Fetal Echocardiography and Magnetocardiography

Number: 0106

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses fetal echocardiography and magnetocardiography.

1. Medical Necessity

   Aetna considers the following interventions medically necessary: 

   1. Fetal echocardiograms, Doppler and color flow mapping after 12 weeks gestation for any of the following conditions:

      1. A mother with type 1 diabetes or pregestational type 2 diabetes on insulin during the first trimester; or
      2. A mother with systemic lupus erythematosus; or
      3. As a screening study in families with a first-degree relative of a fetus with congenital heart disease; or
      4. Fetal nuchal translucency measurement of 3.5 mm or greater in the first trimester; or
      5. Following an abnormal or incomplete cardiac evaluation on an anatomic scan, 4-chamber study
         
         

         Note: When the 4-chambered view is adequate and there are no other indications of a cardiac abnormality, a fetal echocardiogram is not considered medically necessary; or

      6. For ductus arteriosus dependent lesions and/or with other known complex congenital heart disease; or
      7. For fetus with umbilical cord varix when there is a suspicion of fetal hydrops; or
      8. For pregnancies conceived by in vitro fertilization (IVF) or intra-cytoplasmic sperm injection (ICSI); or
      9. In cases of persistent right umbilical vein; or
      10. In cases of single umbilical artery; or
      11. In cases of suspected or known fetal chromosomal abnormalities; or
      12. In suspected or documented fetal arrhythmia: to define the rhythm and its significance, to identify structural heart disease and cardiac function; or
      13. In members with autoimmune antibodies associated with congenital cardiac anomalies [anti-Ro (SSA)/anti-La (SSB)]; or
      14. In members with familial inherited disorders associated with congenital cardiac abnormalities (e.g., Marfan syndrome); or
      15. In cases with monochorionic twins; or
      16. In cases of multiple gestation and suspicion of twin-twin transfusion syndrome; or
      17. In members with seizure disorders, even if they are not presently taking anti-seizure medication; or
      18. In cases with non-immune fetal hydrops or unexplained severe polyhydramnios; or
      19. When members' fetuses have been exposed to drugs known to increase the risk of congenital cardiac abnormalities including but not limited to:
          
          
          1. Anti-seizure medications; or
          2. Excessive alcohol intake; or
          3. Lithium; or
          4. Paroxetine (Paxil); or
          5. Retinoids; or

      20. When other cardiac structural abnormalities are found on fetal ultrasound; or

   2. Repeat studies of fetal echocardiograms, Doppler and color flow mapping for any of the following:

      1. When the initial screening study indicates any of the following:

         1. A ductus arteriosus dependent lesion (e.g., cyanotic lesions such as transposition of the great arteries (TGA), pulmonary atresia/stenosis, tricuspid atresia, severe tetralogy of Fallot; left heart obstructive lesions such as hypoplastic left heart syndrome (HLHS), coarctation of the aorta, interrupted aortic arch critical aortic stenosis); or
         2. Absence of the ductus venosus if ultrasonography suggests any uncertainty that the heart is normal; or
         3. Structural heart disease with a suggestion of hemodynamic compromise; or
         4. Tachycardia other than sinus tachycardia or heart block; or
      2. Fetal surveillance (e.g., congenital heart block) in mother with documented diagnosis of Sjögren’s syndrome or autoimmune antibodies anti-Ro/Sjögren’s syndrome antigen A (SSA) or anti-La/Sjögren’s syndrome antigen B (SSB). Frequency of testing: Doppler fetal echocardiography may be repeated every 1 to 2 weeks starting at 16 weeks gestation continuing through 28 weeks gestation, then every other week until 32 weeks gestation to detect fetal (congenital) heart block; or
      3. For pregnant women with anti-Ro and anti-LA antibodies; or
      4. If there is non-steroidal anti-inflammatory drugs (NSAIDs) use during the late second or third trimester.

2. Experimental, Investigational, or Unproven

   Aetna considers the following interventions experimental, investigational, or unproven because the effectiveness of these approaches has not been established:

   1. Fetal echocardiograms for all other indications including the following (not an all-inclusive list):

      1. As a screening test in advanced maternal age; or
      2. Gestational diabetes even if requiring insulin after the first trimester; or
      3. Modafinil (Provigil) exposure in pregnancy; or
      4. Pregnant women receiving selective serotonin reuptake inhibitors (except paroxetine), or tacrolimus (Prograf); or
      5. Repeat fetal echocardiography for tortuous ductus arteriosus; or
      6. Suspected cystic fibrosis.

