Fetal Growth and Birth Anthropometrics in Metformin-Exposed Offspring Born to Mothers With PCOS

Fetal Growth and Birth Anthropometrics in Metformin-Exposed Offspring Born to Mothers With PCOS Abstract Context Metformin is used in an attempt to reduce pregnancy complications associated with polycystic ovary syndrome (PCOS). Little is known about the effect of metformin on fetal development and growth. Objectives To compare the effect of metformin versus placebo on fetal growth and birth anthropometrics in PCOS offspring compared with a reference population in relation to maternal body mass index (BMI). Design Post hoc analysis of a randomized controlled trial. Setting Double-blind, placebo-controlled, multicenter study. Patients 258 offspring born to mothers with PCOS. Intervention 2000 mg metformin (n = 131) or placebo (n = 121) from first trimester to delivery. Main Outcome Measures Mean abdominal diameter and biparietal diameter (BPD) at gestational weeks 19 and 32. Head circumference (HC), birth length, and weight related to a reference population of healthy offspring, expressed as gestational age– and sex-adjusted z-scores. Results Metformin- versus placebo-exposed offspring had larger heads at gestational week 32 (BPD, 86.1 mm versus 85.2 mm; P = 0.03) and at birth (HC, 35.6 cm versus 35.1 cm; P < 0.01). Analyses stratified by maternal prepregnancy BMI, larger heads were observed only among offspring of overweight/obese mothers. Among normal-weight mothers, the effect of metformin compared with placebo was reduced length (z-score = −0.96 versus -0.42, P = 0.04) and weight (z-score = −0.44 versus 0.02; P = 0.03). Compared with the reference population, offspring born to PCOS mothers (placebo group) had reduced length (z-score = −0.40; 95% confidence interval, −0.60 to −0.40), but similar birth weight and HC. Conclusions Metformin exposure resulted in larger head size in offspring of overweight mothers, traceable already in utero. Maternal prepregnancy BMI modified the effect of metformin on offspring anthropometrics. Anthropometrics of offspring born to PCOS mothers differed from those of the reference population. Polycystic ovary syndrome (PCOS) affects 5% to 13% of women of childbearing age (1). Prevalence varies according to applied criteria and population. Women with PCOS have poorer metabolic health and increased risk for complications in pregnancy, such as gestational diabetes mellitus, preeclampsia, and preterm delivery (2–6). Birth characteristics are associated with metabolic health later in life (7), but evidence on the effect of maternal PCOS status on newborn anthropometric data, as well as metabolic health, is scarce and diverging. A population-based study from Australia reported an increased number of small-for-gestational-age offspring born to mothers with PCOS (8). A retrospective study from Austria (9) showed no increased risk for growth deviation according to PCOS. A population based study from Sweden found more large-for-gestational-age offspring born to mothers with PCOS (3, 10, 11). Metformin is an oral antidiabetic drug used in the treatment of type 2 diabetes mellitus. It is cheap and assumed safe. The effect of metformin on insulin sensitivity, lipid metabolism, and inflammation has induced a wider area of application. During the past decades, women with gestational diabetes mellitus, PCOS and obesity have been treated with metformin in an attempt to improve pregnancy outcome, but this practice is not based on solid scientific evidence. Metformin passes the placental barrier, but teratogenicity is not reported (12). There is little knowledge about possible effects of metformin on growth, metabolism, endocrine, and nervous system development in the fetus and cognitive and psychological effects later in life. In five studies on gestational diabetes, in which mothers were randomly assigned to metformin or insulin, no difference was seen in offspring birth weight (11, 13–15). One study reported increased birth length in newborns (15), and another found shorter and lighter newborns (12) in the metformin group. Two large randomized control trials (RCTs) compared metformin with placebo in obese pregnant women and found no effect on birth weight (16, 17). Our initial analysis of women with PCOS in the PregMet RCT (18) showed no difference in pregnancy complications or newborn data between the metformin and placebo groups, except head size. Head size of the metformin-exposed newborns was larger (18). In the current study, we examined the in utero ultrasound measurements of the fetuses to explore the effect of metformin versus placebo on fetal anthropometrics and birth anthropometrics in PCOS offspring compared with those in a reference population. The results were related to maternal body mass index (BMI). The Committee for Medical Research Ethics of Health Region IV, Norway, and The Norwegian Medicines Agency approved the study. Written, informed consent was obtained from each patient before inclusion, and the declaration of Helsinki was followed throughout the study. Participants and Methods The PregMet study was a prospective, randomized, placebo-controlled, multicenter trial of pregnant women with PCOS (18). The aim of the study was to investigate whether metformin exposure from first trimester to delivery could prevent pregnancy complications. Eleven health care centers in Norway (three university hospitals, seven local hospitals, and one gynecological specialist practice) recruited women to the study during 2005 to 2009. Primary endpoints were prevalence of preeclampsia, preterm delivery, gestational diabetes mellitus, and a composite of the diagnoses. Inclusion criteria in the PregMet study were (1) PCOS diagnosed according to the Rotterdam criteria, (2) age 18 to 45 years, (3) gestational age between 5 and 12 weeks, and (4) singleton viable fetus shown on ultrasonography. Exclusion criteria were alanine transaminase level > 90 IU/L, serum creatinine > 1.70 mg/dL, known alcohol abuse, previously diagnosed diabetes mellitus, or fasting serum glucose level > 126 mg/dL at the time of inclusion. All participants received written and individual verbal counseling on diet and lifestyle at inclusion. Thereafter, treatment with metformin 500 mg (metformin hydrochloride; Weifa AS, Oslo, Norway) or identically coated placebo tablets was initiated. The participants were instructed to take two tablets twice daily, for a total of 2000 mg daily, for the rest of the study period. To counteract a possible metformin action on vitamin B levels, patients were advised to take 0.8 mg of folate daily and one daily multivitamin tablet. Study medication was stopped at delivery. Randomization was performed at the Trondheim University Hospital Pharmacy in blocks of 10 and was stratified according to metformin use at conception. The method was random drawing of an envelope by two pharmacy employees, one executing the drawing and the other monitoring the drawing. This study has been described in detail elsewhere (18). Study population In total, 274 pregnancies were included and randomized. One patient was misdiagnosed, three miscarried, and 12 dropped out (Fig. 1). These 16 pregnancies were excluded because ultrasound data were lacking. The present analyses comprise 258 pregnancies. Eighty-four percent of all participants took more than 85% of the study medication and were classified as having good/acceptable adherence. Figure 1. View largeDownload slide Flow chart of inclusion, exclusion, and randomization of patients. Figure 1. View largeDownload slide Flow chart of inclusion, exclusion, and randomization of patients. Ultrasound measurements All ultrasound examinations were performed by doctors and specialized midwives trained to perform routine ultrasound examinations. The equipment used was the preferred, up-to-date ultrasound devices used in everyday clinical practice during the study period. Estimated date