Case Discussion: Holoprosencephaly*

A  28 year old *Primigravida referred to Promise Fetal Medicine Centre for NT scan at 11+3 weeks with no relevant medical or genetic history.* While performing Ultrasound, *Axial section of the head  revealed the presence of a single sickle shaped ventricle with fused thalami and absence of  characteristic Butterfly shaped choroid plexus in transverse section* ( Follow picture).

A diagnosis of Alobar variety of Holoprosencephaly was made. No other abnormality was detected. *Chorionic villus sampling was done and patient proceeded for termination after proper counselling.*

*What is Holoprosencephaly* ?

Holoprosencephaly is an abnormal development of brain which starts at 6 weeks of embryonic period. It results from Failure of the brain to divide in left and right halves thereby forming a single primitive monoventricle along with fused basal ganglia, absence of corpus callosum and falx cerebri. Other findings which are associated with Holoprosencephaly are: facial anomalies like cleft lip and palate, eye anomalies, nasal abnormalities, renal anomalies, polydactyly, cardiovascular anomalies and omphalocoele.

*How bad is the problem?* 

Most of the foetuses die  intrauterine only and  a few which are born would die in early neonatal period as the defect is associated with severe life threatening anomalies  .Overall if diagnosed the prognosis is grave and termination is the best course.

 *Why did it happen?* 

Most commonly (25-50%) are due to chromosomal problems  with Trisomy 13 being most common apart from Trisomy 18, partial Trisomy 13 and triploidy. Environmental (Diabetes), maternal alkaloids intake, radiation exposure, salicylate, methotraxate,retinoids intake have shown some association with Holoprosencephaly.

For sporadic Non-Chromosomal Holoprosencephaly, The risk of empirical recurrence is 6%. It can be part of genetic syndrome when no chromosomal association is found.

*How to diagnose it and what is the management* *?*

Alobar Holoprosencephaly is diagnosed in first trimester (i.e. during anatomical evaluation at the time of NT/NB) with close to 100% accuracy. Transverse view (with the presence of a single sickle shaped ventricle with fused thalami and absence of the characteristic Butterfly shaped choroid plexus) provide the diagnosis. It must be remembered that although termination is advised, a Fetal invasive procedure (CVS) with Appropriate Genetic test before termination would help us to *prognosticate* the next pregnancy as the *recurrence risk in subsequent pregnancies is 1 percent if it is due to a genetic  abnormality and much higher(33%)*  if either parents are carriers of a balanced translocation. If either parent has some phenotypic abnormality it could indicate an *autosomal dominant form with a recurrence risk as high as 50%.*

*Conclusion* :

*1*  *Defects like Holoprosencephaly can be diagnosed with fair accuracy in the first trimester itself during NT/NB.*

*2*  *Termination of pregnancy is the final management* .

*3*  *Fetal invasive procedure (CVS)/ Amniocentesis with Appropriate Genetic test (MicroArray preferred or minimum Karyotype ) should be offered before termination in all cases as it helps to prognosticate the next pregnancy and provide the couple with the chances of recurrence* .

*4*  *Prenatal Genetic tests are superior to post natal as culture failure rate is much higher ( 20% in post natal samples). It can be the result of improper specimen collection or transport, improper laboratory technique, or the condition of the sample* .

Case Discussion* 

*Selective Fetal reduction in Twins with one fetus discordant for Structural or Chromosomal Anomaly*

A 28yrs Primigravida presented at 12.3 weeks for  NT/NB scan and was found that she was bearing  a *dichorionic twin pregnancy with one fetus having septated cystic hygroma with omphalocoele*  . Rest markers and morphology for this affected  fetus and other fetus were absolutely  normal . *She was planned for Chorionic Villous Sampling of both foetuses* *after detailed genetic counselling  with selective reduction of anomalous foetus*

i.e. foetus with above said defects. Patient followed the advice and Selective reduction of the anomalous fetus was successfully done.