   2. Fetal magnetocardiography.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
CPT codes covered if selection criteria are met:
76825	Echocardiography, fetal, cardiovascular system, real time with image documentation (2D), with or without M-mode recording;
76826	follow-up or repeat study
76827	Doppler echocardiography, fetal, cardiovascular system, pulsed wave and/or continuous wave with spectral display; complete
76828	follow-up or repeat study
+93325	Doppler echocardiography color flow velocity mapping (List separately in addition to codes for echocardiography)
CPT codes not covered for indications listed in the CPB:
0475T	Recording of fetal magnetic cardiac signal using at least 3 channels; patient recording and storage, data scanning with signal extraction, technical analysis and result, as well as supervision, review, and interpretation of report by a physician or other qualified health care professional
0476T	patient recording, data scanning, with raw electronic signal transfer of data and storage
0477T	signal extraction, technical analysis, and result
0478T	review, interpretation, report by physician or other qualified health care professional
0541T - 0542T	Myocardial imaging by magnetocardiography (MCG) for detection of cardiac ischemia, by signal acquisition using minimum 36 channel grid, generation of magnetic-field time-series images, quantitative analysis of magnetic dipoles, machine learning–derived clinical scoring, and automated report generation
Other HCPCS codes related to the CPB:
J7503	Tacrolimus, extended release, (envarsus xr), oral, 0.25 mg
J7507	Tacrolimus, immediate release, oral, 1 mg
J7508	Tacrolimus, extended release, (astagraf xl), oral, 0.1 mg
J7525	Tacrolimus, parenteral, 5 mg
Q9950	Injection, sulfur hexafluoride lipid microspheres, per ml
Maternal ICD-10 codes covered if selection criteria are met:
B97.10, B97.89	Unspecified viral infection
D68.61	Antiphospholipid syndrome
E10.10 - E13.9	Diabetes mellitus [do not report for gestational diabetes]
F10.20 - F10.29	Alcohol dependence
G40.001 - G40.919	Epilepsy and recurrent seizures
I34.0 - I37.9	Mitral valve disorders, aortic valve disorders, tricuspid valve disorders and pulmonary valve disorders, specified as nonrheumatic,
I42.3	Endomyocardial (eosinophilic) disease
I42.4	Endocardial fibroelastosis
I42.6	Alcoholic cardiomyopathy
I50.1 - I50.9	Heart failure
I51.7	Cardiomegaly
I78.0	Hereditary hemorrhagic telangectasia
L93.0 - L93.2	Lupus erythematosus
M05.40 - M06.9	Rheumatoid arthritis
M32.0 - M32.9	Systemic lupus erythematosus
M34.0 - M34.9	Systemic sclerosis [scleroderma]
M35.00 - M35.09	Sicca syndrome [Sjögren]
M35.9, M36.8	Unspecified diffuse connective tissue disease
O24.011 - O24.019, O24.111 - O24.119 O24.311 - O24.319, O24.811 - O24.819 O24.911 - O24.919	Diabetes mellitus in pregnancy [pre-existing, excludes gestational diabetes]
O30.001 - O30.93	Multiple gestation
O36.8310 - O36.8399	Maternal care for abnormalities of the fetal heart rate or rhythm
O98.411 - O98.419, O98.511 - O98.519	Viral hepatitis and other viral diseases complicating pregnancy
O98.611 - O98.619, O98.711 - O98.719 O98.811 - O98.819, O99.830	Other specified infectious and parasitic diseases complicating pregnancy
O98.911 - O98.93	Unspecified maternal infectious and parasitic diseases complicating pregnancy, childbirth and the puerperium
099.111 - O99.119	Other diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism complicating pregnancy with brackets stating [Antiphospholipid syndrome]
O99.350 - O99.353	Diseases of the nervous system complicating pregnancy [epilepsy]
O99.411 - O99.419	Diseases of the circulatory system complicating pregnancy
O99.89	Other specified diseases and conditions complicating pregnancy, childbirth and the puerperium [Systemic lupus erythematosus (SLE)]
Q20.0 - Q28.9	Congenital malformations of the circulatory system
Q79.6	Ehlers-Danlos syndrome
Q87.40 - Q87.43	Marfan's syndrome
Q89.3	Situs inversus
Q89.7	Multiple congenital malformations, not elsewhere classified
Q90.0 - Q90.9	Down syndrome
Q91.0 - Q91.3	Trisomy 18 [Edward's syndrome]
R56.1	Post traumatic seizures
R56.9	Unspecified convulsions [seizure disorder NOS]
R93.1, R93.8	Abnormal findings on diagnostic imaging of heart and coronary circulation and other body structures
T42.1x5+, T42.5x5+ T42.6x5+, T42.75x+	Adverse effects of other and unspecified anticonvulsants
Z3A.13 - Z34.49	13 - 49 Weeks of gestation of pregnancy
Z82.79	Family history of other congenital malformations, deformations and chromosomal abnormalities
Z98.89	Other specified postprocedural states
Fetal ICD-10 codes covered if selection criteria are met:
O09.811 - O09.819	Supervision of pregnancy resulting from assisted reproductive technology
O33.6xx0 - O33.6xx9	Maternal care for disproportion due to hydrocephalic fetus
O35.00X0 - O35.09X9	Maternal care for (suspected) central nervous system malformation or damage in fetus
O35.10X0 to O35.19X9	Maternal care for (suspected) chromosomal abnormality in fetus
O35.2xx0 - O35.2xx9	Maternal care for (suspected) hereditary disease in fetus
O35.3xx0 - O35.3xx9	Maternal care for (suspected) damage to fetus from viral disease in mother
O35.4xx0 - O35.4xx9	Maternal care for (suspected) damage to fetus from alcohol
O35.5xx0 - O35.5xx9	Maternal care for (suspected) damage to fetus from drugs
O35.8xx0 - O35.8xx9	Maternal care for (suspected) fetal abnormality and damage
O35.9xx0 - O35.9xx9	Maternal care for (suspected) fetal abnormality and damage, unspecified
O35.AXX0 - O35.HXX9	Maternal care for other (suspected) fetal abnormality and damage
O36.0110 - O36.0999	Maternal care for rhesus isoimmunization
O36.1110 - O36.1999	Maternal care for other isoimmunization
O36.20x0 - O36.23x9	Maternal care for hydrops fetalis
O36.8310 - O36.8399	Maternal care for abnormalities of the fetal heart rate or rhythm
O40.1XX0 - O40.3XX9	Polyhydramnios
O43.011 - O43.029	Placenta transfusion syndromes
O43.121-O43.129	Velamentous insertion of umbilical cord [umbilical cord varix]
Q27.0	Congenital absence and hypoplasia of umbilical artery
ICD-10 codes covered if selection criteria are met:
O09.811 - O09.819	Supervision of pregnancy resulting from assisted reproductive technology
O24.011 - O24.019, O24.111 - O24.119 O24.311 - O24.319, O24.811 - O24.819 O24.911 - O24.919	Diabetes mellitus in pregnancy [pre-existing, excludes gestational diabetes]
O33.6xx0 - O33.6xx9	Maternal care for disproportion due to hydrocephalic fetus
O35.00X0 - O35.09X9	Maternal care for (suspected) central nervous system malformation or damage in fetus
O35.10X0 to O35.19X9	Maternal care for (suspected) chromosomal abnormality in fetus
O35.2xx0 - O35.2xx9	Maternal care for (suspected) hereditary disease in fetus
O35.3xx0 - O35.3xx9	Maternal care for (suspected) damage to fetus from viral disease in mother
O35.4xx0 - O35.4xx9	Maternal care for (suspected) damage to fetus from alcohol
O35.5xx0 - O35.5xx9	Maternal care for (suspected) damage to fetus from drugs
O35.8xx0 - O35.8xx9	Maternal care for (suspected) fetal abnormality and damage
O35.9xx0 - O35.9xx9	Maternal care for (suspected) fetal abnormality and damage, unspecified
O35.AXX0 - O35.HXX9	Maternal care for other (suspected) fetal abnormality and damage
O36.0110 - O36.0999	Maternal care for rhesus isoimmunization
O36.1110 - O36.1999	Maternal care for other isoimmunization
O40.1xx0 - O40.1xx9	Polyhydramnios
O43.011 - O43.029	Placenta transfusion syndromes
O76	Abnormality in fetal heart rate and rhythm complicating labor and delivery
O98.411 - O98.419, O98.511 - O98.519	Viral hepatitis and other viral diseases complicating pregnancy
O98.611 - O98.619, O98.711 - O98.719 O98.811 - O98.819, O99.830	Other specified infectious and parasitic diseases complicating pregnancy
O98.911 - O98.919	Unspecified maternal infectious and parasitic diseases complicating pregnancy
O99.411 - O99.419	Diseases of the circulatory system complicating pregnancy
Q27.0	Congenital absence and hypoplasia of umbilical artery
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
O09.511 - O09.519	Supervision of elderly primigravida
O09.521 - O09.529	Supervision of elderly multigravida
O24.410 - O24.419	Gestational diabetes mellitus in pregnancy [not covered even if requiring insulin after the first trimester]
O99.810 - O99.815	Abnormal glucose complicating pregnancy, childbirth and the puerperium
Z13.228	Encounter for screening for other metabolic disorders
Repeat studies of Doppler and color flow mapping:
CPT codes covered if selection criteria are met:
76826	Echocardiography, fetal, cardiovascular system, real time with image documentation (2D), with or without M-mode recording; follow-up or repeat study
76828	Doppler echocardiography, fetal, cardiovascular system, pulsed wave and/or continuous wave with spectral display follow-up or repeat study
+93325	Doppler echocardiography color flow velocity mapping (List separately in addition to codes for echocardiography)
ICD-10 codes covered if selection criteria are met:
I51.0 – I51.9	Complications and ill-defined descriptions of heart disease [Structural heart disease with a suggestion of hemodynamic compromise]
M35.00 – M35.09	Sjogren syndrome
O35.8XX0 – O35.8XX9	Maternal care for (suspected) fetal abnormality and damage [absence of ductus venous]
O35.9XX0 – O35.9XX9	Maternal care for (suspected) fetal abnormality and damage, unspecified [absence of ductus venous]
O35.AXX0 – O35.HXX9	Maternal care for other (suspected) fetal abnormality and damage [absence of ductus venous]
O36.0110 - O36.0990	Maternal care for rhesus isoimmunization
Q25.0	Patent ductus arteriosus
Q28.8	Other specified congenital malformations of circulatory system [absence of ductus venous]
Z79.1	Long term (current) use of non-steroidal anti-inflammatories (NSAID)
Z87.74	Personal history of (corrected) congenital malformations of heart and circulatory system
ICD-10 not covered for indications listed in the CPB:
Q25.46	Tortuous aortic arch [Tortous ductus arteriosus]

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Background

Definition of fetal cardiac structures is currently possible at 12 weeks of gestation with the use of vaginal probes with high-resolution transducers.  With current technologies, accurate segmental analysis of cardiac structures and blood flow across valves, shunts, and the ductus arteriosus is possible with a conventional transabdominal approach by 16 to 18 weeks of gestation.

According to the American Institute for Ultrasound in Medicine (AIUM), fetal echocardiography is commonly performed between 18 and 22 weeks’ gestational age. Some forms of congenital heart disease may even be recognized during earlier stages of pregnancy (AIUM, 2013). Newer technology including endovaginal transducers can obtain images of the heart as early as 12 weeks gestation (AHA, 2018).

Hutchinson et al. (2017) states that early fetal echocardiography (FE), performed at 12 to 16 weeks' gestational age (GA), can be used to screen for fetal heart disease similar to that routinely performed in the second trimester; however, the efficacy of FE at earlier GAs has not been as well explored, particularly with recent advances in ultrasound technology. Pregnant women were prospectively recruited for first-trimester FE. All underwent two-dimensional (2D) cardiac imaging combined with color Doppler (CD) assessment, and all were offered second-trimester fetal echocardiographic evaluations. Fetal cardiac anatomy was assessed both in real time during FE and additionally offline by two separate reviewers. Very early FE was performed in 202 pregnancies including a total of 261 fetuses, with 92% (n = 241) being reassessed at greater than or equal to 18 weeks' GA. Transabdominal scanning was used in all cases, and transvaginal scanning was used additionally in most at less than 11 weeks' GA (n = 103 of 117 [88%]). There was stepwise improvement in image resolution of the fetal heart in those pregnancies that presented at later gestation for assessment. CD assisted with definition of cardiac anatomy at all GAs. A four-chambered heart could be identified in 52% of patients in the eighth week (n = 12 of 23), improving to 80% (n = 36 of 45) in the 10th week and 98% (n = 57 of 58) by the 11th week. The inferior vena cava was visualized by 2D imaging in only 4% (n = 1 of 23) in the eighth week, increasing to 13% (n = 6 of 45) by the 10th week and 80% (n = 25 of 31) by the 13th week. CD improved visualization of the inferior vena cava at earlier GAs to greater than 80% (n = 37 of 45) from 10 weeks. Pulmonary veins were not visualized by either 2D imaging or CD until after the 11th week. Both cardiac outflow tracts could be visualized by 2D imaging in the minority from 8+0 to 10+6 weeks (n = 18 of 109 [16%]) but were imaged in most from 11+0 to 13+6 weeks (n = 114 of 144 [79%]). CD imaging improved visualization of both outflow tracts to 64% (n = 29 of 45) in the 10th week. On 2D imaging alone, both the aortic and ductal arches were seen in only 29% of patients in the 10th week (n = 13 of 45), increasing to 58% when CD was used (58% [n = 26 of 45]) and to greater than 80% (n = 47 of 58) using CD in the 11th week. The authors concluded that very early FE, from as early as 8 weeks, can be used to assess cardiac structures; however, the ability to image fetal heart structures between 6 and 8 weeks is currently nondiagnostic. The use of CD significantly increases the detection of cardiac structures on early FE. The ideal timing of complete early FE, excluding pulmonary vein assessment, appears to be after 11 weeks' GA.