of delivery and gestational age were calculated from crown-rump-length and/or biparietal diameter (BPD) in the first trimester. Transvaginal ultrasound examinations in the first trimester were performed at the time of inclusion. Estimated date of delivery and gestational age were calculated from crown-rump-length or BPD at the first trimester scan and were based on the algorithm implemented in the first trimester screening program from the Fetal Medicine Foundation (19, 20). Transabdominal ultrasound measurements were performed at gestational week 19 (±1 week) and week 32 (±1 week), with measurements of BPD (outer to outer measurement of skull diameter) and mean abdominal diameter (MAD). Measurements of BPD and MAD in the second and third trimester referred to references in the eSnurra method (21, 22) Offspring anthropometrics Midwives and nurse assistants measured head circumference (HC), length, and weight of the offspring immediately after delivery. For HC, length, and weight at birth, gestational age– and sex-adjusted z-scores were calculated based on Niklasson’s standard values from a large Swedish population [19]. The standard is based on singleton fetuses without chromosome abnormalities or major birth defects. The z-scores express the deviation between observed values and the standard population mean adjusted for sex and gestational age at birth. Statistical analyses All data entry, data management, and data analyses were analyzed according to the intention-to-treat principle. Baseline characteristics for the two maternal groups were compared by using t tests for continuous variables and χ2 tests for categorical variables. The effect of metformin, as well as the effect of metformin in relation to maternal BMI, was analyzed by using linear regression analyses. Offspring characteristics for different maternal BMI groups were compared by using a t test for both the metformin and placebo group. A P value < 0.05 was considered to indicate a statistically significant difference. The statistical analyses were performed by using SPSS software, version 23 (IBM, Armonk, NY) and R software, version 2.13.1 (R Foundation for Statistical Computing, Vienna, Austria). Results Maternal baseline characteristics did not differ between the placebo and metformin groups in terms of BMI, blood glucose, ethnicity, smoking, and PCOS phenotypes (Table 1). Adherence to study medication was similar in the two groups (Table 1). Table 1. Baseline Data on Women with PCOS at Inclusion, in First Trimester of Pregnancy, in PregMet Study Variable  Metformin (n = 131)  Placebo (n = 127)  P Valuea  Age (y)  29.6 ± 4.3  29.3 ± 4.4  0.558  Height (cm)  167.3 ± 5.8  167.7 ± 5.4  0.549  Weight (kg)  82.9 ± 20.3  79.3 ± 18.0  0.131  BMI (kg/m2)  29.6 ± 7.1  28.2 ± 6.4  0.099  Systolic blood pressure (mm Hg)  119 ± 12  117 ± 11  0.302  Diastolic blood pressure (mm Hg)  74 ± 13  72 ± 9  0.268  Parity (n)      0.825   Para 0  74  70     Para ≥1  57  57    Ethnicity      0.047   White  127 (97)  127 (100)     Nonwhite  4 (3)  0 (0)    GDM at inclusion  10 (4)  11 (4)  0.822  Smokers  14 (4.5)  7 (2.7)  0.172  Diagnostic criteria PCOS         NIH diagnostic criteriab  91 (70)  87 (69)     Rotterdam diagnostic criteria  40 (30)  40 (31)    Androgen status      0.577   Hyperandrogenism  98 (75)  91 (72)     Normoandrogenism  33 (25)  36 (28)    Mode of conception      0.200   Spontaneous conception  76 (58)  75 (59)     Ovulation induction  38 (29)  28 (22)     IVF/ICSI  17 (13)  21 (7)     Other  0 (0)  3 (2)    Adherence to medication      0.552   Taken >85% of all study medication  108 (82)  108 (85)     Taken <85% of all study medication  23 (18)  19 (15)    Variable  Metformin (n = 131)  Placebo (n = 127)  P Valuea  Age (y)  29.6 ± 4.3  29.3 ± 4.4  0.558  Height (cm)  167.3 ± 5.8  167.7 ± 5.4  0.549  Weight (kg)  82.9 ± 20.3  79.3 ± 18.0  0.131  BMI (kg/m2)  29.6 ± 7.1  28.2 ± 6.4  0.099  Systolic blood pressure (mm Hg)  119 ± 12  117 ± 11  0.302  Diastolic blood pressure (mm Hg)  74 ± 13  72 ± 9  0.268  Parity (n)      0.825   Para 0  74  70     Para ≥1  57  57    Ethnicity      0.047   White  127 (97)  127 (100)     Nonwhite  4 (3)  0 (0)    GDM at inclusion  10 (4)  11 (4)  0.822  Smokers  14 (4.5)  7 (2.7)  0.172  Diagnostic criteria PCOS         NIH diagnostic criteriab  91 (70)  87 (69)     Rotterdam diagnostic criteria  40 (30)  40 (31)    Androgen status      0.577   Hyperandrogenism  98 (75)  91 (72)     Normoandrogenism  33 (25)  36 (28)    Mode of conception      0.200   Spontaneous conception  76 (58)  75 (59)     Ovulation induction  38 (29)  28 (22)     IVF/ICSI  17 (13)  21 (7)     Other  0 (0)  3 (2)    Adherence to medication      0.552   Taken >85% of all study medication  108 (82)  108 (85)     Taken <85% of all study medication  23 (18)  19 (15)    Values expressed with a plus/minus sign are the mean ± standard deviation. Unless otherwise noted, all other values are N (%). Abbreviations: GDM, gestational diabetes mellitus; ICSI, intracytoplasmic sperm injection; IVF, in vitro fertilization; NIH, National Institutes of Health. a A t test was performed with equal variances assumed. Pearson χ2 and Fisher exact test was performed. b National Institutes of Health diagnostic criteria. View Large The effects of metformin versus placebo on fetal growth are shown in Table 2. There was no difference between the groups in BPD at gestational week 19, but metformin-exposed offspring had larger BPD than offspring in the placebo group at gestational week 32 (ΔBPD, 0.9 mm; P = 0.027). At birth, HC was larger in the metformin group than in the placebo group (ΔHC, 0.5 cm; P = 0.007). HC in the metformin group was also larger than that in the reference population, expressed as HC z-score (95% confidence interval [CI]) of 0.3 (0.005 to 0.52). MAD at gestational weeks 19 and 32 and the weight and length did not differ between the metformin and placebo groups. Table 2. Anthropometric Characteristics of Offspring Born to Women With PCOS Exposed to Metformin or Placebo Variable  Offspring (n)  Metformin  Offspring (n)  Placebo  ΔM-P (95% CI)a  P Valueb  BPD week 19 (mm)  127  46.4 ± 3.1  121  46.3 ± 3.4  0.1 (−0.72 to 0.92)  0.810  BPD week 32 (mm)  126  86.1 ± 3.2  122  85.2 ± 3.3  0.9 (0.11–1.73)  0.027  MAD week 19 (mm)  125  43.6 ± 3.9  121  43.7 ± 4.9  −0.2 (−1.26 to 0.96)  0.788  MAD week 32 (mm)  126  90.4 ± 5.2  120  89.9 ± 4.8  0.5 (−0.80 to 1.71)  0.476  HC at birth               In cm  130  35.6 ± 1.6  126  35.0 ± 1.6  0.5 (0.15 to 0.92)  0.007   z-score  130  0.3 (0.10–0.49)  126  0.03 (−0.14 to 0.22)  0.3 (0.005 to 0.52)  0.045  Birth weight               In g  131  3567 ± 540  127  3545 ± 617  22 (−120 to 163)  0.763   z-scorec  131  −0.05 (−0.23 to 0.15)  127  0.06 (−0.11 to 0.24)  −0.1 (−0.36 to 0.16)  0.431  Birth lengthc               In cm  130  50.1 ± 2.1  124  50.0 ± 2.5  0.1 (−0.51 to 0.63)  0.826   z-score   130  −0.52 (−0.72 to −0.33)  124  −0.40 (−0.60 to −0.20)  −0.13 (−0.40 to 0.15)  0.375  Birth weight ≥90th percentile,d n (%)  131  15 ± 12  127  15 ± 12  —  0.928  Birth weight ≤10th percentile,d n (%)  131  12 ± 9  127  13 ± 10  —  0.832  Variable  Offspring (n)  Metformin  Offspring (n)  Placebo  ΔM-P (95% CI)a  P Valueb  BPD week 19 (mm)  127  46.4 ± 3.1  121  46.3 ± 3.4  0.1 (−0.72 to 0.92)  0.810  BPD week 32 (mm)  126  86.1 ± 3.2  122  85.2 ± 3.3  0.9 (0.11–1.73)  0.027  MAD week 19 (mm)  125  43.6 ± 3.9  121  43.7 ± 4.9  −0.2 (−1.26 to 0.96)  0.788  MAD week 32 (mm)  126  90.4 ± 5.2  120  89.9 ± 4.8  0.5 (−0.80 to 1.71)  0.476  HC at birth               In cm  130  35.6 ± 1.6  126  35.0 ± 1.6  0.5 (0.15 to 0.92)  0.007   z-score  130  0.3 (0.10–0.49)  126  0.03 (−0.14 to 0.22)  0.3 (0.005 to 0.52)  0.045  Birth weight               In g  131  3567 ± 540  127  3545 ± 617  22 (−120 to 163)  0.763   z-scorec  131  −0.05 (−0.23 to 0.15)  127  0.06 (−0.11 to 0.24)  −0.1 (−0.36 to 0.16)  0.431  Birth lengthc               