1st TRIMESTER PREGNANCY FAILURE Shortened to emphasize medical student curriculum requirements Carlos M. Fernandez, M.D Department of Obstetrics and Gynecology Advocate Illinois Masonic and Medical Center

Ultrasound diagnosis of intrauterine pregnancy

Diagnosis of IUP “Double decidual sign” at 4½ to 5 wks Gestational sac + yolk sac at 5 wks (a definitive sign of IUP) GS + yolk sac + embryo at 5½ to 6 wks CRL >5 mm – fetal cardiac activity present Seeber BE and Barnhart KT. Obstet Gynecol 2006;107:339-413

First sign of IUP: double decidual sign Earliest finding is the “double decidual sign” (arrows) seen around 4½-5 wks gestation initially eccentric in location It excludes pseudogestational sac (free fluid or blood within endometrium)

Double-decidual sign ( 5 weeks' menstrual age) Double-decidual sign ( 5 weeks' menstrual age). The decidua vera (dv) can be discerned from the decidua capsularis (dc) and chorion laeve surrounding the gestational sac. A small subchorionic hemorrhage(*) is present between the unopposed layers of decidua vera.

Gestational Sac (confirmed by double decidual sign) Grows 1 mm per day Usually seen by 4 ½ to 5 weeks of gestation Discriminatory ß-hCG with TVS: usually quoted 1000 - 2000 ß-hCG IU/L. Depends upon: Skill of the sonographer and image magnification Frequency (5-10mHz) and resolution of the transducer Uterine abnormalities, fibroids Multiple gestation

Gestational Sac Discriminatory ß-hCG with TVS : 1000 - 2000 ß-hCG IU/L Discriminatory ß-hCG with TAS: ≥ 6500 ß-hCG IU/L Bhatt & Dogra, Radiol Clin N Am 45 (2007) 549-560

The gestational sac diameter is used to calculate gestational age Long axis Short axis

Second sign of IUP: Yolk Sac First structure visualized within the gestational sac Round , bright ring <6mm A definitive sign of IUP Involutes after 11 weeks Can be seen half a week before normal embryo is seen When enlarged (“hydropic”), solid or duplicated, it is a very poor prognosis sign

Gestational sac and yolk sac (5 weeks' menstrual age) Gestational sac and yolk sac (5 weeks' menstrual age). A normal yolk sac is visualized. The embryo is not identified. The decidua vera (dv) and decidua capsularis (dc) (double-decidual sign) are identified.

Third sign of IUP: GS + yolk sac + embryo GS + yolk sac + fetal pole at 5½ to 6 wks The fetal pole (arrow) is better seen on the zoomed in image GS grows 1mm/day Embryo grows 1mm/day

Fourth sign of IUP: GS + YS + embryo + cardiac activity Double decidual sign +yolk sac+ fetal pole +cardiac activity Cardiac activity confirms a live intrauterine pregnancy Cardiac activity is usually detected at 5 ½ to 6 weeks from last menstrual period CRL ≥5 mm – fetal cardiac activity present

Bhcg and progesterone in early pregnancy

Serum concentrations of ß-hCG in 443 normal pregnancies ß-hCG is first detected in maternal serum 6 to 9 days after conception. The levels rise in a logarithmic fashion, peaking 8 to 10 weeks after the last menstrual period, followed by a decline to a nadir at 18 weeks, with subsequent levels remaining constant until delivery Second International Standard ß-hCG Braunstein G D, et al. Am J Obstet Gynecol 1976; 126:678-81.

Serial ß-hCG The doubling time for a normal IUP is 2 days, with a range of 1.4 to 2.1 days Doubling of ß-hCG is less reliable after 10,000 mIU/ml , at this level pregnancy is better evaluated with U/S 15% of normal IUP can demonstrate an abnormal rise of ß-hCG Kadar N, et al. Obstet Gynecol 1981;52:162-6

ß-hCG up to 10000 mIU/ml The minimal rise in ß-hCG for a viable pregnancy is 53% in 48 hours The minimal decline of a spontaneous abortion is 21-35% in 48 hours A rise or fall in serial ß-hCG values that is slower than this is suggestive of an ectopic pregnancy Seeber BE and Barnhart KT. Obstet Gynecol 2006;107:339-413

Seeber BE and Barnhart KT. Obstet Gynecol 2006;107:339-413 Hypothetical illustration of the rise, or fall, of serial hCG values in women with an EP 53% 21-35% Seeber BE and Barnhart KT. Obstet Gynecol 2006;107:339-413

Serum Progesterone Progesterone level of <10 ng/ml is consistent with an abnormal pregnancy Progesterone level of > 20 ng/ml is consistent with a normal pregnancy Progesterone level of < 5 ng/ml is 99.85 % specific of an abnormal pregnancy 92% of the ectopic pregnancies the progesterone level was < 17.5 ng/ml McCord ML, et al. Fertil Steril 1996; 66:513-16

Spontaneous abortion: background, etiology

Spontaneous abortion or miscarriage Spontaneous abortion is a fetal loss before week 20 of pregnancy Early loss is before menstrual week 12 Late loss refers to losses from weeks 12 to 20 80% of miscarriages occurring in the first trimester Ferri: Ferri's Clinical Advisor 2012, 1st ed.