Ventriglia et al. (2016) state that there is a growing body of evidence that most of the major cardiac abnormalities can be diagnosed from 12-16 weeks of gestation (compared with the usual 18-22 weeks). Furthermore, the reason for performing early fetal echocardiography (EFEC) is that "the combined EFEC-NT (nuchal translucency) approach (11th-13th week) gives a 60-70% increase in detection rate for CHD. Combined EFE-NT analysis is also justified by the high CHD frequency in genetic syndromes and the similarity of anatomic relations between cardiac structures at 11-13 weeks GA and those of the second trimester." "The technical limits of EFEC are CRL < 50 mm, an increase of maternal Body mass index (BMI), unfavorable fetal position and a possible progression of cardiac disease especially in outflow obstructions. This means that the pregnant women should be informed about the limits of early screening and also recommended to have a further scan as from 18 weeks for a more complete diagnosis."

Patients are referred for fetal echocardiography because of an abnormality of structure or rhythm noted on ultrasound examination or because the patient is in a high-risk group for fetal heart disease.  Treatment of the patient is facilitated by the early recognition of the exact nature of the cardiac problem in the fetus.  The correct diagnosis may be difficult because of fetal physiology, the effect on flow across defects and valves, inability to see the fetus for orientation reference, and inability to examine the fetus for clinical findings.  For these reasons, fetal echocardiography should be performed only by trained fetal echocardiographers.

The umbilical cord normally contains two arteries and one vein embedded in Wharton's jelly. The umbilical cord "achieves its final form by the 12th week of gestation". Initially during umbilical cord development, there are two umbilical arteries and two umbilical veins, in which the two veins (left and right) converge into one. Obliteration of the right umbilical vein by the end of the 6th week of gestation results in a single persisting left umbilical vein (Spurway et al, 2012). However, persistence of the right umbilical vein in the fetus is a variant of the intra-abdominal umbilical venous connection. The estimated prevalence of an intrahepatic persistent right umbilical vein is 1 per 786 births; which may be an underestimated calculation in populations that do not undergo targeted sonographic examinations. In addition, the variation in anatomy can be subtle (Lide et al, 2016).

Lide et al (2016) provided a comprehensive review of the current data surrounding an intra-hepatic persistent right umbilical vein in the fetus, including associated anomalies and outcomes, to aid practitioners in counseling and management of affected pregnancies.  These investigators performed a Medline, Embase, Cochrane Central Register of Controlled Trials, and Northern Light database search for articles reporting outcomes on prenatally diagnosed cases of a persistent right umbilical vein.  Each article was independently reviewed for eligibility by the investigators.  Thereafter, the data were extracted and validated independently by 3 investigators.  A total of 322 articles were retrieved, and 16 were included in this systematic review.  The overall prevalence of an intra-hepatic persistent right umbilical vein was found to be 212 per 166,548 (0.13 %).  Of the 240 cases of an intra-hepatic persistent right umbilical vein identified, 183 (76.3 %) were isolated.  The remaining cases had a co-existing abnormality, including 19 (7.9 %) cardiac, 9 (3.8 %) central nervous system, 15 (6.3 %) genito-urinary, 3 (1.3 %) genetic, and 17 (7 %) placental/cord (predominantly a single umbilical artery).  The authors concluded that a persistent right umbilical vein is commonly an isolated finding but may be associated with a co-existing cardiac defect in 8 % of cases.  Therefore, consideration should be given to fetal echocardiography in cases of a persistent right umbilical vein.

Canavan et al (2016) stated that a fetal persistent intrahepatic right umbilical vein has been linked to anomalies and genetic disorders but can be a normal variant.  These researchers conducted a retrospective review to determine other sonographic findings that can stratify fetuses for further evaluation.  A total of 313 fetuses had a persistent intra-hepatic right umbilical vein identified on 17- to 24-week sonography.  The outcome was any major congenital anomaly or an adverse neonatal outcome, which was defined as aneuploidy, fetal demise, or neonatal death.  A total of 217 patients (69.3 %) had a normal neonatal outcome; 69 patients (22.0 %) were lost to follow-up; 5 fetuses (2.1 %) had aneuploidy; 4 of the 5 had additional sonographic findings, and 1 had an isolated persistent intra-hepatic right umbilical vein; 24 fetuses had a major anomaly in association with the persistent right umbilical vein; 26 additional fetuses had soft sonographic markers associated with karyotypic abnormalities but were chromosomally normal.  Of those with adverse neonatal outcomes, 12 had a congenital heart defect (57 %).  An additional sonographic finding with a persistent intra-hepatic right umbilical vein was predictive of a congenital anomaly or an adverse neonatal outcome (p < 0.001), with a positive predictive value of 44.0 % (95 % confidence interval[ CI]: 30.0 % to 58.7 %).  An isolated persistent intra-hepatic right umbilical vein had a 0.4 % risk for a congenital anomaly or an adverse neonatal outcome.  The authors concluded that a persistent intra-hepatic right umbilical vein should prompt an extended anatomic survey and a fetal cardiac evaluation.  If the survey and cardiac anatomy are reassuring, no further follow-up is needed. If additional findings are identified, genetic counseling and invasive testing should be considered.

Kumar et al (2016) appraised the incidence and significance of persistent right umbilical vein (PRUV), the most common fetal venous aberration.  Based on a South Indian antenatal cohort, these researchers identified 23 cases of PRUV amongst 20,452 fetuses of consecutive pregnancies, from 2009 to 2014, yielding an incidence of 1 in 889 total births (0.11 %).  The median maternal age was 24 (inter-quartile range [IQR], 22 to 26) years, and median gestational age at diagnosis was 23 (IQR, 22 to 24) weeks.  Intra-hepatic drainage of PRUV was seen in 91.3 % cases.  In 3 cases (13 %), ductus venosus was absent.  In 52.2 % of the cases, additional major abnormalities were observed - predominantly cardiovascular (39.1 %).  The common minor marker was single umbilical artery (SUA; 13 %).  The karyotype was found to be normal in 6 cases (26 %) that underwent invasive testing.  When associated anomalies were inconsequential or absent, the post-natal outcome was good, which reflected in 60.9 % of these cases.  Fetal echocardiography was one of the keywords listed in this study.

In a prospective, observational study, Hill et al (1994) reviewed their experience with antenatal detection and subsequent neonatal outcome of fetuses with a persistent right umbilical vein.  A total of 33 cases of persistent right umbilical vein were detected during 15,237 obstetric ultrasound examinations performed after 15 weeks' gestation.  Persistent right umbilical vein was detected at a rate of 1 per 476 obstetric ultrasound examinations; 6 of 33 (18.2 %) fetuses with a persistent right umbilical vein had additional important congenital malformations.  The authors concluded that careful 2nd- and 3rd-trimester ultrasound examinations can detect a persistent right umbilical vein.  When this particular anomaly is detected, a thorough fetal anatomic survey, including echocardiography, should be performed to rule out more serious congenital malformations.

Wolman et al (2002) conducted a prospective evaluation of the incidence and neonatal outcome of fetuses with persistent right umbilical vein.  This condition had traditionally been considered to be extremely rare and to be associated with a very poor neonatal prognosis, but later evidence has raised some doubts about the veracity of these contentions.  Between August 1995 and November 1998, a total of 8,950 low-risk patients were prospectively evaluated at 2 medical centers.  The sonographic diagnosis of a persistent right umbilical vein was made in a transverse section of the fetal abdomen when the portal vein was curved toward the stomach, and the fetal gall bladder was located medially to the umbilical vein.  Persistent right umbilical vein was detected in 17 fetuses during the study; 4 of them had additional malformations, of which 3 had been detected antenatally.  The authors established that the incidence of persistent right umbilical vein in a low-risk population was 1:526.  They believed that the sonographic finding of this anomaly was an indication for conducting targeted fetal sonography and echocardiography.  When the persistent right umbilical vein was connected to the portal system and other anomalies were ruled out, the prognosis can generally be expected to be favorable.

