Sunday, March 22, 2009

Question from Elizabeth M - Inheritability of Rh negative factor

Alison Weir mentions a theory in her book THE SIX WIVES OF HENRY VIII, that one of the reasons Anne Boleyn had miscarriages after the healthy birth of Elizabeth might have been because Anne suffered a blood condition that made her Rhesus negative. A woman would have a healthy first child, but then not be able to have healthy births afterwards. My question is, would a Rhesus negative condition be an inherited ailment? Looking at the childbearing records of Anne's close female relatives, I wonder. Her mother, Elizabeth Howard Boleyn, gave birth to at least five children; her grandmother, Elizabeth Tilney Howard, gave birth to twelve by her two husbands. Her paternal grandmother, Margaret Butler Boleyn, had ten children. Her sister Mary Boleyn had two healthy children, and Mary Boleyn's daughter, Catherine Carey Knollys, had no less than fifteen children. And Margaret Wentworth Seymour, the first cousin of Elizabeth Howard Boleyn, gave birth to ten children, including Jane Seymour.

28 comments:

kb said...

This is off your topic slightly so apologies in advance.

Would you please tell me where you read that Catherin Carey Knollys had fifteen children? My count has it at 14 with one of these (Dudley, b.May 1562, d.June 1562) dying in infancy. If you have different information, I would love to know about the source.

Is Rhesus negative a female only condition? I ask because Henry Carey, Catherine's brother had 12 children.

Elizabeth M. said...

Sorry==typo. The fourteen include: Lettice (born 1539), followed in quick succession by Mary, Henry, Elizabeth, William, Edward, Robert, Richard, Thomas, Francis (Jr.), Anne, Catherine, and Cecily. Cecily is mentioned at Tudorplace.com, but not on Katherine's page on the peerage.com, so she may have also died in infancy.

Tudorrose said...

Obviously there had to be something wrong.whether it was anne herself or perhaps Henry.
Because don't forget catherine of Aragon suffered a lot of miscarriages and stillbirths.so would this mean that Catherine too suffered with the same condition as Anne and if so don't you think that this would have been a coincidence!? wouldn't it just make sense to put it down as Henry's problem and failure to have children!? I think it was something wrong in the genetic make up of Henry that's why countless miscarriages and stillbirths kept happening.
P.S what do others think?

kb said...

I think it was Henry. He clearly had no trouble getting people pregnant - at least through his mid-forties. It was just healthy babies born full-term who were strong enough to survive. Certainly Anne's fertility pedigree was strong and Katherine suffered through several pregnancies. I do not have enough medical knowledge to conjecture further.

On the side topic regarding the Knollys children birth order - Lettice was not the first born in 1539. This is an error that has been repeated. Francis Knollys and Katherine Carey did not marry until 26 April 1540. As best as I have been able to determine their children were:
Henry b. 12 Apr 1541
Mary b. 25 Oct 1542
Lettice b. 6 Nov 1543
William b. 20 Mar 1545
Edward b. 18 Oct 1546
Maud b. 30 Mar 1548
Elizabeth b. 16 Jun 1549
Robert b. 8 Nov 1550
Richard b. 21 May 1552
Francis b. 14 Aug 1553
Anne b. 19 Jul 1555
Thomas b. 2 Feb 1558
Katherine b. 21 Oct 1559
Dudley 9 May 1562 (died in June 1562)

[some of the above are christening dates]

There was no Cecily. This eror originated from a misidentified painting and subsequently repeated in several authoritative sources including the ODNB.

Lettice's birth year was traditionally figured by taking the age she claimed at death and working backwards without referencing any other facts - like her parents weren't married yet and Katherine would have been an unwed pregnant 15 year old while maid of honor to Anne of Cleves.

OK - back to our regularly scheduled Q and A - I think it was Henry's fault.

Tudorrose said...

I would say that the RH negative factor is hereditory.

Michelle said...