In cm  130  50.1 ± 2.1  124  50.0 ± 2.5  0.1 (−0.51 to 0.63)  0.826   z-score   130  −0.52 (−0.72 to −0.33)  124  −0.40 (−0.60 to −0.20)  −0.13 (−0.40 to 0.15)  0.375  Birth weight ≥90th percentile,d n (%)  131  15 ± 12  127  15 ± 12  —  0.928  Birth weight ≤10th percentile,d n (%)  131  12 ± 9  127  13 ± 10  —  0.832  Values expressed with a plus/minus sign are the mean ± standard deviation. Abbreviations: M, metformin; P, placebo. aΔM-P expresses the metformin effect on HC, length, and weight z-scores in offspring born to mothers with PCOS. bA t test was performed with equal variances assumed. c Values in parentheses are 95% CIs. d Birth weight adjusted for gestational age. View Large The effect of metformin on birth anthropometrics differed according to maternal prepregnancy weight (BMI < 25 kg/m2 or BMI ≥ 25 kg/m2). The results from the interaction analyses are shown in Table 3. HC at birth was increased in the metformin group, but only among offspring born to overweight women (ΔHC z-score = 0.50; P = 0.002). Among normal-weight women, HC did not differ between the metformin and placebo groups (ΔHC z-score = −0.20; P = 0.367). Thus, the metformin effect on HC differed between maternal weight categories by a z-score of 0.71, and this interaction effect reached statistical significance (P = 0.011). Table 3. Effect of Metformin on Anthropometric Measures at Birth According to Maternal BMI Variable  Maternal BMI <25 kg/m2   Maternal BMI ≥25 kg/m2   (ΔM-P [BMI ≥25]) − (ΔM-P [(BMI <25]) (95% CI)d  P Valueb  Metformin  Placebo  ΔM-P (95% CI)a  P Valueb  Metformin   Placebo  ΔM-P (95% CI)c  P Valued  HC  −0.02 (−0.34 to 0.29)  0.18 (−0.13 to 0.49)  −0.20 (−0.65 to 0.24)  0.367  0.45 (0.23 to 0.67)  −0.05 (−0.28 to 0.18)  0.50 (0.19 to 0.82)  0.002  0.71 (0.16 to 1.25)  0.011  Length  −0.96 (−1.30 to −0.63)  −0.42 (−0.76 to −0.09)  −0.54 (−1.01 to −0.07)  0.025  −0.31 (−0.54 to −0.07)  −0.38 (−0.63 to −0.14)  0.08 (−0.26 to 0.24)  0.655  0.62 (0.033 to 1.20)  0.038  Weight   −0.44 (−0.75 to −0.13)  0.02 (−0.29 to 0.33)  −0.45 (−0.89 to −0.02)  0.041  0.15 (−0.07 to 0.37)  0.08 (−0.14 to 0.31)  0.07 (−0.24 to 0.39)  0.650  0.53 (−0.01 to 1.06)  0.055  Variable  Maternal BMI <25 kg/m2   Maternal BMI ≥25 kg/m2   (ΔM-P [BMI ≥25]) − (ΔM-P [(BMI <25]) (95% CI)d  P Valueb  Metformin  Placebo  ΔM-P (95% CI)a  P Valueb  Metformin   Placebo  ΔM-P (95% CI)c  P Valued  HC  −0.02 (−0.34 to 0.29)  0.18 (−0.13 to 0.49)  −0.20 (−0.65 to 0.24)  0.367  0.45 (0.23 to 0.67)  −0.05 (−0.28 to 0.18)  0.50 (0.19 to 0.82)  0.002  0.71 (0.16 to 1.25)  0.011  Length  −0.96 (−1.30 to −0.63)  −0.42 (−0.76 to −0.09)  −0.54 (−1.01 to −0.07)  0.025  −0.31 (−0.54 to −0.07)  −0.38 (−0.63 to −0.14)  0.08 (−0.26 to 0.24)  0.655  0.62 (0.033 to 1.20)  0.038  Weight   −0.44 (−0.75 to −0.13)  0.02 (−0.29 to 0.33)  −0.45 (−0.89 to −0.02)  0.041  0.15 (−0.07 to 0.37)  0.08 (−0.14 to 0.31)  0.07 (−0.24 to 0.39)  0.650  0.53 (−0.01 to 1.06)  0.055  Unless otherwise noted, values are expressed as z-scores (95% CIs). Abbreviations: M, metformin; P, placebo. aΔM-P (BMI <25) expresses the metformin effect on HC, length, and weight z-scores in offspring of normal-weight mothers. b Statistical testing performed by multiple linear regression analyses. c ΔM-P (BMI ≥25) expresses the metformin effect on HC, length, and weight s-scores in offspring of overweight/obese mothers. d (ΔM-P [BMI <25]) − (ΔM-P [BMI ≥25]) expresses the difference in metformin effect on offspring HC, length, and weight z-scores between overweight and normal-weight mothers. View Large Length was significantly reduced by metformin among normal-weight mothers (Δ length z-score = −0.54; P = 0.025), but not among overweight mothers. The difference in metformin effect on length between maternal BMI categories was 0.62 (P = 0.038). In addition, birth weight was reduced by metformin only in normal-weight mothers (Δ birthweight z-score = −0.45; P = 0.041). The difference in effect of metformin on birth weight z-score between maternal weight groups was 0.53 (P = 0.055). All these interactions are of borderline statistical significance. Subgroup analyses according to hyperandrogen and normoandrogen maternal phenotype showed a larger HC (35.8 cm versus 35.2 cm; P = 0.020) and HC z-score (0.67 versus 0.27; P = 0.008) in metformin- versus placebo-exposed offspring, but only among the hyperandrogen phenotypes. Among normoandrogen phenotypes, there was no difference in HC (35.0 cm versus 34.5 cm; P = 0.237) or HC z-score (0.17 versus 0.17; P = 0.992) between the metformin and placebo groups. In analyses stratified by offspring sex, metformin-exposed girls, but not boys, seemed to have a larger BPD at week 32 and larger HC at birth. After adjustment for maternal BMI, there was no difference in the effect of metformin according to sex (data not shown). We also analyzed data according to adherence. The difference in HC and HC z-score remained significant among those with good adherence (84%) and was not present among those with poor adherence (16%). The effect of PCOS on offspring anthropometrics was analyzed in the placebo group and expressed by z-score deviation from the reference population. The PCOS offspring were shorter than the reference population: Birth length z-score was −0.40 (95% CI, −0.60 to −0.20) (Table 2). Birth weight z-score (0.06; 95% CI, −0.11 to 0.24) and HC z-score (0.03; 95% CI, −0.14 to 0.22) did not differ from those in the reference population. In contrast to the metformin group, maternal BMI (<25 kg/m2 or BMI ≥ 25 kg/m2) had no effect on offspring birth weight, length, or HC (Table 4). Table 4. Characteristics in Offspring Born to Women With PCOS Exposed to Metformin or Placebo In Utero According to Randomization Variable  Placebo   Metformin   BMI <25 kg/m2   BMI ≥25 kg/m2   P Valuea  BMI <25 kg/m2   BMI ≥25 kg/m2   P Valuea  Women (n)  Mean  Women (n)  Mean  Women (n)  Mean  Women (n)  Mean  BPD week 19 (mm)  42  46.5 ± 3.9  79  46.2 ± 3.1  0.640  44  46.5 ± 3.7  83  46.4 ± 2.8  0.798  BPD week 32 (mm)  42  86.1 ± 3.3  80  84.7 ± 3.2  0.020  41  85.9 ± 3.1  85  86.2 ± 3.3  0.663  MAD week 19 (mm)  42  43.1 ± 5.2  72  44.0 ± 4.7  0.326  44  43.5 ± 3.5  81  43.6 ± 4.1  0.886  MAD week 32 (mm)  42  90.5 ± 4.7  78  89.7 ± 4.8  0.071  41  88.5 ± 4.6  85  91.4 ± 5.3  0.003  HC                       In cm  44  35.2 ± 1.8  82  35.0 ± 1.5  0.450  43  35.0 ± 1.5  87  35.9 ± 1.5  0.003   z-score  44  0.18  82  −0.50  0.211  43  −0.02  87  0.45  0.022  Birth weight                       In g  44  3537 ± 655  83  3550 ± 600  0.908  44  3327 ± 510  87  3689 ± 516  0.000   z-scoreb  44  0.02  83  0.08  0.739  44  −0.44  87  0.15  0.003  Birth lengthb                       In cm  43  50.0 ± 2.6  81  50.1 ± 2.4  0.779  43  49.2 ± 1.9  87  50.6 ± 2.1  0.000   z-score   43  −0.42  81  −0.38  0.861  43  −0.96  87  −0.31  0.002  Variable  Placebo   Metformin   BMI <25 kg/m2   BMI ≥25 kg/m2   P Valuea  BMI <25 kg/m2   BMI ≥25 kg/m2   P Valuea  Women (n)  Mean  Women (n)  Mean  Women (n)  Mean  Women (n)  Mean  BPD week 19 (mm)  42  46.5 ± 3.9  79  46.2 ± 3.1  0.640  44  46.5 ± 3.7  83  46.4 ± 2.8  0.798  BPD week 32 (mm)  42  86.1 ± 3.3  80  84.7 ± 3.2  0.020  41  85.9 ± 3.1  85  86.2 ± 3.3  0.663  MAD week 19 (mm)  42  43.1 ± 5.2  72  44.0 ± 4.7  0.326  44  43.5 ± 3.5  81  43.6 ± 4.1  0.886  MAD week 32 (mm)  42  90.5 ± 4.7  78  89.7 ± 4.8  0.071  41  88.5 ± 4.6  85  91.4 ± 5.3  0.003  HC                       In cm  44  35.2 ± 1.8  82  35.0 ± 1.5  0.450  43  35.0 ± 1.5  87  35.9 ± 1.5  0.003   z-score  44  0.18  82  −0.50  0.211  43  −0.02  87  0.45  0.022  Birth weight                       In g  44  3537 ± 655  83  3550 ± 600  0.908  44  3327 ± 510  87  3689 ± 516  0.000   z-scoreb  44  0.02  83  0.08  0.739  44  −0.44  87  0.15  0.003  Birth lengthb                       In cm  43  50.0 ± 2.6  81  50.1 ± 2.4  0.779  43  49.2 ± 1.9  87  50.6 ± 2.1  0.000   z-score   43  −0.42  81  −0.38  0.861  