Supplemental figure 1. Adjusted odds ratios for gestational diabetes, pre-eclampsia, premature birth and miscarriage for women with and without PCOS.

Transcription

1 Supplemental figure 1 Adjusted odds ratios for gestational diabetes, pre-eclampsia, premature birth and miscarriage for women with and without PCOS. * Denominator is all pregnancies, adjusted for age, body mass index, number of previous births and smoking history Adjusted for age, body mass index, number of previous births, multiple gestation and smoking history.

2 Supplemental figure 2 Adjusted * odds ratios for gestational diabetes, pre-eclampsia, premature birth and miscarriage for women with PCOS treated with metformin. Odd ratio (95% CI) Odds ratio 7 Analysis OR 95%CI Events/ Number of patients Pre-conception Gestational diabetes 0.96 ( ) (46/2826) Pre-eclampsia 1.54 ( ) (236/3013) Premature 1.02 ( ) (310/3013) Miscarriage 0.71 ( ) (471/3484) 1st trimester Gestational diabetes 1.51 ( ) (46/2780) Pre-eclampsia 1.54 ( ) (236/3013) Premature 1.35 ( ) (310/3013) Miscarriage 0.97 ( ) (471/3484) *Adjusted for age, body mass index, number of previous births, history of miscarriage and smoking history

3 Supplemental Table 1 Read codes used to identify patients with Polycystic ovary syndrome Read code Description C Polycystic ovarian syndrome C Stein - Leventhal syndrome C Polycystic ovaries

4 Supplemental table 2 Read codes used to identify patients with infertility Read code Description Infertility investigations NOS Infertility investigation -fem Female infertility test abnormal 318Z.00 Female genital test NOS 4Z0..00 Infertility studies A/N care: H/O infertility Procreat/fertility counselling Fertility counselling 7E0A.00 Introduction of gamete into uterine cavity 7E0A000 Implantation of fertilised egg into uterus 7E0A100 Intracervical artificial insemination 7E0A200 Intrauterine artificial insemination 7E0A211 Artficial insemination NEC 7E0A300 Intrauterine insemination superovulation partner sperm 7E0A400 Intrauterine insemination superovulation using donor sperm 7E0A600 Intrauterine insemination without superovulation donor sperm 7E0A700 Transfer of embryo to uterus 7E0Az00 Introduction of gamete into uterine cavity NOS 7E29000 Fertility investigation of female NEC 7E29200 Fertiloscopy 7M0h.00 In vitro fertilisation (IVF) 7M0h000 IVF with donor sperm 7M0h011 In vitro fertilisation with donor sperm 7M0h100 IVF with donor eggs 7M0h111 In vitro fertilisation with donor eggs 7M0h200 IVF with intracytoplasmic sperm injection (ICSI) 7M0h211 In vitro fertilisatn with intra-cytoplasmic sperm injection 7M0h300 IVF intracytoplasmic sperm injection (ICSI) and donor egg 7M0h311 In vitro fertilis intra-cytoplasmic sperm inj and donor egg 7M0h500 IVF with surrogacy

5 Read code Description 7M0h511 In vitro fertilisation with surrogacy 7M0hy00 Other specified in vitro fertilisation (IVF) 7M0hz00 In vitro fertilisation (IVF) NOS 8C8..00 Treatment for infertility 8C81.00 Artificial insemination 8C81.11 Artificial insemin by donor 8C81.12 Artificial insemin by husband 8C81.13 Gamete intrafallopian transfer 8C82.00 Female infertility therapy 8C84.00 In vitro fertilisation procedure 8C84.11 IVF 8C85.00 Gamete intrafallopian transfer 8C85.11 GIFT 8C8Z.00 Treatment for infertility NOS 8C8Z.11 In-vitro fertilisation 8Cf..00 Infertility care 8HTB.00 Referral to fertility clinic 9N07.00 Seen in fertility clinic 9N1y600 Seen in fertility clinic K5B..00 Infertility - female K5B0.00 Female infertility of anovulatory origin K5B0.11 Anovular cycle K5B0000 Primary anovulatory infertility K5B0100 Secondary anovulatory infertility K5B0z00 Female infertility of anovulatory origin NOS K5B1.00 Female infertility of pituitary - hypothalamic origin K5B1000 Primary pituitary - hypothalamic infertility K5B1100 Secondary pituitary - hypothalamic infertility K5B1z00 Female infertility of pituitary - hypothalamic cause NOS K5B2.00 Female infertility of tubal origin K5B2000 Primary tubal infertility K5B2100 Secondary tubal infertility K5B2300 Blocked fallopian tube