Rh negative factor is hereditary.
I disagree that the fertility issues were Henry's. Other than Y chromosome genetic disorders that present in children/adults after birth (such as Turner's syndrome) I'm unaware of a condition from a male that causes miscarriage/stillbirth (Does anyone else know?). There are no vital genes on the Y chromosome, as half the population (women) doesn't have a Y chromosome. And he clearly was not sterile.
Knowing what we know today, it doesn't seem all that unusual to me that so many pregnancies 500 years ago ended in miscarriage/still birth. Between the total lack of pre-natal knowledge and care and the incredible levels of stress that queens were under to produce boys, it's no wonder they lost so many babies.

Elizabeth M. said...

Then if it is a hereditary condition, why the disparity with Anne compared to her other female relations? Seems rather odd. You think the ailment would have stricken someone else closely related to her. So maybe she did not have this condition? Could stress have played a part in the failures of her pregnancies and those of Catherine of Aragon? Seems Catherine of Aragon was hit pretty hard by the death of the New Year's boy in 1511, and Anne was acutely aware that the whole reason Henry got rid of Catherine and married her was to beget sons. Even though Elizabeth wa a healthy baby, there was still the fact that she was considered to have failed in her primary queen consort duty--to bear a healthy, living son for the succession.

Louise said...

I had heard a theory that it was Henry's fault and it had something to do with an STD. I only heard this, I didn't read it, so I have no idea what STD or how likely this theory is.

Joan said...

My background is obstetrical nursing (labor and delivery), I've always had an interest in genetics, and I'm Rh negative myself!- so I guess this question is right up my alley.

To begin with, it isn't really accurate to refer to being Rh negative as having a "blood disorder." In a similar way that a person is A, B, AB, or O blood type, they are also either Rh positive or Rh negative. If I remember correctly, the breakdown is approximately 85% positive and 15% negative in the general population.

KB asked if being Rh negative is a "female only condition." It's a very good question but the answer is no as both males and females have the Rh factor in their blood type with being Rh negative the rarer state.(the before mentioned 15%.)

Rh incompatibility occurs when the mother is Rh negative and the father is Rh positive. ( Just to make it more complicated a positive father could have either two positive Rh genes or one positive and one negative gene-these having been received in turn from his parents. He, of course, could also have two positive Rh genes. I'll just mention that being Rh positive is a dominant trait to being Rh negative.)

As Michelle correctly noted, the problem occurs after the first pregnancy. (It can be either a miscarriage or a birth). If the first fetus is Rh positive and the mother is Rh negative, the mother can form Rh antibodies which can be disastrous for any subsequent Rh positive pregnancy. Nowadays a pregnant woman who is Rh negative is routinely given an injection of RhoGam which prevents the antibody formation.

I would love to go on about this and become more technical-such as the probability statistics of the offspring when the father is heterozygous vs. homozygous for the Rh phenotype...This would factor into examining the Boleyn family tree on this matter which to me would be fascinating.

Anyways, yes the Rh incompatibility issue could have applied to Anne Boleyn but there are certainly other possibilities for her miscarriages. Remember, even today about 20% of pregnancies result in miscarriage. Other factors are chromosomal defects in the fetus, hormonal issues with the mother, stress, alcohol consumption, incompetent cervix, infection, advancing maternal age etc.

PhD Historian said...

Well done, Joan! Since my first career was in medicine, I was all prepared to give exactly the same answer that you did ... but now I don't need to!

Louise, the whole "STD" theory became very popular late in the 19th century and was put forward as a moral lesson ... "many wives and sexually promiscuity equals disease and death" was the moral lesson to be learned. The whole notion was based not in solid evidence and/or medical science, but in religious moralizing. Syphilis was the usual culprit put forth, but that theory has been widely discredited.

I'm not real comfortable with us assigning "fault" for why the women in Henry's life did or did not deliver full-term children or why several of his children died in infancy. To my mind, it's just too difficult to ascertain the facts after almost 500 years, and there are just too many variables involved, many of them having absolutely nothing to do with the genetic makeup of Henry and his wives and mistresses. As I've noted in other threads, the number of miscarriages and infant deaths suffered by Henry and his three childbearing wives were not significantly outside the norm. I know of many Tudor-era women with greater numbers of miscarriages and more infant deaths than both Katherine and Anne. Most modern readers tend to think of them as unusual because they have little to compare them too, and the modern experience is usually much less negative.