43  −0.96  87  −0.31  0.002  Values expressed with a ± sign are the mean ± standard deviation. a A t test was performed with equal variances assumed. View Large Discussion The main finding of the present follow-up study is that metformin-exposed offspring had larger HC compared with offspring in the placebo group. This was evident already at gestational week 32. Birth weight and length did not differ between the metformin and placebo groups. This study on PCOS explored the effect of metformin on fetal and newborn anthropometrics in an RCT setting, in which the metformin group and placebo group were randomly assigned and had no baseline differences in known potential influencing factors. Little is known about the effect of metformin on fetal and newborn head size. In one study on gestational diabetes, metformin was compared with insulin (15). Head size of offspring in the metformin and insulin groups did not differ. Among women with obesity who were randomly assigned to metformin or placebo during pregnancy, offspring had similar HC (17). Our results deviate from these previous studies, and the difference is most likely explained by the variation in underlying diagnoses. Also, differences in study design, population size, aim, medical treatment, maternal weight, and ethnicity may have contributed to the differing results. HC correlates accurately to brain volume (23, 24), and large head size is associated with good cognitive function and cardiovascular health (24, 25). Thus, a large head at birth is a surrogate marker for brain development and potentially has a beneficial effect. The metformin effect of larger HC and HC z-score was seen only among offspring of mothers with hyperandrogenic phenotype; among those with normo-androgenic phenotype, there was no difference between the groups. However, because of the small sample size, a metformin effect according to maternal androgen status must be interpreted with great caution and should be addressed in future studies. The effect of prenatal metformin exposure seems to translate differently depending on maternal BMI and/or metabolic status. Offspring who are exposed to metformin and born to normal-weight mothers had significantly smaller HC and were shorter and lighter than metformin-exposed offspring of overweight/obese mothers. In contrast, in the placebo group we found no difference in head size, birth length, and birth weight between offspring of normal weight and those of overweight/obese mothers. This indicates a growth restrictive effect of metformin among normal-weight mothers with PCOS. Interestingly, Salomäki et al. (26, 27) reported similar findings in a mouse model. Mice that were on a regular diet and received metformin during pregnancy had litters with lower birth weight and higher weight gain on a high-fat postnatal diet (26). In contrast, in mice on a high-fat diet, metformin did not influence offspring birth weight and had a protective effect on the metabolic phenotype of the offspring (27). Salomäki et al. postulated that metformin exposure in utero programs the metabolic phenotype (26) by mimicking a dietary restriction–like state. This corresponds to the actions of metformin at a cellular level, where it acts as a mild inhibitor of the Mannose receptor C-type 1 leading to decreased cellular respiration (28). This activates the adenosine monophosphate–activated protein kinase, which shuts down energy-consuming processes and switches the cell from anabolic to catabolic state, resulting in decreased lipid, glucose, and protein synthesis and cell growth (28). As in the study of Salomäki et al. (26, 27), we observed growth restriction induced by metformin in offspring of normal-weight mothers. This may theoretically result in increased overweight later in life, in line with the “developmental origin of health and disease” hypothesis (29). Another important finding of the study was that offspring born to mothers with PCOS (placebo exposed) had similar birth weight and HC but were shorter at birth compared with the gestational age– and sex-adjusted standard population. This indicates that the PCOS per se has a “growth restrictive” effect on offspring body length at birth. This is interesting because the mean BMI of mothers with PCOS (29.5 kg/m2) was significantly higher than the mean BMI of the standard population (23.8 kg/m2), and one would expect that both birth weight and the prevalence of high birth weight would be increased among women with PCOS. The disproportional anthropometric measures found in the study (offspring were shorter but not lighter) indicate that offspring were born relatively fatter than the reference population. Increased leptin concentration in the umbilical cord blood has been reported in offspring of mothers with PCOS (30). This may reflect fetal adiposity, which is in line with the results from the current study. Another observation in the placebo group was that birth anthropometrics did not differ between offspring of normal-weight and overweight/obese mothers. Thus, our results indicate a growth restrictive effect of PCOS on offspring anthropometrics that is relatively more pronounced in offspring of overweight/obese mothers. Two counteracting physiological mechanisms related to fetal growth may explain a putative stronger growth restrictive effect of PCOS with increasing maternal BMI. First, maternal overweight/obesity promotes fetal growth through high glucose transfer to the fetus and induces increased fetal insulin production, resulting in “fatter” fetuses. Second, elevated maternal androgens induce placental differentiations and lower placental weight and result in growth restriction, as reported in other mouse models (31, 32). If these two counteracting mechanisms are significantly in play, our data indicate that the balance between them differs between organs (skeletal versus fat mass/and growth of other organs). More convincing data are needed on the potential of metformin to decrease pregnancy complications before metformin can be recommended in nondiabetic pregnancies. So far, precaution is advised when metformin is prescribed to normal-weight mothers with PCOS without well-documented indication. Conclusion Metformin altered offspring anthropometrics. Maternal BMI modified the effect of metformin, resulting in increased head size in offspring of overweight/obese mothers and shorter and thinner offspring in normal-weight mothers. Head size alteration was traceable already in utero. Placebo-exposed offspring born to mothers with PCOS were shorter but not lighter than the reference population. Metformin administration to normal-weight mothers with PCOS might restrict fetal growth. Abbreviations: BMI body mass index BPD biparietal diameter CI confidence interval HC head circumference MAD mean abdominal diameter PCOS polycystic ovary syndrome RCT randomized control trial. Acknowledgments Financial Support: The Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology funded the study. Weifa AS, which supplied the study drug free of charge, had no role in the collection, analysis, and interpretation of the data or writing the report or decision to submit the paper. Clinical Trial Information: ClinicalTrials.gov no. NCT00159536 (registered 12 September 2005). Disclosure Summary: The authors have nothing to disclose. References 1. Bozdag G, Mumusoglu S, Zengin D, Karabulut E, Yildiz BO. 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Sun MN, Yang Z, Ma RQ. Effect of high-fat diet on liver and placenta fatty infiltration in early onset preeclampsia-like mouse model. Chin Med J (Engl) . 2012; 125( 19): 3532– 3538. Google Scholar PubMed  32. Beckett EM, Astapova O, Steckler TL, Veiga-Lopez A, Padmanabhan V. Developmental programing: impact of testosterone on placental differentiation. Reproduction . 2014; 148( 2): 199– 209. Google Scholar CrossRef Search ADS PubMed  Copyright © 2018 Endocrine Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Endocrinology and Metabolism Oxford University Press

