using multivariate logistic regression analysis to estimate odds ratios (OR) with 95% CI adjusting for confounding factors
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(maternal age and pregnancy complications for the rate of congenital anomalies;
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pregnancy complications, multi-fetal gestation, and maternal age for the rate of
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Cesarean section; and pregnancy complications, smoking, multi-fetal gestation, and
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maternal age for the rate of preterm delivery). Statistical calculations were done using SPSS Version 24 and Epi Info™ software (Center for Disease Control and
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Prevention, Atlanta Epidemiology Program Office, Atlanta, GA, USA).
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Results
A total of 170 metformin exposed pregnancies (119 for type 2 diabetes and 51 for PCOS) were prospectively followed-up and compared with 93 pregnancies of women with diabetes (78% type 1, 22% type 2) treated in the first trimester and throughout
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pregnancy with insulin, and 530 NTE pregnancies. All women in the metformin group were exposed at least in the first trimester of pregnancy, while 21/170 (12.4%)
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continued the treatment with metformin throughout gestation. There was one
pregnancy with metformin exposure limited to the "all or none" period, which was
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excluded from the analysis of major anomalies. The median metformin daily dose was
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1700mg (IQR 850-1700). Concurrent medications during pregnancy in addition to the
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metformin or insulin are presented in Box 1. Additional antidiabetic drugs were taken
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by 22.7% of the metformin DM group. In 74/119 (62.2%) of the metformin DM group the women were switched to insulin treatment after metformin discontinuation
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during pregnancy. In contrast, only 3/51 (5.9%) of the metformin PCOS group required insulin later in pregnancy. A rather high proportion of women in the metformin DM group were concurrently treated with lipid lowering agents or
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antihypertensive medications. A comparison of maternal characteristics and obstetric
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history between the groups is presented in Table 1. Metformin DM treated women were older, contacted the TIS at an earlier gestational age, had more previous
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pregnancies and miscarriages, and had a higher Body Mass Index (BMI). A comparison of pregnancy outcome between the groups is presented in Table 2. There were more miscarriages and elective terminations of pregnancy in the metformin DM group. The crude HRs for miscarriage were as follows: HRcrude 1.81; 95% CI 0.70-4.67; HRcrude 2.92; 95% CI 1.63-5.24; and HRcrude 1.98; 95% CI 0.9710
4.05 for metformin PCOS, metformin DM, and insulin DM, respectively. After adjustment the risk of miscarriage was not significantly increased compared to the NTE: HRadj 1.29; 95% CI 0.49-3.37 for Metformin PCOS; HRadj 1.27; 95% CI 0.632.57 for Metfrmin DM; and HRadj 1.50; 95% CI 0.65-3.47 for insulin DM. Adding smoking and multi-fetal gestation as covariates did not further attenuate the
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associations.
The median age at follow up was higher in the metformin and insulin groups.
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Cesarean section was performed in more than half of deliveries in both groups with
diabetes. Higher rate of Cesarean section (ORcrude 3.78; 95% CI 2.37-6.04 and ORadj
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3.17; 95% CI 1.93-5.23 for metformin DM, ORcrude 4.23; 95% CI 2.57-6.96 and ORadj
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4.97; 95% CI 2.98-8.29 for insulin DM) and earlier gestational age at delivery were
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observed in both groups with diabetes compared with the NTE group. The rate of
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Cesarean section was also higher in the metformin PCOS group (ORcrude 2.29; 95% CI 1.22-4.30 and ORadj 2.65; 95% CI 1.39-5.06). The rate of preterm deliveries was not
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significantly different in the metformin DM group (ORcrude 1.18; 95% CI 0.50-2.75 and ORadj 1.15 95% CI 0.45-2.90), however, it was higher in the insulin group (ORcrude 3.39; 95% CI 1.71-6.72 and ORadj 4.29; 95% CI 2.07-8.88). The median birth
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weight was higher in the metformin DM group. However, when the analysis of birth
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weight was limited to full-term infants, the mean birth weight was higher in both groups with diabetes compared with the NTE group. To evaluate the relative
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contribution of various predictors to the difference in birth weight linear regression analysis was performed. The model was significant and, collectively, the predictors accounted for 34.8% of the variance in birth weight (R2=0.348). Birth weight was found to be significantly directly associated with gestational age at delivery (β=0.508, p<0.001), metformin DM (β=0.185, p<0.001), and insulin DM (β=0.152, p<0.001) 11
groups, and parity (β=0.100, p=0.005), while inversely related with multi-fetal gestation (β=-0.161, p<0.001). Pregnancy complications were more often reported in the metformin DM. The most common complications in the metformin group were polyhydramnios, pregnancy induced hypertension, and toxemia. Perinatal complications were more frequently
Frequent complications reported in these groups were neonatal jaundice,
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hypoglycemia, polycythemia, as well as respiratory problems.
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reported in both metformin groups and insulin group compared with the NTE group.
A comparison of major anomalies between the groups is presented in Table 3. The
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rate of congenital anomalies excluding spontaneously resolved cardiovascular
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anomalies was 4.4% (2/45) in the metformin PCOS group, 1.1% (1/90) in the
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metformin DM group, compared with 2.5% (2/80) in the insulin group, and 1.7%
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(9/519) in the NTE group. The overall rate of major anomalies was not significantly different between the whole metformin and insulin groups compared with the NTE
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group before (ORcrude 2.34; 95% CI 0.84-6.56 and ORadj 2.88; 95% CI 0.99-8.36 for the metformin group, ORcrude 2.00; 95% CI 0.54-7.42 and ORadj 2.07; 95% CI 0.557.71 for the insulin group) and after excluding spontaneously resolved cardiovascular
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anomalies (ORcrude 1.43; 95% CI 0.38-5.48 and ORadj 1.77; 95% CI 0.45-7.01 for the
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whole metformin group, ORcrude 1.65; 95% CI 0.34-7.91and ORadj 1.69; 95% CI 0.358.11 for the insulin group). There was no case of severe cardiovascular anomaly either
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in the metformin DM or NTE groups. The reported major anomalies, maternal details, and the details of exposures in the metformin and insulin groups are listed in Table 4. In addition to the listed anomalies there were two cases of neurodevelopmental disorders without structural abnormalities in the metformin DM group: a girl born prematurely at gestational week 12
32 with severe mental retardation and disability initially diagnosed at two months of age and a boy born at term initially diagnosed at one year of age with communication problems who attended a special education class when later diagnosed with high functioning pervasive developmental disorder not otherwise specified (PDD-NOS). Another case not considered a major anomaly in the metformin DM group was a boy
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born at gestational week 36 prenatally diagnosed with a complex cyanotic
cardiovascular defect with double outlet right ventricle with non-committed VSD and
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esophageal stenosis, since diagnosed with the genetic disorder, Di George (22q11.2 deletion) syndrome. Many of the reported anomalies in both groups were
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cardiovascular or central nervous system anomalies, some complex. There was a case
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of multiple anomalies. There was no case of caudal regression syndrome. It is
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important to mention that all the anomalies found in the metformin groups, except
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one, were diagnosed prenatally or perinatally.