6 Read code K5B2z00 K5B3.00 K5B3000 K5B3100 K5B3z00 K5B4.00 K5B4000 K5B4100 K5B5.00 K5B5100 K5B7.00 K5By.00 K5By000 K5By100 K5Byz00 K5Byz11 K5Bz.00 Kyu9G00 SP0D.00 SP0D200 SP0DX00 Z4P1.00 ZG9..00 ZG91.00 ZV23000 ZV26.00 ZV26200 ZV26400 ZV26700 ZV26800 ZV26y00 ZV26z00 ZVu2100 Description Female infertility of tubal origin NOS Female infertility of uterine origin Primary uterine infertility Secondary uterine infertility Female infertility of uterine origin NOS Female infertility of cervical origin Primary cervical infertility Secondary cervical infertility Female infertility of vaginal origin Secondary vaginal infertility Female infertility due to diminished ovarian reserve Other female infertility Primary infertility unspecified Secondary infertility unspecified Other female infertility NOS Subfertility Female infertility NOS [X]Female infertility of other origin Complications associated with artificial fertilization Compltns of attemptd intro fertil ovum follow in vitro fert Complication assoc with artific fertilization, unspecif Fertility counselling Advice relating to pregnancy and fertility Advice on fertility and infertility [V]Pregnancy with history of infertility [V]Infertility management [V]Infertility investigation and testing [V]Infertility general advice and counselling [V]In vitro fertilization [V]Other assisted fertilization methods [V]Other specified infertility management [V]Unspecified infertility management [X]Other assisted fertilization methods

7 Supplemental table 3: Read and ICD-10 codes used to define pregnancy complications: gestational diabetes, preeclmapsia and prematurity. Code Description Classification Gestational diabetes 66Ay.00 Gestational diabetes mellitus annual review Read 8CE0000 Gestational diabetes information leaflet given Read L Diabetes mellitus during pregnancy/childbirth/puerperium Read L Diabetes mellitus during pregnancy - baby delivered Read L Diabetes mellitus during pregnancy - baby not yet delivered Read L Diabetes mellitus in pueperium - baby previously delivered Read L Diabetes mellitus arising in pregnancy Read L Gestational diabetes mellitus Read L Gestational diabetes mellitus Read L180z00 Diabetes mellitus in pregnancy/childbirth/puerperium NOS Read ZV13F00 [V]Personal history of gestational diabetes mellitus Read O24 Diabetes mellitus in pregnancy ICD-10 O24.4 Diabetes mellitus arising in pregnancy ICD-10 O24.9 Diabetes mellitus in pregnancy, unspecified ICD-10 Pre-eclampsia L Mild or unspecified pre-eclampsia Read L Mild pre-eclampsia Read L Toxaemia NOS Read L Mild or unspecified pre-eclampsia unspecified Read L Mild or unspecified pre-eclampsia - delivered Read L Mild or unspecified pre-eclampsia - delivered with p/n comp Read L Mild or unspecified pre-eclampsia - not delivered Read L Mild or unspecified pre-eclampsia with p/n complication Read L Mild pre-eclampsia Read L Pre-eclampsia, unspecified Read L124z00 Mild or unspecified pre-eclampsia NOS Read L Severe pre-eclampsia Read L Severe pre-eclampsia unspecified Read L Severe pre-eclampsia - delivered Read L Severe pre-eclampsia - delivered with postnatal complication Read L Severe pre-eclampsia - not delivered Read L Severe pre-eclampsia with postnatal complication Read L125z00 Severe pre-eclampsia NOS Read L Eclampsia Read L Eclampsia unspecified Read L Eclampsia - delivered Read L Eclampsia - delivered with postnatal complication Read L Eclampsia - not delivered Read L Eclampsia with postnatal complication Read