Fetal Growth and Birth Anthropometrics in Metformin-Exposed Offspring Born to Mothers With PCOS

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Endocrine Society
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Copyright © 2018 Endocrine Society
ISSN
0021-972X
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1945-7197
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10.1210/jc.2017-01191
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Abstract

Abstract Context Metformin is used in an attempt to reduce pregnancy complications associated with polycystic ovary syndrome (PCOS). Little is known about the effect of metformin on fetal development and growth. Objectives To compare the effect of metformin versus placebo on fetal growth and birth anthropometrics in PCOS offspring compared with a reference population in relation to maternal body mass index (BMI). Design Post hoc analysis of a randomized controlled trial. Setting Double-blind, placebo-controlled, multicenter study. Patients 258 offspring born to mothers with PCOS. Intervention 2000 mg metformin (n = 131) or placebo (n = 121) from first trimester to delivery. Main Outcome Measures Mean abdominal diameter and biparietal diameter (BPD) at gestational weeks 19 and 32. Head circumference (HC), birth length, and weight related to a reference population of healthy offspring, expressed as gestational age– and sex-adjusted z-scores. Results Metformin- versus placebo-exposed offspring had larger heads at gestational week 32 (BPD, 86.1 mm versus 85.2 mm; P = 0.03) and at birth (HC, 35.6 cm versus 35.1 cm; P < 0.01). Analyses stratified by maternal prepregnancy BMI, larger heads were observed only among offspring of overweight/obese mothers. Among normal-weight mothers, the effect of metformin compared with placebo was reduced length (z-score = −0.96 versus -0.42, P = 0.04) and weight (z-score = −0.44 versus 0.02; P = 0.03). Compared with the reference population, offspring born to PCOS mothers (placebo group) had reduced length (z-score = −0.40; 95% confidence interval, −0.60 to −0.40), but similar birth weight and HC. Conclusions Metformin exposure resulted in larger head size in offspring of overweight mothers, traceable already in utero. Maternal prepregnancy BMI modified the effect of metformin on offspring anthropometrics. Anthropometrics of offspring born to PCOS mothers differed from those of the reference population. Polycystic ovary syndrome (PCOS) affects 5% to 13% of women of childbearing age (1). Prevalence varies according to applied criteria and population. Women with PCOS have poorer metabolic health and increased risk for complications in pregnancy, such as gestational diabetes mellitus, preeclampsia, and preterm delivery (2–6). Birth characteristics are associated with metabolic health later in life (7), but evidence on the effect of maternal PCOS status on newborn anthropometric data, as well as metabolic health, is scarce and diverging. A population-based study from Australia reported an increased number of small-for-gestational-age offspring born to mothers with PCOS (8). A retrospective study from Austria (9) showed no increased risk for growth deviation according to PCOS. A population based study from Sweden found more large-for-gestational-age offspring born to mothers with PCOS (3, 10, 11). Metformin is an oral antidiabetic drug used in the treatment of type 2 diabetes mellitus. It is cheap and assumed safe. The effect of metformin on insulin sensitivity, lipid metabolism, and inflammation has induced a wider area of application. During the past decades, women with gestational diabetes mellitus, PCOS and obesity have been treated with metformin in an attempt to improve pregnancy outcome, but this practice is not based on solid scientific evidence. Metformin passes the placental barrier, but teratogenicity is not reported (12). There is little knowledge about possible effects of metformin on growth, metabolism, endocrine, and nervous system development in the fetus and cognitive and psychological effects later in life. In five studies on gestational diabetes, in which mothers were randomly assigned to metformin or insulin, no difference was seen in offspring birth weight (11, 13–15). One study reported increased birth length in newborns (15), and another found shorter and lighter newborns (12) in the metformin group. Two large randomized control trials (RCTs) compared metformin with placebo in obese pregnant women and found no effect on birth weight (16, 17). Our initial analysis of women with PCOS in the PregMet RCT (18) showed no difference in pregnancy complications or newborn data between the metformin and placebo groups, except head size. Head size of the metformin-exposed newborns was larger (18). In the current study, we examined the in utero ultrasound measurements of the fetuses to explore the effect of metformin versus placebo on fetal anthropometrics and birth anthropometrics in PCOS offspring compared with those in a reference population. The results were related to maternal body mass index (BMI). The Committee for Medical Research Ethics of Health Region IV, Norway, and The Norwegian Medicines Agency approved the study. Written, informed consent was obtained from each patient before inclusion, and the declaration of Helsinki was followed throughout the study. Participants and Methods The PregMet study was a prospective, randomized, placebo-controlled, multicenter trial of pregnant women with PCOS (18). The aim of the study was to investigate whether metformin exposure from first trimester to delivery could prevent pregnancy complications. Eleven health care centers in Norway (three university hospitals, seven local hospitals, and one gynecological specialist practice) recruited women to the study during 2005 to 2009. Primary endpoints were prevalence of preeclampsia, preterm delivery, gestational diabetes mellitus, and a composite of the diagnoses. Inclusion criteria in the PregMet study were (1) PCOS diagnosed according to the Rotterdam criteria, (2) age 18 to 45 years, (3) gestational age between 5 and 12 weeks, and (4) singleton viable fetus shown on ultrasonography. Exclusion criteria were alanine transaminase level > 90 IU/L, serum creatinine > 1.70 mg/dL, known alcohol abuse, previously diagnosed diabetes mellitus, or fasting serum glucose level > 126 mg/dL at the time of inclusion. All participants received written and individual verbal counseling on diet and lifestyle at inclusion. Thereafter, treatment with metformin 500 mg (metformin hydrochloride; Weifa AS, Oslo, Norway) or identically coated placebo tablets was initiated. The participants were instructed to take two tablets twice daily, for a total of 2000 mg daily, for the rest of the study period. To counteract a possible metformin action on vitamin B levels, patients were advised to take 0.8 mg of folate daily and one daily multivitamin tablet. Study medication was stopped at delivery. Randomization was performed at the Trondheim University Hospital Pharmacy in blocks of 10 and was stratified according to metformin use at conception. The method was random drawing of an envelope by two pharmacy employees, one executing the drawing and the other monitoring the drawing. This study has been described in detail elsewhere (18). Study population In total, 274 pregnancies were included and randomized. One patient was misdiagnosed, three miscarried, and 12 dropped out (Fig. 1). These 16 pregnancies were excluded because ultrasound data were lacking. The present analyses comprise 258 pregnancies. Eighty-four percent of all participants took more than 85% of the study medication and were classified as having good/acceptable adherence. Figure 1. View largeDownload slide Flow chart of inclusion, exclusion, and randomization of patients. Figure 1. View largeDownload slide Flow