I realize that it is interesting to speculate, but I don't think we should take any of that speculation too seriously or decide that we have "discovered the answer." Some things will remain forever unknown.

Tudorrose said...

If Anne did have the RH negative factor then this means catherine of Aragon must have had too.Because she suffered counless miscarriages and stillbirths too.
But then this would make it deffinately a coincidence.
It's one thing when it's one but two is something else.
But I personally thought it was something to do with Henry and not his wives.

Merlin said...

Can't resist joining in. I don't think there's any real evidence that there was a problem with Henry- at least, not until later in his life. Admittedly, he didn't have scores of illegitimate children but I think that was more because he wasn't one for 'putting it about' in the way some other monarchs (his grandfather, Edward IV, fo example) routinely did. In his younger years he fathered Henry Fitzroy (by Bessie Bount) as well as a succession of babies by Katherine of Aragon (and possibly one or both of Mary Boleyn's children). I think his health, age and associated bouts of impotence probably prevented him fathering any children after Jane Seymour.

As for the wives- I think there probably was some sort of medical issue with Katherine. Even for the time, she lost so many babies late in pregnancy or at birth that I suspect there was some sort of issue impossible to diagnose and treat in those days. Having said that, she did give birth to two healthy children (the prince Henry who died as a baby as well as Mary) so she couldn't have been rhesus negative. I think Anne's problem was her age (she started her childbearing late for a Tudor-era woman) and stress, plus she never really had a fair crack of the whip. After all, for the time, one living child and two miscarriages within the space of a few years was hardly a bad record. Given more time with Henry, it's quite possible she would have produced more babies. Jane Seymour, of course, died following the birth of Edward (a far from unusual outcome in Tudor childbirth) so again might have gone on to have other healthy children. Anne of Cleves marriage was never consumated and as previously stated, Henry was an ageing and ill man by the time he married the two latter Katherines.

What I do think is interesting is why the bulk of the Tudor boys died as young men (Arthur, Edward, Henry Fitzroy, Henry Brandon, etc) whilst the daughters, if they survived early childhood, generally lived. It would seem to suggest there was some form of weakness/pre-dispossision to TB perhaps?

Luv said...

A lot of historian believe that the reason for KOA` condition was because of her poor diet. It has been said that Katherine continuing fasting while pregnant, and her lack of vegetables /iron contribute to the kids poor health. However, Queen Katherine was able to give birth to 4 kids. 2 boys who both live for 1 full month, 1 girl who lived for a week, and Mary who lived to be 42. So Katherine problem was different from Anne who was only able to give birth to one living child.

@Elizabeth M.

Anne very well could have had a hereditary condition. Hmm do it only affect women in the family? The reason why I ask is because George Boleyn was married for 11 years, and report to be a bit of a womanizer , yet he reportedly had no kids.

Liz said...

@Merlin,

One of the theories I have heard for so many of the Tudors dying young is that they had diabetes. Though the Tudor girls did not die young, they did die with symptoms similar to those of the boys - a "wasting sickness." Henry VIII's health issues later in life can also be contributed to advanced, untreated diabetes.

Penny said...

To those more interested in the genetics behind Rhesus types, here's a link to the wikipedia article on rhesus blood groups:

http://en.wikipedia.org/wiki/Rhesus_blood_group_system

It's definitely not a "hereditary disease", like my von Willenbrand's bleeding condition, every hospital for example stocks my blood type O negative (the negative being the rhesus factor), since it's what can be given to a trauma patient in a transfusion before their own blood type is determined.

The science behind rhesus factors wasn't determined until in the 1940's, and even then, the only known treatment back in the days was blood transfusion to the rhesus baby affected by the mother's antibodies. My granddad was a blood donor through a lot of his working life and was sometimes called in by taxi on the hospital's expense in the 60's even while slightly drunk to give blood to a baby born with blue skin.

These days it's treated with a big needle stuck into the mother within 48 hours of a child's birth, not too bad, not too nice, either, but it saves the lives of her children. Gramps, my mother and me are all O negative, my mother's given birth to four healthy children with rhesus positive fathers.