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Discussion
The results of the present prospective observational comparative study do not show a significantly higher overall rate of major or cardiovascular anomalies in the metformin groups vs. NTE group. The pattern of the reported major anomalies in both
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the metformin DM and insulin groups supports association with diabetes. The study, therefore, suggests that metformin first trimester exposure by itself is not associated
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with an increased risk of overall major anomalies. The absolute overall rate of
anomalies found in the current study, although not significantly different from the
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comparison groups, was higher than the 0.5% summarized by Cassina et al among
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634 pregnancies of women treated with metformin throughout the first trimester for
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PCOS [28]. However, a 0.5% rate is rather low compared to the baseline risk for
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major malformations in the general population of 3.7% reported in Jerusalem Perinatal Study Cohort [33] or 1-3% described in the Collaborative Perinatal Project
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(34). In the present study, most pregnant women with metformin first trimester exposure (70%) were treated for type 2 diabetes, and only 30% received it for PCOS. Offspring of women with pre-gestational diabetes mellitus are at increased risk for
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congenital malformations, largely, attributable to poor periconceptional glycemic
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control [35-37]. Preconception care can decrease first trimester mean glycosylated hemoglobin values, and the risk of anomalies [38]. Starikov et al [39] evaluated the
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incidence of overall and major congenital heart defects among infants of mothers with pre-gestational diabetes by glycemic control and found 8.3% (HbA1C≥8.5), 3.9% (HbA1C<8.5), and 6.4% (HbA1C≥8.5), 2.4% (HbA1C<8.5), respectively. The spectrum of congenital anomalies found at increased risk in pregnancies with pregestational diabetes includes neural tube defects, several subgroups of congenital 14
heart defects [40-41], multiple congenital anomalies, and caudal regression sequence [41]. Lack of a case of caudal regression syndrome in either the metformin DM or the insulin group in the present study is not surprising since this malformation, although more common among offspring of women with diabetes, remains rather uncommon. A sample size of 136 live-births or elective terminations of pregnancy due to
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prenatally diagnosed anomalies in the metformin group with a ratio of 1:3.8 to the
NTE comparison group with 80% power, a baseline risk of 2.1% for major anomalies,
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enables detection of a 3.8-fold increase in the rate of major anomalies. In addition, the study is not powered to find an increase in the rate of specific rare anomalies.
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The higher crude rate of miscarriages found in the metformin DM group was
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associated with an earlier gestational age at initial contact (with a higher miscarriage
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rate in women calling earlier in pregnancy) and with a more advanced maternal age,
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but not with the type of exposure, as verified by the Cox proportional hazards model regression analysis. More than half of the women in both groups with diabetes,
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considerably higher than in the NTE group, were delivered by Cesarean section. Similarly, overall Cesarean section rate of 52-55% has previously been reported among women with type 1 or type 2 diabetes [42]. The higher rate of preterm
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deliveries seen in the insulin group is also consistent with increased risk of preterm
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deliveries reported among women with type 1 diabetes [43]. The higher birth weight seen in the metformin DM group may be associated with diabetes and obesity
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common in this group, both known risk factors for macrosomia [44]. The linear regression analysis performed in the present study for birth weight demonstrated that increased birth weight was associated with gestational age at delivery, parity, and metformin or insulin exposure among the groups with diabetes. The latter means that the underlying disease is a significant risk factor for higher birth weight. The higher 15
rate of pregnancy complications in the metformin DM group may also be explained by maternal diabetes, obesity, or a combination of the two as suggested by Langer [45]. The finding that perinatal complications were more common in both metformin groups and insulin group is consistent with previous reports in the literature [46-47]. The fact that severe cardiovascular malformations were not reported in the present
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study among the offspring of the NTE group raise a question regarding the possibility of under-ascertainment. For this reason, we looked at the rate of cardiovascular
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malformations in the NTE group of the Israeli TIS database between the years 2000-
2013. We found an overall rate of cardiovascular malformations of 0.9% (24/2,595) in
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this group, and a rate of 0.5% after exclusion of those that spontaneously resolved
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within the first year. A similar rate of heart malformations (8 of every 1,000 births)
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has been reported in the general population [48-49]. Since the NTE group in the
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current study was randomly selected from the database, we assume that the lack of severe cardiovascular malformations in the present study's NTE group is a chance
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finding, rather than a result of under-ascertainment. A similar risk of major birth defects of 5.1% (20/392) among pregnancies exposed to metformin during the first trimester was found in a recently published multi-center
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TIS study [50].
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The present study has certain limitations and advantages. It is based on TIS population, which may not represent the general population, but has two comparison
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groups from the same TIS. Other limitations of the study are: lack of an untreated PCOS group, relatively small metformin and insulin groups, limited power for specific rare defects, reliance on maternal interview as a source for outcome data in most cases, variation in time of follow-up, and a nonrandomized design. However, applying the same procedure to all arms of the study and the prospective nature 16
minimize the potential biases. Due to ethical considerations randomized controlled trials are often not feasible in pregnancy. The fact that all data are from a single center also minimizes some potential biases. In addition, there were two comparison groups: an insulin group with a similar, though not the same, disease without exposure to metformin and a group counseled for NTE. Moreover, the data on metformin were
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compared according to two different indications, PCOS and diabetes. The study
design enables to distinguish between the possible effect of glycemic control and
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obesity, both potential confounders for congenital anomalies. Indeed, insulin
resistance is common among women with PCOS, resulting in pre-diabetes and a high
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risk of developing type 2 diabetes. However, if the woman reported on diabetes she
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would have been assigned to the metformin DM group. Another advantage of the
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present study is that data on major anomalies were available on elective terminations
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of pregnancies and were included in the analysis.
In conclusion, the present prospective observational comparative cohort study
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suggests that metformin first trimester exposure by itself is not associated with an increased risk for overall major congenital anomalies. This is in line with the results of other studies. However, one should still keep in mind that this conclusion is based
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on relatively small numbers of exposed pregnancies, and should be interpreted with
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caution. Larger studies are still needed to establish the pregnancy safety of metformin, especially in the context of pre-gestational diabetes. The pattern of anomalies in both
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the metformin DM and insulin groups supports association with hyperglycemia. The underlying hyperglycemia is known to be associated with an increased risk for major anomalies, especially cardiovascular, CNS, and multiple congenital anomalies.
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Conflict of interest The authors have no conflict of interest to disclose.
*Acknowledgments:
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This work is part of the Pharm D thesis in Clinical Pharmacy of the Hebrew University of Mrs. Salit Steinmetz-Shoob.
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The authors would like to thank Irena Liphshiz (MSc.) from the Health Information
Division of Israel Ministry of Health, for her valuable advice and contribution to the
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statistical analysis and presentation of data.
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[14] Vandermolen DT, Ratts VS, Evans WS, Stovall DW, Kauma SW, Nestler JE. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril. 2001 Feb;75(2):310-5.
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[20] Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, et al;
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Cooperative Multicenter Reproductive Medicine Network. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007 Feb 8;356(6):551-66.
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[21] Nawaz FH, Khalid R, Naru T, Rizvi J. Does continuous use of metformin throughout pregnancy improve pregnancy outcomes in women with polycystic ovarian syndrome? J Obstet Gynaecol Res. 2008 Oct;34(5):832-7. [22] Rai L, Meenakshi D, Kamath A. Metformin - a convenient alternative to insulin
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[23] Johnson NP, Stewart AW, Falkiner J, Farquhar CM, Milsom S, Singh VP, et al;
REACT-NZ (Reproduction And Collaborative Trials in New Zealand), a multi-centre fertility trials group. PCOSMIC: a multi-center randomized trial in women with
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[24] Begum MR, Akhter S, Ehsan M, Begum MS, Khan F. Pretreatment and coadministration of oral anti-diabetic agent with clomiphene citrate or rFSH for
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ovulation induction in clomiphene-citrate-resistant polycystic ovary syndrome. J Obstet Gynaecol Res. 2013 May;39(5):966-73. [25] Feig DS, Murphy K, Asztalos E, Tomlinson G, Sanchez J, Zinman B, et al.
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randomized controlled trial. BMC Pregnancy Childbirth. 2016 Jul 19; 16(1):173. [26] Gilbert C, Valois M, Koren G. Pregnancy outcome after first-trimester exposure
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to metformin: a meta-analysis. Fertil Steril. 2006 Sep;86(3):658-63. [27] Boomsma CM, Eijkemans MJ, Hughes EG, Visser GH, Fauser BC, Macklon NS. A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome. Hum Reprod Update. 2006 Nov-Dec;12(6):673-83.
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[28] Cassina M, Donà M, Di Gianantonio E, Litta P, Clementi M. First-trimester exposure to metformin and risk of birth defects: a systematic review and metaanalysis. Hum Reprod Update. 2014 Sep-Oct;20(5):656-69. [29] Tan X, Li S, Chang Y, Fang C, Liu H, Zhang Y, et al. Effect of metformin
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31. Rasmussen SA, Olney RS, Holmes LB, Lin AE, Keppler-Noreuil KM, Moore CA,
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and National Birth Defects Prevention Study. Guidelines for case classification for the
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Mar;67(3):193-201.