chart of inclusion, exclusion, and randomization of patients. Ultrasound measurements All ultrasound examinations were performed by doctors and specialized midwives trained to perform routine ultrasound examinations. The equipment used was the preferred, up-to-date ultrasound devices used in everyday clinical practice during the study period. Estimated date of delivery and gestational age were calculated from crown-rump-length and/or biparietal diameter (BPD) in the first trimester. Transvaginal ultrasound examinations in the first trimester were performed at the time of inclusion. Estimated date of delivery and gestational age were calculated from crown-rump-length or BPD at the first trimester scan and were based on the algorithm implemented in the first trimester screening program from the Fetal Medicine Foundation (19, 20). Transabdominal ultrasound measurements were performed at gestational week 19 (±1 week) and week 32 (±1 week), with measurements of BPD (outer to outer measurement of skull diameter) and mean abdominal diameter (MAD). Measurements of BPD and MAD in the second and third trimester referred to references in the eSnurra method (21, 22) Offspring anthropometrics Midwives and nurse assistants measured head circumference (HC), length, and weight of the offspring immediately after delivery. For HC, length, and weight at birth, gestational age– and sex-adjusted z-scores were calculated based on Niklasson’s standard values from a large Swedish population [19]. The standard is based on singleton fetuses without chromosome abnormalities or major birth defects. The z-scores express the deviation between observed values and the standard population mean adjusted for sex and gestational age at birth. Statistical analyses All data entry, data management, and data analyses were analyzed according to the intention-to-treat principle. Baseline characteristics for the two maternal groups were compared by using t tests for continuous variables and χ2 tests for categorical variables. The effect of metformin, as well as the effect of metformin in relation to maternal BMI, was analyzed by using linear regression analyses. Offspring characteristics for different maternal BMI groups were compared by using a t test for both the metformin and placebo group. A P value < 0.05 was considered to indicate a statistically significant difference. The statistical analyses were performed by using SPSS software, version 23 (IBM, Armonk, NY) and R software, version 2.13.1 (R Foundation for Statistical Computing, Vienna, Austria). Results Maternal baseline characteristics did not differ between the placebo and metformin groups in terms of BMI, blood glucose, ethnicity, smoking, and PCOS phenotypes (Table 1). Adherence to study medication was similar in the two groups (Table 1). Table 1. Baseline Data on Women with PCOS at Inclusion, in First Trimester of Pregnancy, in PregMet Study Variable  Metformin (n = 131)  Placebo (n = 127)  P Valuea  Age (y)  29.6 ± 4.3  29.3 ± 4.4  0.558  Height (cm)  167.3 ± 5.8  167.7 ± 5.4  0.549  Weight (kg)  82.9 ± 20.3  79.3 ± 18.0  0.131  BMI (kg/m2)  29.6 ± 7.1  28.2 ± 6.4  0.099  Systolic blood pressure (mm Hg)  119 ± 12  117 ± 11  0.302  Diastolic blood pressure (mm Hg)  74 ± 13  72 ± 9  0.268  Parity (n)      0.825   Para 0  74  70     Para ≥1  57  57    Ethnicity      0.047   White  127 (97)  127 (100)     Nonwhite  4 (3)  0 (0)    GDM at inclusion  10 (4)  11 (4)  0.822  Smokers  14 (4.5)  7 (2.7)  0.172  Diagnostic criteria PCOS         NIH diagnostic criteriab  91 (70)  87 (69)     Rotterdam diagnostic criteria  40 (30)  40 (31)    Androgen status      0.577   Hyperandrogenism  98 (75)  91 (72)     Normoandrogenism  33 (25)  36 (28)    Mode of conception      0.200   Spontaneous conception  76 (58)  75 (59)     Ovulation induction  38 (29)  28 (22)     IVF/ICSI  17 (13)  21 (7)     Other  0 (0)  3 (2)    Adherence to medication      0.552   Taken >85% of all study medication  108 (82)  108 (85)     Taken <85% of all study medication  23 (18)  19 (15)    Variable  Metformin (n = 131)  Placebo (n = 127)  P Valuea  Age (y)  29.6 ± 4.3  29.3 ± 4.4  0.558  Height (cm)  167.3 ± 5.8  167.7 ± 5.4  0.549  Weight (kg)  82.9 ± 20.3  79.3 ± 18.0  0.131  BMI (kg/m2)  29.6 ± 7.1  28.2 ± 6.4  0.099  Systolic blood pressure (mm Hg)  119 ± 12  117 ± 11  0.302  Diastolic blood pressure (mm Hg)  74 ± 13  72 ± 9  0.268  Parity (n)      0.825   Para 0  74  70     Para ≥1  57  57    Ethnicity      0.047   White  127 (97)  127 (100)     Nonwhite  4 (3)  0 (0)    GDM at inclusion  10 (4)  11 (4)  0.822  Smokers  14 (4.5)  7 (2.7)  0.172  Diagnostic criteria PCOS         NIH diagnostic criteriab  91 (70)  87 (69)     Rotterdam diagnostic criteria  40 (30)  40 (31)    Androgen status      0.577   Hyperandrogenism  98 (75)  91 (72)     Normoandrogenism  33 (25)  36 (28)    Mode of conception      0.200   Spontaneous conception  76 (58)  75 (59)     Ovulation induction  38 (29)  28 (22)     IVF/ICSI  17 (13)  21 (7)     Other  0 (0)  3 (2)    Adherence to medication      0.552   Taken >85% of all study medication  108 (82)  108 (85)     Taken <85% of all study medication  23 (18)  19 (15)    Values expressed with a plus/minus sign are the mean ± standard deviation. Unless otherwise noted, all other values are N (%). Abbreviations: GDM, gestational diabetes mellitus; ICSI, intracytoplasmic sperm injection; IVF, in vitro fertilization; NIH, National Institutes of Health. a A t test was performed with equal variances assumed. Pearson χ2 and Fisher exact test was performed. b National Institutes of Health diagnostic criteria. View Large The effects of metformin versus placebo on fetal growth are shown in Table 2. There was no difference between the groups in BPD at gestational week 19, but metformin-exposed offspring had larger BPD than offspring in the placebo group at gestational week 32 (ΔBPD, 0.9 mm; P = 0.027). At birth, HC was larger in the metformin group than in the placebo group (ΔHC, 0.5 cm; P = 0.007). HC in the metformin group was also larger than that in the reference population, expressed as HC z-score (95% confidence interval [CI]) of 0.3 (0.005 to 0.52). MAD at gestational weeks 19 and 32 and the weight and length did not differ between the metformin and placebo groups. Table 2. Anthropometric Characteristics of Offspring Born to Women With PCOS Exposed to Metformin or Placebo Variable  Offspring (n)  Metformin  Offspring (n)  Placebo  ΔM-P (95% CI)a  P Valueb  BPD week 19 (mm)  127  46.4 ± 3.1  121  46.3 ± 3.4  0.1 (−0.72 to 0.92)  0.810  BPD week 32 (mm)  126  86.1 ± 3.2  122  85.2 ± 3.3  0.9 (0.11–1.73)  0.027  MAD week 19 (mm)  125  43.6 ± 3.9  121  43.7 ± 4.9  −0.2 (−1.26 to 0.96)  0.788  MAD week 32 (mm)  126  90.4 ± 5.2  120  89.9 ± 4.8  0.5 (−0.80 to 1.71)  0.476  HC at birth               In cm  130  35.6 ± 1.6  126  35.0 ± 1.6  0.5 (0.15 to 0.92)  0.007   z-score  130  0.3 (0.10–0.49)  126  0.03 (−0.14 to 0.22)  0.3 (0.005 to 0.52)  0.045  Birth weight               In g  131  3567 ± 540  127  3545 ± 617  22 (−120 to 163)  0.763   z-scorec  131  −0.05 (−0.23 to 0.15)  127  0.06 (−0.11 to 0.24)  −0.1 (−0.36 to 0.16)  0.431  Birth lengthc               In cm  130  50.1 ± 2.1  124  50.0 ± 2.5  0.1 (−0.51 to 0.63)  0.826   z-score   130  −0.52 (−0.72 to −0.33)  124  −0.40 (−0.60 to −0.20)  −0.13 (−0.40 to 0.15)  0.375  Birth weight ≥90th percentile,d n (%)  131  15 ± 12  127  15 ± 12  —  0.928  Birth weight ≤10th percentile,d n (%)  131  12 ± 9  127  13 ± 10  —  0.832  Variable  Offspring (n)  Metformin  Offspring (n)  Placebo  ΔM-P (95% CI)a  P Valueb  BPD week 19 (mm)  127  46.4 ± 3.1  121  46.3 ± 3.4  0.1 (−0.72 to 0.92)  0.810  BPD week 32 (mm)  126  86.1 ± 3.2  122  85.2 ± 3.3  0.9 (0.11–1.73)  0.027  MAD week 19 (mm)  125  43.6 ± 3.9  121  43.7 ± 4.9  −0.2 (−1.26 to 0.96)  0.788  MAD week 32 (mm)  126  90.4 ± 5.2  120  89.9 ± 4.8  0.5 (−0.80 to 1.71)  0.476  HC at birth               In