Discussion
The case reported is interesting due to the unique association between
NF1 and HIV infection, the complexity of genetic counseling, the
possible effects of pregnancy on NF1, the possible complications of
pregnancy, mode of delivery and complexity of anesthesia that needs a
specialized team in a tertiary level hospital.
HIV infection has been reported only in few cases in non pregnant NF1
patients. de Castro et al (4) described a 38-year-old woman with NF1 and
AIDS with peripheral T-cells lymphoma with good response to chemotherapy
and Isa et al (5) a 30 years old woman with HIV infection whose disease
remained stable with an adequate response to antiretroviral therapy.
More recently Hiesgen and Variava (6) discussed about a 30-years-old
woman with NF1 and somatostatinoma who died soon after diagnosis. Also
Forte (7) described a case of a 41-year-old female patient with NF1 and
uncontrolled HIV infection with simultaneously supratentorial and
infratentorial pilocytic astrocytoma. At best knowledge of the Authors
there is no case of NF1 pregnant woman with HIV infection described in
the literature.
Prenatal genetic counseling may be complex because no phenotype-genotype
correlation in NF1 patients and the rare association between NF1 and
HIV. Many options are available. Preimplantation diagnosis is only
possible trough planned pregnancy obtained by assisted reproduction but
is performed only in some centers (Scoot et al 2019) (8). Villocentesis
or amniocentesis may be proposed when viral load is undetectable or low,
because there is no increase in the risk of fetal infection (Floridia et
al 2017, Eppes 2017) (9,10). Furthermore the diagnosis of NF1 has been
performed by evidence of NF1 paternal mutation detected in free DNA in
maternal blood (Gruber et al 2018) (11). Request of prenatal diagnosis
for NF1however seems correlated to many factor such as cultural
background, educational level, previous child affected, longer
follow-up, awareness on the natural history of NF1 with specific
knowledges of the disease (Farhi et al 2008) (12) and many NF1 patients
choose not to receive prenatal diagnosis (Terzi et al 2009 (13). Our
couple refused prenatal diagnosis for NF1, because no willingness to
interrupt pregnancy in an affected fetus by NF1.
Current data show that fertility in NF1 young women is not compromised,
but miscarriage can occur frequently. Pregnancies have been reported in
women with NF1, but concerns exist for the mother and the fetus. Stroke,
acute vascular rupture, hypertension, preeclampsia, low platelet count,
HELLP syndrome and eclampsia have been reported (Terry et al 2015,
Leppavirta et al 2017) (14,15). Particularly hypertension due to
pheochromocytoma or paragangliocytoma may change the prognosis for the
mother and the fetus (Walther et al 1999) (16). Nevertheless, maternal
mortality in compliant patient with NF1 is rare.
Fetal pathologies such as Intrauterine Growth Retard (IUGR),
oligohydramnios, preterm delivery, sudden fetal death and emergency
cesarean section have been described. Fetuses may also be affected by
NF1 and may present higher incidence of malformations (Leppavirta et al
2018 (17). Our patient had two preterm deliveries, one due to abruptio
placentae in the absence of hypertension and two out three child had
clinical signs of NF1. Vaginal delivery wasn’t contraindicated due to
normal pelvic examination and undetectable viral load. However in HIV
patient during vaginal delivery fetal contact with maternal blood should
be minimized and there are no definitive data if operative vaginal
delivery may increase the risk of fetal infection (Peters et al 2017)
(18).
The association of NF1 with HIV infection warrant an experienced
multidisciplinary team. Generally general anesthesia should be avoided
in pregnant women, but neuraxial anesthesia in asymptomatic spinal
neurofibroma may be cause of specific concern in NF1 patients, because
asymptomatic neurofibromas are not rare (Dounas the al 1995 et al 1999)
(19). Before neuraxial anesthesia and analgesia, may be useful a MRI of
the spine to detect such tumor that may contraindicate regional
anesthesia (Spiegel 2005) (20). Furthermore it should be remembered that
HIV infection with undetectable or low viral load is not a
contraindication to local anesthesia (Gaisen 2003, Benton et Reese 2009,
Gronwald et al 2011) (21,22,23).
Finally, an unknown issue is if natural pregnancy immunomodulation may
increase the risk of malignancy when associated with HIV and NF1. It is
known that 4-15% of NF1 patients, affected by plexiform neurofibromas,
develop malignant degeneration during their life, with a latency period
of about 10-20 years. Tumors usually arise before 39 years of age (Korf
et al 2000) (24). This risk is cause of concerns. More rare tumors may
affect NF1 patient such as pheochromocytoma, neuroblastoma and melanoma
that arise from neural crest and also Wilms tumor, malignant nodular
hidradenoma, leukemia, rhabdomyosarcoma, T-cell-lymphoma. Causes of high
prevalence of neoplasm in NF1 patients, both benign and malignant, are
not completely known, and genetic, environmental and hormonal factors
may be implicated. Actually, it is unknown the possible effect, if any,
of many pregnancies in the incidence of malignant degeneration in NF1
patients, but a relevant effect of pregnancy on tumor growth is well
known, because up to 80% of skin tumors increases in dimensions in
pregnancy (Schmutz 2003) (25). Moreover, during pregnancy many new
tumors may be diagnosed, and up to 3% of NF1 patients are diagnosed
during pregnancy due to the appearance of neurofibromas (Nebesio et al
2007, Cesaretti et al 2013) (26,27).
Our patient was HIV positive but maintained low viral loud and normal
CD4 count throughout each pregnancy, showing no evident HIV
immunosuppression so probably it did not affect significantly
neurofibromas growth. However through seven year of observation no
relevant transformation or malignant degeneration of neurofibromas was
observed.