8 Code Description Classification L Eclampsia in pregnancy Read L Eclampsia in labour Read L126z00 Eclampsia NOS Read L Pre-eclampsia or eclampsia with pre-existing hypertension Read L Pre-eclampsia or eclampsia with hypertension unspecified Read L Pre-eclampsia or eclampsia with hypertension - delivered Read L Pre-eclampsia or eclampsia with hypertension - del+p/n comp Read L Pre-eclampsia or eclampsia with hypertension - not delivered Read L127z00 Pre-eclampsia or eclampsia + pre-existing hypertension NOS Read L Moderate pre-eclampsia Read O14 Gestational [pregnancy-induced] hypertension with significant proteinuria ICD-10 O14.0 Moderate pre-eclampsia ICD-10 O14.1 Severe pre-eclampsia ICD-10 O14.2 HELLP syndrome ICD-10 O14.9 Pre-eclampsia, unspecified ICD-10 O15 Eclampsia ICD-10 O15.0 Eclampsia in pregnancy ICD-10 O15.1 Eclampsia in labour ICD-10 O15.2 Eclampsia in the puerperium ICD-10 O15.9 Eclampsia, unspecified as to time period ICD-10 Pre-maturity 1546 H/O: premature delivery Read Premature baby Read 6351 Baby premature weeks Read 6352 Baby v. premature weeks Read 6353 Baby extremely prem week Read 6356 Baby premature weeks Read 6357 Baby premature weeks Read 6358 Baby premature 39 weeks Read 6359 Baby premature 38 weeks Read 635A.00 Baby premature 37 weeks Read 635B.00 Baby premature 36 weeks Read L Premature separation of placenta with coagulation defect Read L Early or threatened labour Read L Premature labour Read L Threatened premature labour Read L False labour Read L Threatened premature labour unspecified Read L Threatened premature labour - not delivered Read L False labour at or after 37 completed weeks of gestation Read L140z00 Threatened premature labour NOS Read L Other threatened labour Read L Other threatened labour unspecified Read L Other threatened labour - not delivered Read

9 Code Description Classification L141z00 Other threatened labour NOS Read L Early onset of delivery Read L Premature delivery Read L Early onset of delivery unspecified Read L Early onset of delivery - delivered Read L142z00 Early onset of delivery NOS Read L Premature labour and delivery Read L Premature labour without delivery Read L Premature labour with premature delivery Read L14z.00 Early or threatened labour NOS Read L Premature rupture of membranes Read L Premature rupture of membranes unspecified Read L Premature rupture of membranes - delivered Read L Premature rupture of membranes with antenatal problem Read L Premature rupture of membranes, labour delayed by therapy Read L281z00 Premature rupture of membranes NOS Read Q Fetus/neonate affected maternal premature rupture membrane Read Q Fetus or neonate affected by premature placental separation Read Q Baby born premature Read Q Very premature - less than 1000g or less than 28 weeks Read Q Premature - weight 1000g-2499g or gestation of 28-37weeks Read Q Extreme prematurity - less than 28 weeks Read Q Premature infant weeks Read Q11z.00 Born premature NOS Read Q Prematurity with interstitial pulmonary fibrosis Read Q Anaemia of prematurity Read Z23AP00 Premature uterine contraction Read O60 Preterm labour and delivery ICD-10 O60.0 Preterm labour without delivery ICD-10 O60.1 Preterm spontaneous labour with preterm delivery ICD-10 O60.2 Preterm spontaneous labour with term delivery ICD-10 O60.3 Preterm delivery without spontaneous labour ICD-10