cm  130  35.6 ± 1.6  126  35.0 ± 1.6  0.5 (0.15 to 0.92)  0.007   z-score  130  0.3 (0.10–0.49)  126  0.03 (−0.14 to 0.22)  0.3 (0.005 to 0.52)  0.045  Birth weight               In g  131  3567 ± 540  127  3545 ± 617  22 (−120 to 163)  0.763   z-scorec  131  −0.05 (−0.23 to 0.15)  127  0.06 (−0.11 to 0.24)  −0.1 (−0.36 to 0.16)  0.431  Birth lengthc               In cm  130  50.1 ± 2.1  124  50.0 ± 2.5  0.1 (−0.51 to 0.63)  0.826   z-score   130  −0.52 (−0.72 to −0.33)  124  −0.40 (−0.60 to −0.20)  −0.13 (−0.40 to 0.15)  0.375  Birth weight ≥90th percentile,d n (%)  131  15 ± 12  127  15 ± 12  —  0.928  Birth weight ≤10th percentile,d n (%)  131  12 ± 9  127  13 ± 10  —  0.832  Values expressed with a plus/minus sign are the mean ± standard deviation. Abbreviations: M, metformin; P, placebo. aΔM-P expresses the metformin effect on HC, length, and weight z-scores in offspring born to mothers with PCOS. bA t test was performed with equal variances assumed. c Values in parentheses are 95% CIs. d Birth weight adjusted for gestational age. View Large The effect of metformin on birth anthropometrics differed according to maternal prepregnancy weight (BMI < 25 kg/m2 or BMI ≥ 25 kg/m2). The results from the interaction analyses are shown in Table 3. HC at birth was increased in the metformin group, but only among offspring born to overweight women (ΔHC z-score = 0.50; P = 0.002). Among normal-weight women, HC did not differ between the metformin and placebo groups (ΔHC z-score = −0.20; P = 0.367). Thus, the metformin effect on HC differed between maternal weight categories by a z-score of 0.71, and this interaction effect reached statistical significance (P = 0.011). Table 3. Effect of Metformin on Anthropometric Measures at Birth According to Maternal BMI Variable  Maternal BMI <25 kg/m2   Maternal BMI ≥25 kg/m2   (ΔM-P [BMI ≥25]) − (ΔM-P [(BMI <25]) (95% CI)d  P Valueb  Metformin  Placebo  ΔM-P (95% CI)a  P Valueb  Metformin   Placebo  ΔM-P (95% CI)c  P Valued  HC  −0.02 (−0.34 to 0.29)  0.18 (−0.13 to 0.49)  −0.20 (−0.65 to 0.24)  0.367  0.45 (0.23 to 0.67)  −0.05 (−0.28 to 0.18)  0.50 (0.19 to 0.82)  0.002  0.71 (0.16 to 1.25)  0.011  Length  −0.96 (−1.30 to −0.63)  −0.42 (−0.76 to −0.09)  −0.54 (−1.01 to −0.07)  0.025  −0.31 (−0.54 to −0.07)  −0.38 (−0.63 to −0.14)  0.08 (−0.26 to 0.24)  0.655  0.62 (0.033 to 1.20)  0.038  Weight   −0.44 (−0.75 to −0.13)  0.02 (−0.29 to 0.33)  −0.45 (−0.89 to −0.02)  0.041  0.15 (−0.07 to 0.37)  0.08 (−0.14 to 0.31)  0.07 (−0.24 to 0.39)  0.650  0.53 (−0.01 to 1.06)  0.055  Variable  Maternal BMI <25 kg/m2   Maternal BMI ≥25 kg/m2   (ΔM-P [BMI ≥25]) − (ΔM-P [(BMI <25]) (95% CI)d  P Valueb  Metformin  Placebo  ΔM-P (95% CI)a  P Valueb  Metformin   Placebo  ΔM-P (95% CI)c  P Valued  HC  −0.02 (−0.34 to 0.29)  0.18 (−0.13 to 0.49)  −0.20 (−0.65 to 0.24)  0.367  0.45 (0.23 to 0.67)  −0.05 (−0.28 to 0.18)  0.50 (0.19 to 0.82)  0.002  0.71 (0.16 to 1.25)  0.011  Length  −0.96 (−1.30 to −0.63)  −0.42 (−0.76 to −0.09)  −0.54 (−1.01 to −0.07)  0.025  −0.31 (−0.54 to −0.07)  −0.38 (−0.63 to −0.14)  0.08 (−0.26 to 0.24)  0.655  0.62 (0.033 to 1.20)  0.038  Weight   −0.44 (−0.75 to −0.13)  0.02 (−0.29 to 0.33)  −0.45 (−0.89 to −0.02)  0.041  0.15 (−0.07 to 0.37)  0.08 (−0.14 to 0.31)  0.07 (−0.24 to 0.39)  0.650  0.53 (−0.01 to 1.06)  0.055  Unless otherwise noted, values are expressed as z-scores (95% CIs). Abbreviations: M, metformin; P, placebo. aΔM-P (BMI <25) expresses the metformin effect on HC, length, and weight z-scores in offspring of normal-weight mothers. b Statistical testing performed by multiple linear regression analyses. c ΔM-P (BMI ≥25) expresses the metformin effect on HC, length, and weight s-scores in offspring of overweight/obese mothers. d (ΔM-P [BMI <25]) − (ΔM-P [BMI ≥25]) expresses the difference in metformin effect on offspring HC, length, and weight z-scores between overweight and normal-weight mothers. View Large Length was significantly reduced by metformin among normal-weight mothers (Δ length z-score = −0.54; P = 0.025), but not among overweight mothers. The difference in metformin effect on length between maternal BMI categories was 0.62 (P = 0.038). In addition, birth weight was reduced by metformin only in normal-weight mothers (Δ birthweight z-score = −0.45; P = 0.041). The difference in effect of metformin on birth weight z-score between maternal weight groups was 0.53 (P = 0.055). All these interactions are of borderline statistical significance. Subgroup analyses according to hyperandrogen and normoandrogen maternal phenotype showed a larger HC (35.8 cm versus 35.2 cm; P = 0.020) and HC z-score (0.67 versus 0.27; P = 0.008) in metformin- versus placebo-exposed offspring, but only among the hyperandrogen phenotypes. Among normoandrogen phenotypes, there was no difference in HC (35.0 cm versus 34.5 cm; P = 0.237) or HC z-score (0.17 versus 0.17; P = 0.992) between the metformin and placebo groups. In analyses stratified by offspring sex, metformin-exposed girls, but not boys, seemed to have a larger BPD at week 32 and larger HC at birth. After adjustment for maternal BMI, there was no difference in the effect of metformin according to sex (data not shown). We also analyzed data according to adherence. The difference in HC and HC z-score remained significant among those with good adherence (84%) and was not present among those with poor adherence (16%). The effect of PCOS on offspring anthropometrics was analyzed in the placebo group and expressed by z-score deviation from the reference population. The PCOS offspring were shorter than the reference population: Birth length z-score was −0.40 (95% CI, −0.60 to −0.20) (Table 2). Birth weight z-score (0.06; 95% CI, −0.11 to 0.24) and HC z-score (0.03; 95% CI, −0.14 to 0.22) did not differ from those in the reference population. In contrast to the metformin group, maternal BMI (<25 kg/m2 or BMI ≥ 25 kg/m2) had no effect on offspring birth weight, length, or HC (Table 4). Table 4. Characteristics in Offspring Born to Women With PCOS Exposed to Metformin or Placebo In Utero According to Randomization Variable  Placebo   Metformin   BMI <25 kg/m2   BMI ≥25 kg/m2   P Valuea  BMI <25 kg/m2   BMI ≥25 kg/m2   P Valuea  Women (n)  Mean  Women (n)  Mean  Women (n)  Mean  Women (n)  Mean  BPD week 19 (mm)  42  46.5 ± 3.9  79  46.2 ± 3.1  0.640  44  46.5 ± 3.7  83  46.4 ± 2.8  0.798  BPD week 32 (mm)  42  86.1 ± 3.3  80  84.7 ± 3.2  0.020  41  85.9 ± 3.1  85  86.2 ± 3.3  0.663  MAD week 19 (mm)  42  43.1 ± 5.2  72  44.0 ± 4.7  0.326  44  43.5 ± 3.5  81  43.6 ± 4.1  0.886  MAD week 32 (mm)  42  90.5 ± 4.7  78  89.7 ± 4.8  0.071  41  88.5 ± 4.6  85  91.4 ± 5.3  0.003  HC                       In cm  44  35.2 ± 1.8  82  35.0 ± 1.5  0.450  43  35.0 ± 1.5  87  35.9 ± 1.5  0.003   z-score  44  0.18  82  −0.50  0.211  43  −0.02  87  0.45  0.022  Birth weight                       In g  44  3537 ± 655  83  3550 ± 600  0.908  44  3327 ± 510  87  3689 ± 516  0.000   z-scoreb  44  0.02  83  0.08  0.739  44  −0.44  87  0.15  0.003  Birth lengthb                       In cm  43  50.0 ± 2.6  81  50.1 ± 2.4  0.779  43  49.2 ± 1.9  87  50.6 ± 2.1  0.000   z-score   43  −0.42  81  −0.38  0.861  43  −0.96  87  −0.31  0.002  Variable  Placebo   Metformin   BMI <25 kg/m2   BMI ≥25 kg/m2   P Valuea  BMI <25 kg/m2   BMI ≥25 kg/m2   P Valuea  Women (n)  Mean  Women (n)  Mean  Women (n)  Mean  Women (n)  Mean  BPD week 19 (mm)  42  46.5 ± 3.9  79  46.2 ± 3.1  0.640  44  46.5 ± 3.7  83  46.4 ± 2.8  0.798  BPD week 32 (mm)  42  86.1 ± 3.3  80  84.7 ± 3.2  0.020  41  85.9 ± 3.1  85  86.2 ± 3.3  0.663  MAD week 19 (mm)  42  43.1 ± 5.2  72  44.0 ± 4.7  0.326  44  43.5 ± 3.5  81  43.6 ± 4.1  0.886  MAD week 32 (mm)  42  90.5 ± 4.7  78  89.7 ± 4.8  0.071  41  88.5 ± 4.6  85  91.4 ± 5.3  0.003  HC                       In cm  44  35.2 ± 1.8  82  35.0 ± 1.5  0.450  43  35.0 ± 1.5  87  35.9 ± 1.5  0.003   z-score  44  0.18  82  −0.50  0.211  43  −0.02  