[32] Merks JH, van Karnebeek CD, Caron HN, Hennekam RC. Phenotypic
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abnormalities: terminology and classification. Am J Med Genet. 2003 Dec 15;123A(3):211-230.
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[33] Harlap S, Davies AM, Deutsch L, Calderon-Margalit R, Manor O, Paltiel O, et al. The Jerusalem Perinatal Study Cohort, 1964-2005: methods and a review of the
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main results. Paediatr Pernat Epidemiol. 2007 May;21(3):256-73. [34] Heinonen OP, Sloan D, Shapiro S. Birth defects and drugs in pregnancy.
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Publishing Sciences Group Inc., Littleton, Massachusetts. 1977. [35] Yinen K, Aula P, Stenman UH, Kesäniemi-Kuokkanen T, Teramo K. 1984. Risk of minor and major fetal malformations in diabetics with high hemoglobin A1c values in early pregnancy. Br Med J (Clin Res Ed). 1984 Aug 11;289(6441):345-6. 23
[36] Miodovnik M, Mimouni F, Dignan PS, Berk MA, Ballard JL, Siddiqi TA, et al. Major malformations in infants of IDDM women. Vasculopathy and early firsttrimester poor glycemic control. Diabetes care. 1988 Oct; 11(9):713-8. [37] Correa A, Gilboa SM, Besser LM, Botto LD, Moore CA, Hobbs CA, et al. Diabetes mellitus and birth defects. Am J Obstet Gynecol. 2008 Sep;199(3):237.e1-9.
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[38] Ray JG, O'Brien TE, Chan WS. Preconception care and the risk of congenital
anomalies in the offspring of women with diabetes mellitus: a meta-analysis. QJM.
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2001 Aug;94(8):435-44.
[39] Starikov R, Bohrer J, Goh W, Kuwahara M, Chien EK, Lopes V, et al.
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LT, Wang H. Insulin analogues in pregnancy and specific congenital anomalies; a literature review. Diabetes Metan Res Rev. 2016 May;32(4):366-75.
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[41] Garne E, Loane M, Dolk H, Barisic I, Addor MC, Arriola L, et al. Spectrum of congenital anomalies in pregnancies with pregestational diabetes. Birth Defects Res A Clin Mol Teratol. 2012 Mar;94(3):134-40.
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[42] Cundy T, Morgan J, O'Beirne C, Gamble G, Budden A, Ivanova V, et al.
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Obstetric interventions for women with type 1 or type 2 diabetes. Int J Gynaecol Obstet. 2013 Oct;123(1):50-3.
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[43] Murphy HR, Steel SA, Roland JM, Morris D, Ball V, Campbell PJ, et al; East Anglia Study Group for Improving Pregnancy Outcomes in Women with Diabetes (EASIPOD). Obstetric and perinatal outcomes in pregnancies complicated by Type 1 and Type 2 diabetes: influences of glycemic control, obesity and social disadvantage. Diabet Med. 2011 Sep;28(9):1060-7. 24
[44] Ehrenberg HM, Mercer BM, Catalano PM. The influence of obesity and diabetes on the prevalence of macrosomia. Am J Obstet Gynecol. 2004 Sep;191(3):964-8. [45] Langer O. 2015. Obesity or diabetes: which is more hazardous to the health of the offspring? J Matern Fetal Neonatal Med. 2016;29(2):186-90. [46] Negrato CA, Mattar R, Gomes MB. Adverse pregnancy outcomes in women with
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[47] Mitanchez D, Yzydorczyk C, Siddeek B, Boubred F, Benahmed M, Simeoni U.
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The offspring of the diabetic mother - Short- and long-term implications. Best Pract Res Clin Obstet Gynaecol. 2015 Feb;29(2):256-69.
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[48] Campbell M. Incidence of cardiac malformations at birth and later, and neonatal
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mortality. Br Heart J. 1973 Feb;35(2):189-200.
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[49] Ban L, Gibson JE, West J, Fiaschi L, Sokal R, Smeeth L, et al. Maternal
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depression, antidepressant prescriptions, and congenital anomaly risk in offspring: a population-based cohort study. BJOG. 2014 Nov;121(12):1471-81.
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[50] Panchaud A, Rousson V, Vial T, Bernard N, Baud D, Amar E, et al. Pregnancy outcomes in women on metformin for diabetes or other indications among those
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seeking teratology information services. Br J Clin Pharmacol 2018 Mar;84(3):568-78.
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Tables
Table 1 Comparison of Maternal Characteristics and Obstetric History
n
30.9 ± 4.9
PT
CC E A
DM n=119
Comparison groups Insulin DM NTE n=93 n=530
36.4 ± 5.4
32.0 ± 5.2
31.0 ± 4.8
7 (5-9)
7 (6-10)
8 (6-14)
10 (7-18)
22/46 (47.8) 17/46 (37.0) 7/46 (15.2)
18/100 (18.0) 32/100 (32.0) 50/100 (50.0)
25/81 (30.9) 39/81 (48.1) 17/81 (21.0)
172/498 (34.5) 245/498 (49.2) 81/498 (16.3)
27/47 (57.4) 19/47 (40.4) 1/47 (2.1)
26/107 (24.3) 61/107 (57.0) 20/107 (18.7)
31/83 (37.3) 49/83 (59.0) 3/83 (3.6)
208/501 (41.5) 271/501 (54.1) 22/501 (4.4)
35/46 (76.1) 9/46 (19.6) 2/46 (4.3) 0/46 (0) 4/46 (8.7)
67/102 (65.7) 29/102 (28.4) 6/102 (5.9) 2/101 (2.0) 11/102 (10.8)
66/79 (83.5) 11/79 (13.9) 2/79 (2.5) 0/79 (0) 9/79 (11.4)
417/497 (83.9) 72/497 (14.5) 8/497 (1.6) 3/497 (0.6) 29/497 (5.8)
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Maternal age mean ±SD (y) GA at initial contact, w median (IQR) Pregnancy order, n (%) 1 2-3 4 Parity, n (%) 0 1-3 4 Past miscarriages, n (%) 0 1-2 3 Past stillbirth, n (%) Past ETOP1, n (%)
M
PCOS n=51
A
Metformin
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I 2/101 (2.0) 9/101 (8.9) n=90 31 (27-35) 13/64 (20.3)
M
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2/41 (4.9) 1/41 (2.4) n=40 29 (24-37) NR
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Cigarette smoking <10cigarettes/day 10cigarettes /day BMI, n BMI, median (IQR)
1/74 (1.4) 4/74 (5.4) n=77 23 (21-29) 8/74 (10.8)
10/484 (2.1) 5/484 (1.0) n=456 23 (21-29) NR
A
CC E
PT
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HbA1C≥8.5 in first trimester, n (%) SD - standard deviation, y - years, GA - gestational age, w - weeks, IQR - interquartile range, ETOP - elective termination of pregnancy, BMI body mass index, HbA1C - glycosylated hemoglobin test, PCOS - polycystic ovary syndrome, DM - diabetes mellitus, NTE - non-teratogenic exposure, NR - not relevant.