Martínez et al (2012) described the ultrasound findings, maternal and perinatal variables in cases with a prenatal diagnosis of persistence of right umbilical vein. This was a descriptive analysis of cases with prenatal diagnosis of persistence of right umbilical vein in the Fetal Medicine Unit, Department of Obstetrics and Gynecology, Hospital Universitario Severo Ochoa.  These investigators described ultrasound findings, maternal and perinatal variables.  They examined 9,198 fetuses and 6 cases (0.06 %) were diagnosis prenatally of persistent right umbilical vein, between 20 and 29 weeks of gestation.  The male/female ratio was 1/1.  Ductus venosus was presented in all cases; 2  fetuses (33 %) were proved to have other structural anomalies and their parents opted for termination of the pregnancy.  All cases had no chromosomal anomaly associated and after birth, neonatal developments were favorable.  The authors concluded that based on these findings and a literature review, after prenatal diagnosis of persistent right umbilical vein, an exhaustive morphological study, which included a fetal echocardiography, is mandatory in order to rule out other structural malformations.  Indication for fetal karyotype study has to be individualized considering persistence right umbilical vein type and other ultrasound findings.

A single umbilical artery (SUA) is present in 0.2 % to 0.6 % of live births, occurring more frequently in twins and in small for gestational age and premature infants.  In infants with SUA, there is an increased rate of chromosomal and other congenital anomalies.  Studies have shown that 20 % to 30 % of neonates with SUA had major structural anomalies, frequently involving multiple organs (Palazzi and Brandt, 2009; Thummala et al, 1998).  The most commonly affected organ is the heart.  Single umbilical artery is an isolated finding in the remaining 70 % to 80 % of infants.

Conception by in vitro fertilization (IVF) or intra-cytoplasmic sperm injection (ICSI) has been associated with an increased incidence of fetal heart defects.  A meta-analyses on the prevalence of birth defects in infants conceived following IVF and/or ICSI compared with spontaneously conceived infants reported a 30 % to 40 % increased risk of birth defects associated with IVF and/or ICSI (Hansen et al, 2005).  Researchers have reported that infants conceived with the use of IVF and/or ICSI have a 2-to-4-fold increase of heart malformations compared with naturally conceived infants.

Kurinczuk and Bower (1997) examined the prevalence of birth defects on 420 liveborn infants who were conceived after ICSI in Belgium compared with 100,454 liveborn infants in Western Australia delivered during the same period.  Infants born after ICSI were twice as likely as Western Australian infants to have a major birth defect [odds ratio (OR) 2.03, 95 % confidence interval (CI): 1.40 to 2.93); p = 0.0002] and nearly 50 % more likely to have a minor defect (OR 1.49 (0.48 to 4.66); p = 0.49).  Secondary data-led analyses found an excess of major cardiovascular defects (OR 3.99).

Koivurova et al (2002) evaluated the neonatal outcome and the prevalence of congenital malformations in children born after IVF in northern Finland in a population-based study with matched controls.  Children born after IVF (n = 304) in 1990 to1995 were compared with controls (n = 569), representing the general population in proportion of multiple births, randomly chosen from the Finnish Medical Birth Register (FMBR) and matched for sex, year of birth, area of residence, parity, maternal age and social class.  Plurality matched controls were randomly chosen from the FMBR and analyzed separately.  Additionally, IVF singletons were compared with singleton controls. The prevalence of heart malformations was four-fold in the IVF population than in the controls representing the general population (OR 4.0, 95 % CI: 1.4 to 11.7). 

Reefhuis et al (2009) analyzed data from the National Birth Defects Prevention Study, a population-based, multi-center, case-control study of birth defects.  Included were mothers of fetuses or live-born infants with a major birth defect (case infants) and mothers who had live-born infants who did not have a major birth defect (control infants), delivered during the period October 1997 to December 2003.  Mothers who reported IVF or ICSI use were compared with those who had unassisted conceptions.  Among singleton births, IVF or ICSI use was associated with septal heart defects (adjusted odds ratio [aOR] = 2.1, 95 % CI: 1.1 to 4.0).

As fetal heart disease is typically associated with structural abnormalities and consequent aberrant blood flow through the heart, it is necessary to perform Doppler studies and color flow mapping when such abnormalities are detected with 2D fetal echocardiography.

The American College of Obstetricians and Gynecologists' Committee Opinion on the treatment with selective serotonin reuptake inhibitors during pregnancy (ACOG, 2006) noted that paroxetine use among pregnant women and women planning pregnancy should be avoided, if possible.  Fetal echocardiography should be considered for women who were exposed to paroxetine in early pregnancy.

In a practice bulletin on screening for fetal chromosomal anomalies, ACOG (2007) has stated that patients who have a fetal nuchal translucency measurement of 3.5 mm or greater in the first trimester, despite a negative result on an aneuploidy screen, normal fetal chromosomes, or both, should be offered a targeted ultrasound examination, fetal echocardiogram, or both, because such fetuses are at a significant risk for non-chromosomal anomalies, including congenital heart defects, abdominal wall defects, diaphragmatic hernias, and genetic syndromes.

Twin-twin transfusion syndrome (TTTS) is a severe complication of monochorionic (1 placenta) twin pregnancies, characterized by the development of unbalanced chronic blood transfer from one twin, defined as donor twin, to the other, defined as recipient, through placental anastomoses.  If left untreated, TTTS is associated with very high peri-natal mortality and morbidity rates; and fetuses who survive are at risk of severe cardiac, neurological, and developmental disorders.

The American Society of Echocardiography's guidelines and standards for performance of the fetal echocardiogram (Rychik et al, 2004) stated that multiple gestation and suspicion of TTTS is an indication of fetal echocardiography.

Bahtiyar et al (2007) noted that congenital heart defects (CHDs) affect approximately 0.5 % of all neonates.  Recent literature points to a possible increase in the CHD prevalence among monochorionic/diamniotic (MC/DA) twin gestations.  These researchers hypothesized that MC/DA twin pregnancy is a risk factor for CHD.  A systematic review of all published English literature was conducted on MEDLINE (Ovid and PubMed) from January 2000 through April 2007 using the medical subject heading terms "congenital heart defect" and "monozygotic twins".  Four observational studies were included in the final analysis.  Published historical data were used for the population background risk of CHD.  Relative risk (RR) estimates with 95 % confidence intervals (CIs) were calculated by fixed and random effect models.  These investigators included a total of 40 fetuses with CHDs among 830 fetuses from MC/DA twin gestations.  Compared with the population, CHDs were significantly more prevalent in MC/DA twins regardless of the presence of TTTS (RR, 9.18; 95 % CI: 5.51 to 15.29; p < 0.001).  Monochorionic/diamniotic twin gestations affected by TTTS were more likely to be complicated by CHDs than those that did not have TTTS (RR, 2.78; 95 % CI: 1.03 to 7.52; p = 0.04).  Ventricular septal defects were the most frequent heart defects.  Pulmonary stenosis and atrial septal defects were significantly more prevalent in pregnancies complicated with TTTS.  The authors concluded that MC/DA twin gestation appears to be a risk factor for CHDs.  Conditions that lead to abnormal placentation may also contribute to abnormal heart development, especially in MC/DA twin pregnancies complicated with TTTS.  Fetal echocardiography may be considered for all MC/DA twin gestations because ventricular septal defects and pulmonary stenosis are the most common defects.

The Royal College of Obstetricians and Gynaecologists' clinical practice guidelines on "Management of monochorionic twin pregnancy" (RCOG, 2008) stated that a fetal echocardiographic assessment should be considered in the assessment of severe TTTS.

Pregnant Women Receiving Selective Serotonin Reuptake Inhibitors

Reefhuis and colleagues (2015) followed up on previously reported associations between peri-conceptional use of selective serotonin reuptake inhibitors (SSRIs) and specific birth defects using an expanded dataset from the National Birth Defects Prevention Study.  These researchers performed a Bayesian analysis combining results from independent published analyses with data from a multi-center population based case-control study of birth defects.  A total of 17,952 mothers of infants with birth defects and 9,857 mothers of infants without birth defects, identified through birth certificates or birth hospitals, with estimated dates of delivery between 1997 and 2009 were included in this analysis; exposures were citalopram, escitalopram, fluoxetine, paroxetine, or sertraline use in the month before through the 3rd month of pregnancy.  Posterior OR estimates were adjusted to account for maternal race/ethnicity, education, smoking, and pre-pregnancy obesity.  Main outcome measure was 14 birth defects categories that had associations with SSRIs reported in the literature.  Sertraline was the most commonly reported SSRI, but none of the 5 previously reported birth defects associations with sertraline was confirmed.  For 9 previously reported associations between maternal SSRI use and birth defect in infants, findings were consistent with no association.  High posterior ORs excluding the null value were observed for 5 birth defects with paroxetine (anencephaly 3.2, 95 % CI: 1.6 to 6.2; atrial septal defects 1.8, 95 % CI: 1.1 to 3.0; right ventricular outflow tract obstruction defects 2.4, 95 % CI: 1.4 to 3.9; gastroschisis 2.5, 95 % CI: 1.2 to 4.8; and omphalocele 3.5, 95 % CI: 1.3 to 8.0) and for 2 defects with fluoxetine (right ventricular outflow tract obstruction defects 2.0, 95 % CI: 1.4 to 3.1 and craniosynostosis 1.9, 95 % CI: 1.1 to 3.0).  The authors concluded that these data provided reassuring evidence for some SSRIs; but suggested that some birth defects occurred 2 to 3.5 times more frequently among the infants of women treated with paroxetine or fluoxetine early in pregnancy.