The abnormal colouration of babies born affected by the mother's antigens could be a partial reason to why Anne's miscarried baby boy raised rumours of witchcraft. I've been told they are not pretty by any standards.

The statistical odds for a mother being rhesus negative and the father being rhesus positive is about 11%, the odds for the father also carrying the gene for the negative factor is roughly 50-75% if one of his parents was also rhesus negative or one parent was a positive carrier.

All in all, there's probably about a chance of 1 in 10 for Anne and Henry to have been affected by this complication, and I'm not too surprised, if her maternal family tree looks fertility-wise promising, since it could have been caused by her mother being a positive carrier of the negative gene, and her dad either negative or a positive carrier of the gene. It's all a matter of genetic luck.

The hereditary mechanisms are complex...
http://www.paternityangel.com/Articles_zone/Blood/BloodType2.htm

http://www.paternityangel.com/Articles_zone/Blood/BloodType3.htm

The above link is for the ABO system, the below for the Rh factor. Combining the two, you start realising the odds are a matter of luck and a massive juggling of numbers...

The only way to be sure would be to be able to genetically test the royal remains to be able to exclude this theory.

Laura said...

I think it should be noted that it wouldn't be completely outside the realm of possibility that Katherine and Anne suffered from the same rare hereditary conditions. Anne and Katherine (and the rest of the wives, for that matter) were all distantly related. All the noble families of the time were so intermarried that finding a suitable mate who wasn't a blood relative would have been impossible.

However, I tend to believe that childbirth in the Tudor era was simply a medically unsafe practice. Between the lack of proper nutrition and hygiene, the regular consumption of alcohol and practices such as "lying in" I think the question shouldn't be why didn't more babies survive, it should be why didn't more babies die in infancy.

Scott said...

Rh negative blood is not a hereditary disorder. I am a nurse and I will try to explain this. Everyone has either positive and/or negative blood types: A+, B+, AB+, O+, etc.. and vice versa. Negative blood types are much rarer than positive, but not so that it is a phenomenon. It is desirable to have to same Rhesus types of the male and female, either both mates being positive or both mates being negative. These matching will cause in no spontaneous abortions or fetal death due to blood issues. But if you have a positive mate and negative mate, you run into problems and more so when the mother is negative. Often the mother will abort within a few weeks of conceiving. But in the event she does carry the fetus for a trimester or two,the fetus would have to inherit the same Rhesus type as the mother for her to be able to carry it without incident or to full term. If mother is negative and the child inherits the father's positive blood type, a barrage of problems ensue. The mother's body sees the fetus as a foreign body or intruder and begins to attack the fetus. This is what often causes the abortion. Of course in today's medicine the mother can receive injections to keep these negative side effects at bay.

Wendy said...

It is also possible that Catherine of Aragon and/or Anne Boleyn were carriers of Group B Streptococcus (GBS). Approximately 15% to 40% of healthy women carry Group B Strep which can colonize in the vagina or rectum. GBS can cause infant death in the form of meningitis, sepsis and pneumonia. Only a small percentage of infants become ill with this today owing to IV antibiotics given to the mother during labor and delivery.

There are two forms of GBS; early onset and late onset. This could explain why Henry, Duke of Cornwall, appeared to be healthy but died around six weeks later. I also believe Catherine may very well have had the Rh Negative factor along with Group B Strep. Any Rh- children born from a Rh+ father and a Rh- mother are at risk of illness or death. However, Rh- children would not be affected.

It's entirely plausible that Mary was Rh-, accounting for her survival.

Back then infant mortality was high. GBS tends to infect people with compromised immune systems. Perhaps the stress for the queens to produce a male heir lowered their immune systems enough to cause a GBS infection in some or all of their babies and that, along with the Rh- factor, caused so many deaths.

Wendy said...

It is also possible that Catherine of Aragon and/or Anne Boleyn were carriers of Group B Streptococcus (GBS). Approximately 15% to 40% of healthy women carry Group B Strep which can colonize in the vagina or rectum. GBS can cause infant death in the form of meningitis, sepsis and pneumonia. Only a small percentage of infants become ill with this today owing to IV antibiotics given to the mother during labor and delivery.