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Table 2 Comparison of Pregnancy Outcome
Metformin
PT
(IQR)
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Mode of delivery Vaginal uncomplicated, n (%) Cesarean section, n (%) Assisted delivery, n (%) GA at delivery, w median (IQR) Preterm delivery, <37 w, n (%) Birth weight, g median (IQR) Birth weight of fullterm infants, g mean
A
89/119 (74.8)
79/93 (84.9)
495/530 (93.4)
6/51 (11.8) 1/51 (2.0) 0 33 (14-65)
19/119 (16.0) 10/119 (8.4) 1 (0.8) 27 (10-58)
11/93 (11.8) 3/93 (3.2) 0 35 (16-70)
30/530 (5.7) 5/530 (0.9) 0 14 (8-20)
23/43 (53.5)
38/90 (42.2)
31/79 (39.2)
338/503 (67.2)
19/43 (44.2)
51/90 (56.7)
45/79 (57.0)
138/503 (27.4)
1/43 (2.3)
1/90 (1.1)
3/79 (3.8)
27/503 (5.4)
39 (38-40) 5/44 (11.4)
38 (38-40) 9/89 (10.1)
38 (36-38) 21/79 (26.6)
39 (38-40) 37/495 (7.5)
3200 (2725-3700) 3323±607
3400 (3100-3750) 3444±467
3258 (2660-3700) 3417±517
3183 (2838-3486) 3210±456
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44/51 (86.3)
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Pregnancy Outcome Delivery of live-born infant, n (%) Miscarriage, n (%) ETOP, n (%) Stillbirth, n (%) Age at FU, median, m
DM
A
PCOS
Comparison groups Insulin DM NTE
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I N U SC R
A
CC E
PT
ED
M
A
(±SD) Pregnancy 13/44 (29.5) 30/90 (33.3) 13/79 (16.5) 106/516 (20.5) complications, n (%) Perinatal 17/44 (38.6) 38/90 (42.2) 45/79 (57.0) 74/516 (14.3) complications, n (%) ETOP - elective termination of pregnancy, FU - follow-up, IQR - interquartile range, m - months, GA - gestational age, w - weeks, g - grams, SD - standard deviation, PCOS - polycystic ovary syndrome, DM - diabetes mellitus, NTE - non-teratogenic exposure.
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Table 3 Comparison of Congenital Anomalies Metformin* PCOS DM
Comparison groups Insulin DM NTE
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Major anomalies, n 3/45 (6.7) 3/90 (3.3) 3/80 (3.8) 11/519 (2.1) (%) All cardiovascular, n 2/45 (4.4) 2/90 (2.2) 2/80 (2.5) 2/519 (0.4) (%) Major anomalies, 2/45 (4.4) 1/90 (1.1) 2/80 (2.5) 9/519 (1.7) excluding spontameously resolved cardiovascular anomalies, n (%) *among pregnancies exposed to metformin in the period of organogenesis, i.e. weeks 4-13 after the last menstrual period, PCOS - polycystic ovary syndrome, DM diabetes mellitus, NTE - non-teratogenic exposure
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Table 4 List of Major Congenital Anomalies in the Metformin and Insulin Groups Type of anomaly
Maternal indication, age, GC, BMI, exposure details, additional exposures
Pregnancy outcome, GA (w), sex, BW (g)
FU comments
Dandy Walker syndrome
PCOS, 30y, NR, NA 1700mg/d ongoing
ETOP, 17
Diagnosed on prenatal U/S
Tetralogy of Fallot
PCOS, 26y, NR, 25, 850mg/d till w 8
Delivery, 39, M
Died at 3 m while operated
Small PDA, mild PS*
PCOS, 23, NR, 29, till w5
Delivery, 38, M, 4400
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Metformin PCOS group
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Diagnosed on echocardiography at 2 m, resolved before 6 m
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Metformin DM group Type 2 DM, 42y, P, 34, 2550mg/d till w 6, losartan simvastatin till w 5
ETOP, 18
Septal defect, 'hole' in heart*
Type 2 DM, 37y, P 11.1, >30, 1700mg/d till w 20
Delivery, 38, F, 3800
Spontaneously resolved at 1 y
VSD*
Type 2 DM, 35y, NA, NA
Delivery, 40, M, 4555
Diagnosed on prenatal echocardiography, spontaneously resolved at 2 m
Levocardia, VSD, situs inversus abdominis, abnormal venous drainage
Type 1 DM, 27y, P, 29, losartan simvastatin till w 5
Delivery, 36, F, 2600,
Open heart surgery at 4.5 y
Dandy Walker syndrome
Type 1 DM, 35y, NA, 29, enalapril
ETOP, 13
Diagnosed on prenatal U/S
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M
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Multiple anomalies including spina bifida
Diagnosed on prenatal U/S
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Insulin group
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simvastatin till w 5 Type 1 DM, 26y, NA, 21
Delivery, 38, M, 3250
Spontaneously closed at 1 y
Inguinal hernia, ASD/P FO, mild left pulmonary artery stenosis*
DM, 36y, G 6.8, 22
Delivery, 38, F, 3380
Inguinal hernia operated at 6 m, CV anomaly spontaneously resolved at 3 m
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VSD*
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M
A
N
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PCOS - polycystic ovary syndrome, PDA - patent ductus arteriosus, PS - pulmonary stenosis, * - not included in the final analysis since spontaneously resolved, DM diabetes mellitus, VSD - ventricular septal defect, ASD - atrial septal defect, PFO patent foramen ovale, GC - glycemic control, G – good to fair (HbA1C - glycosylated hemoglobin test <8.5), P - poor (HbA1C - glycosylated hemoglobin test ≥8.5), BMI body mass index, NR - not relevant, NA - not available, y - years, w - week, d - day, GA - gestational age at delivery, BW - birth weight, g - grams, F - female, M - male, ETOP elective termination of pregnancy, FU - follow-up, NICU - neonatal intensive care unit, m months, U/S - ultrasound, CV - cardiovascular
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Box 1 Distribution of Concomitant Medications in the Metformin and Insulin Groups Concomitant Medications
Metformin
Insulin DM
PCOS
DM
n=51
n=119
n=93
-
27
3
ACEI/ARBs
2
32
Beta blockers
1
4
Calcium channel blockers
-
4
Others**
1
No
47
Lipid lowering agents
1
Concomitant anti diabetic drugs*
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Antihypertensives: 17
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2 -
2
77
72
35
10
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2
A
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M
A
N
* glibenclamide, repaglinide, acarbose ** alpha agonist, thiazide, diuretic, vasodilator ACEI/ARBs - angiotensin converting enzyme inhibitors/angiotensin II receptor blockers, PCOS - polycystic ovary syndrome, DM - diabetes mellitus
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S0890-6238(18)30047-9 https://doi.org/10.1016/j.reprotox.2018.05.007 RTX 7673
To appear in:
Reproductive Toxicology
Received date: Revised date: Accepted date:
13-2-2018 14-5-2018 26-5-2018
Please cite this article as: Diav-Citrin Orna, Steinmetz-Shoob Salit, Shechtman Svetlana, Ornoy Asher.In-utero exposure to metformin for type 2 diabetes or polycystic ovary syndrome: a prospective comparative observational study.Reproductive Toxicology (2018), https://doi.org/10.1016/j.reprotox.2018.05.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
In-utero exposure to metformin for type 2 diabetes or polycystic ovary syndrome: a prospective comparative observational study
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Running Heading: Metformin for type 2 diabetes or PCOS in pregnancy
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Orna Diav-Citrin1,2**, MD, Salit Steinmetz-Shoob1,3, PharmD*, Svetlana Shechtman1, PhD, and Asher Ornoy2, MD.
The Israeli Teratology Information Service, Israel Ministry of Health, Jerusalem.
2
The Hebrew University Hadassah Medical School, Jerusalem, Israel.
3
The Division of Clinical Pharmacy, the Hebrew University of Jerusalem, Israel.
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Previous presentation at the 2nd international ENTIS (European Network of Teratology Information Services) and OTIS (Organization of Teratology Information Specialists) joint meeting, Toronto, Canada, September 19th-21st, 2014 **
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Corresponding author: Orna Diav-Citrin, MD The Israeli Teratology Information Service, Israel Ministry of Health, P.O. Box 1176 Jerusalem, 9446724, Israel, Tel: 972-2-5080441, Fax: 972-2-6474822 e-mail address: [email protected]
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Highlights:
The present study is a prospective comparative observational cohort
Metformin first trimester exposure per se is not associated with a teratogenic
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risk The pattern of anomalies in the groups with diabetes may be hyperglycemia-
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related
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Abstract
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Objective: To evaluate the rate of major anomalies after first trimester (T1)-
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metformin exposure. Design: Comparative, observational cohort study done at the
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Israeli Teratology Information Service between 2000 and 2013. Results: 170 T1-
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metformin-exposed pregnancies [119 for diabetes and 51 for polycystic ovary syndrome (PCOS)] were prospectively followed-up and compared with 93 pregnancies of T1-insulin treated women and 530 non-teratogenic exposed (NTE)
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pregnancies. The differences in the rate of major anomalies excluding
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genetic/cytogenetic, and spontaneously resolved cardiovascular anomalies were not significant [4.4% (2/45) - metformin-PCOS, 1.1% (1/90) - metformin-diabetes, 2.5%
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(2/80) - insulin, and 1.7% (9/519) - NTE; ORadj metformin /NTE 1.77; 95% CI 0.45-7.01; ORadj insulin /NTE 1.69; 95% CI 0.35-8.11]. The rate of Cesarean section was higher in both the metformin-diabetes 51/90 (56.7%) and insulin 45/79 (57.0%) compared with the NTE group [138/503 (27.4%)]. Conclusion: Metformin-T1-exposure per se is not associated with an increased risk of major anomalies. 2
Keywords: metformin, diabetes mellitus, polycystic ovary syndrome, pregnancy,
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congenital anomalies.