Normal first-trimester pregnancy Miscarriage Diagram representing placentation in (a) a normal first‐trimester pregnancy and (b) miscarriage. Note trophoblast plugging of maternal spiral arteries and trophoblast invasion of the decidua and superficial myometrium in the central area of the normally developing placenta (a). By contrast, in the miscarriage (b) there is a shallow trophoblastic invasion and the plugs are loose, allowing premature entry of maternal blood (arrows). © This slide is made available for non-commercial use only. Please note that permission may be required for re-use of images in which the copyright is owned by a third party. Trophoblast plugging of maternal spiral arteries with invasion of the decidua and superficial myometrium in the central area of the normally developing placenta There is a shallow trophoblastic invasion and the plugs are loose, allowing premature entry of maternal blood (arrows)

Miscarriage Miscarriage is the most common serious pregnancy complication affecting approximately 30% of biochemical pregnancies and 11–20% of clinically recognized pregnancies The diagnosis of miscarriage is made most commonly by trans-vaginal ultrasound (TVS) assessment After a diagnosis of miscarriage, half the women undergo significant psychological effects, which may last for up to 12 months Cecilia Bottomley, Tom Bourne. Diagnosing miscarriage. Best Practice & Research Clinical Obstetrics & Gynecology 2009; 23:463-77

Miscarriage The crucial role of chromosomal imbalance in abnormal early human development is well established Approximately 50–60% of first-trimester spontaneous abortions have karyotype abnormalities Igor N Lebedev, Nadezhda V Ostroverkhova, Tatyana V Nikitina, Natalia N Sukhanova and Sergey A Nazarenko. Features of chromosomal abnormalities in spontaneous abortion cell culture failures detected by interphase FISH analysis. European Journal of Human Genetics 2004; 12:513–20

Miscarriage The most frequent type of chromosomal abnormalities detected are: Autosomal trisomies ─ 52 % Monosomy X ─ 19 % Polyploidies ─ 22 % Other ─ 7 % Hsu, LYF. Prenatal diagnosis of chromosomal abnormalities through amniocentesis. In: Genetic Disorders and the Fetus, 4th ed, Milunsky, A (Ed), The Johns Hopkins University Press, Baltimore 1998. p.179

Classification of miscarriage

Clinical classification of spontaneous abortion Laifer-Narin SL. Ultrasound for Obstetrics Emergencies. Ultrasound Clin . 2011; 6: 177-193 Type Definition Threatened abortion Vaginal bleeding during the first 20 weeks of pregnancy and no evidence of cervical dilation <50% of threatened abortions will progress to loss of pregnancy Missed abortion Intrauterine demise of the conceptus without either vaginal bleeding or expulsion of the products of conception Incomplete abortion Vaginal bleeding with dilation of the cervix and partial expulsion of the conceptus Complete abortion Vaginal bleeding with expulsion of all of the products of conception Inevitable abortion Abortion in progress in which the bleeding is profuse with cervical dilation but a maintained intrauterine pregnancy

Threatened Abortion Pregnant patient who is symptomatic with: Vaginal bleeding Mild abdominal cramps Closed cervical os Complication affecting 16-25% of pregnant patients SAB rate as high as 50% before ultrasound evaluation of fetal viability Chung TKH. Aust N Z J Obstet Gynaecol 1999; 39:443-447

Differential Diagnosis of Threatened Abortion Undetermined or physiologic (implantation related) Ectopic pregnancy Sub-chorionic bleed, found in ~20% of threatened Ab Gestational trophoblastic disease Impending spontaneous miscarriage Cervix, vaginal or uterine pathology

Ultrasound diagnosis of miscarriage (comparing international criteria) This section is too in-depth for most medical students; use it only for the most interested students! Ultrasound diagnosis of miscarriage (comparing international criteria)

TVS features of pregnancy failure Non visualization of the yolk sac by the time the mean sac diameter is 13 mm Non visualization of the embryo by the time the mean sac diameter is 20 mm Non visualization of cardiac activity by the time the embryo is 5 mm in length Specificity for diagnosis of nonviable pregnancy is 100% Levine D. Radiology 2007; 245:385-397

How to define miscarriage using ultrasound-comparing and contrasting national guidelines Royal College of Obstetricians and Gynaecologists. The Management of Early Pregnancy Loss. Green-Top Guideline No. 25. October 2006 Miscarriage: Miscarriage is defined at first scan when gestational sac with MSD greater than 20 mm an no embryonic contents or CRL > 6 mm with no heart beat Or subsequently if sac remain empty after at least one week or still no cardiac activity 1 week after initial

Transvaginal Ultrasound Gestational sac > 20 mm How to define miscarriage using ultrasound-comparing and contrasting national guidelines The Institute of Obstetricians and Gynaecologists Royal College of Physicians of Ireland Transvaginal Ultrasound Embryo > 7 mm No cardiac activity Miscarriage Gestational sac > 20 mm No embryo or yolk sac