There are two forms of GBS; early onset and late onset. This could explain why Henry, Duke of Cornwall, appeared to be healthy but died around six weeks later. I also believe Catherine may very well have had the Rh Negative factor along with Group B Strep. Any Rh- children born from a Rh+ father and a Rh- mother are at risk of illness or death. However, Rh- children would not be affected.

It's entirely plausible that Mary was Rh-, accounting for her survival.

Back then infant mortality was high. GBS tends to infect people with compromised immune systems. Perhaps the stress for the queens to produce a male heir lowered their immune systems enough to cause a GBS infection in some or all of their babies and that, along with the Rh- factor, caused so many deaths.

Anonymous said...

The theory that Catherine of Aragon was rh negative is flawed, an dher obstetrical history will prove it. An rh negative mother who conceives a child with an rh positive father will have a healthy first child, but her body, sensitized to the rh factor in her fetus's blood upon delivery, will attack and destroy the red blood cells of future unborn children. Modern medicine counteracts this immune reaction with a substance called Rho-Gam given after each miscarriage, abortion, stillbirth or live delivery (I am pro-life- I just mention each scenario in which this treatment is used). In Tudor times, no such remedy existed. Her first pregnancy ended in miscarriage.The second produced a son, Henry x, born January 1, 1511(?), who lived less than 60 days. Nary, born February 18, 1516, lived 42 yesrs. Had Catherinr been rh negative, none of her pregnancies would have been carried to term. It is a valid theory in the case of Anne Boleyn, but not her predecessor.

CaliGirl9 said...

Another RN (former OB nurse) chiming in ...

It is impossible to prove Queen Catherine’s Rh type, but her obstetrical history could have been complicated by her being Rh-negative. Today 15% of the population is Rh-negative, meaning they do not have Rh antigens.

In order for Rh incompatibility problems to kick in, two things must happen—first, the mother must be Rh negative, and second, the baby MUST be Rh-positive. This comes about with an Rh-positive father. But just because the father is Rh-positive does not guarantee his child will be the same—it is necessary to know if the father is homozygous or heterozygous for the Rh factor (homozygous meaning he carries two copies of the Rh-positive gene; heterozygous means he carries one copy of the gene). If the fetus inherits the gene carrying the Rh factor, then the baby will be Rh positive, as the gene is dominant.

For a female to be Rh-negative she must have two copies of the gene, meaning she does not have the Rh antigen.

So, in Queen Catherine’s case, her first pregnancy that ended in a miscarriage could have been enough to kick in Rh incompatibility in subsequent pregnancies (it takes only a few drops of fetal blood in the maternal circulatory systen, and that happens with placental rupture from the uterine wall). Prince Henry could have been Rh negative, but it is also possible he was Rh positive and was perhaps born anemic and went on to suffer from full-blown jaundice. All babies were breast-fed, but with the crummy knowledge of nutrition, it’s possible that Tudor neonates really didn’t get quality breast milk from their wet-nurses, especially important for a newborn who needs to grow red blood cells quickly. Maybe Prince Henry became more progressively anemic and died from that cause. Of course we will never know the actual reason he died. He was also the prime age for SIDS.

In Queen Catherine, subsequent failed pregnancies could have been of Rh-positive fetuses who were miscarried in part because the risk of complications rises with each pregnancy. Henry VIII may have been heterozygous for the Rh factor, and Mary may have been Rh-negative herself. She had a pretty crummy obstetrical history herself, didn’t she?

Very interesting blog; I plan on visiting often. I adore the history of the British monarchy!

Anonymous said...

I love this convo, and it is very important that people are educated in the RH business and know that it is not a disorder, disease, or condition as previously stated. It is just a blood type.

I spoke with my pathology professor who is also a surgeon, and he and I talked about this. Many environmental factors like eating with lead utensils, lead bowls, plates and cups, the water, the food could cause a woman to miscarry. Honestly I think in Tudor time to have a healthy child was a damn miracle.