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Introduction
Metformin is a biguanide oral antihyperglycemic agent. It is a first line drug in the treatment of type 2 diabetes mellitus [1]. Additionally, it is commonly used in
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polycystic ovary syndrome (PCOS) [2-3]. Its mechanism of action is primarily by inhibiting hepatic gluconeogenesis and by increasing the action of insulin in certain
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peripheral tissues [4]. Studies suggest that metformin could also affect pituitary
gonadotropin secreting cells [5]. According to the American Diabetes Association [6], insulin is the preferred agent for management of pre-gestational type 1 diabetes and
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type 2 diabetes that are not adequately controlled with diet, exercise and metformin.
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In contrast to insulin, human placental transfer of metformin has been documented
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[7]. Animal reproductive studies have been inconsistent. Metformin has not been
M
teratogenic in rats and rabbits at doses up to 600mg/kg/d [8]; however, in some rat
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studies neural tube defects and anophthalmia were observed in less than 0.5% of the fetuses [9]. Studies on the use of metformin for gestational diabetes often deal with late exposure beyond the period of organogenesis. Human first trimester pregnancy
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experience with metformin has been reassuring but limited [10-25], especially for pregestational diabetes. The data have been summarized in several published meta-
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analyses [26-30]. All support lack of increased risk for major anomalies and show
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some benefits for metformin treatment. In the meta-analysis published by Cassina et al [28] the rate of major anomalies was 3/351 among pregnancies of women treated with metformin during the first trimester for PCOS with an OR of 0.86 (95% CI 0.184.08). The overall rate of major anomalies was 0.6% in the group of 517 women who discontinued the therapy upon pregnancy confirmation and 0.5% in the sample of 634 4
who were treated with metformin throughout the first trimester, after inclusion of uncontrolled PCOS studies reported in the literature. The number of pregnancies among women treated with metformin in the first trimester for type 2 diabetes was too small to perform a meta-analysis. Even in the various meta-analyses the data regarding congenital anomalies after early pregnancy exposure to metformin are
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relatively scant, and for the indication of pre-gestational diabetes are even more
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limited.
The primary objective of the present study was to evaluate the rate of major anomalies after first trimester (T1) metformin exposure among women with pre-gestational
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diabetes or PCOS compared with two groups: 1) women with pre-gestational diabetes
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treated with insulin, and 2) women counseled for non-teratogenic exposure.
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Secondary objectives were to compare the rate of pregnancy outcome (i.e. live-birth,
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miscarriage, elective termination of pregnancy, stillbirth), mode of delivery, birth
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weight, rate of preterm delivery, and neonatal effects between the groups.
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Materials and Methods
Pregnant women counseled by the Israeli Teratology Information Service (TIS), Jerusalem, in regard to metformin between the years 2000 and 2013 were enrolled in the present prospective comparative observational study. The metformin group was
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divided by indication to those receiving the medication for diabetes (metformin DM) or PCOS (metformin PCOS). In the case of known diagnosis of diabetes in the
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presence of PCOS the woman was assigned to the metformin DM group. Outcome
was compared with two comparison groups consisting of: 1) pregnant women with
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pre-gestational diabetes treated with insulin (insulin) at a convenience sample of
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approximately a hundred, and 2) women counseled for non-teratogenic exposure
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(NTE) at a ratio of 1:3 in a similar time frame. The NTE group was randomly selected
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from the Israeli TIS database and included women counseled during pregnancy in regard to exposures known to be non-teratogenic or fetal toxic such as analgesics
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(paracetamol or dipyrone), low dose diagnostic radiation, topical preparations with negligible systemic exposure, antibiotics (penicillins or cephalosporins), oral contraceptives taken no longer than the 5th week of pregnancy, hair dye or house-
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cleaning agents. Pregnancies of women, who have chronic diseases, including pre-
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gestational diabetes, were not included in the NTE group. Details of exposure were collected at the initial contact with the TIS during pregnancy and before pregnancy
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outcome was known, using a structured questionnaire. Retrospective cases were not included in the study. Verbal consent to participate in the study was given by the woman. The study protocol was approved by the ethics committee of Hadassah Medical Centre in Jerusalem. In addition, the following information was recorded at the initial contact: maternal demographics, medical and obstetric histories, and 6
exposure details (dose, duration, and timing in pregnancy, additional exposures). Women with diabetes treated either with metformin or with insulin were asked for their glycosylated hemoglobin (HbA1C) test results performed in the first trimester of pregnancy. Poor glycemic control was defined in women with HbA1C≥8.5 or in women with reported unbalanced disease. Pregnancy outcome was actively sought
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after the expected date of delivery in the exposed and comparison groups. Follow-up was conducted by a telephone interview with the woman to obtain details on the
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pregnancy outcome, gestational age at delivery, birth weight, congenital anomalies, and neonatal complications. In cases of anomalies an attempt was made to obtain
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medical records. In addition, all exposures were ascertained. It was verified that the
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exposure/s the woman was counseled for indeed occurred during pregnancy. Details
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on dose modifications during pregnancy, exact timing and duration of treatment, and
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additional exposures during pregnancy were also ascertained. The vast majority of infants in Israel are delivered in hospitals. Each neonate in Israel undergoes at least
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two physical examinations before being discharged from the hospital. All neonates in the present study were delivered in hospitals. The interview was conducted after discharge from the nursery units. Data collection methods were similar in the exposed
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and comparison groups. Major anomalies were defined as structural abnormalities in
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the offspring that have serious medical, surgical or cosmetic consequences. The classification of anomalies was done by a certified pediatrician blinded to the
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exposure group using guidelines of two classification systems [31-32]. Genetic (e.g. Di George syndrome) or cytogenetic anomalies were excluded from the analysis. Children with minor anomalies or functional problems without any morphological changes (e.g. ankyloglossia, birth marks not requiring a medical intervention, systolic heart murmur with normal echocardiography) or infants with complications of 7
preterm delivery were not considered as having major anomalies. Children with neurodevelopmental disorders without structural abnormalities were not included in the comparison of major anomalies but are mentioned in the text. Cardiac septal defects are structural anomalies of the heart and were considered major anomalies in the initial analysis, but were not considered major anomalies at a later comparison, if
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spontaneously resolved within the first year of life. Anomalies such as developmental hip dysplasia requiring braces or casting, that often are not formed during the first
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trimester of pregnancy, were not considered major anomalies in the present study. Thus, the analysis of major congenital anomalies was performed among live-born
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infants, pregnancy losses with confirmed anomalies, and elective terminations of
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pregnancy due to prenatally diagnosed anomalies. In the metformin groups the rate of
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congenital anomalies was calculated only among pregnancies exposed to metformin
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in the period of organogenesis, from four completed weeks after the last menstrual period (LMP) till the end of the first trimester i.e. week 12 and 6 days post LMP. In
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the case of multiple births, each live-born offspring was included separately in the analysis. Gestational age was defined from LMP. Spontaneous pregnancy loss before or at 20 completed weeks was considered a miscarriage, whereas spontaneous
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pregnancy loss beyond 20 completed weeks was termed stillbirth. Preterm delivery
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was defined as birth before 37 completed weeks.