10 Supplemental table 4: OPCS codes relating to birth outcomes Code Description R171 Elective caesarean delivery, Elective upper uterine segment caesarean R172 Elective caesarean delivery, Elective lower uterine segment caesarean R178 Elective caesarean delivery, Other specified R179 Elective caesarean delivery, Unspecified R181 R182 R188 R189 R191 R198 R199 R201 R202 R208 R209 R211 R212 R213 R214 R215 R218 R219 R221 R222 R223 R228 R229 R231 R232 R238 R239 R249 Other caesarean delivery, Upper uterine segment caesarean delivery nec Other caesarean delivery, Lower uterine segment caesarean delivery nec Other caesarean delivery, Other specified Other caesarean delivery, Unspecified Breech extraction delivery, Breech extraction delivery with version Breech extraction delivery, Other specified Breech extraction delivery, Unspecified Other breech delivery, Spontaneous breech delivery Other breech delivery, Assisted breech delivery Other breech delivery, Other specified Other breech delivery, Unspecified Forceps cephalic delivery, High forceps cephalic delivery with rotation Forceps cephalic delivery, High forceps cephalic delivery nec Forceps cephalic delivery, Mid forceps cephalic delivery with rotation Forceps cephalic delivery, Mid forceps cephalic delivery nec Forceps cephalic delivery, Low forceps cephalic delivery Forceps cephalic delivery, Other specified Forceps cephalic delivery, Unspecified Vacuum delivery, High vacuum delivery Vacuum delivery, Low vacuum delivery Vacuum delivery, Vacuum delivery before full dilation of cervix Vacuum delivery, Other specified Vacuum delivery, Unspecified Cephalic vaginal delivery with abnormal presentation of head at delivery Cephalic vaginal delivery with abnormal presentation of head at delivery Cephalic vaginal delivery with abnormal presentation of head at delivery Cephalic vaginal delivery with abnormal presentation of head at delivery Normal delivery, All R251 Other methods of delivery, Caesarean hysterectomy R258 Other methods of delivery, Other specified R259 Other methods of delivery, Unspecified

11 Supplemental table 5. Fertility treatments undertaken in PCOS subjects and controls, defined by Read and ICD-10 codes. Description PCOS Non-PCOS Patients Events Patients Events CPRD GOLD - Read codes [V]Artificial insemination from donor [V]Artificial insemination from husband [V]Artificial insemination NOS [V]IVF Artificial insemination by donor Artificial insemination by husband Artificial insemination Donor status Female infertility therapy Implantation of fertilized egg into uterus In vitro fertilization (IVF) In vitro fertilization (IVF) NOS In vitro fertilization procedure In vitro fertilization with surrogacy In vitro fertilization with intra-cytoplasmic sperm injection Infection associated with artificial insemination Intracervical artificial insemination Intrauterine artificial insemination In-vitro fertilisation IVF IVF intracytoplasmic sperm injection (ICSI) and donor egg IVF with intracytoplasmic sperm injection (ICSI) Other specified in vitro fertilization (IVF) Transfer of embryo to uterus Treatment for infertility Treatment for infertility NOS HES - ICD-10 In vitro fertilization Other assisted fertilization methods Prescriptions Gonadotropins Letrozole Clomifene

12 Supplemental table 6: Sensitivity analysis for adjusted odds ratios for gestational diabetes, pre-eclampsia and premature birth for women with and without PCOS excluding multiple gestation. Prior Post Overall Odds ratio p Odds ratio p Odds ratio p Gestational diabetes 1.23 ( ) ( ) < ( ) <0.001 Premature 1.25 ( ) ( ) ( ) Pre-eclampsia 1.22 ( ) ( ) < ( ) <0.001 Adjusted for age, body mass index, number of previous births and smoking history.