A 2015 study by the Centers for Disease Control and Prevention (CDC) used new data to examine previous reported links between use of specific SSRIs medications just before or during early pregnancy and the occurrence of certain birth defects.  Researchers looked at links with 5 different SSRI medications: citalopram, escitalopram, fluoxetine, paroxetine, and sertraline.  Although the new data confirmed the risks seen with paroxetine, it did not appear to suggest that the risk is across the board with all SSRIs.  Therefore, fetal echocardiography is still recommended for women exposed to paroxetine, but there doesn’t seem to be enough evidence to recommend coverage of fetal echocardiograms for all pregnant members receiving any SSRI.  The study concluded that despite the increased risks for certain birth defects from some SSRIs found in this study, the actual risk for a birth defect among babies born to women taking one of these medications is still very low.  Because these specific types of birth defects are rare, even doubling the risk still results in a low absolute risk.  For example, the risks for heart defects with obstruction of the right ventricular outflow tract could increase from 10 per 10,000 births to about 24 per 10,000 births among babies of women who are treated with paroxetine early in pregnancy. 

Fetal Magnetocardiography

Fetal magnetocardiography (fMCG) is a new, non-invasive technique used to monitor the spontaneous electrophysiological activity of the fetal heart.  Hrtankova and associates (2015) reviewed the evidence on the clinical value of fMCG.  These investigators performed an analysis of the literature using database search engines PubMed, and SCOPE in field of fMCG.  Compared to cardiotocography and fetal electrocardiography, fMCG is a more effective method with a higher resolution.  The signal obtained from the fetal heart is sufficiently precise and the quality allows an assessment of PQRST complex alterations, and to detect fetal arrhythmia.  Thanks to early diagnosis of fetal arrhythmia, there is the possibility for appropriate therapeutic intervention and the reduction of unexplained fetal death in late gestation.  These investigators also noted that fMCG with high temporal resolution also increased the level of clinical trials that recorded fetal heart rate (FHR) variability.  According to the latest theories, FHR variability is a possible indicator of fetal status and enabled the study of the fetal autonomic nervous system indirectly. The authors concluded that fMCG is an experimental method that requires expensive equipment; it has yet to be shown in the future if this method will get any application in clinical practice.

Eswaran and colleagues (2017) stated that fMCG provides the requisite precision for diagnostic measurement of electrophysiological events in the fetal heart.  Despite its significant benefits, this technique with current cryogenic based sensors has been limited to few centers, due to high cost of maintenance.  In this study, these researchers demonstrated that a less expensive non-cryogenic alternative, optically pumped magnetometers, can provide similar electrophysiological and quantitative characteristics when subjected to direct comparison with the current technology.  They concluded that further research can potentially increase its clinical use for fMCG.

Furthermore, an UpToDate review on "Overview of the general approach to diagnosis and treatment of fetal arrhythmias" (Levine and Alexander, 2017) states that "Magnetocardiography shifts the electrical signals into an evoked magnetic signal that can be processed to create a beat-to-beat magnetocardiogram that looks much like a traditional electrocardiogram (ECG).  Continuous recordings can be performed for relatively sustained periods and have permitted elegant demonstration of arrhythmia onset/offset and more direct observation of mechanisms.  The equipment is not widely available, requires careful shielding and requires skilled technical support, so the technology remains investigational".

Fetal Surveillance in Sjögren’s Syndrome

Gupta and Gupta (2017) state that studies show a high incidence of poor fetal outcomes for women with Sjögren’s syndrome; however pregnancy outcomes in these women have not been extensively studied. The authors conducted a literature review to evaluate Sjögren’s syndrome and pregnancy.  Gupta and Gupta found that well-known fetal outcomes in Sjögren syndrome-complicated pregnancies include neonatal lupus and congenital heart block (CHB), of which CHB is the most severe fetal complication. CHB is thought to occur because of damage to the atrioventricular node by anti-SS-A or anti-SS-B antibodies, or both. The reported prevalence of CHB in the offspring of an anti-SS-A-positive woman is 1% to 2%. The recurrence rate in a patient with antibodies, who has a previous child affected, is approximately 10 times higher. Based on Gupta’s review, frequent surveillance by serial echocardiograms and obstetric sonograms between 16 to 20 weeks of gestation and thereafter is required for at-risk pregnancies, with the goal of early diagnosis and early treatment of incomplete CHB, thus improving the outcome for the fetus.

Although there are no formal guidelines for type or frequency of testing to detect fetal heart block, it is recommended that pregnant women with Sjögren’s syndrome receive weekly pulsed Doppler fetal echocardiography from the 18th through the 26th week of pregnancy and then every other week until 32 weeks. "The most vulnerable period for the fetus is during the period from 18 to 24 weeks gestation. Normal sinus rhythm can progress to complete block in seven days during this high-risk period. New onset of heart block is less likely during the 26th through the 30th week, and it rarely develops after 30 weeks of pregnancy" (eviCore, 2018).

A scientific statement from the American Heart Association by Donofrio et al. (2014) states that maternal factors of Sjögren’s syndrome are associated with the absolute risk of 1 to 5 percent of live births that will have congenital heart block (CHB), risk increases to 11 to 19 percent for prior affected child with CHB or neonatal lupus. It is recommended that fetal echocardiography be performed at 16 weeks, then weekly or every other week to 28 weeks. The authors state that studies have suggested that high SSA values (≥50 U/mL) correlate with increased fetal risk, and that concern for late myocardial involvement may justify additional assessments in the third trimester. In addition to abnormalities in the conduction system, up to 10% to 15% of SSA-exposed fetuses with conduction system disease may also develop myocardial inflammation, endocardial fibroelastosis, or  atrioventricular (AV) valve apparatus dysfunction. "Although the value of serial assessment for the detection of the progression of myocardial inflammation or conduction system disease from first-degree block (PR prolongation) to CHB has not been proved, serial assessment at 1- to 2-week intervals starting at 16 weeks and continuing through 28 weeks of gestation is reasonable to perform because the potential benefits outweigh the risks. For women who have had a previously affected child, more frequent serial assessment, at least weekly, is recommended."

Fetal Surveillance in Autoimmune Antibodies Anti-Ro/Sjögren’s Syndrome Antigen A (SSA) or Anti-La/Sjögren’s Syndrome Antigen B (SSB)

Friedman et al (2008) state that anti-SSA/Ro-associated third-degree congenital heart block is irreversible, prompting a search for early markers and effective therapy. One hundred twenty-seven pregnant women with anti-SSA/Ro antibodies were enrolled; 95 completed an evaluable course in 98 pregnancies. The protocol included fetal echocardiograms performed weekly from 16 to 26 weeks' gestation and biweekly from 26 to 34 weeks. PR intervals >150 ms were considered prolonged, consistent with first-degree block. Ninety-two fetuses had normal PR intervals. Neonatal lupus developed in 10 cases; 4 were neonatal lupus rash only. Three fetuses had third-degree block; none had a preceding abnormal PR interval, although in 2 fetuses >1 week elapsed between echocardiographic evaluations. Tricuspid regurgitation preceded third-degree block in 1 fetus, and an atrial echodensity preceded block in a second. Two fetuses had PR intervals >150 ms. Both were detected at or before 22 weeks, and each reversed within 1 week with 4 mg dexamethasone. The ECG of 1 additional newborn revealed a prolonged PR interval persistent at 3 years despite normal intervals throughout gestation. No first-degree block developed after a normal ECG at birth. Heart block occurred in 3 of 16 pregnancies (19%) in mothers with a previous child with congenital heart block and in 3 of 74 pregnancies (4%) in mothers without a previous child with congenital heart block or rash (P=0.067). The authors concluded that prolongation of the PR interval was uncommon and did not precede more advanced block. There was a trend toward more congenital heart block in fetuses of women with previously affected offspring than those without previously affected offspring. Advanced block and cardiomyopathy can occur within 1 week of a normal echocardiogram without initial first-degree block. Echodensities and moderate/severe tricuspid regurgitation merit attention as early signs of injury.