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Statistical Analysis Categorical data are expressed as ratios or percentages. Continuous data are presented using mean±SD or median with interquartile range (IQR). Hazard ratios (HR) and 95% confidence interval (CI) for miscarriages after various exposures were estimated using Cox proportional hazards modeling, while accounting for left truncation due to 8
varying time of gestation at enrollment. The analyses were adjusted for maternal age, gestational age at initial contact, and number of previous miscarriages. Linear regression analysis was used to evaluate the relative contribution of various predictors [i.e. exposure groups (metformin PCOS, metformin DM and insulin DM), maternal
and pregnancy complication] to the differences in birth weight.
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age, smoking, parity, multi-fetal gestation, maternal age, gestational age at delivery,
The associations between metformin exposure and the risk of major anomalies as well
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as other outcomes of pregnancy were evaluated using multivariate logistic regression analysis to estimate odds ratios (OR) with 95% CI adjusting for confounding factors
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(maternal age and pregnancy complications for the rate of congenital anomalies;
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pregnancy complications, multi-fetal gestation, and maternal age for the rate of
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Cesarean section; and pregnancy complications, smoking, multi-fetal gestation, and
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maternal age for the rate of preterm delivery). Statistical calculations were done using SPSS Version 24 and Epi Info™ software (Center for Disease Control and
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Prevention, Atlanta Epidemiology Program Office, Atlanta, GA, USA).
9
Results
A total of 170 metformin exposed pregnancies (119 for type 2 diabetes and 51 for PCOS) were prospectively followed-up and compared with 93 pregnancies of women with diabetes (78% type 1, 22% type 2) treated in the first trimester and throughout
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pregnancy with insulin, and 530 NTE pregnancies. All women in the metformin group were exposed at least in the first trimester of pregnancy, while 21/170 (12.4%)
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continued the treatment with metformin throughout gestation. There was one
pregnancy with metformin exposure limited to the "all or none" period, which was
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excluded from the analysis of major anomalies. The median metformin daily dose was
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1700mg (IQR 850-1700). Concurrent medications during pregnancy in addition to the
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metformin or insulin are presented in Box 1. Additional antidiabetic drugs were taken
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by 22.7% of the metformin DM group. In 74/119 (62.2%) of the metformin DM group the women were switched to insulin treatment after metformin discontinuation
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during pregnancy. In contrast, only 3/51 (5.9%) of the metformin PCOS group required insulin later in pregnancy. A rather high proportion of women in the metformin DM group were concurrently treated with lipid lowering agents or
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antihypertensive medications. A comparison of maternal characteristics and obstetric
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history between the groups is presented in Table 1. Metformin DM treated women were older, contacted the TIS at an earlier gestational age, had more previous
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pregnancies and miscarriages, and had a higher Body Mass Index (BMI). A comparison of pregnancy outcome between the groups is presented in Table 2. There were more miscarriages and elective terminations of pregnancy in the metformin DM group. The crude HRs for miscarriage were as follows: HRcrude 1.81; 95% CI 0.70-4.67; HRcrude 2.92; 95% CI 1.63-5.24; and HRcrude 1.98; 95% CI 0.9710
4.05 for metformin PCOS, metformin DM, and insulin DM, respectively. After adjustment the risk of miscarriage was not significantly increased compared to the NTE: HRadj 1.29; 95% CI 0.49-3.37 for Metformin PCOS; HRadj 1.27; 95% CI 0.632.57 for Metfrmin DM; and HRadj 1.50; 95% CI 0.65-3.47 for insulin DM. Adding smoking and multi-fetal gestation as covariates did not further attenuate the
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associations.
The median age at follow up was higher in the metformin and insulin groups.
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Cesarean section was performed in more than half of deliveries in both groups with
diabetes. Higher rate of Cesarean section (ORcrude 3.78; 95% CI 2.37-6.04 and ORadj
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3.17; 95% CI 1.93-5.23 for metformin DM, ORcrude 4.23; 95% CI 2.57-6.96 and ORadj
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4.97; 95% CI 2.98-8.29 for insulin DM) and earlier gestational age at delivery were
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observed in both groups with diabetes compared with the NTE group. The rate of
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Cesarean section was also higher in the metformin PCOS group (ORcrude 2.29; 95% CI 1.22-4.30 and ORadj 2.65; 95% CI 1.39-5.06). The rate of preterm deliveries was not
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significantly different in the metformin DM group (ORcrude 1.18; 95% CI 0.50-2.75 and ORadj 1.15 95% CI 0.45-2.90), however, it was higher in the insulin group (ORcrude 3.39; 95% CI 1.71-6.72 and ORadj 4.29; 95% CI 2.07-8.88). The median birth
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weight was higher in the metformin DM group. However, when the analysis of birth
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weight was limited to full-term infants, the mean birth weight was higher in both groups with diabetes compared with the NTE group. To evaluate the relative
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contribution of various predictors to the difference in birth weight linear regression analysis was performed. The model was significant and, collectively, the predictors accounted for 34.8% of the variance in birth weight (R2=0.348). Birth weight was found to be significantly directly associated with gestational age at delivery (β=0.508, p<0.001), metformin DM (β=0.185, p<0.001), and insulin DM (β=0.152, p<0.001) 11
groups, and parity (β=0.100, p=0.005), while inversely related with multi-fetal gestation (β=-0.161, p<0.001). Pregnancy complications were more often reported in the metformin DM. The most common complications in the metformin group were polyhydramnios, pregnancy induced hypertension, and toxemia. Perinatal complications were more frequently
Frequent complications reported in these groups were neonatal jaundice,
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hypoglycemia, polycythemia, as well as respiratory problems.
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reported in both metformin groups and insulin group compared with the NTE group.
A comparison of major anomalies between the groups is presented in Table 3. The
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rate of congenital anomalies excluding spontaneously resolved cardiovascular
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anomalies was 4.4% (2/45) in the metformin PCOS group, 1.1% (1/90) in the
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metformin DM group, compared with 2.5% (2/80) in the insulin group, and 1.7%
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(9/519) in the NTE group. The overall rate of major anomalies was not significantly different between the whole metformin and insulin groups compared with the NTE
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group before (ORcrude 2.34; 95% CI 0.84-6.56 and ORadj 2.88; 95% CI 0.99-8.36 for the metformin group, ORcrude 2.00; 95% CI 0.54-7.42 and ORadj 2.07; 95% CI 0.557.71 for the insulin group) and after excluding spontaneously resolved cardiovascular
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anomalies (ORcrude 1.43; 95% CI 0.38-5.48 and ORadj 1.77; 95% CI 0.45-7.01 for the
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whole metformin group, ORcrude 1.65; 95% CI 0.34-7.91and ORadj 1.69; 95% CI 0.358.11 for the insulin group). There was no case of severe cardiovascular anomaly either
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in the metformin DM or NTE groups. The reported major anomalies, maternal details, and the details of exposures in the metformin and insulin groups are listed in Table 4. In addition to the listed anomalies there were two cases of neurodevelopmental disorders without structural abnormalities in the metformin DM group: a girl born prematurely at gestational week 12
32 with severe mental retardation and disability initially diagnosed at two months of age and a boy born at term initially diagnosed at one year of age with communication problems who attended a special education class when later diagnosed with high functioning pervasive developmental disorder not otherwise specified (PDD-NOS). Another case not considered a major anomaly in the metformin DM group was a boy
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born at gestational week 36 prenatally diagnosed with a complex cyanotic
cardiovascular defect with double outlet right ventricle with non-committed VSD and
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esophageal stenosis, since diagnosed with the genetic disorder, Di George (22q11.2 deletion) syndrome. Many of the reported anomalies in both groups were
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cardiovascular or central nervous system anomalies, some complex. There was a case
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of multiple anomalies. There was no case of caudal regression syndrome. It is
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important to mention that all the anomalies found in the metformin groups, except
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one, were diagnosed prenatally or perinatally.