I know there is still alot of speculation on whether the last miscarried child was deformed or not, but if it was true, and the fetus did have a splayed back, etc. my professor said this would be due to a vitamin B deficiency. A vitamin deficiency could definitely be a factor.

Briony Coote said...

Re Mary having a crummy obstetric history:

Mary was never pregnant or bore any children. She did have two bouts of what she thought was pregnancy. Even by modern standards she started out dangerously late for motherhood - she was in her forties. She had bouts of illness stemming from the trauma of her parents' divorce, and it was known her periods were irregular. At the time they put it down to 'strangulation of the womb'aka 'suffocation of the mother' i.e. the woman's womb was raging because she was not married.

Alison Weir argues that phantom pregnancy is the strongest possibility for the first instance, on balance on the evidence available. She admits this can't be certain, given how sketchy the evidence is and being over 400 years after the event.

For the second instance, the evidence is even sketchier, but does not look like a real phantom pregnancy. Weir argues that menopause, illness, or self-delusion are better candidates.

Anonymous said...

Between all this talk of Rh-negative and what the consequences are nobody really talked about the opening question concerning genetics. In fact, by comparing the fertility of Anne's female relatives to her own you cannot prove that she wasn't Rh-negative because it is, as some people mentioned before, a recessive trait. That means someone can carry it in their genetic material without actually "showing" it, because the dominant Rh-positive trait takes over. Those women would be able to have children just like any other woman who does not carry the trait. That means for someone to be rhesus-negative, both parents have to carry the trait.

R = rhesus positive (dominant)
r = rhesus negative (recessive)
(everyone carries 2 of those genes, one from the mother, one from the father and the dominant one determines the blood type)


Anne Boleyn's mother: Rr (Rhesus positive)
Anne Boleyn's father: Rr (Rhesus positive)

now there is a 50% chance that their offspring will be rhesus negative. With males that would not really be a problem, seeing as they do not bear children and will only pass the condition on to their children if the mother carries the rhesus negative trait as well.

Anne Boleyn: rr (rhesus negative)

so the Rhesus negative trait definitely must have ocurred somewhere in the Boleyn family but maybe Anne was the only unlucky female to actually be rhesus negative.

Sanja said...

I'm rhesus negative, both of my parents were rhesus positive. It's recessive. My father was one of nine children - which only means his mother wasn't negative with a rh-positive father. My mother on the other hand, surely had a family wherein her mother was rh- negative, father postive - she was the first child, and the only one that lived. Several siblings did not survive long after birth, including one requiring blood transfusions (in the 1930s). I often wondered about the rh factor in terms of the Tudor history - I have two children, the second one thanks to Rhogam (which enables subsequent live births). Both of my children are weak rh-positives - that is, carry one rh- negative and one rh-positive gene

petersenje said...

By all means correct me if I am wrong but all of the research I have done shows that King Henry VIII was RH negative as was his daughter Mary. In Mary's case I feel strongly this is why she could not bare children.

petersenje said...

I am O negative. My father is o pos and my mother is ab positive. I am the only one of five children that are negative. The neg runs on my father's side as well as mothers side. My bloodline is of Stuart decent from Scotland until they fled to Ireland to remain alive in the 1400's. My mothers side is mostly brittish DNA ,yet stemming from northern Spain in the Iberian peninsula. I can back this up as I've had my DNA tested. I have four children and they are all neg rh factor. I have a 5th which I donated my sperm to a couple in need and although I've only met him once I'm confident he also is rh neg. That said, I have always felt "when I say felt, I mean that to be truth" as in if there is something strong enough for me to feel it is true...that there is something very much different about rh neg. Our eye color changes, Read emotions and thoughts, shouldn't breed with other types, sense feel and hear things other people cant. Just to many coincidences. anyone else have thoughts?

Holly Carol said...

I believe that it was the RJ factor as most royals where RH negative as today they still are.The thing that troubles me why did Ann believe she would have a son, and why did she not wonder as to the consequences if she did'nt. She should have made negotiations with her psycho husband. The Tudor hussled the crown from the Plantagenet Kings whose wives had several children. The Royal RH negative bloodline.