13 Supplemental table 7: Method of delivery for women with and without PCOS before and after index date Delivery method PCOS Non PCOS Number (%) Length of stay (days) Number (%) Length of stay (days) Mean (sd) Median (IQR) Mean (sd) Median (IQR) Before index date Normal delivery 1,694 (61.0%) 3.1 (2.4) 3 (2-4) 5,654 (66.5%) 2.9 (4.2) 2 (2-3) Elective Caesarean 278 (10.0%) 5.1 (4.1) 4 (3-5) 699 (8.2%) 5.5 (4.6) 4 (3-6) Emergency Caesarean 493 (17.7%) 6.2 (3.8) 5 (4-7) 1,188 (14.0%) 5.8 (3.2) 5 (4-7) Forceps delivery 105 (3.8%) 4.6 (3.6) 4 (3-5) 332 (3.9%) 3.9 (2.1) 3 (3-5) Vacuum delivery 202 (7.3%) 3.7 (1.8) 3 (3-5) 599 (7.0%) 3.7 (2.4) 3 (2-4) Breech delivery 6 (0.2%) 3.3 (1.9) 3 (2-5) 31 (0.4%) 3.2 (2.1) 3 (2-4) Total 2,778 (100.0%) 4.0 (3.1) 3 (2-5) 8,503 (100.0%) 3.6 (4.1) 3 (2-4) After index date Normal delivery 1,778 (58.9%) 2.9 (2.4) 2 (2-3) 3,291 (63.3%) 2.6 (1.7) 2 (2-3) Elective Caesarean 348 (11.5%) 4.7 (3.4) 4 (3-5) 616 (11.8%) 4.6 (4.8) 3 (3-4) Emergency Caesarean 487 (16.1%) 5.5 (3.1) 5 (4-6) 740 (14.2%) 5.1 (2.6) 5 (4-6) Forceps delivery 183 (6.1%) 4.3 (5.0) 4 (3-5) 246 (4.7%) 3.7 (2.0) 3 (2-4) Vacuum delivery 215 (7.1%) 3.6 (1.9) 3 (2-4) 291 (5.6%) 3.3 (1.6) 3 (2-4) Breech delivery 10 (0.3%) 3.8 (2.4) 4 (2-6) 16 (0.3%) 3.4 (2.7) 2.5 (2-4) Total 3,021 (100.0%) 3.7 (3.0) 3 (2-4) 5,200 (100.0%) 3.3 (2.6) 3 (2-4) Combined Normal delivery 3,472 (59.9%) 3.0 (2.4) 2 (2-3) 8,945 (65.3%) 2.8 (3.4) 2 (2-3) Elective Caesarean 626 (10.8%) 4.9 (3.7) 4 (3-5) 1,315 (9.6%) 5.0 (4.7) 4 (3-5) Emergency Caesarean 980 (16.9%) 5.8 (3.4) 5 (4-7) 1,928 (14.1%) 5.5 (3.0) 5 (4-6) Forceps delivery 288 (5.0%) 4.4 (4.6) 4 (3-5) 578 (4.2%) 3.8 (2.0) 3 (2-5) Vacuum delivery 417 (7.2%) 3.6 (1.9) 3 (2-4) 890 (6.5%) 3.6 (2.2) 3 (2-4) Breech delivery 16 (0.3%) 3.6 (2.1) 3 (2-5) 47 (0.3%) 3.3 (2.3) 3 (2-4) Total 5,799 (100.0%) 3.8 (3.1) 3 (2-5) 13,703 (100.0%) 3.5 (3.6) 3 (2-4)

14 Supplemental table 8: Delivery outcomes for women with and without PCOS before and after index date Birth outcome PCOS Non PCOS Crude RR (95% CI) p Single live birth 5620 (97.6%) (98.3%) ( ) <0.001 Twins, both liveborn 106 (1.8%) 165 (1.2%) ( ) <0.001 Other multiple births, all liveborn 2 (0.0%) 3 (0.0%) ( ) Single stillbirth 23 (0.4%) 52 (0.4%) ( ) Twins, both stillborn 1 (0.0%) 0 (0.0%) Twins, one liveborn and one stillborn 4 (0.1%) 5 (0.0%) ( ) Outcome of delivery, unspecified 1 (0.0%) 1 (0.0%) Total 5757 (100.0%) (100.0%)