A scientific statement from the American Heart Association (Donofrio et al, 2014) states that "referral for fetal cardiac evaluation is reasonable for maternal conditions including SSA/SSB-autoantibodies without a previously affected child (Class IIA; Level of Evidence B)". "Because of the perception that the inflammatory effects resulting from antibody exposure may be preventable if detected and treated at an early stage, it has been recommended that SSA/SSB-positive women be referred for fetal echocardiography surveillance beginning in the early second trimester (16–18 weeks)." "Although the value of serial assessment for the detection of the progression of myocardial inflammation or conduction system disease from first-degree block (PR prolongation) to CHB has not been proved, serial assessment at 1- to 2-week intervals starting at 16 weeks and continuing through 28 weeks of gestation is reasonable to perform because the potential benefits outweigh the risks. For women who have had a previously affected child, more frequent serial assessment, at least weekly, is recommended."

Hansahiranwadee (2020) states “Autoimmune congenital atrioventricular block (CAVB) has been extensively studied in recent decades. The American Heart Association published guidelines for monitoring pregnant women with anti-Ro/Sjögren’s syndrome antigen A (SSA) or anti-La/Sjögren’s syndrome antigen B (SSB) autoantibodies, which are considered to increase the risk of CAVB. Information about the natural history of the disease in utero has contributed to the detection of fetuses with CAVB in the treatable stage. Hydroxychloroquine (HCQ) may be used to prevent CAVB. The lack of large randomized control trials is a major drawback to fully confirm the benefits of fluorinated steroids such as dexamethasone. Although, when combined with a β-sympathomimetic agent, the outcome of administering a fluorinated steroid in complete CAVB is still controversial. Novel treatments targeting the immunological process might prevent the recurrence of CAVB in pregnant women with previously affected children.”

Keller et al (2023) state that anti-Ro antibody-mediated endocardial fibroelastosis (EFE) without atrioventricular (AV) block at presentation is a rare cardiac phenotype. The authors “present 11 fetuses with this rare presentation of anti-Ro-mediated cardiac involvement presenting as a distinctive echocardiographic phenotype pattern of EFE. Eleven fetuses with isolated EFE at presentation were included from four cardiac centers, and experienced fetal cardiologists reached consensus around EFE location in the presenting echocardiogram; interval changes to subsequent fetal and postnatal echocardiograms were assessed for response to therapy. Echocardiographic markers of cardiac performance, including diastolic function and AV conduction, were reviewed. 10/11 fetuses was found to have EFE of the aortic root, proximal aorta, and/or LVOT, 10/11 of the pulmonary root, artery, and/or RVOT; 7/11 had atrial involvement, 6/11 had involvement of the crux. 4/11 cases had known anti-Ro antibody status prior to diagnosis, in seven the echo findings prompted testing and resulted positive. In all cases the AV interval at presentation was normal; one fetus subsequently developed AV block. Nine cases were treated with transplacental dexamethasone, five subjects also received intravenous immune globulin (IVIG); one received IVIG alone. Of the nine treated cases with serial imaging, five had improvement in EFE and in four the severity was unchanged. All patients were liveborn. In [their] cohort, EFE involvement of the aortic and pulmonary arteries and outflow tracts was nearly universal, and involvement of the atria and the crux of the heart was also common. High survival and low burden of AV block is also suggestive of a phenotype of anti-Ro-mediated cardiac disease with a favorable prognosis”.

An UpToDate review on "Congenital heart disease: Prenatal screening, diagnosis, and management" (Copel, 2023) states that fetal echocardiography indications with a high-risk profile (estimated greater than 2% absolute risk) include maternal autoantibodies (SSA/SSB), especially if a previous child had SSA/SSB-related heart disease.

An UpToDate review on "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis" (Buyon, 2022) states that "More intensive monitoring during pregnancy, with frequent fetal echocardiographic surveillance, has been advised for individuals who test positive for Ro/SSA and La/SSB autoantibodies since detection of heart block at earlier stages may improve outcomes".

Fetal Echocardiography for Prediction of Fetal Demise After Laser Coagulation for Twin-Twin Transfusion Syndrome

In a systematic review and meta-analysis, Gijtenbeek and colleagues (2019) examined the value of echocardiography and Doppler before fetoscopic laser coagulation for TTTS in the prediction of intra-uterine fetal demise (IUFD).  These investigators compared pre-operative parameters between fetuses with and without demise following laser surgery.  A total of 18 studies were included.  Recipient twins have an increased risk of demise in case of pre-operative absent/reversed flow (A/REDF) in the umbilical artery (OR 2.76, 95 % CI: 1.78 to 4.28), absent or reversed a-wave in the ductus venosus (OR 2.32, 95 % CI: 1.70 to 3.16), or a middle cerebral artery peak systolic velocity of greater than 1.5 multiples of the median (MoM) (OR 7.59, 95 % CI: 2.56 to 22.46).  In donors, only A/REDF in the umbilical artery (OR 3.40, 95 % CI: 2.68 to 4.32) and absent or reversed a-wave in the ductus venosus (OR 1.66, 95 % CI: 1.12 to 2.47) were associated with IUFD.  No association was found between donor-IUFD and pre-operative myocardial performance index (MPI).  Two studies found an association between abnormal MPI and recipient demise.  With this study, these researchers identified a set of pre-operative Doppler parameters predictive of fetal demise following laser surgery.  The authors concluded that the utility of pre-operative parameters that reflect cardiac function such as the MPI in predicting IUFD remains unclear; more research is needed to examine the utility of pre-operative echocardiographic parameters such as the MPI in predicting IUFD.

The authors stated that this was the first review and meta‐analysis of pre-operative echocardiography and Doppler in the prediction of IUFD following fetoscopic laser surgery.  To maximize the sample size, these researchers included all studies that examined fetal demise before birth, not only early‐IUFD (less than 7 days).  Other causes of demise such as placental insufficiency or IUGR could therefore have influenced these findings, even though the majority of IUFD following laser occurred in the 1st week after laser surgery.  Other drawbacks of this study included the following: Most studies were single-center reports, 50 % of the reports were retrospective studies.  In all but 1 study, selective coagulation was used for all or for a proportion of cases.  It is known that incomplete laser coagulation is a risk factor for recurrent TTTS or post‐laser twin anemia polycythemia sequence (TAPS) and therewith for possible subsequent fetal demise.  Finally, these investigators did not include fetal growth discordance, selective fetal growth restriction (sFGR), or TAPS prior to laser surgery in this study.  They noted that future large‐scale prospective studies could allow for multi-variate analysis into the interference of sFGR and TAPS on fetal echocardiography and Doppler parameters for IUFD.  Incorporating signs of sFGR or TAPS, and factors such as Quintero stage, hydrops, and gestational age at TTTS diagnosis, into a prediction model together with the before‐mentioned Doppler parameters could be useful in daily clinical care in cases where the risk of fetal demise turns out to be high, to spend additional counseling time on cord occlusion as a back‐up plan if laser surgery appears technically challenging.  A prediction model could also be useful in future clinical trials investigating innovations in treatment of TTTS.

Absence of the Ductus Venosus

Durakovic et al (2005) noted that congenital absence of the ductus venosus is a rare anomaly in the fetus.  These investigators examined the clinical and ultrasonographic (US) features and outcome of the fetuses with ductus venosus agenesis.  They described 12 cases in the period between 1992 and 2004.  The umbilical vein drained either into the right atrium directly (2 cases) or by the coronary sinus (1 case), or in the inferior vena cava (5 cases), or in the azygos vein (1 case), or in the portal vein (3 cases).  These data were analyzed with the cases published in the literature.  Two groups of anastomoses were defined on the basis of the hemodynamic consequences: the group of extra-hepatic anastomoses (53 cases) and the group of intra-hepatic anastomoses (22 cases).  In the group of extra-hepatic anastomoses, cardiomegaly was the most common ante-natal finding (39 %), while in the intra-hepatic group hydrops fetalis occurred most frequently (23 %).  Malformation rate was high in both groups (56 % and 45 %) and chromosomal anomalies were present in 9 % of cases.  The authors concluded that careful assessment of the umbilical venous return and the ductus venosus should be a part of examination of every fetus with cardiomegaly, polyhydramnios, ascites or hydrops.  In case of absence of the ductus venosus a referral scan, a fetal echocardiography and a karyotype should be performed.

Madrid-Pinilla et al (2022) stated that a fetal echocardiogram, in a 27-week fetus referred for cardiomegaly, demonstrated dextrocardia, absence of the ductus venosus, and an unrestricted unusual umbilical venous drainage to a left posterior intercostal vein, which continued to the left hemiazygos vein and drained into the coronary sinus.  Progressive cardiomegaly led to early delivery.  The authors concluded that to their best knowledge, no case with similar umbilical venous drainage has been previously reported.