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Discussion
The results of the present prospective observational comparative study do not show a significantly higher overall rate of major or cardiovascular anomalies in the metformin groups vs. NTE group. The pattern of the reported major anomalies in both
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the metformin DM and insulin groups supports association with diabetes. The study, therefore, suggests that metformin first trimester exposure by itself is not associated
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with an increased risk of overall major anomalies. The absolute overall rate of
anomalies found in the current study, although not significantly different from the
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comparison groups, was higher than the 0.5% summarized by Cassina et al among
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634 pregnancies of women treated with metformin throughout the first trimester for
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PCOS [28]. However, a 0.5% rate is rather low compared to the baseline risk for
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major malformations in the general population of 3.7% reported in Jerusalem Perinatal Study Cohort [33] or 1-3% described in the Collaborative Perinatal Project
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(34). In the present study, most pregnant women with metformin first trimester exposure (70%) were treated for type 2 diabetes, and only 30% received it for PCOS. Offspring of women with pre-gestational diabetes mellitus are at increased risk for
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congenital malformations, largely, attributable to poor periconceptional glycemic
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control [35-37]. Preconception care can decrease first trimester mean glycosylated hemoglobin values, and the risk of anomalies [38]. Starikov et al [39] evaluated the
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incidence of overall and major congenital heart defects among infants of mothers with pre-gestational diabetes by glycemic control and found 8.3% (HbA1C≥8.5), 3.9% (HbA1C<8.5), and 6.4% (HbA1C≥8.5), 2.4% (HbA1C<8.5), respectively. The spectrum of congenital anomalies found at increased risk in pregnancies with pregestational diabetes includes neural tube defects, several subgroups of congenital 14
heart defects [40-41], multiple congenital anomalies, and caudal regression sequence [41]. Lack of a case of caudal regression syndrome in either the metformin DM or the insulin group in the present study is not surprising since this malformation, although more common among offspring of women with diabetes, remains rather uncommon. A sample size of 136 live-births or elective terminations of pregnancy due to
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prenatally diagnosed anomalies in the metformin group with a ratio of 1:3.8 to the
NTE comparison group with 80% power, a baseline risk of 2.1% for major anomalies,
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enables detection of a 3.8-fold increase in the rate of major anomalies. In addition, the study is not powered to find an increase in the rate of specific rare anomalies.
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The higher crude rate of miscarriages found in the metformin DM group was
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associated with an earlier gestational age at initial contact (with a higher miscarriage
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rate in women calling earlier in pregnancy) and with a more advanced maternal age,
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but not with the type of exposure, as verified by the Cox proportional hazards model regression analysis. More than half of the women in both groups with diabetes,
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considerably higher than in the NTE group, were delivered by Cesarean section. Similarly, overall Cesarean section rate of 52-55% has previously been reported among women with type 1 or type 2 diabetes [42]. The higher rate of preterm
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deliveries seen in the insulin group is also consistent with increased risk of preterm
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deliveries reported among women with type 1 diabetes [43]. The higher birth weight seen in the metformin DM group may be associated with diabetes and obesity
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common in this group, both known risk factors for macrosomia [44]. The linear regression analysis performed in the present study for birth weight demonstrated that increased birth weight was associated with gestational age at delivery, parity, and metformin or insulin exposure among the groups with diabetes. The latter means that the underlying disease is a significant risk factor for higher birth weight. The higher 15
rate of pregnancy complications in the metformin DM group may also be explained by maternal diabetes, obesity, or a combination of the two as suggested by Langer [45]. The finding that perinatal complications were more common in both metformin groups and insulin group is consistent with previous reports in the literature [46-47]. The fact that severe cardiovascular malformations were not reported in the present
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study among the offspring of the NTE group raise a question regarding the possibility of under-ascertainment. For this reason, we looked at the rate of cardiovascular
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malformations in the NTE group of the Israeli TIS database between the years 2000-
2013. We found an overall rate of cardiovascular malformations of 0.9% (24/2,595) in
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this group, and a rate of 0.5% after exclusion of those that spontaneously resolved
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within the first year. A similar rate of heart malformations (8 of every 1,000 births)
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has been reported in the general population [48-49]. Since the NTE group in the
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current study was randomly selected from the database, we assume that the lack of severe cardiovascular malformations in the present study's NTE group is a chance
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finding, rather than a result of under-ascertainment. A similar risk of major birth defects of 5.1% (20/392) among pregnancies exposed to metformin during the first trimester was found in a recently published multi-center
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TIS study [50].
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The present study has certain limitations and advantages. It is based on TIS population, which may not represent the general population, but has two comparison
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groups from the same TIS. Other limitations of the study are: lack of an untreated PCOS group, relatively small metformin and insulin groups, limited power for specific rare defects, reliance on maternal interview as a source for outcome data in most cases, variation in time of follow-up, and a nonrandomized design. However, applying the same procedure to all arms of the study and the prospective nature 16
minimize the potential biases. Due to ethical considerations randomized controlled trials are often not feasible in pregnancy. The fact that all data are from a single center also minimizes some potential biases. In addition, there were two comparison groups: an insulin group with a similar, though not the same, disease without exposure to metformin and a group counseled for NTE. Moreover, the data on metformin were
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compared according to two different indications, PCOS and diabetes. The study
design enables to distinguish between the possible effect of glycemic control and
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obesity, both potential confounders for congenital anomalies. Indeed, insulin
resistance is common among women with PCOS, resulting in pre-diabetes and a high
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risk of developing type 2 diabetes. However, if the woman reported on diabetes she
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would have been assigned to the metformin DM group. Another advantage of the
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present study is that data on major anomalies were available on elective terminations
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of pregnancies and were included in the analysis.
In conclusion, the present prospective observational comparative cohort study
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suggests that metformin first trimester exposure by itself is not associated with an increased risk for overall major congenital anomalies. This is in line with the results of other studies. However, one should still keep in mind that this conclusion is based
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on relatively small numbers of exposed pregnancies, and should be interpreted with
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caution. Larger studies are still needed to establish the pregnancy safety of metformin, especially in the context of pre-gestational diabetes. The pattern of anomalies in both
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the metformin DM and insulin groups supports association with hyperglycemia. The underlying hyperglycemia is known to be associated with an increased risk for major anomalies, especially cardiovascular, CNS, and multiple congenital anomalies.
17
Conflict of interest The authors have no conflict of interest to disclose.
*Acknowledgments:
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This work is part of the Pharm D thesis in Clinical Pharmacy of the Hebrew University of Mrs. Salit Steinmetz-Shoob.
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The authors would like to thank Irena Liphshiz (MSc.) from the Health Information
Division of Israel Ministry of Health, for her valuable advice and contribution to the
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statistical analysis and presentation of data.
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CC
EP
seeking teratology information services. Br J Clin Pharmacol 2018 Mar;84(3):568-78.
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I N U SC R
Tables
Table 1 Comparison of Maternal Characteristics and Obstetric History
n
30.9 ± 4.9
PT
CC E A
DM n=119
Comparison groups Insulin DM NTE n=93 n=530
36.4 ± 5.4
32.0 ± 5.2
31.0 ± 4.8
7 (5-9)
7 (6-10)
8 (6-14)
10 (7-18)
22/46 (47.8) 17/46 (37.0) 7/46 (15.2)
18/100 (18.0) 32/100 (32.0) 50/100 (50.0)
25/81 (30.9) 39/81 (48.1) 17/81 (21.0)
172/498 (34.5) 245/498 (49.2) 81/498 (16.3)
27/47 (57.4) 19/47 (40.4) 1/47 (2.1)
26/107 (24.3) 61/107 (57.0) 20/107 (18.7)
31/83 (37.3) 49/83 (59.0) 3/83 (3.6)
208/501 (41.5) 271/501 (54.1) 22/501 (4.4)
35/46 (76.1) 9/46 (19.6) 2/46 (4.3) 0/46 (0) 4/46 (8.7)
67/102 (65.7) 29/102 (28.4) 6/102 (5.9) 2/101 (2.0) 11/102 (10.8)
66/79 (83.5) 11/79 (13.9) 2/79 (2.5) 0/79 (0) 9/79 (11.4)
417/497 (83.9) 72/497 (14.5) 8/497 (1.6) 3/497 (0.6) 29/497 (5.8)
ED
Maternal age mean ±SD (y) GA at initial contact, w median (IQR) Pregnancy order, n (%) 1 2-3 4 Parity, n (%) 0 1-3 4 Past miscarriages, n (%) 0 1-2 3 Past stillbirth, n (%) Past ETOP1, n (%)
M
PCOS n=51
A
Metformin
26
I 2/101 (2.0) 9/101 (8.9) n=90 31 (27-35) 13/64 (20.3)
M
A
2/41 (4.9) 1/41 (2.4) n=40 29 (24-37) NR
N U SC R
Cigarette smoking <10cigarettes/day 10cigarettes /day BMI, n BMI, median (IQR)
1/74 (1.4) 4/74 (5.4) n=77 23 (21-29) 8/74 (10.8)
10/484 (2.1) 5/484 (1.0) n=456 23 (21-29) NR
A
CC E
PT
ED
HbA1C≥8.5 in first trimester, n (%) SD - standard deviation, y - years, GA - gestational age, w - weeks, IQR - interquartile range, ETOP - elective termination of pregnancy, BMI body mass index, HbA1C - glycosylated hemoglobin test, PCOS - polycystic ovary syndrome, DM - diabetes mellitus, NTE - non-teratogenic exposure, NR - not relevant.