We all know that multifetal pregnancies (Triplets and beyond) can be reduced to twins for one simple reason that it improves the perinatal and obstetrical outcome.

*The other lesser known indication where fetal reduction might be of a help is when one of the twin is carrying a structural or genetic anomaly and other foetus is absolutely normal.*

*In this broadcast, PROMISE ULTRASOUND AND FETAL MEDICINE CENTRE discusses the issues related to selective feticide of foetuses with major or lethal abnormalities.*

*Question 1: Compared to singleton, do twins carry more chances of being genetically or structurally abnormal?*

It must be kept in mind that Compared to women with a single pregnancy, women with a twin pregnancy *have increased chances of carrying one foetus with a structural abnormality.* Also due to the rapid and ongoing advancements in prenatal diagnosis and screening , these abnormalities are now being diagnosed at an earlier gestation. This has lead to a Consequence, where more and more obstetricians are facing the circumstances of a twin pregnancy with one abnormal foetus i.e. DISCORDANT FOR ANOMALY twins.

Compared to Dizygotic (DZ) twins, the frequency of malformations in Monozygotic (MZ) pairs has been reported to be 2-3 times higher.

Obviously  Structural or developmental malformations can occur in any twin independent of the zygosity but  chromosomal malformations if present theoretically should occur in both twins in monozygotic pairs as they arise from a common gene pool or embryo, but again it’s not a rule. Remember chromosomal malformations too have been reported in one fetus of monozygotic due to post zygotic gene modification. *Hence sampling of both fetuses is highly advisable*

 *Question 2:  What is the next mode of action after such a situation arises?*

As soon as the dilemma of discordant anomaly arises proper evaluation of both twins including echocardiography and counselling  regarding the antenatal and postnatal issues and outcome is required. Prognosis and recurrence risk are discussed. Approximately 1–2% of twin pregnancies may face the dilemma of expectant management versus selective termination following diagnosis of an anomaly affecting only one fetus.

*Question 3: Expectant management versus selective feticide?*

In expectant management the pregnancy continues as such in view of ascertaining best perinatal outcome for the normal fetus. *It has published in various international studies that  The presence of a fetus with a major anomaly in a twin gestation increases the risk of preterm delivery, low birth weight and perinatal mortality of the normal co-twin.* This gave the concept of selective fetal reduction.

The second concern obviously is about the optimum gestational age at which the termination is to be performed. Classically in modern era, Elective multifetal reduction to twins is *done at 11-13 weeks after assessing Nuchal translucency and other potential markers.* *Some professionals advocate doing it at 13-15 weeks so that an early detailed anatomical scan can also be incorporated,* Thus reducing the chance of leaving a genetically or structurally abnormal child

*However in some cases where an abnormality is detected late (for example at 22 weeks, one fetus having AVSD with DORV with other being fine), Reduction raises a lot of legal and ethical issues.*

*Remeber late reductions are associated with increased chance of miscarriage or preterm delivery and hence in these cases, some professionals advocate (debatable) to reduce at the age of viability of foetus (generally 28 weeks, subject to legal boundaries).*

*Does type of twin affect the reduction technique?*

If the option of selective fetocide is considered, the main variable determining the technique to achieve this aim is chorionicity. In a dichorionic pregnancy, passage of substances from one twin into the circulation of the co‐twin is unlikely due to the lack of placental anastomoses, hence KCl can be injected safely into the circulation of the affected twin to produce fetal asystole.

In monochorionic twin pregnancies, selective termination needs to be performed by ensuring complete and permanent occlusion of both the arterial and venous flows in the umbilical cord of the affected twin, in order to avoid acute haemorrhage from the co‐twin into the dying fetus, which may lead to death or organ damage. Bipolar cord coagulation under ultrasound guidance is associated with approximately 70–80% survival rates.

*Conclusion:* *Selective  Fetal reduction is a reasonably good  option in twins with one  structurally or chromosomally or early onset severe TTTS.*