What is the evidence to support the cut-offs used to diagnose miscarriage? Conclusions First systematic review of ultrasound diagnosis of miscarriage Studies are 15–20 years old, small numbers of miscarriage, reference standards were poor (method of miscarriage confirmation) Various cut-off values used (4–6mm for CRL, 13–25mm for MSD), making pooling of data impossible Best (most specific) criteria appeared to be MSD > 25mm with a missing embryo or MSD > 20mm with a missing yolk sac These criteria had a 95% CI of 0.96–1.00, therefore up to 4 out of 100 diagnoses of early fetal demise may be wrong. A single incorrect diagnosis of miscarriage is one too many A confidence interval (CI) is a particular kind of interval estimate of a population parameter and is used to indicate the reliability of an estimate. Jeve Y et al., UOG 2011 Nov

Prospective multicenter study 1060 patients of IPUV Conclusions Abdallah Y, et al. Limitations of current definitions of miscarriage using mean gestational sac diameter and crown–rump length measurements: a multicenter observational study. Ultrasound Obstet Gynecol 2011; 38: 497–502 Prospective multicenter study 1060 patients of IPUV Conclusions Current definitions used to diagnose miscarriage by ultrasound are potentially unsafe In order to minimize the risk of a false-positive diagnosis of miscarriage the following cut-off could be introduced Empty gestational sac or sac with a yolk sac but no embryo seen with MSD >25 mm Embryo with an absent heartbeat and CRL > 7 mm

Summary Summary Data from these studies show that current definitions used to diagnose miscarriage are potentially unsafe Significant interobserver variability may be associated with a misdiagnosis of miscarriage Current national guidelines should be reviewed to avoid inadvertent termination of wanted pregnancy Large prospective studies with agreed reference standards are urgently required

Ectopic pregnancy

Risk Factors for Ectopic Pregnancy Prior ectopic Previous tubal surgery History of tubal ligation Intra-uterine contraceptive device History of infertility History of PID History of chlamydia or gonorrhea Smoking

TVS Criteria for Ectopic Pregnancy TVS Findings Likelihood of ectopic Extrauterine embryo + heartbeat 100% Adnexal fluid + Yolk sac or Embryo without heart beat Tubal ring 95% Complex or solid adnexal mass. No tubal ring, yolk sac, embryo 91.9% Brown and Doubilet. J Ultrasound Med 1994, 13:259-266

Pregnancy of uknown location

Pregnancies of unknown location (PUL) Definition Positive pregnancy test with no signs of intra- or extrauterine pregnancy on transvaginal sonography (TVS) The women should have no signs of hemoperitoneum on ultrasound scan Condous G, Timmerman D, Golstein S, Valentin L, Jurkovic D, Bourne T. Pregnancies of unknown location: consensus statement. Ultrasound Obstet Gynecol 2006; 28:121-2

Pregnancies of unknown location (PUL) It is well accepted that women with a PUL can be safely managed expectantly Banerjee S, et al. Ultrasound Obstet Gynecol 1999; 14:231-6 Condous G, et al. Int J Gynecol Obstet 2004; 86:351-7 Condous G, et al. BJOG 2006; 113:1-7 Kirk E, et al. Ultrasound Obstet Gynecol 2006; 27:311-5

Follow up of PULs ß-hCG levels taken at 0 and 48 h Kirk E, et al. Hum Reprod 2007;22:1744-50 ß-hCG levels taken at 0 and 48 h TVS on day 1 and repeat TVS on day 7 Still PUL after TVS on day 7 Repeat ß-hCG Repeat TVS as indicated All women with PUL were given: Details of follow up 24-h contact numbers in case of emergency Return to EPU or ED if increase of pain or vaginal bleeding

Final clinical outcome of 363 PULs Kirk E, et al. Hum Reprod 2007;22:1744-50 229 (63.1%) failing PULs 111 (30.6%) IUPs 23 (6.3%) EP Within 7 days of follow-up, 97.5% (354/363) of PULs had a final diagnosis Only 1 patient (0.3%) required a diagnostic laparoscopy for pregnancy location

Retained products of conception

Retained Products of Conception (RPOC) Oscar Sadan, Abraham Golan, Ofer Girtler, Samuel Lurie, Abraham Debby, Ron Sagiv, Shmuel Evron, Marek Glezerman. Role of Sonography in the Diagnosis of Retained Products of Conception. JUM 2004 23:371-4 RPOC are well-known and troublesome complications after spontaneous or induced abortion and parturition Patients usually have abdominal pain, bleeding, fever, and an open cervical external os The diagnosis is based on the sonographic appearance of intrauterine echogenic material Retained products of conception are generally treated by D&C to empty the uterine cavity. This exposes the uterus to additional potential trauma, with immediate risks such as bleeding, perforation, and infection and late sequelae such as intrauterine adhesions

Retained products of conception Retained products of conception. Intrauterine heterogeneous, mixed echogenic mass with marked internal vascularity in a patient who recently underwent spontaneous abortion

Transvaginal sagittal sonogram of a uterus immediately after repeated D&C. A thin hyperechoic echo is shown, characteristic of an empty uterus.