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I N U SC R
Table 2 Comparison of Pregnancy Outcome
Metformin
PT
(IQR)
CC E
Mode of delivery Vaginal uncomplicated, n (%) Cesarean section, n (%) Assisted delivery, n (%) GA at delivery, w median (IQR) Preterm delivery, <37 w, n (%) Birth weight, g median (IQR) Birth weight of fullterm infants, g mean
A
89/119 (74.8)
79/93 (84.9)
495/530 (93.4)
6/51 (11.8) 1/51 (2.0) 0 33 (14-65)
19/119 (16.0) 10/119 (8.4) 1 (0.8) 27 (10-58)
11/93 (11.8) 3/93 (3.2) 0 35 (16-70)
30/530 (5.7) 5/530 (0.9) 0 14 (8-20)
23/43 (53.5)
38/90 (42.2)
31/79 (39.2)
338/503 (67.2)
19/43 (44.2)
51/90 (56.7)
45/79 (57.0)
138/503 (27.4)
1/43 (2.3)
1/90 (1.1)
3/79 (3.8)
27/503 (5.4)
39 (38-40) 5/44 (11.4)
38 (38-40) 9/89 (10.1)
38 (36-38) 21/79 (26.6)
39 (38-40) 37/495 (7.5)
3200 (2725-3700) 3323±607
3400 (3100-3750) 3444±467
3258 (2660-3700) 3417±517
3183 (2838-3486) 3210±456
M
44/51 (86.3)
ED
Pregnancy Outcome Delivery of live-born infant, n (%) Miscarriage, n (%) ETOP, n (%) Stillbirth, n (%) Age at FU, median, m
DM
A
PCOS
Comparison groups Insulin DM NTE
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I N U SC R
A
CC E
PT
ED
M
A
(±SD) Pregnancy 13/44 (29.5) 30/90 (33.3) 13/79 (16.5) 106/516 (20.5) complications, n (%) Perinatal 17/44 (38.6) 38/90 (42.2) 45/79 (57.0) 74/516 (14.3) complications, n (%) ETOP - elective termination of pregnancy, FU - follow-up, IQR - interquartile range, m - months, GA - gestational age, w - weeks, g - grams, SD - standard deviation, PCOS - polycystic ovary syndrome, DM - diabetes mellitus, NTE - non-teratogenic exposure.
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Table 3 Comparison of Congenital Anomalies Metformin* PCOS DM
Comparison groups Insulin DM NTE
A
CC
EP
TE D
M
A
N
U
SC R
IP T
Major anomalies, n 3/45 (6.7) 3/90 (3.3) 3/80 (3.8) 11/519 (2.1) (%) All cardiovascular, n 2/45 (4.4) 2/90 (2.2) 2/80 (2.5) 2/519 (0.4) (%) Major anomalies, 2/45 (4.4) 1/90 (1.1) 2/80 (2.5) 9/519 (1.7) excluding spontameously resolved cardiovascular anomalies, n (%) *among pregnancies exposed to metformin in the period of organogenesis, i.e. weeks 4-13 after the last menstrual period, PCOS - polycystic ovary syndrome, DM diabetes mellitus, NTE - non-teratogenic exposure
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Table 4 List of Major Congenital Anomalies in the Metformin and Insulin Groups Type of anomaly
Maternal indication, age, GC, BMI, exposure details, additional exposures
Pregnancy outcome, GA (w), sex, BW (g)
FU comments
Dandy Walker syndrome
PCOS, 30y, NR, NA 1700mg/d ongoing
ETOP, 17
Diagnosed on prenatal U/S
Tetralogy of Fallot
PCOS, 26y, NR, 25, 850mg/d till w 8
Delivery, 39, M
Died at 3 m while operated
Small PDA, mild PS*
PCOS, 23, NR, 29, till w5
Delivery, 38, M, 4400
SC R
IP T
Metformin PCOS group
U
Diagnosed on echocardiography at 2 m, resolved before 6 m
N
Metformin DM group Type 2 DM, 42y, P, 34, 2550mg/d till w 6, losartan simvastatin till w 5
ETOP, 18
Septal defect, 'hole' in heart*
Type 2 DM, 37y, P 11.1, >30, 1700mg/d till w 20
Delivery, 38, F, 3800
Spontaneously resolved at 1 y
VSD*
Type 2 DM, 35y, NA, NA
Delivery, 40, M, 4555
Diagnosed on prenatal echocardiography, spontaneously resolved at 2 m
Levocardia, VSD, situs inversus abdominis, abnormal venous drainage
Type 1 DM, 27y, P, 29, losartan simvastatin till w 5
Delivery, 36, F, 2600,
Open heart surgery at 4.5 y
Dandy Walker syndrome
Type 1 DM, 35y, NA, 29, enalapril
ETOP, 13
Diagnosed on prenatal U/S
CC
EP
TE D
M
A
Multiple anomalies including spina bifida
Diagnosed on prenatal U/S
A
Insulin group
31
simvastatin till w 5 Type 1 DM, 26y, NA, 21
Delivery, 38, M, 3250
Spontaneously closed at 1 y
Inguinal hernia, ASD/P FO, mild left pulmonary artery stenosis*
DM, 36y, G 6.8, 22
Delivery, 38, F, 3380
Inguinal hernia operated at 6 m, CV anomaly spontaneously resolved at 3 m
IP T
VSD*
A
CC
EP
TE D
M
A
N
U
SC R
PCOS - polycystic ovary syndrome, PDA - patent ductus arteriosus, PS - pulmonary stenosis, * - not included in the final analysis since spontaneously resolved, DM diabetes mellitus, VSD - ventricular septal defect, ASD - atrial septal defect, PFO patent foramen ovale, GC - glycemic control, G – good to fair (HbA1C - glycosylated hemoglobin test <8.5), P - poor (HbA1C - glycosylated hemoglobin test ≥8.5), BMI body mass index, NR - not relevant, NA - not available, y - years, w - week, d - day, GA - gestational age at delivery, BW - birth weight, g - grams, F - female, M - male, ETOP elective termination of pregnancy, FU - follow-up, NICU - neonatal intensive care unit, m months, U/S - ultrasound, CV - cardiovascular
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Box 1 Distribution of Concomitant Medications in the Metformin and Insulin Groups Concomitant Medications
Metformin
Insulin DM
PCOS
DM
n=51
n=119
n=93
-
27
3
ACEI/ARBs
2
32
Beta blockers
1
4
Calcium channel blockers
-
4
Others**
1
No
47
Lipid lowering agents
1
Concomitant anti diabetic drugs*
IP T
Antihypertensives: 17
SC R
2 -
2
77
72
35
10
U
2
A
CC
EP
TE D
M
A
N
* glibenclamide, repaglinide, acarbose ** alpha agonist, thiazide, diuretic, vasodilator ACEI/ARBs - angiotensin converting enzyme inhibitors/angiotensin II receptor blockers, PCOS - polycystic ovary syndrome, DM - diabetes mellitus
33