Furthermore, an UpToDate review on “Fetal growth restriction: Evaluation and management” (Mari, 2022) states that “Triploidy of maternal origin is characterized early, severe asymmetrical FGR and triploidy of paternal origin is characterized by mild FGR with either proportionate head size or slight microcephaly.  Most fetuses have structural anomalies, most commonly involving the brain, heart, and limbs.  A fetal echocardiogram is indicated if results of an expert (level II) ultrasound examination suggest any uncertainty that the heart is normal”.

Modafinil (Provigil) Exposure in Pregnancy

There is insufficient evidence to support the use of fetal echocardiography for modafinil (Provigil) exposure in pregnancy.

The Prescribing Information of modafinil (Provigil)

Pregnancy:

Based on animal data, may cause fetal harm.

Pregnancy Category C:

There are no adequate and well-controlled studies of modafinil in pregnant women.  Intrauterine growth restriction and spontaneous abortion have been reported in association with modafinil (a mixture of R- and S-modafinil) and armodafinil (the R-enantiomer of modafinil).  Although the pharmacology of modafinil is not identical to that of the sympathomimetic amines, it does share some pharmacologic properties with this class.  Certain of these drugs have been associated with intrauterine growth restriction and spontaneous abortions.  Whether the cases reported with modafinil are drug-related is unknown.  In studies of modafinil and armodafinil conducted in rats (modafinil, armodafinil) and rabbits (modafinil), developmental toxicity was observed at clinically relevant plasma exposures.  PROVIGIL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Modafinil (50, 100, or 200 mg/kg/day) administered orally to pregnant rats throughout organogenesis caused, in the absence of maternal toxicity, an increase in resorptions and an increased incidence of visceral and skeletal variations in the offspring at the highest dose tested.  The higher no-effect dose for embryofetal developmental toxicity in rats (100 mg/kg/day) was associated with a plasma modafinil AUC less than that in humans at the recommended human dose (RHD) of PROVIGIL (200 mg/day).  However, in a subsequent study of up to 480 mg/kg/day of modafinil, no adverse effects on embryofetal development were observed.  Oral administration of armodafinil (60, 200, or 600 mg/kg/day) to pregnant rats throughout organogenesis resulted in increased incidences of fetal visceral and skeletal variations and decreased fetal body weight at the highest dose tested.  The highest no-effect dose for embryofetal developmental toxicity in rats (200 mg/kg/day) was associated with a plasma armodafinil AUC less than that in humans at the RHD of PROVIGIL. 

Modafinil administered orally to pregnant rabbits throughout organogenesis at doses of up to 100 mg/kg/day had no effect on embryofetal development; however, the doses used were too low to adequately assess the effects of modafinil on embryofetal development.  In a subsequent developmental toxicity study evaluating doses of 45, 90, and 180 mg/kg/day in pregnant rabbits, the incidences of fetal structural alterations and embryofetal death were increased at the highest dose.  The highest no-effect dose for developmental toxicity (100 mg/kg/day) was associated with a plasma modafinil AUC similar to that in humans at the RHD of PROVIGIL. 

Modafinil administration to rats throughout gestation and lactation at oral doses of up to 200 mg/kg/day resulted in decreased viability in the offspring at doses greater than 20 mg/kg/day, a dose resulting in a plasma modafinil AUC less than that in humans at the RHD of PROVIGIL.  No effects on postnatal developmental and neurobehavioral parameters were observed in surviving offspring. 

Pregnancy Registry:

A pregnancy registry has been established to collect information on the pregnancy outcomes of women exposed to PROVIGIL.  Healthcare providers are encouraged to register pregnant patients, or pregnant women may enroll themselves in the registry by calling 1-866-404-4106 (toll free).

Furthermore, an UpToDate review on “Treatment of narcolepsy in adults” (Scammell, 2022) states that “Modafinil/armodafinil -- A pregnancy registry reported an elevated rate of major congenital anomalies (17 %) and cardiac anomalies (4 %) among women in the United States exposed to modafinil and/or armodafinil (some took additional drugs).  Based on these and other data, Health Canada updated product labeling in 2019 to include a warning that modafinil is contraindicated in women who are pregnant or may become pregnant.  Subsequent registry data from other countries have reported conflicting results, and more studies are needed”.

Fetal Echocardiography If there is Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Use During the Late Second or Third Trimester

The Prescribing Information for Indocin notes that “Use of NSAIDs, including Indomethacin Capsules, USP, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus.  Avoid use of NSAIDs, including Indomethacin Capsules, USP, in pregnant women starting at 30 weeks of gestation (third trimester)”. 

Furthermore, American Heart Association (AHA)’s scientific statement on “Diagnosis and treatment of fetal cardiac disease” (Donofrio et al, 2014) recommended the use of fetal echocardiography if there is NSAID use during the late 2nd or 3rd trimester.

Pregnant Women with Anti-Ro and Anti-LA Antibodies

Jaeggi et al (2010) stated that autoantibody-positive mothers are often referred for serial echocardiography because of the elevated fetal risk of developing immune-mediated heart block; however, little is known why only some and not all offspring are affected.  These researchers examined if cardiac complications of neonatal lupus erythematosus (NLE) were related to maternal anti-Ro and anti-La autoantibody-levels.  All cases referred since 2000 for serial fetal echocardiography or cardiac complications related to maternal antibodies were included.  Patients without cardiac NLE (group 1) and with cardiac NLE (group 2) were compared.  Antibody levels were measured by enzyme-linked immunosorbent assay (ELISA) with a cut-off value of 8 U/ml for a positive test result.  Group 1 included 146 serially screened fetuses with normal pregnancy outcomes.  Group 2 consisted of 40 fetuses/neonates with a diagnosis of heart block or endocardial fibroelastosis (EFE) or both, and included 4 fetuses diagnosed during serial screening.  All cardiac complications were associated with moderate (greater than or equal to 50 U/ml; 15 %) or high (greater than or equal to 100 U/ml; 85 %) maternal anti-Ro levels, independently of anti-La antibody titers.  The event rate of complete heart block was 5 % for prospectively screened fetuses with Ro-values of greater than or equal to 50 U/ml (OR: 7.8) and 0 % for fetuses with lower titers (p < 0.0001).  Infants with pre-natal exposure to high-titer anti-La levels of greater than or equal to 100 U/ml were the most likely to have non-cardiac features of NLE (event rate: 57 %; OR: 4.7).  The authors concluded that these findings supported that the titer of maternal antibodies, rather than their presence, was associated with fetal tissue injury.  As anti-Ro levels correlated with the risk of cardiac complications, serial echocardiography should be limited to women with high anti-Ro-titers.

Yoshimi et al (2012) noted that anti-Ro/SSA antibodies are among the most frequently detected autoantibodies against extractable nuclear antigens and have been associated with systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS). Although the presence of these autoantibodies is one of the criteria for the diagnosis and classification of SS, they are also sometimes seen in other systemic autoimmune diseases. In the last few decades, the knowledge of the prevalence of anti-Ro/SSA antibodies in various autoimmune diseases and symptoms has been expanded, and the clinical importance of these antibodies is increasing. Nonetheless, the pathological role of the antibodies is still poorly understood. In this paper, we summarize the milestones of the anti-Ro/SSA autoantibody system and provide new insights into the association between the autoantibodies and the pathogenesis of autoimmune diseases.

These investigators stated that a recent study (Jaeggi et al, 2010) described that all cardiac complications observed in neonates were associated with moderate-to-high (50 U/ml or higher) maternal anti-Ro antibody levels, independently of anti-La antibody titers.  The event rate of congenital heart block (CHB) was 5 % for prospectively screened fetuses with high anti-Ro antibody levels (50 U/ml or higher; OR: 7.8) and 0 % for those exposed to lower titers.  On the other hand, infants with prenatal exposure to high titers of anti-La antibodies (100 U/ml or higher) were most likely to have non-cardiac manifestations of NLE, with an event rate of 57 % (OR: 4.7).  These findings suggested that the concentration of maternal autoantibodies, rather than their presence, was associated with the development of NLE; therefore, fetal echocardiography should be reserved for women with high anti-Ro antibody titers.

Brito-Zeron et al (2015) stated that autoimmune CHB is an immune-mediated acquired disease that is associated with the placental transference of maternal antibodies specific for Ro and La autoantigens.  The disease develops in a fetal heart without anatomical abnormalities that could otherwise explain the block, and which is usually diagnosed in-utero, but also at birth, or within the neonatal period.  Autoantibody-mediated damage of fetal conduction tissues causes inflammation and fibrosis and results in blockage of signal conduction at the AV node.  Irreversible complete AV block is the principal cardiac manifestation of CHB, although some babies might develop other severe cardiac complications, such as endocardial fibroelastosis or valvular insufficiency, even in the absence of cardiac block.  The advent of fetal echocardiography and the discovery of anti-Ro antibodies in the mothers of affected babies paved the way for a more specific definition of the disease currently known as autoimmune CHB.  The authors discussed the epidemiology, classification, and management of women whose pregnancies were affected by autoimmune CHB, with a particular focus on the autoantibodies associated with autoimmune CHB and how clinicians should test for these antibodies and diagnose this disease.