87  0.45  0.022  Birth weight                       In g  44  3537 ± 655  83  3550 ± 600  0.908  44  3327 ± 510  87  3689 ± 516  0.000   z-scoreb  44  0.02  83  0.08  0.739  44  −0.44  87  0.15  0.003  Birth lengthb                       In cm  43  50.0 ± 2.6  81  50.1 ± 2.4  0.779  43  49.2 ± 1.9  87  50.6 ± 2.1  0.000   z-score   43  −0.42  81  −0.38  0.861  43  −0.96  87  −0.31  0.002  Values expressed with a ± sign are the mean ± standard deviation. a A t test was performed with equal variances assumed. View Large Discussion The main finding of the present follow-up study is that metformin-exposed offspring had larger HC compared with offspring in the placebo group. This was evident already at gestational week 32. Birth weight and length did not differ between the metformin and placebo groups. This study on PCOS explored the effect of metformin on fetal and newborn anthropometrics in an RCT setting, in which the metformin group and placebo group were randomly assigned and had no baseline differences in known potential influencing factors. Little is known about the effect of metformin on fetal and newborn head size. In one study on gestational diabetes, metformin was compared with insulin (15). Head size of offspring in the metformin and insulin groups did not differ. Among women with obesity who were randomly assigned to metformin or placebo during pregnancy, offspring had similar HC (17). Our results deviate from these previous studies, and the difference is most likely explained by the variation in underlying diagnoses. Also, differences in study design, population size, aim, medical treatment, maternal weight, and ethnicity may have contributed to the differing results. HC correlates accurately to brain volume (23, 24), and large head size is associated with good cognitive function and cardiovascular health (24, 25). Thus, a large head at birth is a surrogate marker for brain development and potentially has a beneficial effect. The metformin effect of larger HC and HC z-score was seen only among offspring of mothers with hyperandrogenic phenotype; among those with normo-androgenic phenotype, there was no difference between the groups. However, because of the small sample size, a metformin effect according to maternal androgen status must be interpreted with great caution and should be addressed in future studies. The effect of prenatal metformin exposure seems to translate differently depending on maternal BMI and/or metabolic status. Offspring who are exposed to metformin and born to normal-weight mothers had significantly smaller HC and were shorter and lighter than metformin-exposed offspring of overweight/obese mothers. In contrast, in the placebo group we found no difference in head size, birth length, and birth weight between offspring of normal weight and those of overweight/obese mothers. This indicates a growth restrictive effect of metformin among normal-weight mothers with PCOS. Interestingly, Salomäki et al. (26, 27) reported similar findings in a mouse model. Mice that were on a regular diet and received metformin during pregnancy had litters with lower birth weight and higher weight gain on a high-fat postnatal diet (26). In contrast, in mice on a high-fat diet, metformin did not influence offspring birth weight and had a protective effect on the metabolic phenotype of the offspring (27). Salomäki et al. postulated that metformin exposure in utero programs the metabolic phenotype (26) by mimicking a dietary restriction–like state. This corresponds to the actions of metformin at a cellular level, where it acts as a mild inhibitor of the Mannose receptor C-type 1 leading to decreased cellular respiration (28). This activates the adenosine monophosphate–activated protein kinase, which shuts down energy-consuming processes and switches the cell from anabolic to catabolic state, resulting in decreased lipid, glucose, and protein synthesis and cell growth (28). As in the study of Salomäki et al. (26, 27), we observed growth restriction induced by metformin in offspring of normal-weight mothers. This may theoretically result in increased overweight later in life, in line with the “developmental origin of health and disease” hypothesis (29). Another important finding of the study was that offspring born to mothers with PCOS (placebo exposed) had similar birth weight and HC but were shorter at birth compared with the gestational age– and sex-adjusted standard population. This indicates that the PCOS per se has a “growth restrictive” effect on offspring body length at birth. This is interesting because the mean BMI of mothers with PCOS (29.5 kg/m2) was significantly higher than the mean BMI of the standard population (23.8 kg/m2), and one would expect that both birth weight and the prevalence of high birth weight would be increased among women with PCOS. The disproportional anthropometric measures found in the study (offspring were shorter but not lighter) indicate that offspring were born relatively fatter than the reference population. Increased leptin concentration in the umbilical cord blood has been reported in offspring of mothers with PCOS (30). This may reflect fetal adiposity, which is in line with the results from the current study. Another observation in the placebo group was that birth anthropometrics did not differ between offspring of normal-weight and overweight/obese mothers. Thus, our results indicate a growth restrictive effect of PCOS on offspring anthropometrics that is relatively more pronounced in offspring of overweight/obese mothers. Two counteracting physiological mechanisms related to fetal growth may explain a putative stronger growth restrictive effect of PCOS with increasing maternal BMI. First, maternal overweight/obesity promotes fetal growth through high glucose transfer to the fetus and induces increased fetal insulin production, resulting in “fatter” fetuses. Second, elevated maternal androgens induce placental differentiations and lower placental weight and result in growth restriction, as reported in other mouse models (31, 32). If these two counteracting mechanisms are significantly in play, our data indicate that the balance between them differs between organs (skeletal versus fat mass/and growth of other organs). More convincing data are needed on the potential of metformin to decrease pregnancy complications before metformin can be recommended in nondiabetic pregnancies. So far, precaution is advised when metformin is prescribed to normal-weight mothers with PCOS without well-documented indication. Conclusion Metformin altered offspring anthropometrics. Maternal BMI modified the effect of metformin, resulting in increased head size in offspring of overweight/obese mothers and shorter and thinner offspring in normal-weight mothers. Head size alteration was traceable already in utero. Placebo-exposed offspring born to mothers with PCOS were shorter but not lighter than the reference population. Metformin administration to normal-weight mothers with PCOS might restrict fetal growth. Abbreviations: BMI body mass index BPD biparietal diameter CI confidence interval HC head circumference MAD mean abdominal diameter PCOS polycystic ovary syndrome RCT randomized control trial. Acknowledgments Financial Support: The Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology funded the study. Weifa AS, which supplied the study drug free of charge, had no role in the collection, analysis, and interpretation of the data or writing the report or decision to submit the paper. Clinical Trial Information: ClinicalTrials.gov no. NCT00159536 (registered 12 September 2005). Disclosure Summary: The authors have nothing to disclose. References 1. Bozdag G, Mumusoglu S, Zengin D, Karabulut E, Yildiz BO. 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Journal

Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: Feb 1, 2018

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