These investigators noted that not all mothers with CHB-affected pregnancies are diagnosed (at the same time) with a specific autoimmune disease.  In this systematic review of underlying maternal autoimmune diseases, of 856 affected mothers more than 50 % were classified as asymptomatic carriers of anti-Ro and anti-La antibodies, and approximately 14 % were classified as incomplete or undifferentiated autoimmune disease.  The remaining cases were mothers diagnosed with a specific autoimmune disease, almost all with primary SS (pSS) or SLE, or both; only 13 cases were diagnosed with other autoimmune diseases, including 5 with rheumatoid arthritis (RA).  More than 50 % the affected mothers might have been asymptomatic, as anti-Ro and anti-La antibodies can be detected several years before SLE or pSS were diagnosed.  In fact, autoimmune CHB could be one of the first “indirect” signs of pSS in women of child-bearing age.

Brooks (2015) noted that CHB is a potentially fatal condition occurring in approximately 1:10000 fetuses.  While it is well-recognized that maternal anti‐Ro and La antibodies are associated with fetal CHB, there are multiple other manifestations of fetal exposure to these autoantibodies that are not widely appreciated and rarely diagnosed.  The importance of identifying affected fetuses lies in the significantly increased risk of recurrence in future pregnancies, and the potential for treatments that may modify this risk.  The author presented several cases to highlight the varying fetal presentations of maternal anti‐Ro and La antibodies.  In case 1, the fetus was referred for fetal echocardiography which identified a structurally normal heart with no abnormally echogenic myocardium, no tricuspid or mitral valve regurgitation.  M‐mode assessment through the atrial/ventricular myocardium simultaneously and Doppler assessment of superior vena cava (SVC)/aortic flow confirmed the clinical diagnosis of CHB.  Maternal anti‐Ro antibodies were strongly positive (weakly positive anti‐La antibodies) with no clinical features to suggest maternal SLE.  The fetus was closely followed with repeat fetal echocardiography and maintained a heart rate (HR) between 55 and 65 beats/min for the remainder of pregnancy.  In case 2, the fetus was followed closely with Doppler assessment of HR and fetal well‐being scans.  Repeat fetal echocardiography at 33/40 gestation showed generalized thickening of both left and right ventricular myocardium measuring up to 5.2 mm (normal in the 2nd and 3rd trimesters approximately 0.1 mm per week of gestation, and subjectively reduced myocardial contractility (fractional shortening 43 %)).  There was borderline cardiomegaly.  The fetal HR was approximately 105 beats/min with up to 1:3 beats being blocked.  Maternal dexamethasone was started 8 mg daily for the 1st week and then reduced to 4 mg daily.

Tonello et al (2017) stated that CHB is an auto-antibody-mediated disorder presumably caused by placental transmission of maternal auto-antibodies to Ro/SSA 52 kd, p200, Ro/SSA 60 kd, La/SSB ribonucleo-proteins.  These investigators examined the clinical significance of isolated anti-Ro/SSA 52 kd, anti-p200, anti-Ro/SSA 60 kd, and anti-La/SSB antibodies in positive pregnant patients.  A total of 163 pregnant women positive to anti-Ro/SSA 52 kd and/or anti-Ro/SSA 60 kd and/or anti-La/SSB antibodies were prospectively enrolled in the study.  Anti-Ro52, anti-Ro60, anti-p200, and anti-La antibodies were assayed using home-made ELISA assays.  Isolated antibody positivity was found in 25 women (15.3 %), while multiple antibody positivity in 138 (84.7 %); 24 subjects developed CHB, and the remaining 139 had a favorable pregnancy outcome.  The prevalence of isolated anti-Ro/SSA 60 kd antibodies was significantly higher (p < 0.046) as the prevalence of lower mean antibody titers (p < 0.0001) in the latter group.  The authors concluded that confirmation of these findings by large-scale studies could lead clinicians to recommend less stringent fetal echocardiography monitoring in women with isolated anti-Ro/SSA 60 kd antibodies.

Brito-Zeron et al (2020) characterized autoimmune CHB associated with a maternal diagnosis of pSS confirmed either before, concomitant or following the 1st pregnancy complicated with CHB.  The following inclusion criteria were applied: Mothers with positive Ro/La auto-antibodies detected previously or at the time of diagnosis of the 1st case of CHB; diagnosis of CHB confirmed by fetal echocardiography; AV block diagnosed in uterus, at birth, or within the neonatal period (0 to 27 days after birth); absence of anatomical cardiac abnormalities which might be causal of AV block; and maternal fulfillment of the 2002 SS criteria before, during, or after having a pregnancy complicated with CHB.  These investigators identified 49 cases of autoimmune CHB in children born from 44 mothers who had a mean age at the time of pregnancy of 30.3 years (range of 18 to 41 years).  At the time of diagnosis of autoimmune CHB, all mothers had positive anti-Ro antibodies and 28/44 (64 %) were positive for anti-La antibodies.  Only 10 (22 %) mothers with affected pregnancies had a diagnosis of primary SS at the time of diagnosis of the 1st pregnancy complicated by CHB (a mean of 4 years before, ranging from 1 to 10 years).  In 6 (14 %) mothers, primary SS was diagnosed during pregnancy or less than 12 months after the delivery/termination.  In the remaining 28 (64 %) mothers, pSS was confirmed 1 to 5 years after CHB diagnosis (n = 19, 68 %), 6 to 10 years after (n = 2, 7 %), or more than 10 years after the 1st case of CHB was diagnosed (n = 7, 25 %).  CHB was diagnosed in uterus in all cases but 2.  AV block was initially incomplete in 11 fetuses and complete in 36 (no available data in 2 cases).  Among the 35 (71 %) surviving children with CHB, 5 (14 %) developed other features of NLE.  After the index pregnancy, 12 women had 20 subsequent pregnancies: 5 were complicated by a CHB (recurrence rate of CHB of 25 %).  The 4 women who had recurrent CHB were double-positive for anti-Ro and anti-La antibodies, and all had a confirmed pSS before having the 1st index case of CHB.  The authors concluded that in pSS, autoimmune CHB could be one of the first "indirect" signs of the disease in women of child-bearing age, in whom the diagnosis was confirmed several years later.  Some maternal characteristics could be related with recurrent CHB, such as having an already-confirmed diagnosis of pSS and carrying the 2 Ro/La autoantibodies.

Furthermore, an UpToDate review on “The anti-Ro/SSA and anti-La/SSB antigen-antibody systems” (Bloch, 2023) states that “Women with anti-Ro (with or without co-occurring anti-La) autoantibodies are at increased risk for having a child with neonatal lupus syndrome.  Anti-Ro antibodies may be the only autoantibodies present in more than half of the patients with "antinuclear antibody (ANA)-negative" SLE.  The combination of anti-Ro and anti-La antibodies is relatively specific for the diagnoses of SLE and Sjogren's disease”.

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Appendix

Documentation Requirements for Fetal Echocardiography

According to guidelines from the American Institute for Ultrasound in Medicine (AIUM), fetal echocardiography should include the following cardiac images:

• Aortic arch;
• Ductal arch;
• Four-chamber view;
• Inferior vena cava;
• Left ventricular outflow tract;
• Right ventricular outflow tract;
• Short-axis views ("low" for ventricles and "high" for outflow tracts);
• Superior vena cava; and
• Three-vessel and trachea view.

According to the 2013 AIUM's practice parameter for the "Performance of Fetal Echocardiography", indications for fetal echocardiography are often based on a variety of parental and fetal risk factors for congenital heart disease.  However, most cases are not associated with known risk factors.  Common indications for a detailed scan of the fetal heart include but are not limited to:

Maternal Indications Associated with Congenital Heart Disease

• Autoimmune antibodies [anti-Ro (SSA)/anti-La (SSB)]
• Familial inherited disorders (e.g., 22q11.2 deletion syndrome)
• In-vitro fertilization
• Metabolic disease (e.g., diabetes mellitus and phenylketonuria)
• Teratogen exposure (e.g., lithium and retinoids)

Fetal Indications

• Abnormal cardiac screening examination
• Abnormal heart rate or rhythm
• Fetal chromosomal anomaly
• Extra-cardiac anomaly
• First-degree relative of a fetus with congenital heart disease
• Hydrops
• Increased nuchal translucency
• Monochorionic twins

This AIUM (2013) practice parameter was published in conjunction with the American College of Obstetricians and Gynecologists (ACOG), and the Society for Maternal-Fetal Medicine (SMFM), and the American Society of Echocardiography (ASE).  Furthermore, this practice parameter was endorsed by the American College of Radiology (ACR).

Source: AIUM Practice Parameter – Fetal Echocardiography (2013).

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References